Use of maribavir in treatment regimens

Abstract

The drug-drug interaction and pharmacological characteristics of maribavir are designed to inform potential drug-drug interactions and dosing strategies when administered with other drugs.

Description

Prior Technology

[0001] Cellular cytomegalovirus (CMV) infection and disease are serious post-transplant complications, characterized by substantial morbidity and reduced long-term survival in transplant recipients. Currently, there are no approved therapies for treating CMV infection in transplant recipients.

[0002] Transplant patients often receive multiple combination therapies to manage their combination symptoms. The drug-drug interaction and pharmacological characteristics of maribavir are used to inform potential drug-drug interactions and dosing strategies when administered with combination therapies. Summary of the Invention

[0003] Maribavir is a benzimidazole riboside and an orally effective antiviral drug against cellular giant cell virus (CMV). Maribavir is also known by its brand name LIVTENCITY™. Typically, when administered orally, maribavir is given to patients (e.g., adults and / or children aged 12 years and older and weighing at least 35 kg) orally twice daily at a dose of 400 mg. However, in some embodiments, the present invention recognizes that when co-administered with certain drugs (e.g., cytochrome P450 3A4 (CYP3A4) inducers (such as carbamate, phenytoin, or phenobarbital), p-glycoprotein inducers (P-gp), immunosuppressants, antiarrhythmic drugs (such as digoxin, ganciclovir, or valganciclovir)), the dose of maribavir and / or co-administered drugs must be monitored, modified (e.g., increased or decreased), or interrupted.

[0004] In some embodiments, the present invention particularly demonstrates how potential drug-drug interactions with maribavir and exposure to maribavir and / or CYP3A4 inducers are affected. In some embodiments, the present invention provides a method for treating CMV infection in patients, comprising: Administer a therapeutically effective dose of maribavir to patients who were receiving or had received a CYP3A4 inducer prior to administration of maribavir; and Interrupt the administration of CYP3A4 inducers before administering maribavir.

[0005] In some embodiments, the present invention provides a method for treating CMV infection in patients, comprising: Administer an initial therapeutically effective dose of maribavir to the patient who is receiving a CYP3A4 inducer; and Increase the amount of maribavir administered to the patient.

[0006] In some embodiments, the present invention provides a method for treating CMV infection in patients, comprising: Administer a therapeutically effective dose of maribavir to patients who have received a CYP3A4 inducer prior to administration of maribavir.

[0007] In some embodiments, the CYP3A4 inducer is selected from the group consisting of rifampin, avamarib, carbamate, phenytoin, rifabutin, phenobarbital, and St. John's wort. In some embodiments, the CYP3A4 inducer reduces maribavir exposure. In some embodiments, the patient is given an initial therapeutically effective dose of maribavir, and the dose of maribavir is increased when co-administered with a CYP3A4 inducer. In some embodiments, the initial therapeutically effective dose of maribavir is approximately 400 mg orally twice daily. In some embodiments, the dose of maribavir is increased to an amount between approximately 800 mg and approximately 1200 mg orally twice daily. In some embodiments, the provided method further includes the step of monitoring the patient's blood (e.g., whole blood or plasma) concentrations of maribavir and / or the CYP3A4 inducer.

[0008] In some embodiments, the present invention particularly illustrates how potential drug-drug interactions with maribavir and exposure to maribavir and / or immunosuppressants are affected. In some embodiments, the present invention provides a method for treating a patient with cellular giant virus (CMV) infection, comprising administering a therapeutically effective amount of maribavir to the patient, wherein the patient is receiving or has received an immunosuppressant. In some embodiments, the immunosuppressant is selected from the group consisting of tacrolimus, cyclosporine, everolimus, sirolimus, presbyronone, and mycophenolate mofetil. In some embodiments, the immunosuppressant is selected from the group consisting of tacrolimus, cyclosporine, everolimus, and sirolimus. In some embodiments, the immunosuppressant is tacrolimus. In some embodiments, the provided method further includes the step of monitoring the level of the immunosuppressant (e.g., compared to a reference or standard level) after discontinuation of maribavir administration. In some embodiments, the provided method further includes the step of increasing the amount of immunosuppressant administered to the patient (e.g., increasing to the amount of immunosuppressant administered before the start of maribavir administration).

[0009] In some embodiments, tacrolimus is administered at an initial dose and whole blood trough concentrations are monitored. In some embodiments, the initial dose of tacrolimus (e.g., before or when co-administering maribavir) is between about 0.075 mg / kg / day and about 0.3 mg / kg / day. In some embodiments, tacrolimus is administered orally in capsules of 0.5 mg, 1.0 mg, or 5.0 mg each. In some embodiments, tacrolimus is administered by injection at a concentration of 5.0 mg / mL. In some embodiments, tacrolimus is administered orally as a 1 mg unit dose granule packet. In some embodiments, tacrolimus whole blood trough concentration observations are monitored over a period between about 0 months and about 12 months after the initial tacrolimus administration. In some embodiments, tacrolimus whole blood trough concentration observations are monitored at initial administration, during co-administration, and upon discontinuation of maribavir administration. In some embodiments, tacrolimus whole blood trough concentration observations are between about 4 and about 20 ng / mL. In some embodiments, tacrolimus is administered at an initial dose between about 0.03% and about 0.1% (w / w) per gram of ointment. In some embodiments, tacrolimus is topically administered in a base selected from the group consisting of: mineral oil, paraffin, propyl carbonate, white petrolatum, and beeswax.

[0010] In some embodiments, the dose of tacrolimus is adjusted when co-administered with maribavir. In some embodiments, maribavir is co-administered with maribavir at a concentration of 400 mg, 800 mg, or 1200 mg twice daily. In some embodiments, co-administration of maribavir increases tacrolimus exposure by approximately 50%.

[0011] In some embodiments, the present invention specifically illustrates how potential drug-drug interactions with maribavir and exposure to maribavir and / or antiarrhythmic drugs (e.g., digoxin) are affected. In some embodiments, the present invention provides a method for treating a patient with CMV infection, comprising administering a therapeutically effective amount of maribavir to the patient, wherein the patient is receiving or has received an antiarrhythmic drug (e.g., digoxin). In some embodiments, the provided method further comprises monitoring the level of digoxin in the patient's serum. In some embodiments, the provided method further comprises the step of reducing the amount of digoxin administered to the patient (e.g., reducing to the amount of antiarrhythmic drug administered before the initiation of maribavir administration).

[0012] In some embodiments, the present invention particularly illustrates how potential drug-drug interactions with maribavir and exposure to maribavir and / or ganciclovir or valganciclovir are affected. In some embodiments, the present invention provides a method for treating a patient with cellular giant virus (CMV) infection, comprising: Administering a therapeutically effective dose of maribavir to a patient who was or had previously received ganciclovir or valganciclovir prior to administration of maribavir; and Discontinue the administration of ganciclovir or valganciclovir before administering malibavir.

[0013] In some embodiments, the concentrations of maribavir and / or co-administered with another drug (e.g., CYP3A4 inducers (such as carbamapin, phenytoin, or phenobarbital), p-glycoprotein inducers (P-gp), immunosuppressants, or antiarrhythmic drugs (such as digoxin, ganciclovir, or valganciclovir)) are monitored at the initial administration, during co-administration, and upon discontinuation of maribavir administration.

[0014] In some embodiments, the patient is refractory to CMV infection and is being treated with one or more other medications for treating CMV infection (e.g., ganciclovir, valganciclovir, cidofovir, or foscarnet). In some embodiments, maribavir is administered with or without food. In some embodiments, the patient is a transplant recipient (e.g., a hematopoietic stem cell transplant recipient or a solid organ transplant recipient). In some embodiments, the patient is an adult or a child aged 12 years or older and weighing more than 35 kg. Simple Explanation of the Diagram

[0015] Figure 1. IC50 shift of maribavir in concentration-dependent analysis of HLM targeting CYP3A using midazolam (A) or testosterone (B) as probe receptors. CYP: Cytochrome P450; HLM: Human liver microsomes; IC50: Half-maximal inhibitory concentration; NADPH: Nicotinamide-adenine dinucleotide phosphate.

[0016] Figure 2. Comparison of observed enzyme inactivation rate constants using (A) midazolam or (B) testosterone as probes with the TDI inhibitor concentration of maribavir against CYP3A. CYP: Cytochrome P450; KI: Inhibitor concentration at half-maximal enzyme inactivation; kinact: Maximum enzyme inactivation rate constant; kobs: Observed enzyme inactivation rate constant; TDI: Time-dependent inhibition.

[0017] Figure 3. Emax and EC50 of malivabavir's induction of CYP3A4 mRNA expression, estimated by nonlinear regression using data from three human hepatocyte donors. Sigmoidicity coefficient for the shape of the 3,n-lineage adaptation curve for donors; EC50: half-maximal effect concentration; Emax: maximum effect.

[0018] Figure 4. Estimation of the IC50 of malivavir against digoxin's P-gp efflux (as determined by corrected efflux ratio) in cultured Caco-2 cells. IC50: half-maximal inhibitory concentration; P-gp: P-glycoprotein. Implementation

[0019] [] [Cross-reference to related applications] [] This application claims priority to U.S. Provisional Application No. 63 / 281,206, filed November 19, 2021, which is incorporated herein by reference in its entirety.

[0020] Maribavir ((2S,3S,4R,5S)-2-(5,6-dichloro-2-(isopropylamino)-1H-benzo[d]imidazol-1-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol), a compound having the following chemical structure: Maribavir is a potent, orally available antiviral agent used to treat cellular macrocytic virus (CMV) infection and disease in transplant recipients. Transplant recipients are at significant risk of CMV infection and often receive multiple combination therapies to manage their comorbidities. Therefore, assessing the potential drug-drug interactions between maribavir and prospective therapies is useful. Furthermore, understanding the clinical pharmacology of maribavir is essential for defining the optimal dosing strategy in transplant recipients who typically suffer from multiple comorbidities and require complex combination therapy regimens. [, 1. , ] [, definition , ] [, , ]

[0021] As used herein, when used in conjunction with numerical values, the term "about" means ±10% of that value. For example, a dose of maribavir containing "about 100 mg" covers any amount of maribavir in the range of 90 mg to 110 mg.

[0022] As used herein, the term "reference" describes a standard or control for comparison. For example, in some embodiments, the reagent, animal, individual, population, sample, process, or value of interest is compared with a reference or control reagent, animal, individual, population, sample, process, or value. In some embodiments, the reference or control is tested and / or measured substantially simultaneously with the test or determination of interest. In some embodiments, the reference or control is a historical reference or control performed in a tangible medium, as appropriate. Generally, those skilled in the art will understand that the reference or control is determined or characterized under conditions or circumstances equivalent to those being evaluated. Those skilled in the art will understand when sufficient similarity exists to justify reliance on and / or comparison with a particular possible reference or control.

[0023] As used herein, the term "treatment" refers to the partial or complete reduction, suppression, improvement, and / or relief of one or more symptoms of a condition or illness. In some embodiments, treatment may be administered after one or more symptoms have been present. In some embodiments, the term "treatment" includes halting the progression of a disease or illness. Treatment may also continue after symptoms have subsided, for example, to prevent or delay their recurrence. Therefore, in some embodiments, the term "treatment" includes preventing the recurrence or recurrence of a disease or illness. [, 2. , ] [, Dosage regimen , ] [, , ]

[0024] In some embodiments, the present invention recognizes that when maribavir is co-administered with certain drugs (e.g., CYP3A4 inducers such as carbamate, phenytoin, or phenobarbital), p-glycoprotein inducers (P-gp), immunosuppressants, or antiarrhythmic drugs such as digoxin, ganciclovir, or valganciclovir), the dosage of maribavir and / or co-administered drugs must be monitored, altered (e.g., increased or decreased) or interrupted.

[0025] In some embodiments, maribavir is administered to the patient orally at a dose of approximately 400 mg twice daily (the "standard dose"). In some embodiments, such as prior to receiving additional co-administration, the patient has already received an initial therapeutically effective dose of maribavir. In some embodiments, the initial therapeutically effective dose of maribavir is the standard dose (400 mg orally twice daily). In some embodiments, maribavir is administered in tablet form. In some embodiments, maribavir is administered in tablet form containing 200 mg of maribavir. In some embodiments, the provided method includes administering maribavir to the patient with or without food.

[0026] In some embodiments, when co-administered with certain drugs (e.g., CYP3A4 inducers such as carbamate, phenytoin, or phenobarbital), p-glycoprotein inducers (P-gp), immunosuppressants, or antiarrhythmic drugs such as digoxin, ganciclovir, or valganciclovir), the dose of maribavir may be varied (e.g., increased or decreased) relative to the standard dose (400 mg orally twice daily). In some embodiments, the dose of maribavir may be increased to about 800 mg or about 1200 mg orally twice daily. In some embodiments, the dose of maribavir may be increased to about 800 mg orally twice daily. In some embodiments, the dose of maribavir may be increased to about 1200 mg orally twice daily.

[0027] In some embodiments, when co-administered with certain medications (e.g., CYP3A4 inducers such as carbamate, phenytoin, or phenobarbital, p-glycoprotein inducers (P-gp), immunosuppressants, or antiarrhythmic drugs such as digoxin, ganciclovir, or valganciclovir)), the dose of the co-administered medication is varied (e.g., increased or decreased) relative to the recommended dose provided on the label. In some embodiments, the dose of the co-administered medication is reduced compared to its standard dosing regimen. In some embodiments, the provided method further includes the step of monitoring the level of the co-administered medication (e.g., compared to a reference or standard level) after discontinuation of maribavir administration. In some embodiments, the provided method further includes increasing the amount of the co-administered medication administered to the patient (e.g., increasing to the amount of the co-administered medication administered before the start of maribavir administration). a. Maribavir and CYP3A4 inducers

[0028] In some embodiments, the present invention provides the understanding that maribavir is primarily metabolized by CYP3A4. Alternatively or additionally, the present invention provides the understanding that drugs acting as CYP3A4 inducers reduce maribavir plasma concentrations and can lead to a reduced viral response. In some embodiments, co-administration of maribavir with certain CYP3A4 inducers is not recommended, and / or the dosing regimen of one or both drugs should be modified.

[0029] In some embodiments, the present invention provides a method for treating a patient with CMV infection, comprising administering a therapeutically effective amount of maribavir to the patient, wherein the patient is receiving or has received a CYP3A4 inducer prior to administering maribavir. In some embodiments, the method further comprises discontinuing the administration of the CYP3A4 inducer prior to administering maribavir. In some embodiments, the method further comprises increasing the amount of maribavir administered to the patient.

[0030] In some embodiments, the CYP3A4 inducer is selected from the group consisting of rifampin, avamarib, carbamate, phenytoin, rifabutin, phenobarbital, and St. John's wort. In some embodiments, the CYP3A4 inducer is selected from the group consisting of rifampin, carbamate, phenytoin, rifabutin, phenobarbital, and St. John's wort. In some embodiments, the CYP3A4 inducer is selected from the group consisting of rifampin, rifabutin, and St. John's wort. In some embodiments, the CYP3A4 inducer is selected from the group consisting of carbamate, phenytoin, and phenobarbital. In some embodiments, the CYP3A4 inducer is a strong CYP3A4 inducer. Strong CYP3A4 inducers include, for example, rifampin, rifabutin, and St. John's wort. In some embodiments, the CYP3A4 inducer may be administered according to a dosing regimen approved for the treatment of a patient (e.g., a dose approved by the U.S. FDA for a given indication).

[0031] In some embodiments, the CYP3A4 inducer is a p-Gp inducer. In some embodiments, the CYP3A4 inducer also reduces maribavir exposure.

[0032] In some embodiments, the present invention provides a method for treating CMV infection in patients, comprising: Administer a therapeutically effective dose of maribavir (e.g., approximately 400 mg orally twice daily) to patients who are receiving or have received a cytochrome P450 3A4 (CYP3A4) inducer prior to administration of maribavir; and Interrupt the administration of CYP3A4 inducers before administering maribavir.

[0033] In some embodiments, the present invention provides a method for treating CMV infection in patients, comprising: Administer an initial therapeutically effective dose of maribavir (e.g., 400 mg orally twice daily) to patients who are receiving a cytochrome P450 3A4 (CYP3A4) inducer; and Increase the amount of maribavir administered to the patient.

[0034] In some embodiments, the initial therapeutically effective dose of maribavir is the standard dose (400 mg orally twice daily). In some embodiments, the dose of maribavir is increased to about 800 mg or about 1200 mg orally twice daily. In some embodiments, the dose of maribavir is increased to about 800 mg orally twice daily. In some embodiments, the dose of maribavir is increased to about 1200 mg orally twice daily. In some embodiments, where the CYP3A4 inducer is carbamapine, the dose of maribavir is increased to about 800 mg orally twice daily. In some embodiments, where the CYP3A4 inducer is phenytoin or phenobarbital, the dose of maribavir is increased to about 1200 mg orally twice daily.

[0035] In some embodiments, the present invention provides a method for treating CMV infection in patients, comprising: Administer a therapeutically effective dose of maribavir (e.g., about 800 mg or about 1200 mg orally twice daily) to patients who have received a cytochrome P450 3A4 (CYP3A4) inducer prior to administration of maribavir.

[0036] In some embodiments, where the patient has received a CYP3A4 inducer prior to administration of maribavir, the therapeutically effective dose of maribavir is approximately 800 mg orally twice daily or approximately 1200 mg. In some embodiments, where the CYP3A4 inducer is carbamapine, the dose of maribavir administered is approximately 800 mg orally twice daily. In some embodiments, where the CYP3A4 inducer is phenytoin or phenobarbital, the dose of maribavir administered is approximately 1200 mg orally twice daily.

[0037] The drug-drug interaction potential of maribavir in the presence of cytochrome P450 enzymes and P-glycoprotein (P-gp) was thoroughly characterized. Reversible inhibition, time-dependent inhibition, and CYP-induced inhibition were assessed using human cells or human-derived cell lines in the presence of maribavir. Inhibition of P-gp was also evaluated.

[0038] Maribavir is not a reversible inhibitor of CYP2A6, CYP2B6, CYP2C8, CYP2D6, CYP2E1 or CYP3A4, but it is a weak inhibitor of CYP1A2, CYP2C9 and CYP2C19 (half-maximum inhibitory concentration or IC50 is 40, 18 and 35 µM, respectively).

[0039] Maribavir is not a time-dependent inhibitor of CYP1A2, CYP2C8, CYP2C9, CYP2C19, or CYP2D6. However, it is a time-dependent inhibitor of CYP3A4, as clearly shown by the IC50 shift values ​​presented in Figure 1. With midazolam and testosterone as probe acceptors, the IC50 values ​​of maribavir are greater than 1.9 and 3.2 μM, respectively. With midazolam and testosterone, the maribavir concentrations (or KI) at half-maximal inactivation of CYP3A are 41.2 μM and 167 μM, respectively, as shown in Figure 2.

[0040] Maribavir is not an inducer of CYP1A2 or CYP2B6 mRNA, but it is a weak in vitro inducer of CYP3A4 mRNA, showing a more than 14-fold increase in mRNA induction and a more than 30% increase in the positive control concentration. However, the effect varied among donors, as shown in Figure 3. For all donors, the half-maximal effector concentration or EC50 of maribavir exceeded 5 μM.

[0041] As shown in Figure 4, maribavir demonstrated a concentration-dependent inhibition of P-gp-mediated digoxin efflux. In this case, the IC50 of maribavir was 33.8 μM.

[0042] In this article, specifically the data presented in Example 1, indicates the concentration of malibavir required for the observed levels of P-gp and / or some CYP to be inhibited or induced in vitro. b. Maribavir and immunosuppressants

[0043] In some embodiments, the present invention recognizes that maribavir has the potential to increase the drug concentration of certain immunosuppressant drugs that act as CYP3A4 and / or P-gp receptors, where even a minimal concentration change can lead to serious adverse events. Alternatively or additionally, immunosuppressant drug levels should be monitored frequently during treatment with maribavir, especially after initiation and after discontinuation of maribavir, and the immunosuppressant dose should be adjusted as needed.

[0044] In some embodiments, the present invention provides a method for treating a patient with CMV infection, comprising administering to the patient a therapeutically effective amount of maribavir (e.g., 400 mg orally twice daily), wherein the patient is receiving or has received immunosuppressants. In some embodiments, the method further comprises monitoring the level of immunosuppressants (e.g., in whole blood or plasma). In some embodiments, the method further comprises reducing the amount of immunosuppressants administered to the patient. In some embodiments, maribavir also increases immunosuppressant exposure. In some embodiments, the provided method further comprises the step of monitoring immunosuppressant levels (e.g., compared to a reference or standard level) after interruption of maribavir administration. In some embodiments, the provided method further comprises increasing the amount of immunosuppressants administered to the patient (e.g., increasing to the amount of immunosuppressants administered before the start of maribavir administration).

[0045] In some embodiments, the immunosuppressant is selected from the group consisting of: tacrolimus, cyclosporine, everolimus, sirolimus, prysosone, and mycophenolate mofetil. In some embodiments, the immunosuppressant is selected from the group consisting of: tacrolimus, cyclosporine, everolimus, and sirolimus. In some embodiments, the immunosuppressant is tacrolimus. In some embodiments, the immunosuppressant is selected from the group consisting of: tacrolimus, cyclosporine, everolimus, prysosone, and mycophenolate mofetil. In some embodiments, the immunosuppressant is tacrolimus. In some embodiments, the immunosuppressant is everolimus. In some embodiments, the immunosuppressant is cyclosporine. In some embodiments, the immunosuppressant is sirolimus.

[0046] In some embodiments, the immunosuppressant may be administered according to a dosing regimen approved for the treatment of the patient (e.g., the FDA-approved dose of tacrolimus). In some embodiments, tacrolimus is administered at a stable dose twice daily, with a total daily dose between about 0.5 mg and about 16 mg.

[0047] In some embodiments, tacrolimus is administered at an initial dose and whole blood trough concentrations are monitored. In some embodiments, the initial dose of tacrolimus (e.g., before or when co-administering maribavir) is between about 0.075 mg / kg / day and about 0.3 mg / kg / day. In some embodiments, tacrolimus is administered orally in capsules of 0.5 mg, 1.0 mg, or 5.0 mg each. In some embodiments, tacrolimus is administered by injection at a concentration of 5.0 mg / mL. In some embodiments, tacrolimus is administered orally as a 1 mg unit dose granule packet. In some embodiments, tacrolimus whole blood trough concentration observations are monitored over a period between about 0 months and about 12 months after the initial tacrolimus administration. In some embodiments, tacrolimus whole blood trough concentration observations are monitored at initial administration, during co-administration, and upon discontinuation of maribavir administration. In some embodiments, tacrolimus whole blood trough concentration observations are between about 4 and about 20 ng / mL. In some embodiments, the initial dose of tacrolimus administered is between about 0.03% and about 0.1% (w / w) per gram of ointment. In some embodiments, tacrolimus is administered topically in a base selected from the group consisting of: mineral oil, paraffin, propyl carbonate, white petrolatum, and beeswax. In some embodiments, co-administration of maribavir increases tacrolimus exposure by about 50%.

[0048] In some embodiments, the present invention provides a method for administering a therapeutically effective amount of an immunosuppressant to a patient in need to prevent or treat organ rejection and / or graft-versus-host disease, an improvement comprising administering a therapeutically effective amount of maribavir to the patient. In some embodiments, the improvement further comprises the step of reducing the amount of immunosuppressant received. In some embodiments, the improvement further comprises the step of reducing the amount of immunosuppressant received, wherein the immunosuppressant is tacrolimus.

[0049] In some embodiments, the present invention provides a method for preventing or treating organ rejection and / or graft-versus-host disease to patients in need, wherein the patient is receiving or has received a therapeutically effective amount of an immunosuppressant, and the modification includes administering a therapeutically effective amount of maribavir to the patient. In some embodiments, the modification further includes the step of reducing the amount of immunosuppressant received. In some embodiments, the modification further includes the step of reducing the amount of immunosuppressant received, wherein the immunosuppressant is tacrolimus.

[0050] In some embodiments, the present invention provides a method for preventing or treating organ rejection and / or graft-versus-host disease to patients in need, wherein the patient is receiving or has received a therapeutically effective dose of maribavir, and the modification includes administering a therapeutically effective dose of an immunosuppressant to the patient. In some embodiments, the modification further includes the step of reducing the amount of immunosuppressant received. In some embodiments, the modification further includes the step of reducing the amount of immunosuppressant received, wherein the immunosuppressant is tacrolimus. c. Maribavirin and digoxin

[0051] Digoxin is the most commonly used antiarrhythmic drug for atrial fibrillation, atrial flutter, and heart failure. In some embodiments, the present invention recognizes that maribavir has the potential to increase the drug concentration of digoxin as a P-gp receptor, where even a minimal concentration change can lead to serious adverse events. Alternatively or additionally, digoxin levels should be monitored frequently with maribavir treatment, especially after initiation and after discontinuation of maribavir, and the immunosuppressant dose should be adjusted as needed.

[0052] In some embodiments, the present invention provides a method for treating a patient with cellular giant virus (CMV) infection, comprising administering a therapeutically effective dose of maribavir to the patient, wherein the patient is receiving or has received digoxin. In some embodiments, the provided method further comprises monitoring the level of digoxin (e.g., in whole blood or plasma). In some embodiments, the provided method further comprises, for example, reducing the amount of digoxin administered to the patient compared to the amount prior to co-administration of maribavir (such as a dose approved by the U.S. FDA). In some embodiments, digoxin is administered at a dose of 0.5 mg once daily. d. Maribavir and Ganciclovir or Valganciclovir

[0053] In some embodiments, the present invention recognizes that maribavir can antagonize the antiviral activity of ganciclovir and / or valganciclovir by inhibiting the human CMV pUL97 kinase required for the activation / phosphorylation of ganciclovir and valganciclovir.

[0054] In some embodiments, the present invention provides a method for treating a patient with cellular giant cell virus (CMV) infection, comprising administering a therapeutically effective amount of maribavir to the patient, wherein the patient is receiving or has received ganciclovir and / or valganciclovir. In some embodiments, the provided method further comprises discontinuing the administration of ganciclovir and / or valganciclovir prior to the administration of maribavir. In some embodiments, the provided method further comprises monitoring the levels of ganciclovir and / or valganciclovir (e.g., in whole blood or plasma) (e.g., compared to reference or standard levels) after discontinuation of maribavir administration. In some embodiments, the provided method further comprises increasing the amount of ganciclovir and / or valganciclovir administered to the patient (e.g., increasing to the amount of ganciclovir and / or valganciclovir administered before the initiation of maribavir administration). [, 3. , ] [, Patient , ] [, , ]

[0055] As described above and herein, the method of the present invention provides administration of maribavir and co-administration of drugs (e.g., CYP3A4 inducers (such as carbamate, phenytoin, or phenobarbital), p-glycoprotein inducers (P-gp), immunosuppressants, and antiarrhythmic drugs (such as digoxin, ganciclovir, or valganciclovir)) to patients in need. In some embodiments, the patient has CMV infection. In some embodiments, the patient has post-transplant CMV infection. In some embodiments, the patient is a transplant recipient. In some embodiments, the patient is a hematopoietic stem cell transplant recipient. In some embodiments, the patient is a solid organ transplant recipient (e.g., liver, kidney, lung, heart, pancreas, intestine).

[0056] In some embodiments, the patient is refractory to one or more other drugs used to treat CMV infection. In some embodiments, the patient is refractory to one or more other drugs used to treat CMV infection and has genotypic resistance. In some embodiments, the patient is refractory to one or more other drugs used to treat CMV infection and does not have genotypic resistance. In some embodiments, the patient is refractory to one or more of ganciclovir, valganciclovir, cidofovir, or phosphonoformic acid. In some embodiments, the patient is refractory to one or more of ganciclovir or valganciclovir. In some embodiments, the patient is refractory to one or more of ganciclovir. In some embodiments, the patient is refractory to one or more of ganciclovir. In some embodiments, the patient is refractory to one or more of valganciclovir.

[0057] In some embodiments, the patient is an adult or child aged 12 years or older and weighing more than 35 kg. In some embodiments, the patient is an adult. In some embodiments, the patient is a child. In some embodiments, the patient is a child aged 12 years or older. In some embodiments, the patient is a child weighing more than 35 kg. In some embodiments, the patient is a child aged 12 years or older and weighing more than 35 kg. [, 4. , ] [, Used from , ] [, 1 , ] [, Evaluation of maribavir drug based on data from phase II clinical studies and non-clinical in vitro studies , ] [, - , ] [, Drug interaction potential , ] [, , ]

[0058] The drug-drug interaction potential of maribavir is described in Example 3.

[0059] Accumulated data show that maribavir is primarily metabolized in the liver, with renal clearance being a secondary pathway (less than 5%). VP 44469 (N-dealkylated maribavir) is the main metabolite of maribavir in urine and feces. In plasma, unaltered maribavir and VP 44469 exhibit approximately 69% and 9.8% of total radioactivity, respectively. Hepatic metabolism of maribavir is primarily driven by cytochrome P450. CYP3A4 and CYP1A2 are responsible for 70%–85% and 15%–30% of the CYP-driven pathways, respectively. Glucuronization accounts for less than 20% of metabolism.

[0060] Significant clinical drug interactions are summarized in Table 1-A of Example 3. Potent inducers of CYP34A and P-gp reduce maribavir exposure, necessitating dose increases. Inhibitors of CYP3A4 and / or P-gp can increase maribavir exposure. However, prior safety and tolerability data indicate that dose reduction is not necessary with CYP3A4 and / or P-gp inhibitors. Maribavir can increase exposure to immunosuppressants; therefore, monitoring for concomitant immunosuppressants should be considered. [, 5. , ] [, Clinical Pharmacology of Maribavirin , ] [, , ]

[0061] Following oral administration, maribavir is rapidly and adequately absorbed, with peak concentrations typically achieved within 1 to 3 hours; exposure is not affected by food; and bioavailability is not affected by squeeze tablets or when taken with antacids.

[0062] Maribavir is metabolized in the liver via the cytochrome P450 3A4 and 1A2 pathways. Less than 5% of maribavir is cleared by the kidneys. Maribavir has a half-life of approximately 5 to 7 hours.

[0063] Maribavir was found to present a low risk of drug-drug interactions. Co-administration with potent CYP3A4 inducers was found to reduce maribavir exposure, necessitating an increase in maribavir dose. Some immunosuppressants (such as tacrolimus) can be affected by maribavir, resulting in a 51% increase in tacrolimus exposure.

[0064] In summary, maribavir is suitable for the treatment of CMV infection in a wide range of transplant recipients. It can be taken with or without food, and no dose adjustment is required in patients with mild to moderate hepatic or renal impairment. Maribavir has a low potential for drug interactions and requires minimal dose adjustment (e.g., only when concomitantly taken with CYP3A4 inducers or certain immunosuppressants) and has no effect on the QT interval. [, Exemplary embodiments , ] [, , ]

[0065] The following numbered but not limiting embodiments are examples of certain aspects of the present invention: 1. A method for treating the infection in a patient suffering from cell giant virus (CMV) infection, comprising: Administer a therapeutically effective dose of maribavir to patients who were receiving or had received a cytochrome P450 3A4 (CYP3A4) inducer prior to administration of maribavir; and Interrupt the administration of CYP3A4 inducers before administering maribavir. 2. The method of Example 1, wherein the CYP3A4 inducer is selected from the group consisting of: rifampin, avamirbein, cabamopin, phenytoin, rifabutin, phenobarbital and St. John's wort. 3. The method as described in Example 1 or 2, wherein the CYP3A4 inducer is a strong CYP3A4 inducer. 4. The method of any one of Examples 1 to 3, wherein the CYP3A4 inducer is selected from the group consisting of rifampin, rifabutin and St. John's wort. 5. The method of any one of Examples 1 to 4, comprising administering approximately 400 mg of maribavir orally to a patient twice daily. 6. The method of any one of Examples 1 to 5, comprising administering maribavir to the patient with or without food. 7. A method for treating the infection in a patient suffering from cell giant virus (CMV) infection, comprising: Patients receiving an initial therapeutically effective dose of maribavir, who were also receiving a cytochrome P450 3A4 (CYP3A4) inducer, were administered the following: Increase the amount of maribavir administered to the patient. 8. The method of Example 7, wherein the CYP3A4 inducer is selected from the group consisting of: rifampin, avamirin, cabamopin, phenytoin, rifabutin, phenobarbital and St. John's wort. 9. The method of Example 7 or 8, wherein the CYP3A4 inducer is selected from the group consisting of: rifampin, carbamate, phenytoin, rifabutin, phenobarbital and St. John's wort. 10. The method of any one of Examples 7 to 9, wherein the CYP3A4 inducer is selected from the group consisting of: carbamate, phenytoin and phenobarbital. 11. The method of any one of Examples 7 to 10, wherein the patient has received approximately 400 mg of maribavir orally twice daily as the therapeutically effective dose of maribavir ("initial therapeutically effective dose") prior to receiving the CYP3A4 inducer. 12. The method of any one of Examples 7 to 11, wherein the amount of maribavir is increased to about 800 or about 1200 mg of maribavir orally twice daily. 13. The method of any one of Examples 7 to 12, wherein the CYP3A4 inducer is carbamopine, and the amount of maribavir is increased to approximately 800 mg of maribavir orally twice daily. 14. The method of any one of Examples 7 to 12, wherein the CYP3A4 inducer is phenytoin or phenobarbital, and the amount of maribavir is increased to approximately 1200 mg of maribavir orally twice daily. 15. A method for treating the infection in a patient suffering from cell giant virus (CMV) infection, comprising: Administer a therapeutically effective dose of maribavir to patients who have received a cytochrome P450 3A4 (CYP3A4) inducer prior to administration of maribavir. 16. The method of Example 15, wherein the CYP3A4 inducer is selected from the group consisting of: rifampin, avamirbe, cabamopin, phenytoin, rifabutin, phenobarbital and St. John's wort. 17. The method of Example 15 or 16, wherein the CYP3A4 inducer is selected from the group consisting of: rifampin, carbamate, phenytoin, rifabutin, phenobarbital and St. John's wort. 18. The method of any one of Examples 15 to 17, wherein the CYP3A4 inducer is selected from the group consisting of: carbamate, phenytoin and phenobarbital. 19. The method of any one of Examples 15 to 18, wherein the amount of maribavir administered is about 800 or about 1200 mg orally twice daily. 20. The method of any one of claims 15 to 19, wherein the CYP3A4 inducer is carbamopine, and the amount of maribavir administered to it is approximately 800 mg orally twice daily. 21. The method of any one of claims 15 to 19, wherein the CYP3A4 inducer is phenytoin or phenobarbital, and the amount of maribavir administered to it is approximately 1200 mg orally twice daily. 22. The method of any of claims 1 to 21, wherein the CYP3A4 inducer reduces maribavir exposure. 23. A method of treating a patient with cellular giant virus (CMV) infection, comprising administering a therapeutically effective dose of maribavir to the patient, wherein the patient is receiving or has received an immunosuppressant. 24. The method of Example 23 further includes the step of monitoring the level of the immunosuppressant (e.g., compared with a reference or standard level) after the initiation of maribavir administration. 25. The method of Example 23 or 24 further includes the step of reducing the amount of immunosuppressant administered to the patient. 26. The method of any one of Examples 23 to 25, further comprising the step of monitoring the level of the immunosuppressant (e.g., compared with a reference or standard level) after interruption of maribavir administration. 27. The method of Example 26 further includes increasing the amount of immunosuppressant administered to the patient (e.g., increasing to the amount of immunosuppressant administered before starting maribavir administration). 28. The method of any one of Examples 23 to 27, wherein the immunosuppressant is selected from the group consisting of: tacrolimus, cyclosporine, everolimus, sirolimus, prysosone and mycophenolate mofetil. 29. The method of any one of Examples 23 to 28, wherein the immunosuppressant is selected from the group consisting of tacrolimus, cyclosporine, everolimus and sirolimus. 30. A method of treating a patient with cellular giant virus (CMV) infection, comprising administering a therapeutically effective dose of maribavir to the patient, wherein the patient is receiving or has received digoxin. 31. The method of Example 30 further includes the step of monitoring the content of digoxin. 32. The method of Example 30 or 31 further includes the step of reducing the amount of digoxin administered to the patient. 33. The method of any one of Examples 1 to 32, wherein the patient is difficult to cure with one or more other drugs for treating CMV infection. 34. The method of any one of Examples 1 to 33, wherein the patient is difficult to cure with one or more of ganciclovir, valganciclovir, cidofovir or foscarnet. 35. The method of any one of Examples 1 to 34, wherein the patient is difficult to treat and has genotypic drug resistance. 36. The method of any one of Examples 1 to 34, wherein the patient is difficult to treat and has no genotype drug resistance. 37. A method for treating the infection in a patient suffering from cellular giant virus (CMV) infection, comprising: Administering a therapeutically effective dose of maribavir to a patient who was or had previously received ganciclovir or valganciclovir prior to administration of maribavir; and Discontinue the administration of ganciclovir or valganciclovir before administering malibavir. 38. The method of any one of Examples 7 to 37, comprising administering maribavir to the patient with or without food. 39. The method of any one of Examples 1 to 38, wherein the patient is a solid organ transplant recipient. 40. The method of any one of Examples 1 to 39, wherein the patient is a hematopoietic stem cell transplant recipient. 41. The method of any one of Examples 1 to 39, wherein the patient is a solid organ transplant recipient. 42. The method of any one of Examples 1 to 41, wherein the patient is an adult or a child aged 12 years or older and weighing more than 35 kg. [Example] [Example] [1] [-] [, Potential cytochromes in malibavir , ] [, P450 , ] [, drug , ] [, - , ] [, In vitro profile of drug interactions , ] []

[0066] Inhibition or induction of cytochrome P450 enzymes (CYP) is one of the most common mechanisms of drug-drug interactions.

[0067] In vitro systems such as human liver microsomes (HLM), recombinases, human hepatocytes and other human-derived cell lines have long been used as validation systems to characterize potential drug-drug interactions prior to clinical studies. [reversible] [CYP] [inhibition]

[0068] The half-maximal inhibitory concentration (IC50) of maribavir, which inhibits the activity of nine CYP isomers, was assessed using HLM. The probe receptors were phenacetin (CYP1A2), coumarin (CYP2A6), bupropion (CYP2B6), paclitaxel (CYP2C8), tolbutamide (CYP2C9), (S)-tosylate (CYP2C19), dextromethorphan (CYP2D6), clorzoxazone (CYP2E1), and midazolam and testosterone (CYP3A4).

[0069] CYP activity was evaluated at 0, 0.1, 0.3, 1, 3, 10, 30 and 100 μM of maribavir.

[0070] Culturing maribavir in HLM at concentrations up to 100 μM did not induce significant inhibition of CYP2A6, CYP2B6, CYP2C8, CYP2D6, CYP2E1, and CYP3A4. Maribavir is a weak inhibitor of CYP1A2, CYP2C9, and CYP2C19, with IC50 values ​​of 40, 18, and 35 μM, respectively. [Time Dependency] [CYP] [inhibition]

[0071] The time-dependent inhibition (TDI) potential of different CYP enzymes was evaluated by pre-incubating with HLM for 30 minutes in the presence and absence of nicotinamide-adenine dinucleotide phosphate (NADPH) followed by CYP enzyme activity assay.

[0072] Using midazolam and testosterone as probes and substrates, the enzymatic inactivation kinetics of maribavir targeting CYP3A was evaluated by pre-incubating HLMs with different concentrations of maribavir under NADPH conditions for six different pre-incubation time ranges. CYP3A activity was measured by determining the formation of CYP3A probe metabolites. Nonlinear least square regression was used to estimate the inhibitor concentration (KI) at half-maximum enzyme inactivation and the maximum enzyme inactivation rate constant (kinact).

[0073] In HLM, the IC50 offset of maribavir against CYP1A2, CYP2C8, CYP2C9, CYP2C19, and CYP2D6 is <1 μM. With midazolam and testosterone as probe acceptors, the IC50 offset of maribavir against CYP3A is greater than 1.9 and 3.2 μM, respectively (Figure 1). Therefore, maribavir at concentrations up to 100 μM is unlikely to be a TDI for CYP1A2, CYP2C8, CYP2C9, CYP2C19, or CYP2D6; however, it is likely a TDI for CYP3A.

[0074] With midazolam as the acceptor, the TDI for CYP3A, KI and k intact for maribavir (Figure 2A) were 41.2 μM and 0.0117 min⁻¹, respectively. With testosterone as the acceptor, the TDI for CYP3A, KI and k intact for maribavir (Figure 2B) were 167 μM and 0.0357 min⁻¹, respectively. [CYP] [Inducement]

[0075] Fresh human hepatocytes were treated with culture media containing 36 μM, 144 μM, and 480 μM maribavir.

[0076] Positive controls were 50 μM omeprazole (CYP1A2), 1 mM phenobarbital (CYP2B6), and 50 μM rifampin (CYP3A).

[0077] The culture medium containing the compound was replaced daily at 37°C for 72 hours. Total RNA was isolated, and cDNA was synthesized from up to 1 μg of the total isolated RNA. CYP expression was analyzed by qPCR using a CYP-specific probe.

[0078] The half-maximal effect concentration (EC50) and maximum effect (Emax) induced by CYP3A4 mRNA were further determined by the concentration-response curves of maribavir at concentrations ranging from 0 to 100 μM in three donors.

[0079] Maribavir showed varying degrees of CYP1A2 and CYP2B6 mRNA induction in human hepatocytes. The fold increase in mRNA was not concentration-dependent, varied between donors, and did not exceed 11% of the positive control concentration. Therefore, maribavir is unlikely to be an inducer of CYP1A2 or CYP2B6 mRNA at clinically relevant concentrations.

[0080] At 36 μM, maribavir showed a more than 14-fold increase in CYP3A4 mRNA induction and exceeded the positive control (rifampin) by 30%. The EC50 and Emax values ​​for CYP3A4 induction were subsequently determined using concentration-response curves from the three donors.

[0081] Maribavir also showed donor-dependent induction of CYP3A4 mRNA when its induction Emax and EC50 characteristics were measured (Figure 3). [Example] [2-] [Using previous in vitro and in vivo data] [Quantitative Prediction of Maribavirin Exposure] []

[0082] A physiology-based pharmacokinetic (PBPK) model, based on previous in vitro and in vivo information on the metabolism and pharmacokinetics of maribavir, was constructed to predict the plasma concentration-time profile of maribavir and to assess the potential effects of co-administration of CYP3A4 inhibitors and inducers on the pharmacokinetics of maribavir in healthy individuals. [Model Development]

[0083] A combination of in vitro and clinical pharmacokinetic data obtained after a single 400 mg dose of maribavir was used to develop a PBPK model. The mean concentration of the total virtual population (n=100) is shown, and the relevant mean Cmax and AUC (0–∞) values ​​are compared in Table 2A. Furthermore, the predicted mean maribavir AUC is within 1.25 times the observed values. Cmax is more or less below the prediction, as the PBPK model was optimized to better predict Cmax at 12h, which is to be expected. Table 2A. Predicted and observed Cmax and AUC (0 - ∞) values ​​of maribavir after a single oral dose (400 mg). [AUC, (0- , ] [, ∞ , ] [, ) , ] [mg / L*h] [C, max , mg / L [predict] average value 97.98 11.98 Median 91.97 11.48 Geometric Mean 90.40 11.56 Approximately 90% of the geometric mean CI (lower limit) 84.45 11.06 Approximately 90% of the geometric mean CI (upper limit) 96.76 12.08 5th percentile 46.52 7.61 95th percentile 165.11 18.08 SD 39.33 3.26 %CV 40 27 [Observation] average value 97.8 16.7 SD 28.6 5.72 %CV 29.2 34.3 [Average Forecast Value] [ / ] [Ratio of Observations] [1.00] [0.72]

[0084] Renal clearance of 0.051 L / H was achieved after a single oral dose of 50 mg to 1600 mg of maribavir. In vitro human liver microsomal and recombinant CYP data were combined with oral clearance values ​​reported in two studies (n=46 individuals; Ma et al., 2006) to assign the relative weight of CYP3A4 to maribavir clearance. Distribution models assessed included the full PBPK model and the minimum PBPK model, both of which examined hepatic and intestinal metabolism. Mass balance data from the [14C] DME study indicated an absorption fraction of 0.83 or greater after an oral dose of 400 mg of maribavir. Absorption models assessed included the simple first-order absorption model and the more mechanistic Advanced Absorption and Metabolism (ADAM) model. Although maribavir has been shown to be a live P-gp receptor, the relatively linear pharmacokinetics within the dose range of interest (400 mg to 1600 mg) informs the choice of a simpler first-order absorption model for this PBPK study. [Model Validation]

[0085] Following single oral doses of 800 mg and 1600 mg to healthy patients, observed and predicted maribavir plasma concentrations were compared. The mean concentration for the total hypothetical population (n=100) is shown, and the relevant mean Cmax and AUC (0-∞) values ​​in Tables 3A and 4A are compared. Simulated and observed maribavir concentrations are reasonably consistent. Furthermore, the predicted mean maribavir AUC is within 1.25 times the observed values. Table 3A. Predicted and observed Cmax and AUC (0 - ∞) values ​​of maribavir after a single oral dose (800 mg). [AUC, (0- , ] [, ∞ , ] [, ) , ] [mg / L*h] [C, max , mg / L [predict] average value 195.71 24.05 Median 179.48 23.22 Geometric Mean 180.00 23.23 Approximately 90% of the geometric mean CI (lower limit) 167.95 22.23 Approximately 90% of the geometric mean CI (upper limit) 192.91 24.27 5th percentile 93.03 15.22 95th percentile 330.22 36.17 SD 80.04 6.47 %CV 41 27 [Observation] average value 183 26.4 SD 69.1 6.85 %CV 38.0 26.0 [Average Forecast Value] [ / ] [Ratio of Observations] [1.07] [0.91] Table 4A. Predicted and observed Cmax and AUC (0 - ∞) values ​​of maribavir after a single oral dose (1600 mg). [AUC, (0- , ] [, ∞ , ] [, ) , ] [mg / L*h] [C, max , mg / L [predict] average value 391.43 48.10 Median 358.95 46.45 Geometric Mean 359.99 46.45 Approximately 90% of the geometric mean CI (lower limit) 335.89 44.46 Approximately 90% of the geometric mean CI (upper limit) 385.82 48.54 5th percentile 186.06 30.44 95th percentile 660.44 72.34 SD 106.09 12.94 %CV 41 27 [Observation] average value 437 48.8 SD 163 7.88 %CV 37.4 16.1 [Average Forecast Value] [ / ] [Ratio of Observations] [0.90] [-0.99%]

[0086] Following multiple oral doses of 400 mg BID maribavir, observed and predicted plasma concentrations of maribavir were compared. The mean concentration of the total hypothetical population (n=150) is shown, and the relevant mean Cmax and AUC (0-∞) values ​​are compared in Table 5A. Simulated and observed maribavir concentrations are reasonably consistent. Furthermore, the predicted mean maribavir AUC is within 1.25 times that of the observed data. Table 5A. Predicted and observed values ​​of C12h, Cmax, and AUC (0 - ∞) of maribavir after multiple oral doses (400 mg BBID, 5 doses). [AUC, (0- , ] [, ∞ , ] [, ) , ] [mg / L*h] [C, max , mg / L [C, 12h , mg / L [predict] average value 96.49 14.31 2.99 Median 90.13 14.05 2.44 Geometric Mean 89.31 13.78 2.13 Approximately 90% of the geometric mean CI (lower limit) 85.01 13.31 1.89 Approximately 90% of the geometric mean CI (upper limit) 93.82 14.26 2.15 5th percentile 46.35 8.80 0.36 95th percentile 162.88 20.59 7.76 SD 37.93 3.96 2.2 %CV 39 28 73 [Observation] average value 89.9 16.9 2.54 SD 24.5 5.22 1.37 %CV 27.2 30.8 53.8 [Average Forecast Value] [ / ] [Ratio of Observations] [1.07] [0.85] [1.18]

[0087] Observed and predicted plasma concentrations of maribavir were compared in healthy individuals one hour after a single oral dose of 400 mg in the absence of ketoconazole (a CYP3A4 inhibitor) and one hour after a single 400 mg dose in the presence of ketoconazole. The simulated and observed mean plasma maribavir concentrations were compared, and the geometric mean of the Cmax and AUC (0-∞) for maribavir in the presence and absence of ketoconazole is shown in Table 6A and is within 1.25 times the observed data. Table 6A. Simulated and observed PK parameters and Cmax and AUC (0 - ∞) geometric mean ratios of maribavir after a single oral dose in healthy adults with and without ketoconazole and under relevant changes. [Malibawe] [Malibawe] [+] Ketoconazole [ratio] [AUC, (0- , ] [, ∞ , ] [, ) , ] [mg / L*h] [C, max , mg / L [AUC, (0- , ] [, ∞ , ] [, ) , ] [mg / L*h] [C, max , mg / L [AUC, (0- , ] [, ∞ , ] [, ) , ] [C, max , ] [predict] average value 98.96 12.27 150.60 14.31 1.54 1.17 Median 93.51 11.91 140.38 13.75 1.49 1.15 Geometric Mean 92.29 11.81 141.16 13.77 1.53 1.17 Approximately 90% of the geometric mean CI (lower limit) 88.30 11.43 135.28 13.32 1.51 1.16 Approximately 90% of the geometric mean CI (upper limit) 96.45 12.20 147.30 14.23 1.55 1.17 5th percentile 48.52 7.50 77.98 8.85 1.27 1.09 95th percentile 169.37 17.86 246.30 21.20 1.97 1.29 SD 37.19 3.4 54.7 4.0 0.21 0.06 %CV 38 28 36 28 14 5 [Observation] average value 126 19.8 194 21.8 1.55 1.12 SD 41.6 3.9 64.3 4.4 0.23 0.22 %CV 33 20 33 20 15 20 Geometric Mean 119 19.4 183 21.3 1.53 1.10 Approximately 90% of the geometric mean CI (lower limit) 1.44 1.01 Approximately 90% of the geometric mean CI (upper limit) 1.63 1.19 [Average Forecast Value] [ / ] [Ratio of Observations] [0.79] [0.62] [0.78] [0.66] [0.99] [1.05] [predict] [ / ] [Ratio of Observed Geometric Means] [0.78] [0.61] [0.77] [0.65] [1.00] [1.06]

[0088] Observed and predicted plasma concentrations of maribavir were compared in the absence of rifampin and after multiple oral doses of 400 mg during concurrent treatment with rifampin. Individuals received 400 mg maribavir via a BID (5 doses) on days 1–3, followed by 600 mg rifampin via QD on days 4–12, then 400 mg maribavir via BID and 600 mg rifampin via QD on days 13 and 14, and the final dose of maribavir and rifampin on the morning of day 15. The geometric mean of the relevant C12h, Cmax, and AUC (0–12h) for maribavir in the presence or absence of rifampin is shown in Table 7A. Predicted values ​​for Cmax and AUC were within 1.25 times the observed values. Table 7A. Simulated and observed PK parameters and the ratio of geometric mean Cmax and AUC (0–12 h) of maribavir after a single oral dose in healthy adults with and without rifampin and under relevant changes. [Malibawe]

[0400] [] [mg] [] [BID]

[0400] [] [mg] [] [BID] [Malibawe] [+]

[0600] [] [mg] [] [QD] [] [Rifampin] [ratio] [AUC, (0-12h) , ] [C, max , ] [C, 12h , ] [AUC, (0-12h) , ] [C, max , ] [C, 12h , ] [AUC, (0-12h) , ] [C, max , ] [C, 12h , ] [] [mg / L*h] [mg / L] [mg / L] [mg / L*h] [mg / L] [mg / L] [predict] average value 95.28 14.26 2.88 35.13 7.97 0.340 0.37 0.56 0.09 Median 90.02 13.98 2.61 30.52 7.57 0.145 0.35 0.55 0.06 Geometric Mean 88.77 13.78 2.07 30.53 7.44 0.088 0.34 0.54 0.04 Approximately 90% of the geometric mean CI (lower limit) 84.25 13:30 2.03 28.36 7.07 0.083 0.33 0.52 0.04 Approximately 90% of the geometric mean CI (upper limit) 93.54 14.29 2.10 32.86 7.83 0.093 0.36 0.56 0.04 5th percentile 41.15 8.76 0.39 12.44 3.95 0.002 0.17 0.33 0.01 95th percentile 151.23 20.23 6.49 67.37 13.43 1.507 0.62 0.79 0.33 SD 35.28 3.7 2.1 18.64 2.93 0.53 0.14 0.14 0.11 %CV 37 26 73 53 37 151 37 25 112 [Observation] average value 89.9 16.9 2.54 35.1 10.2 0.41 0.41 0.65 0.17 SD 24.5 5.22 1.37 7.07 2.3 0.21 0.08 0.24 0.07 %CV 86.6 16.2 2.24 34.5 9.88 0.41 0.40 0.61 0.18 [Average Forecast Value] [ / ] [Ratio of Observations] [1.06] [0.84] [1.14] [1.00] [0.78] [0.83] [0.91] [0.87] [0.56] [predict] [ / ] [Geometric Mean of Observational Ratios] [1.03] [0.85] [0.92] [0.88] [0.75] [0.22] [0.85] [0.89] [0.24] [Model Validation] Simulation of plasma concentration-time profiles of 800 mg BID of maribavir in the presence and absence of 600 mg rifampin QD

[0089] Predicted plasma concentration-time profiles of maribavir were generated during a 3-day (5 doses) administration of 800 mg BID once daily from day 1 to day 12, with and without rifampin. For each simulation, the mean concentration-time profiles of each trial were used from 20 individuals, with a total hypothetical population of 200 individuals. Predicted PK parameters (Cmax, AUC (0–12h), and C12h) for the population are shown in Table 8A. The predicted PK parameters (Cmax, AUC (0–12h), and C12h) used for this interaction were compared with the PK parameters for maribavir at a 400 mg BID dose in Table 9A.

[0090] The Cmax of maribavir obtained from an 800 mg BID in the presence of a 600 mg rifampin QD was similar to that of maribavir alone at a 400 mg BID; however, the AUC (0–12) decreased by 23% and C12h decreased by 75%. This indicates that increasing the maribavir dose from 400 mg BID to 800 mg BID does not offset the effect of rifampin on reduced maribavir treatment exposure. Table 8A. Predicted PK parameters for maribavir 800 mg BID in the presence and absence of rifampin 600 mg QD. [Malibawe]

[0800] [] [mg] [] [BID] [Malibawe]

[0800] [] [mg] [] [BID] [+]

[0600] [] [mg] [] [QD] [Rifampin] [ratio] [AUC, (0-12h) , ] [C, max , ] [C, 12h , ] [AUC, (0-12h) , ] [C, max , ] [C, 12h , ] [AUC, (0-12h) , ] [C, max , ] [C, 12h , ] [] [mg / L*h] [mg / L] [mg / L] [mg / L*h] [mg / L] [mg / L] [Prediction] average value 194.99 28.96 5.95 73.25 16.40 0.73 0.37 0.56 0.10 Median 189.24 28.37 5.34 68.57 15.57 0.31 0.37 0.56 0.06 Geometric Mean 182.49 27.95 4.39 63.52 15.22 0.20 0.35 0.54 0.04 Approximately 90% of the geometric mean CI (lower limit) 174.67 27.09 4.36 59.54 14.54 0.18 0.33 0.53 0.04 Approximately 90% of the geometric mean CI (upper limit) 190.66 28.85 4.43 67.77 15.94 0.21 0.36 0.56 0.05 5th percentile 94.23 17.97 0.93 24.65 7.93 0.00 0.18 0.35 0.00 95th percentile 311.05 43.06 13.85 136.31 27.80 2.82 0.62 0.79 0.34 SD 68.94 7.68 4.00 38.65 6.25 1.09 0.14 0.14 0.11 %CV 35 26 67 53 38 149 37 25 108 Table 9A. Predicted PK parameters of 800 mg bID of maribavir compared with PK parameters of 400 mg maribavir. [Malibawe]

[0400] [] [mg] [] [BID] [Malibawe]

[0800] [] [mg] [] [BID] [+]

[0600] [] [mg] [] [QD] [Rifampin] [ratio] [AUC, (0-12h) , ] [C, max , ] [C, 12h , ] [AUC, (0-12h) , ] [C, max , ] [C, 12h , ] [AUC, (0-12h) , ] [C, max , ] [C, 12h , ] [] [mg / L*h] [mg / L] [mg / L] [mg / L*h] [mg / L] [mg / L] [Prediction] average value 95.28 14.26 2.88 73.25 16.40 0.73 0.77 1.15 0.25 Median 90.02 13.98 2.61 68.57 15.57 0.31 0.76 1.11 0.12 Geometric Mean 88.77 13.78 2.07 63.52 15.22 0.20 0.72 1.10 0.10 Approximately 90% of the geometric mean CI (lower limit) 84.25 13.3 2.03 59.54 14.54 0.18 0.71 1.09 0.09 Approximately 90% of the geometric mean CI (upper limit) 93.54 14.29 2.1 67.77 15.94 0.21 0.72 1.12 0.10 5th percentile 41.15 8.76 0.39 24.65 7.93 0.00 0.60 0.91 0.00 95th percentile 151.23 20.34 6.49 136.31 27.80 2.82 0.90 1.37 0.43 SD 35.28 3.7 2.1 38.65 6.25 1.09 1.10 1.69 0.52 %CV 37 26 73 53 38 149 1.43 1.46 2.04 Simulation of plasma concentration-time profiles of 1200 mg BID of maribavir in the presence and absence of 600 mg rifampin QD

[0091] Predicted plasma concentration-time profiles of maribavir were generated during a 3-day (5 doses) administration of 1200 mg BID once daily from day 1 to day 12, in the absence and presence of rifampin. For each simulation, the mean concentration-time profiles of each trial were used from 20 individuals, with a total hypothetical population of 200 individuals. Predicted PK parameters (Cmax, AUC (0–12h), and C12h) for the population are shown in Table 10A. Predicted PK parameters for maribavir 1200 mg BID in the presence of rifampin 600 mg QD, compared to those for maribavir 400 mg BID, are presented in Table 11A.

[0092] The AUC of maribavir obtained from a 1200 mg BID in the presence of a 600 mg rifampin QD was similar to that of maribavir alone at a 400 mg BID; however, the Cmax was slightly higher. However, the C12h geometric mean was reduced by 86%, indicating that increasing the maribavir dose from 400 mg BID to 1200 mg BID, from an efficacy perspective, did not offset the effect of rifampin (primarily driven by C12h). Increasing the maribavir dose to 1600 mg BID had the least effect on the C12h geometric mean, which was 81% lower than the geometric mean of maribavir at a 400 mg BID dose. Table 10A. Predicted PK parameters for maribavir 1200 mg BID in the presence and absence of rifampin 600 mg QD. [Malibawe]

[1200] [] [mg] [] [BID] [Malibawe]

[1200] [] [mg] [] [BID] [+]

[0600] [] [mg] [] [QD] [Rifampin] [ratio] [AUC, (0-12h) , ] [C, max , ] [C, 12h , ] [AUC, (0-12h) , ] [C, max , ] [C, 12h , ] [AUC, (0-12h) , ] [C, max , ] [C, 12h , ] [] [mg / L*h] [mg / L] [mg / L] [mg / L*h] [mg / L] [mg / L] [predict] average value 292.48 43.44 8.93 109.87 24.59 1.10 0.37 0.56 0.10 Median 283.87 42.55 8.00 102.85 23.35 0.47 0.37 0.56 0.06 Geometric Mean 273.73 41.93 6.59 95.28 22.84 0.30 0.35 0.54 0.04 Approximately 90% of the geometric mean CI (lower limit) 262.00 40.63 6.55 89.31 21.81 0.28 0.33 0.53 0.04 Approximately 90% of the geometric mean CI (upper limit) 285.99 43.27 6.62 101.65 23.91 0.31 0.36 0.56 0.05 5th percentile 141.35 26.96 1.40 36.97 11.90 0.00 0.18 0.35 0.00 95th percentile 466.58 64.59 20.77 204.46 41.71 4.23 0.62 0.79 0.34 SD 108.42 11.45 6.00 57.57 9.37 1.63 0.14 0.14 0.11 %CV 35 26 67 53 38 149 37 25 108 Table 11A. Predicted PK parameters of 1200 mg BID of maribavir in the presence of 600 mg QD in the presence of rifampin, compared with PK parameters of maribavir 400 mg BID. [Malibawe]

[0400] [] [mg] [] [BID] [Malibawe]

[1200] [] [mg] [] [BID] [+]

[0600] [] [mg] [] [QD] [Rifampin] [ratio] [AUC, (0-12h) , ] [C, max , ] [C, 12h , ] [AUC, (0-12h) , ] [C, max , ] [C, 12h , ] [AUC, (0-12h) , ] [C, max , ] [C, 12h , ] [] [mg / L*h] [mg / L] [mg / L] [mg / L*h] [mg / L] [mg / L] [predict] average value 95.28 14.26 2.89 109.87 24.59 1.10 1.15 1.72 0.38 Median 90.02 13.98 2.61 102.85 23.35 0.47 1.14 1.67 0.18 Geometric Mean 88.77 13.78 2.07 95.28 22.84 0.30 1.07 1.66 0.14 Approximately 90% of the geometric mean CI (lower limit) 84.25 13.3 2.03 89.31 21.81 0.28 1.06 1.64 0.14 Approximately 90% of the geometric mean CI (upper limit) 93.54 14.29 2.1 101.65 23.91 0.31 1.09 1.67 0.15 5th percentile 41.15 8.76 0.39 36.97 11.90 0.00 0.90 1.36 0.00 95th percentile 151.23 20.34 6.49 204.46 41.71 4.23 1.35 2.05 0.65 SD 35.28 3.7 2.1 57.57 9.37 1.63 1.63 2.53 0.78 %CV 37 26 73 53 38 149 1.43 1.46 2.04 Simulation of plasma concentration-time profiles of 400 mg BID of maribavir in the presence and absence of 100 mg phenobarbital QD

[0093] Predicted plasma concentration-time profiles of maribavir were generated during the administration of 100 mg phenobarbital once daily for 3 days (5 doses) in the absence and presence of 400 mg BID from day 1 to day 12. For each simulation, the mean concentration-time profiles of each trial were used from 20 individuals, with a total hypothetical population of 200 individuals. Predicted PK parameters (Cmax, AUC (0–12h), and C12h) for the population are shown in Table 12A. Phenobarbital-induced CYP3A4 resulted in mean reductions of 39%, 27%, and 63% in AUC (0–12h), Cmax, and C12h, respectively. Table 12A. Predicted PK parameters for maribavir 400 mg BID in the presence and absence of phenobarbital 100 mg QD. [Malibawe]

[0400] [] [mg] [] [BID] [Malibawe]

[0400] [] [mg] [] [BID] [+]

[0100] [] [mg] [] [QD] Phenobarbital [ratio] [AUC, (0-12h) , ] [C, max , ] [C, 12h , ] [AUC, (0-12h) , ] [C, max , ] [C, 12h , ] [AUC, (0-12h) , ] [C, max , ] [C, 12h , ] [] [mg / L*h] [mg / L] [mg / L] [mg / L*h] [mg / L] [mg / L] [Prediction] average value 99.72 14.66 3.12 61.20 10.66 1.33 0.61 0.73 0.37 Median 93.26 14.23 2.40 55.41 10.44 0.85 0.63 0.75 0.37 Geometric Mean 92.65 14.09 2.29 55.66 10.21 0.72 0.60 0.72 0.31 Approximately 90% of the geometric mean CI (lower limit) 88.54 13.63 2.27 52.88 9.86 0.70 0.59 0.71 0.31 Approximately 90% of the geometric mean CI (upper limit) 96.96 14.57 2.31 58.60 10.57 0.73 0.62 0.74 0.31 5th percentile 47.52 9.12 0.50 27.75 6.18 0.07 0.39 0.56 0.07 95th percentile 169.70 21.94 7.30 112.27 16.47 4.17 0.78 0.86 0.65 SD 38.6 4.1 2.26 26.96 3.12 1.25 0.12 0.09 0.18 %CV 38 28 72 44 29 101 20 13 47 Simulation of plasma concentration-time profiles of 800 mg BID of maribavir in the presence and absence of 100 mg phenobarbital QD

[0094] Predicted plasma concentration-time profiles of maribavir were generated during 3 days (5 doses) of 800 mg BID administered once daily at 100 mg phenobarbital in the absence and presence of phenobarbital from day 1 to day 12. For each simulation, the mean concentration-time profiles of each trial were used from 10 individuals, with a total hypothetical population of 200 individuals. Predicted PK parameters (Cmax, AUC (0–12h), and C12h) for the population are shown in Table 13A. Predicted PK parameters for maribavir at 800 mg BID in the presence of phenobarbital at 400 mg BID, compared to those for 400 mg BID, are presented in Table 14A.

[0095] The AUC and Cmax of maribavir obtained from an 800 mg BID in the presence of a 100 mg phenobarbital QD were more or less lower than those obtained from an 800 mg BID of maribavir alone. However, the Cmin was 63% lower than that of maribavir alone. Increasing the dose of maribavir administered with phenobarbital from 400 mg BID to 800 mg BID resulted in a mean Cmin that was 15% lower than that of maribavir alone at 400 mg BID. Therefore, by increasing the dose of maribavir to 800 mg BID, the interaction was significantly offset. Table 13A. Predicted PK parameters for maribavir 800 mg BID in the presence and absence of phenobarbital 100 mg QD. [Malibawe]

[0800] [] [mg] [] [BID] [Malibawe]

[0800] [] [mg] [] [BID] [+]

[0100] [] [mg] [] [QD] Phenobarbital [ratio] [AUC, (0-12h) , ] [C, max , ] [C, 12h , ] [AUC, (0-12h) , ] [C, max , ] [C, 12h , ] [AUC, (0-12h) , ] [C, max , ] [C, 12h , ] [] [mg / L*h] [mg / L] [mg / L] [mg / L*h] [mg / L] [mg / L] [Prediction] average value 199.43 29.32 6.24 122.40 21.32 2.66 0.61 0.73 0.37 Median 186.51 28.46 4.81 110.83 20.88 1.70 0.63 0.75 0.37 Geometric Mean 185.31 28.19 4.58 111.33 20.42 1.43 0.60 0.72 0.31 Approximately 90% of the geometric mean CI (lower limit) 177.07 27.26 4.54 105.75 19.72 1.41 0.59 0.71 0.31 Approximately 90% of the geometric mean CI (upper limit) 193.93 29.14 4.62 117.20 21.14 1.45 0.62 0.74 0.31 5th percentile 95.04 18.24 1.00 55.49 12.35 0.14 0.39 0.56 0.07 95th percentile 339.40 43.89 14.60 224.54 32.93 8.33 0.78 0.86 0.65 SD 36.3 8.2 4.53 53.9 6.24 2.7 0.12 0.09 0.18 %CV 38 28 73 44 29 101 20 13 48 Table 14A. Predicted PK parameters of 800 mg BID of maribavir in the presence of phenobarbital 100 mg QD, compared with PK parameters of maribavir 400 mg BID. [Malibawe]

[0400] [] [mg] [] [BID] [Malibawe]

[0800] [] [mg] [] [BID] [+]

[0100] [] [mg] [] [QD] Phenobarbital [ratio] [AUC, (0-12h) , ] [C, max , ] [C, 12h , ] [AUC, (0-12h) , ] [C, max , ] [C, 12h , ] [AUC, (0-12h) , ] [C, max , ] [C, 12h , ] [] [mg / L*h] [mg / L] [mg / L] [mg / L*h] [mg / L] [mg / L] [Prediction] average value 99.72 14.66 3.12 122.40 21.32 2.66 1.23 1.45 0.85 Median 93.26 14.23 2.40 110.83 20.88 1.70 1.19 1.47 0.71 Geometric Mean 92.65 14.09 2.29 111.33 20.42 1.43 1.20 1.45 0.62 Approximately 90% of the geometric mean CI (lower limit) 88.54 13.63 2.27 105.75 19.72 1.41 1.19 1.45 0.62 Approximately 90% of the geometric mean CI (upper limit) 96.96 14.57 2.31 117.20 21.14 1.45 1.21 1.45 0.63 5th percentile 47.52 9.12 0.50 55.49 12.35 0.14 1.17 1.35 0.28 95th percentile 169.70 21.94 7.30 224.54 32.93 8.33 1.32 1.50 1.14 SD 38.6 4.1 2.26 53.9 6.24 2.7 1.40 1.52 1.19 %CV 38 28 72 44 29 101 1.16 1.04 1.40 Simulation of plasma concentration-time profiles of 1200 mg BID of maribavir in the presence and absence of 100 mg phenobarbital QD

[0096] Predicted plasma concentration-time profiles of maribavir were generated during a 3-day (5 doses) administration of 1200 mg BID once daily from day 1 to day 12, in the absence and presence of phenobarbital. For each simulation, the mean concentration-time profiles of each trial were used from 10 individuals, with a total hypothetical population of 200 individuals. Predicted PK parameters (Cmax, AUC (0–12h), and C12h) for the population are shown in Table 15A. Predicted PK parameters of 1200 mg BID of maribavir in the presence of phenobarbital 100 mg QD, compared to those of 400 mg BID, are presented in Table 16A.

[0097] The AUC and Cmax of maribavir obtained from a 1200 mg BID in the presence of 100 mg phenobarbital QD were approximately twice those obtained from a 400 mg BID of maribavir alone, with a Cmin approximately 28% higher. Increasing the maribavir dose from 400 mg BID to 1200 mg BID could counteract the effects of phenobarbital. If the higher exposure (as seen in AUC and Cmax) is not harmful to treatment, it can be concluded that when co-administered with phenobarbital, the maribavir dose should be adjusted from 400 mg BID to 1200 mg BID. Table 15A. Predicted PK parameters for maribavir 1200 mg BID in the presence and absence of phenobarbital 100 mg QD. [Malibawe]

[1200] [] [mg] [] [BID] [Malibawe]

[1200] [] [mg] [] [BID] [+]

[0100] [] [mg] [] [QD] Phenobarbital [ratio] [AUC, (0-12h) , ] [C, max , ] [C, 12h , ] [AUC, (0-12h) , ] [C, max , ] [C, 12h, ] [AUC, (0-12h) , ] [C, max , ] [C, 12h , ] [] [mg / L*h] [mg / L] [mg / L] [mg / L*h] [mg / L] [mg / L] [predict] average value 299.15 43.98 9.36 183.60 31.98 3.99 0.61 0.73 0.37 Median 279.77 42.69 7.21 166.24 31.31 2.55 0.63 0.75 0.37 Geometric Mean 277.96 42.28 6.88 166.99 30.63 2.15 0.60 0.72 0.31 Approximately 90% of the geometric mean CI (lower limit) 265.61 40.90 6.82 158.62 29.58 2.11 0.59 0.71 0.31 Approximately 90% of the geometric mean CI (upper limit) 290.89 43.71 6.94 175.80 31.71 2.18 0.62 0.74 0.31 5th percentile 142.56 27.35 1.50 83.24 18.53 0.21 0.39 0.56 0.07 95th percentile 509.10 65.83 21.89 336.81 49.40 12.50 0.78 0.86 0.65 SD 114.5 12.3 6.8 80.9 9.36 4.04 0.12 0.09 0.18 %CV 38 28 73 44 29 101 20 13 47.97 Table 16A. Predicted PK parameters of 1200 mg BID of maribavir in the presence of phenobarbital 100 mg QD compared with PK parameters of maribavir 400 mg BID. [Malibawe]

[0400] [] [mg] [] [BID] [Malibawe]

[1200] [] [mg] [] [BID] [+]

[0100] [] [mg] [] [QD] Phenobarbital [ratio] [AUC, (0-12h) , ] [C, max , ] [C, 12h , ] [AUC, (0-12h) , ] [C, max , ] [C, 12h , ] [AUC, (0-12h) , ] [C, max , ] [C, 12h , ] [] [mg / L*h] [mg / L] [mg / L] [mg / L*h] [mg / L] [mg / L] [predict] average value 99.72 14.66 3.12 183.60 31.98 3.99 1.84 2.18 1.28 Median 93.26 14.23 2.40 166.24 31.31 2.55 1.78 2.20 1.06 Geometric Mean 92.65 14.09 2.29 166.99 30.63 2.15 1.80 2.17 0.94 Approximately 90% of the geometric mean CI (lower limit) 88.54 13.63 2.27 158.62 29.58 2.11 1.79 2.17 0.93 Approximately 90% of the geometric mean CI (upper limit) 96.96 14.57 2.31 175.80 31.71 2.18 1.81 2.18 0.94 5th percentile 47.52 9.12 0.50 83.24 18.53 0.21 1.75 2.03 0.42 95th percentile 169.70 21.94 7.30 336.81 49.40 12.50 1.98 2.25 1.71 SD 38.6 4.1 2.26 80.9 9.36 4.04 2.10 2.28 1.79 %CV 38 28 72 44 29 101 1.16 1.04 1.40 Simulation of plasma concentration-time profiles of 400 mg BID of maribavir in the presence and absence of 300 mg phenytoin QD

[0098] Predicted plasma concentration-time profiles of maribavir were generated during the period of 300 mg once daily for 3 days (5 doses) in the absence and presence of phenytoin, from day 1 to day 12. For each simulation, the mean concentration-time profiles of each trial were used from 10 individuals, with a total hypothetical population of 200 individuals. Predicted PK parameters (Cmax, AUC (0–12h), and C12h) for the population are shown in Table 17A.

[0099] Phenytoin-induced CYP3A4 resulted in an average decrease of 42%, 31%, and 64% in AUC (0-12), Cmax, and C12h, respectively. Table 17A. Predicted PK parameters for maribavir 400 mg BID in the presence and absence of phenytoin 300 mg QD. [Malibawe]

[0400] [] [mg] [] [BID] [Malibawe]

[0400] [] [mg] [] [BID] [+]

[0300] [] [mg] [] [QD] [Phenytoin] [ratio] [AUC, (0-12h) , ] [C, max , ] [C, 12h , ] [AUC, (0-12h) , ] [C, max , ] [C, 12h , ] [AUC, (0-12h) , ] [C, max , ] [C, 12h , ] [] [mg / L*h] [mg / L] [mg / L] [mg / L*h] [mg / L] [mg / L] [Prediction] average value 99.72 14.66 3.12 56.81 10.04 1.16 0.58 0.69 0.36 Median 93.26 14.23 2.40 56.31 9.95 0.81 0.58 0.69 0.35 Geometric Mean 92.65 14.09 2.29 52.42 9.63 0.68 0.57 0.68 0.30 Approximately 90% of the geometric mean CI (lower limit) 88.54 13.63 2.27 49.99 9.30 0.67 0.55 0.67 0.30 Approximately 90% of the geometric mean CI (upper limit) 96.96 14.57 2.31 54.98 9.96 0.69 0.58 0.70 0.30 5th percentile 47.52 9.12 0.50 26.75 5.59 0.09 0.35 0.50 0.09 95th percentile 169.70 21.94 7.30 99.79 14.78 3.33 0.82 0.88 0.68 SD 38.6 4.1 2.26 23.0 2.91 1.1 0.14 0.11 0.18 %CV 38 28 72 40 29 95 twenty four 17 51.07 Simulation of plasma concentration-time profiles of 800 mg BID of maribavir in the presence and absence of 300 mg phenytoin QD

[0100] Predicted plasma concentration-time profiles of maribavir were generated during 3 days (5 doses) of 800 mg BID administered once daily at 300 mg phenytoin in the absence and presence of phenytoin, from day 1 to day 12. For each simulation, the mean concentration-time profiles of each trial were used from 10 individuals, with a total hypothetical population of 200 individuals. Predicted PK parameters (Cmax, AUC (0–12h), and C12h) for the population are shown in Table 18A. Predicted PK parameters for maribavir 800 mg BID in the presence of phenytoin 300 mg QD, compared to those for maribavir 400 mg BID, are presented in Table 19A.

[0101] In the presence of phenytoin QD, the AUC and Cmax of maribavir obtained from 800 mg BID were more or less higher than those obtained from maribavir alone from 400 mg BID; however, Cmin was reduced by 26%. From an efficacy perspective, increasing the maribavir dose from 400 mg BID to 800 mg BID did not counteract the effects of phenytoin (primarily driven by Cmin). Table 18A. Predicted PK parameters for maribavir 800 mg BID in the presence and absence of phenytoin 300 mg QD. [Malibawe]

[0800] [] [mg] [] [BID] [Malibawe] 800 [] [mg] [] [BID] [+]

[0300] [] [mg] [] [QD] [Phenytoin] [ratio] [AUC, (0-12h) , ] [C, max , ] [C, 12h , ] [AUC, (0-12h) , ] [C, max , ] [C, 12h , ] [AUC, (0-12h) , ] [C, max , ] [C, 12h , ] [] [mg / L*h] [mg / L] [mg / L] [mg / L*h] [mg / L] [mg / L] [Prediction] average value 199.43 29.32 6.24 113.63 20.08 2.32 0.58 0.69 0.36 Median 186.51 28.46 4.81 112.62 19.90 1.62 0.58 0.69 0.35 Geometric Mean 185.31 28.19 4.58 104.85 19.26 1.36 0.57 0.68 0.30 Approximately 90% of the geometric mean CI (lower limit) 177.07 27.26 4.54 99.97 18.61 1.34 0.55 0.67 0.30 Approximately 90% of the geometric mean CI (upper limit) 193.93 29.14 4.62 109.96 19.93 1.38 0.58 0.70 0.30 5th percentile 95.04 18.24 1.00 53.51 11.18 0.18 0.35 0.50 0.09 95th percentile 339.40 43.89 14.60 199.59 29.57 6.65 0.82 0.88 0.68 SD 76.33 8.2 4.53 46.1 5.83 2.2 0.14 0.11 0.18 %CV 38 28 73 40 29 95 twenty four 17 51 Table 19A. Predicted PK parameters of 800 mg BID of maribavir in the presence of phenytoin 300 mg QD, compared with PK parameters of maribavir 400 mg BID. [Malibawe]

[0400] [] [mg] [] [BID] [Malibawe]

[0800] [] [mg] [] [BID] [+]

[0300] [] [mg] [] [QD] [Phenytoin] [ratio] [AUC, (0-12h) , ] [C, max , ] [C, 12h , ] [AUC, (0-12h) , ] [C, max , ] [C, 12h , ] [AUC, (0-12h) , ] [C, max , ] [C, 12h , ] [] [mg / L*h] [mg / L] [mg / L] [mg / L*h] [mg / L] [mg / L] [Prediction] average value 99.72 14.66 3.12 113.63 20.08 2.32 1.14 1.37 0.74 Median 93.26 14.23 2.40 112.62 19.90 1.62 1.21 1.40 0.68 Geometric Mean 92.65 14.09 2.29 104.85 19.26 1.36 1.13 1.37 0.59 Approximately 90% of the geometric mean CI (lower limit) 88.54 13.63 2.27 99.97 18.61 1.34 1.13 1.37 0.59 Approximately 90% of the geometric mean CI (upper limit) 96.96 14.57 2.31 109.96 19.93 1.38 1.13 1.37 0.60 5th percentile 47.52 9.12 0.50 53.51 11.18 0.18 1.13 1.23 0.36 95th percentile 169.70 21.94 7.30 199.59 29.57 6.65 1.18 1.35 0.91 SD 38.6 4.1 2.26 46.1 5.83 2.2 1.21 1.42 0.97 %CV 38 28 72 40 29 95 1.05 1.04 1.30 Simulation of plasma concentration-time profiles of 1200 mg BID of maribavir in the presence and absence of 300 mg phenytoin QD

[0102] Predicted plasma concentration-time profiles of maribavir were generated during 3 days (5 doses) of 1200 mg BID administered once daily at 300 mg phenytoin in the absence and presence of phenytoin, from day 1 to day 12. For each simulation, the mean concentration-time profiles of each trial were used from 10 individuals, with a total hypothetical population of 200 individuals. Predicted PK parameters (Cmax, AUC (0–24h), and C12h) for the population are shown in Table 20A. Predicted PK parameters of maribavir 1200 mg BID in the presence of phenytoin 300 mg QD, compared to those of maribavir 400 mg BID, are presented in Table 21A.

[0103] The AUC and Cmax of maribavir obtained from a 1200 mg BID in the presence of phenytoin QD were approximately twice those obtained from a 400 mg BID of maribavir alone, but the Cmin was similar to that of 400 mg maribavir alone, indicating that, from an efficacy standpoint, increasing the maribavir dose from 400 mg BID to 1200 mg BID could offset the effects of phenytoin (primarily driven by Cmin). The impact of higher exposure (AUC and Cmax) must be evaluated. Table 20A. Predicted PK parameters for maribavir 1200 mg BID in the presence and absence of phenytoin 300 mg QD. [Malibawe]

[1200] [] [mg] [] [BID] [Malibawe]

[1200] [] [mg] [] [BID] [+]

[0300] [] [mg] [] [QD] [Phenytoin] [ratio] [AUC, (0-12h) , ] [C, max , ] [C, 12h , ] [AUC, (0-12h) , ] [C, max , ] [C, 12h , ] [AUC, (0-12h) , ] [C, max , ] [C, 12h , ] [] [mg / L*h] [mg / L] [mg / L] [mg / L*h] [mg / L] [mg / L] [predict] average value 299.15 43.98 9.36 170.44 30.13 3.48 0.58 0.69 0.36 Median 279.77 42.69 7.21 168.93 29.85 2.42 0.58 0.69 0.35 Geometric Mean 277.96 42.28 6.88 157.27 28.88 2.05 0.57 0.68 0.30 Approximately 90% of the geometric mean CI (lower limit) 265.61 40.90 6.82 149.96 27.91 2.02 0.55 0.67 0.30 Approximately 90% of the geometric mean CI (upper limit) 290.89 43.71 6.94 164.94 29.89 2.08 0.58 0.70 0.30 5th percentile 142.56 27.35 1.50 80.26 16.76 0.27 0.35 0.50 0.09 95th percentile 509.10 65.83 21.89 299.38 44.35 9.98 0.82 0.88 0.68 SD 114.5 12.3 6.8 69.01 8.7 3.29 0.14 0.11 0.18 %CV 38 28 73 40 29 95 twenty four 17 52 Table 21A. Predicted PK parameters of 1200 mg BID of maribavir in the presence of phenytoin 300 mg QD, compared with PK parameters of maribavir 400 mg BID. [Malibawe]

[0400] [] [mg] [] [BID] [Malibawe]

[1200] [] [mg] [] [BID] [+]

[0300] [] [mg] [] [QD] [Phenytoin] [ratio] [AUC, (0-12h) , ] [C, max , ] [C, 12h , ] [AUC, (0-12h) , ] [C, max , ] [C, 12h , ] [AUC, (0-12h) , ] [C, max , ] [C, 12h , ] [] [mg / L*h] [mg / L] [mg / L] [mg / L*h] [mg / L] [mg / L] [predict] average value 99.72 14.66 3.12 170.44 30.13 3.48 1.71 2.06 1.12 Median 93.26 14.23 2.40 168.93 29.85 2.42 1.81 2.10 1.01 Geometric Mean 92.65 14.09 2.29 157.27 28.88 2.05 1.70 2.05 0.90 Approximately 90% of the geometric mean CI (lower limit) 88.54 13.63 2.27 149.96 27.91 2.02 1.69 2.05 0.89 Approximately 90% of the geometric mean CI (upper limit) 96.96 14.57 2.31 164.94 29.89 2.08 1.70 2.05 0.90 5th percentile 47.52 9.12 0.50 80.26 16.76 0.27 1.69 1.84 0.54 95th percentile 169.70 21.94 7.30 299.38 44.35 9.98 1.76 2.02 1.37 SD 38.2 4.1 2.26 69.01 8.7 3.29 1.81 2.12 1.46 %CV 38 28 72 40 29 95 1.05 1.04 1.30 Simulation of plasma concentration-time profiles of 400 mg BID of maribavir in the presence and absence of cabamopin

[0104] Predicted plasma concentration-time profiles of maribavir were generated during a 3-day (5 doses, starting on day 15) administration of 400 mg twice daily (BID) with or without carbamapine QD (200 mg on days 1 and 2 and 400 mg on days 3 through 17). For each simulation, the mean concentration-time profiles of each trial were used from 10 individuals, with a total hypothetical population of 200 individuals. The predicted PK parameters (Cmax, AUC (0–12h), and C12h) for the population are shown in Table 22A.

[0105] When 400 mg BID maribavir is combined with carbamapine, due to the induction of CYP3A4 by carbamapine, the predicted average reduction in maribavir C12h (efficacy marker) is 46%, and the average reduction in AUC and Cmax is 29% and 23%, respectively. Table 22A. Predicted PK parameters for maribavir 400 mg BID in the presence and absence of cabamopin. [Malibawe]

[0400] [] [mg] [] [BID] [Malibawe]

[0400] [] [mg] [] [BID] [+]

[0400] [] [mg] [] [QD] [Kabamapin] [ratio] [AUC, (0-12h) , ] [C, max , ] [C, 12h , ] [AUC, (0-12h) , ] [C, max , ] [C, 12h , ] [AUC, (0-12h) , ] [C, max , ] [C, 12h , ] [] [mg / L*h] [mg / L] [mg / L] [mg / L*h] [mg / L] [mg / L] [predict] average value 98.93 14.60 3.11 67.85 11.12 1.65 0.71 0.77 0.54 Median 88.34 13.91 2.34 63.37 10.80 1.29 0.71 0.79 0.56 Geometric Mean 91.25 14.01 2.18 63.82 10.74 1.15 0.70 0.77 0.53 Approximately 90% of the geometric mean CI (lower limit) 87.05 13.54 2.16 61.25 10.41 1.14 0.69 0.76 0.53 Approximately 90% of the geometric mean CI (upper limit) 95.66 14.49 2.21 66.49 11.08 1.16 0.71 0.78 0.53 5th percentile 48.05 8.74 0.52 36.23 7.02 0.25 0.54 0.61 0.36 95th percentile 176.30 21.99 7.77 108.25 16.29 4.07 0.84 0.90 0.70 SD 40.96 4.23 2.53 24.40 2.99 1.34 0.10 0.09 0.11 %CV 41 29 81.28 36 27 81.02 14 12 20.20 Third quartile 123.18 17.26 4.22 82.72 12.92 2.34 0.77 0.09 0.61 1st quartile 69.63 11.43 1.20 51.60 8.95 0.63 0.65 0.84 0.46 10th percentile 55.45 9.76 0.75 40.08 7.78 0.42 0.58 0.72 0.39 90th percentile 154.24 20.66 6.58 100.38 15.22 3.34 0.82 0.65 0.67 Simulation of plasma concentration-time profiles of 800 mg BID of maribavir in the presence and absence of cabamopin

[0106] Predicted plasma concentration-time profiles of maribavir administered at a BID of 800 mg for 3 days (5 doses, starting on day 15) in the absence and presence of once-daily carbamapine QD (200 mg on days 1 and 2 and 400 mg on days 3 through 17). For each simulation, the mean concentration-time profiles of each trial were used from 10 individuals, with a total hypothetical population of 200 individuals. Predicted PK parameters (Cmax, AUC (0–12h), and C12h) for the population are shown in Table 23A. Predicted PK parameters of maribavir at a BID of 800 mg in the presence of carbamapine, compared to those of maribavir at a BID of 400 mg, are presented in Table 24A.

[0107] The AUC and Cmax of maribavir obtained from 800 mg BID in the presence of 400 mg carbamapine QD were more or less higher than those obtained from 400 mg BID of maribavir alone, but the Cmin was similar to that of 400 mg maribavir alone, indicating that, from an efficacy point of view, increasing the maribavir dose from 400 mg BID to 800 mg BID could counteract the effects of carbamapine (primarily driven by Cmin). Table 23A. Predicted PK parameters for maribavir 800 mg BID in the presence and absence of cabamopin. [Malibawe]

[0800] [] [mg] [] [BID] [Malibawe]

[0800] [] [mg] [] [BID] [+]

[0400] [] [mg] [] [QD] [Kabamapin] [ratio] [AUC, (0-12h) , ] [C, max , ] [C, 12h , ] [AUC, (0-12h) , ] [C, max , ] [C, 12h , ] [AUC, (0-12h) , ] [C, max , ] [C, 12h , ] [] [mg / L*h] [mg / L] [mg / L] [mg / L*h] [mg / L] [mg / L] [predict] average value 197.86 29.19 6.21 135.70 22.25 3.30 0.71 0.77 0.54 Median 176.68 27.81 4.68 126.73 21.61 2.58 0.71 0.79 0.56 Geometric Mean 182.50 28.01 4.37 127.63 21.48 2.30 0.70 0.77 0.53 Approximately 90% of the geometric mean CI (lower limit) 174.10 27.08 4.35 122.50 20.82 2.29 0.69 0.76 0.52 Approximately 90% of the geometric mean CI (upper limit) 191.31 28.97 4.39 132.99 22.16 2.31 0.71 0.78 0.53 5th percentile 96.09 17.47 1.03 72.46 14.03 0.50 0.54 0.61 0.36 95th percentile 352.60 43.98 15.54 216.50 32.57 8.13 0.84 0.90 0.70 SD 81.92 8.47 5.05 48.79 5.97 2.67 0.10 0.09 0.11 %CV 41 29 81.28 36 27 81.02 14 12 20.2 Third quartile 246.37 34.52 8.44 165.43 25.84 4.67 0.77 0.84 0.61 1st quartile 139.25 22.86 2.41 103.20 17.89 1.27 0.65 0.72 0.46 10th percentile 110.89 19.53 1.50 80.17 15.56 0.85 0.58 55.45 0.39 90th percentile 308.48 41.32 13.15 200.76 30.43 6.68 0.82 154.24 0.67 Table 24A. Predicted PK parameters of 800 mg BID of maribavir in the presence of 400 mg QD of cabamopin compared to 400 mg BID of maribavir. [Malibawe]

[0400] [] [mg] [] [BID] [Malibawe]

[0800] [] [mg] [] [BID] [+]

[0400] [] [mg] [] [QD] [Kabamapin] [ratio] [AUC, (0-12h) , ] [C, max , ] [C, 12h , ] [AUC, (0-12h) , ] [C, max , ] [C, 12h , ] [AUC, (0-12h) , ] [C, max , ] [C, 12h , ] [] [mg / L*h] [mg / L] [mg / L] [mg / L*h] [mg / L] [mg / L] [predict] average value 98.93 14.60 3.11 135.70 22.25 3.30 1.37 1.52 1.06 Median 88.34 13.91 2.34 126.73 21.61 2.58 1.43 1.55 1.10 Geometric Mean 91.25 14.01 2.18 127.63 21.48 2.30 1.40 1.53 1.06 Approximately 90% of the geometric mean CI (lower limit) 87.05 13.54 2.16 122.50 20.82 2.29 1.41 1.54 1.06 Approximately 90% of the geometric mean CI (upper limit) 95.66 14.49 2.21 132.99 22.16 2.31 1.39 1.53 1.05 5th percentile 48.05 8.74 0.52 72.46 14.03 0.50 1.51 1.61 0.96 95th percentile 176.30 21.99 7.77 216.50 32.57 8.13 1.23 1.48 1.05 SD 40.96 4.23 2.53 48.79 5.97 2.67 1.19 1.41 1.06 %CV 41 29 81.28 36 27 81.02 0.88 0.93 1.00 Third quartile 123.18 17.26 4.22 165.43 25.84 4.67 1.34 1.50 1.11 1st quartile 69.63 11.43 1.20 103.20 17.89 1.27 1.48 1.57 1.06 10th percentile 55.45 9.76 0.75 80.17 15.56 0.85 1.45 1.59 1.13 90th percentile 154.24 20.66 6.58 200.76 30.43 6.68 1.30 1.47 1.02 Simulation of plasma concentration-time profiles of 1200 mg BID of maribavir in the presence and absence of cabamopin

[0108] Predicted plasma concentration-time profiles of maribavir administered at a BID of 1200 mg for 3 days (5 doses, starting on day 15) in the absence and presence of once-daily carbamapine QD (200 mg on days 1 and 2 and 400 mg on days 3 through 17). For each simulation, the mean concentration-time profiles of each trial were used from 10 individuals, with a total hypothetical population of 200 individuals. Predicted PK parameters (Cmax, AUC (0–12h), and C12h) for the population are shown in Table 25A. Predicted PK parameters of maribavir at a BID of 1200 mg in the presence of carbamapine, compared to those of maribavir at a BID of 400 mg, are presented in Table 26A.

[0109] The AUC and Cmax of maribavir obtained from a 1200 mg BID in the presence of 400 mg carbamapine QD were significantly higher (approximately twice) than those obtained from a 400 mg BID of maribavir alone. The Cmin value was approximately 50% higher than that of 400 mg maribavir alone, indicating that, from an efficacy standpoint, increasing the maribavir dose from 400 mg BID to 800 mg BID is superior to increasing it to 1200 mg BID in order to counteract the effects of carbamapine. Table 25A. Predicted PK parameters for maribavir 1200 mg BID in the presence and absence of cabamopin. [Malibawe]

[1200] [] [mg] [] [BID] [Malibawe]

[1200] [] [mg] [] [BID] [+]

[0400] [] [mg] [] [QD] [Kabamapin] [ratio] [AUC,(0-12h) , ] [C, max , ] [C, 12h , ] [AUC, (0-12h) , ] [C, max , ] [C, 12h , ] [AUC, (0-12h) , ] [C, max , ] [C, 12h , ] [] [mg / L*h] [mg / L] [mg / L] [mg / L*h] [mg / L] [mg / L] [Prediction] average value 296.79 43.79 9.32 203.54 33.37 4.95 0.71 0.77 0.54 Median 265.02 41.72 7.02 190.10 32.41 3.88 0.71 0.79 0.56 Geometric Mean 273.75 42.02 6.55 191.45 32.22 3.45 0.70 0.77 0.53 Approximately 90% of the geometric mean CI (lower limit) 261.14 40.62 6.48 183.75 31.23 3.42 0.69 0.76 0.53 Approximately 90% of the geometric mean CI (upper limit) 286.97 43.46 6.62 199.48 33.24 3.49 0.71 0.78 0.53 5th percentile 144.14 26.21 1.55 108.68 21.05 0.76 0.54 0.61 0.36 95th percentile 528.90 65.97 23.31 324.74 48.86 12.20 0.84 0.90 0.70 SD 122.87 12.70 7.58 73.19 8.96 4.01 0.10 0.09 0.11 %CV 41 29 81.28 36 27 81.02 14 12 20.2 Third quartile 369.55 51.78 12.65 248.14 38.76 7.01 0.77 0.84 0.61 1st quartile 208.88 34.29 3.61 154.80 26.84 1.90 0.65 0.72 0.46 10th percentile 166.34 29.29 2.26 120.25 23.34 1.27 0.58 55.45 0.39 90th percentile 462.72 61.98 19.73 301.14 45.65 10.02 0.82 154.24 0.67 Table 26A. Predicted PK parameters of 1200 mg BID of maribavir in the presence of 400 mg QD compared with 400 mg BID of maribavir. [Malibawe]

[0400] [] [mg] [] [BID] [Malibawe]

[1200] [] [mg] [] [BID] [+]

[0400] [] [mg] [] [QD] [Kabamapin] [ratio] [AUC, (0-12h) , ] [C, max , ] [C, 12h , ] [AUC, (0-12h) , ] [C, max , ] [C, 12h , ] [AUC, (0-12h) , ] [C, max , ] [C, 12h , ] [] [mg / L*h] [mg / L] [mg / L] [mg / L*h] [mg / L] [mg / L] [predict] average value 98.93 14.60 3.11 203.54 33.37 4.95 2.06 2.29 1.59 Median 88.34 13.91 2.34 190.10 32.41 3.88 2.15 2.33 1.66 Geometric Mean 91.25 14.01 2.18 191.45 32.22 3.45 2.10 2.30 1.58 Approximately 90% of the geometric mean CI (lower limit) 87.05 13.54 2.16 183.75 31.23 3.42 2.11 2.31 1.58 Approximately 90% of the geometric mean CI (upper limit) 95.66 14.49 2.21 199.48 33.24 3.49 2.09 2.29 1.58 5th percentile 48.05 8.74 0.52 108.68 21.05 0.76 2.26 2.41 1.46 95th percentile 176.30 21.99 7.77 324.74 48.86 12.20 1.84 2.22 1.57 SD 40.96 4.23 2.53 73.19 8.96 4.01 1.79 2.12 1.58 % CV 41 29 81.28 36 27 81.02 0.88 0.93 1.00 123.18 17.26 4.22 248.14 38.76 7.01 2.01 2.25 1.66 69.63 11.43 1.20 154.80 26.84 1.90 2.22 2.35 1.58 55.45 9.76 0.75 120.25 23.34 1.27 2.17 2.39 1.69 154.24 20.66 6.58 301.14 45.65 10.02 1.95 2.21 1.52 [Discussion]

[0110] The prospective use of models used to predict possible outcomes of interactions with rifampin (800 mg and 1200 mg BID maribavir), phenobarbital (400 mg, 800 mg and 1200 mg BID maribavir), phenytoin (400 mg, 800 mg and 1200 mg BID maribavir), and carbamapine (400 mg, 800 mg and 1200 mg BID maribavir) indicated geometric mean (arithmetic mean) ratios for Cmax against maribavir of 0.54 (0.56), 0.72 (0.73), 0.68 (0.69), and 0.77 (0.77), respectively. Corresponding geometric mean (arithmetic mean) ratios for predicted AUC 0-12h were 0.35 (0.37), 0.60 (0.61), 0.57 (0.58), and 0.70 (0.71), respectively. The corresponding predicted C 12h geometric mean (arithmetic mean) ratios were 0.04 (0.10), 0.31 (0.37), 0.30 (0.36), and 0.53 (0.54), respectively. Because the PBPK model for maribavir does not exhibit nonlinearity, the changes in exposure induced by the perpetrator-mediated CYP3A4 do not depend on the dose of maribavir.

[0111] The efficacy of maribavir is related to its trough concentration (C12h). A significant reduction in C12h was predicted when the standard dose of 400 mg BID maribavir was combined with CYP3A4 inducers (such as rifampin, phenobarbital, phenytoin, and carbamate). Simulations were performed using higher doses of maribavir (i.e., 800 mg BID, 1200 mg BID, and 1600 mg BID) to determine whether the reduction in C12h (and therefore the reduction in maribavir efficacy) could be overcome by dose increases. The reduction in C12h induced by rifampin CYP3A4 could not be corrected by using up to 1600 mg BID maribavir. A dose of 800 mg BID maribavir with phenobarbital resulted in a 15% lower C12h than that of 400 mg BID maribavir alone, while 1200 mg BID resulted in a 1.28-fold increase in C12h. Due to CYP3A4 induction, a 1200 mg BID dose of maribavir in combination with phenytoin is also predicted to overcome C12h reduction. Increasing the maribavir dose to 800 or 1200 mg BID can also overcome C12h reduction due to carbamapine. In a phase 2 study for the treatment of CMV infection / disease, maribavir showed an acceptable safety / tolerability profile with no limiting toxicities at doses up to 1200 mg BID, and the predicted AUC (0–12 h) and Cmax mean for 1200 mg BID maribavir were 292 mg / L*h and 43.4 mg / L, respectively. As discussed above, in the presence of an inducer, the predicted AUC (0–12 h) and Cmax values ​​observed with increased maribavir doses were lower than the predicted exposure for maribavir at only 1200 mg BID. Therefore, there are no safety concerns regarding increasing maribavir doses from 400 mg to 800 mg or 1200 mg in the presence of an inducer. Overall, CYP3A4 inducers significantly reduce systemic exposure to maribavir; therefore, when co-administered with CYP3A4 inducers, the maribavir dose should be increased. When co-administered with carbamate or phenobarbital, it is recommended to increase the maribavir dose to 800 or 1200 mg BID. When co-administered with phenytoin, it is recommended to increase the maribavir dose to 1200 mg BID. Rifampin causes a significant reduction in maribavir exposure, which cannot be overcome by increasing the maribavir dose to 1600 mg BID. Therefore, co-administration with rifampin should be prohibited, or alternative antimicrobial therapies with lower CYP3A4 induction potential should be considered.

[0112] General Note: Dosage recommendations for inducers are based on the ratio of the arithmetic mean to the deviation from the geometric mean of the co-administered dose. However, the geometric mean ratio is used for dosage recommendations for inhibitors. [Example] [3] [-] [Co-administration of maribavir with other drugs] []

[0113] Drug interaction studies were compiled based on Example 2 and other available data (e.g., in vitro and clinical data). Considerations for each co-administered drug are provided in Table 1-A, and the pharmacokinetic effects of co-administration of other drugs on maribavir are summarized in Tables 1-B and 1-C. Table 1-A. Summary of existing and other potentially significant drug interactions (observations and predictions). [Types of accompanying medications] [:] [Drug Name] [Effect on concentration] [Considerations] [Antiarrhythmic drugs] Digoxin ↑Digoxin Use with caution when maribavir and digoxin are administered together. Monitor serum digoxin levels. A reduction in digoxin dosage may be necessary when co-administered with maribavir. [Antibacterial agents] Kabamaping ↓Malibawe When co-administered with cabamopin, the dose of maribavir should be adjusted to 800 mg twice daily. Phenobarbital ↓Malibawe When co-administered with phenobarbital, the dose of maribavir should be adjusted to 1200 mg twice daily. Phenytoin ↓Malibawe When co-administered with phenytoin, the dose of maribavir should be adjusted to 1200 mg twice daily. [Anti-mycobacterial agent] Lifubutin ↓Malibawe The combined administration of maribavir and rifabutin can reduce the efficacy of maribavir. Rifampicin ↓Malibawe The combined administration of maribavir and rifampin can reduce the efficacy of maribavir. [Herbal Products] St. John's wort ↓Malibawe The combined administration of maribavir and St. John's wort can reduce the efficacy of maribavir. [Immunosuppressants] Cyclosporine ↑Cyclosporine Throughout the course of treatment with maribavir, especially after initiation and discontinuation, cyclosporine levels should be monitored frequently, and the dosage adjusted as needed. Everolimus ↑Everolimus Everolimus levels should be monitored frequently throughout the entire course of treatment with maribavir, especially after initiation and after discontinuation of maribavir, and the dosage should be adjusted as needed. Sirolimus ↑Sirolimus Sirolimus levels should be monitored frequently throughout the entire course of treatment with maribavir, especially after initiation and after discontinuation of maribavir, and the dosage should be adjusted as needed. Tacrolimus ↑ Tacrolimus Tacrolimus levels should be monitored frequently throughout the entire course of maribavir treatment, especially after initiation and after discontinuation of maribavir, and the dosage should be adjusted as needed. Table 1-B. Summary of changes in the pharmacokinetics of maribavir in the presence of co-administered drugs. [Joint administration of drugs and regimens] [Malibave Protocol] [N] [In the presence of co-administered drugs] [ / ] [Malibawe does not exist] [PK] [Geometric mean ratio] [[]

[90] [%] [CI] [](] [No effect] [=] [1] [.]

[00] [)] [AUC] [C, max , ] [C, tau , , C , ] Antispasmodics Kabama Ping A 400 mg once daily 800 mg twice daily / 400 mg twice daily 200 1.40 (1.09, 1.67) 1.53 (1.22, 1.79) 1.05 (0.71, 1.40) Phenobarbital A 100 mg once daily 1,200 mg twice daily / 400 mg twice daily 200 1.80 (1.18, 2.35) 2.17 (1.69, 2.57) 0.94 (0.22, 1.97) Phenytoin A 300 mg once daily 1,200 mg twice daily / 400 mg twice daily 200 1.70 (1.06, 2.46) 2.05 (1.49, 2.63) 0.89 (0.26, 2.04) Anti-mycobacterial agents Rifampicin 600 mg once daily 400 mg twice daily 14 0.40(0.36,0.44) 0.61(0.52,0.72) 0.18 (0.14, 0.25) antifungal agents Ketoconazole 400 mg single dose 400 mg single dose 19 1.53 (1.44, 1.63) 1.10 (1.01, 1.19) - Aluminum hydroxide and magnesium hydroxide acid resistant agents 20 mL b Single dose 100 mg single dose 15 0.89 (0.83, 0.96) 0.84 (0.75, 0.94) A physiologically based pharmacokinetic (PBPK) model based on the results of 10 trials involving 20 individuals each. The dosing regimens and geometric mean ratios (5th percentile, 95th percentile) of maribavir correspond to dose-adjusted maribavir with an inducer versus 400 mg twice daily without an inducer. b contains 800 mg of aluminum hydroxide and 800 mg of magnesium hydroxide. Ctau series maribavir dosing interval: 12 hours. Table 1-C. Pharmacokinetic changes of co-administered drugs in the presence of 400 mg twice daily maribavir. [Joint administration of drugs and regimens] [N] [In the presence of a joint investment in Malibawe] [ / ] [Malibawe does not exist] [PK] [Geometric mean ratio] [[]

[90] [%] [CI] [](] [No effect] [=] [1] [.]

[00] [)] [AUC] [C, max , ] [C] [, 最低 , ] Immunosuppressants Tacrolimus Stable dose, twice daily (total daily dose: 0.5 to 16 mg). 20 1.51 (1.39, 1.65) 1.38 (1.20, 1.57) 1.57 (1.41, 1.74) P-gp is subject to mass Digoxin 0.5 mg single dose 18 1.21(1.10,1.32) 1.25 (1.13, 1.38) -

[0114] Although we have described several embodiments of the invention, it will be apparent that our basic examples may be modified to provide other embodiments utilizing the compounds and methods of the invention. Therefore, it should be understood that the scope of the invention should be defined by the appended claims rather than by the specific embodiments illustrated.

Claims

1. A use of maribavir for the preparation of a pharmaceutical product for treating patients suffering from cellular giant virus (CMV) infection, wherein the treatment comprises: Maribavir is administered orally twice daily in doses of approximately 800 mg or 1200 mg for patients who are transplant recipients, who are currently receiving carbamazepine, phenytoin, or phenobarbital, or who have received carbamazepine, phenytoin, or phenobarbital prior to administration of maribavir; and for patients who are currently receiving phenobarbital or phenobarbital, or who have received phenobarbital or phenobarbital prior to administration of maribavir, the dose of maribavir administered is 1200 mg orally twice daily.

2. As requested in item 1, wherein the patient is receiving carbamopine, or has received carbamopine prior to administration of maribavir, and the amount of maribavir administered is 800 mg orally twice daily.

3. As requested in item 1, wherein the patient is receiving phenobarbital or phenytoin, or has received phenobarbital or phenytoin prior to administration of maribavir, and the dose of maribavir administered is 1200 mg orally twice daily.

4. As requested in claim 1, wherein the treatment comprises administering 1200 mg of maribavir orally to the patient twice daily.

5. For any of the uses requested in items 1 to 4, wherein the patient is receiving cabamopeptide, phenobarbital or phenytoin, and maribavir is administered co-administered with cabamopeptide, phenobarbital or phenytoin.

6. For any of the uses described in items 1 to 4, where the patient is receiving or has received immunosuppressants.

7. As requested in paragraph 6, wherein the immunosuppressant is selected from the group consisting of tacrolimus, cyclosporine, everolimus, and sirolimus.

8. As requested in claim 7, wherein the immunosuppressant is tacrolimus.

9. As requested in item 6, wherein the patient is receiving the immunosuppressant and maribavir is co-administered with the immunosuppressant.

10. As requested in claim 1, wherein the patient is refractory to treatment with one or more of ganciclovir, valganciclovir, cidofovir, or foscarnet.

11. For the purposes of claim 1, wherein the patient is a hematopoietic stem cell transplant recipient.

12. For the purposes of claim 1, wherein the patient is a recipient of a solid organ transplant.

13. For any of the uses requested in items 1 to 4 and 10 to 12, wherein the patient is an adult or a child aged 12 years or older and weighing at least 35 kg.

14. As requested in paragraph 1, wherein the patient is receiving carbamopine, or has received carbamopine prior to administration of maribavir, and the amount of maribavir administered is 1200 mg orally twice daily.

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