Use of Maribavir for the Treatment of and Treatment Regimens Thereof

Abstract

Characterization of the drug-drug interaction and pharmacological properties of maribavir will be useful in informing potential drug-drug interactions and dosing strategies when used with concomitant medications.

Description

[Technical field]

[0001] 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 by reference herein in its entirety. [Background technology]

[0002] Cytomegalovirus (CMV) infection and disease are significant post-transplant complications, with substantial morbidity and reduced long-term survival in transplant recipients. Currently, there are no approved therapies for the treatment of CMV infection in transplant recipients.

[0003] Transplant patients often take many concomitant medications to manage comorbidities. Characterization of maribavir's drug-drug interaction and pharmacodynamic properties will be useful in informing potential drug-drug interactions and dosing strategies when used with concomitant medications. Summary of the Invention

[0004] Maribavir is a benzimidazole riboside and is an orally available antiviral drug against cytomegalovirus (CMV). Maribavir is also known by the trade name LIVTENCITY™. Typically, patients (e.g., adults and / or children aged 12 years or older and weighing 35 kg or more) are orally administered 400 mg of maribavir twice daily. However, in some embodiments, the present disclosure recognizes that when used in combination with certain drugs (e.g., cytochrome P450 3A4 (CYP3A4) inducers (e.g., carbamazepine, phenytoin, or phenobarbital), p-glycoprotein inducers (P-gp), immunosuppressants, antiarrhythmic drugs (e.g., digoxin, ganciclovir, or valganciclovir)), the administration of maribavir and / or the concomitant drug must be monitored, altered (e.g., increased or decreased), or discontinued.

[0005] In some aspects, the disclosure provides, among other things, potential drug-drug interactions with maribavir and how exposure to maribavir and / or CYP3A4 inducers is affected. In some embodiments, the disclosure provides a method of treating a CMV infection in a patient suffering from a CMV infection, the method comprising: administering a therapeutically effective amount of maribavir to a patient, the patient being or having been administered a CYP3A4 inducer prior to administration of maribavir; and Discontinue CYP3A4 inducers prior to administration of maribavir.

[0006] In some embodiments, the disclosure provides a method of treating a CMV infection in a patient suffering from a CMV infection, the method comprising: administering an initial therapeutically effective dose of maribavir to the patient (the patient is receiving a CYP3A4 inducer); and Increasing the amount of maribavir administered to patients.

[0007] In some embodiments, the disclosure provides a method of treating a CMV infection in a patient suffering from a CMV infection, the method comprising: administering a therapeutically effective amount of maribavir to a patient, the patient being administered a CYP3A4 inducer prior to administration of maribavir;

[0008] In some embodiments, the CYP3A4 inducer is selected from the group consisting of rifampin, avasimibe, carbamazepine, phenytoin, rifabutin, phenobarbital, and St. John's wort. In some embodiments, the CYP3A4 inducer reduces the exposure of maribavir. In some embodiments, an initial therapeutically effective amount of maribavir is administered to the patient, and if a CYP3A4 inducer is co-administered, the amount of maribavir is increased. In some embodiments, the initial therapeutically effective amount of maribavir is about 400 mg orally twice daily. In some embodiments, the amount of maribavir is increased to an amount of about 800 mg to about 1200 mg orally twice daily. In some embodiments, the methods provided further include monitoring the patient's blood (e.g., whole blood or plasma) concentration of maribavir and / or the CYP3A4 inducer.

[0009] In some aspects, the disclosure provides, among other things, potential drug-drug interactions with maribavir and how exposure to maribavir and / or immunosuppressants is affected. In some embodiments, the disclosure provides a method of treating a cytomegalovirus (CMV) infection in a patient suffering from CMV infection, the method comprising administering a therapeutically effective amount of maribavir to the patient, the patient being administered or receiving an immunosuppressant. In some embodiments, the immunosuppressant is selected from the group consisting of tacrolimus, cyclosporine, everolimus, sirolimus, prednisone, and mycophenolate. 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, a method is provided that further comprises monitoring the level of the immunosuppressant (e.g., compared to a reference level or standard level) after discontinuing administration of maribavir. In some embodiments, a method is provided that further includes increasing the amount of immunosuppressant administered to the patient (e.g., the amount of immunosuppressant administered prior to initiating administration of maribavir).

[0010] 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 administered (e.g., prior to administration of maribavir or during co-administration of maribavir) is about 0.075 mg / kg / day to 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, respectively. In some embodiments, tacrolimus is administered by injection at a concentration of 5.0 mg / mL. In some embodiments, tacrolimus is administered in oral suspension in granule packets of 1 mg unit doses. In some embodiments, observed whole blood trough concentrations of tacrolimus are monitored over a period of about 0 months to about 12 months from the initial administration of tacrolimus. In some embodiments, observed whole blood trough concentrations of tacrolimus are monitored at the initiation of administration of maribavir, during co-administration, and upon discontinuation of administration of maribavir. In some embodiments, the observed whole blood trough concentration of tacrolimus is about 4 to about 20 ng / mL. In some embodiments, tacrolimus is administered at an initial dose of about 0.03% to 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, propylene carbonate, white petrolatum, and white wax.

[0011] In some embodiments, the dose of tacrolimus is adjusted when co-administered with maribavir. In some embodiments, maribavir is co-administered at a concentration of 400 mg, 800 mg, or 1200 mg, administered twice daily. In some embodiments, co-administration of maribavir increases exposure to tacrolimus by about 50%.

[0012] In some aspects, the disclosure provides, among other things, potential drug-drug interactions with maribavir and how exposure to maribavir and / or antiarrhythmic drugs (e.g., digoxin) is affected. In some embodiments, the disclosure provides a method of treating a CMV infection in a patient suffering from a CMV infection, the method comprising administering a therapeutically effective amount of maribavir to the patient, the patient being administered or receiving 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 reducing the amount of digoxin administered to the patient (e.g., the amount of the antiarrhythmic drug administered prior to initiating administration of maribavir).

[0013] In some aspects, the disclosure provides, among other things, potential drug-drug interactions with maribavir and how exposure to maribavir and / or ganciclovir or valganciclovir is affected. In some embodiments, the disclosure provides a method of treating a cytomegalovirus (CMV) infection in a patient suffering from a CMV infection, the method comprising: administering a therapeutically effective amount of maribavir to a patient, the patient being or having been administered ganciclovir or valganciclovir prior to administration of maribavir; and Discontinue ganciclovir or valganciclovir prior to administration of maribavir.

[0014] In some embodiments, concentrations of maribavir and / or other co-administered medications (e.g., CYP3A4 inducers (e.g., carbamazepine, phenytoin, or phenobarbital), p-glycoprotein inducers (P-gp), immunosuppressants, antiarrhythmics (e.g., digoxin, ganciclovir, or valganciclovir)) are monitored upon initial administration, during co-administration, and upon discontinuation of maribavir administration.

[0015] In some embodiments, the patient is refractory to treatment with one or more other drugs that treat 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 over 12 years of age and over 35 kg. [Brief description of the drawings]

[0016] [Figure 1] IC50 shift of maribavir in concentration-dependent assays with HLM of CYP3A using midazolam (A) or testosterone (B) as probe substrates. CYP, cytochrome P450; HLM, human liver microtome; IC50, half maximal inhibitory concentration; NADPH, nicotinamide adenine dinucleotide phosphate. [Diagram 2] Relationship of observed enzyme inactivation rate constant versus inhibitor concentration for TDI of CYP3A by maribavir in combination with (A) midazolam or (B) testosterone as probe substrate. CYP, cytochrome P450; KI, inhibitor concentration at half-maximal enzyme inactivation; kinactiv, maximal enzyme inactivation rate constant; kob, observed enzyme inactivation rate constant; TDI, time-dependent inhibition. [Diagram 3] Estimation of Emax and EC50 for induction of CYP3A4 mRNA expression by maribavir by nonlinear regression of data obtained from three human hepatocyte donors. For donor 3, n is the sigmoid coefficient corresponding to the shape of the curve; EC50 is the half-maximal effective concentration; Emax is the maximum effect. [Figure 4] Estimated IC50 of maribavir on P-gp efflux of digoxin in cultured Caco-2 cells (determined by corrected efflux ratio). IC50, half maximal inhibitory concentration; P-gp, P-glycoprotein. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0017] Detailed Description 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 chemical structure: [ka] It is a potent, orally bioavailable antiviral agent for the treatment of cytomegalovirus (CMV) infection and disease in transplant recipients. Transplant recipients are at significant risk for CMV infection and, moreover, often receive many concomitant medications to manage comorbid conditions. Thus, evaluation of potential drug-drug interactions between maribavir and future therapies is useful. Furthermore, understanding of the clinical pharmacology of maribavir is needed to define optimal dosing strategies for transplant recipients, who often have multiple comorbidities and require complex concomitant medication regimens.

[0018] 1.Definition As used herein, the term "about" when used in reference to a numerical value means ±10% of that value. For example, a dose containing "about 100 mg" of maribavir encompasses any amount of maribavir within the range of 90 mg to 110 mg.

[0019] As used herein, the term "reference" describes a standard or control against which a comparison is made. For example, in some embodiments, an agent, animal, individual, population, sample, sequence, or value of interest is compared to a reference or control substance, animal, individual, population, sample, sequence, 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, optionally embodied in a definite medium. Typically, as understood by those skilled in the art, a reference or control is measured or characterized under comparable conditions or circumstances during their evaluation. Those skilled in the art will understand when there are sufficient similarities to justify reliance on and / or comparison to a particular possible reference or control.

[0020] The term "treat" or "treating" as used herein refers to partially or completely alleviating, inhibiting, improving, and / or relieving a disorder or condition, or one or more symptoms of a disorder or condition. As used herein, the terms "treatment", "treat", and "treating" refer to partially or completely alleviating, inhibiting, improving, and / or relieving a disorder or condition, or one or more symptoms of a disorder or condition, as described herein. In some embodiments, treatment may be administered after one or more symptoms appear. In some embodiments, the term "treating" includes halting the progression of a disease or disorder. Treatment may also be continued after symptoms have been cured, for example, to prevent or delay recurrence. Thus, in some embodiments, the term "treating" includes preventing the recurrence or recurrence of a disease or disorder.

[0021] 2. Dosing Regimen In some aspects, the present disclosure recognizes that when used in combination with certain medications (e.g., CYP3A4 inducers (e.g., carbamazepine, phenytoin, or phenobarbital), p-glycoprotein inducers (P-gp), immunosuppressants, antiarrhythmics (e.g., digoxin, ganciclovir, or valganciclovir)), administration of maribavir and / or the concomitant medication must be monitored, altered (e.g., increased or decreased), or discontinued.

[0022] In some embodiments, maribavir is administered to a patient at about 400 mg orally twice daily (a "standard dose"). In some embodiments, the patient has been administered an initial therapeutically effective amount of maribavir, e.g., before receiving additional concomitant medications. In some embodiments, the initial therapeutically effective amount of maribavir is a standard dose (400 mg orally twice daily). In some embodiments, maribavir is administered as a tablet. In some embodiments, maribavir is administered as a tablet containing 200 mg of maribavir. In some embodiments, the methods provided include administering maribavir to a patient with or without food.

[0023] In some embodiments, the dose of maribavir is altered (e.g., increased or decreased) from the standard dose (400 mg orally twice daily) when co-administered with certain drugs (e.g., CYP3A4 inducers (e.g., carbamazepine, phenytoin, or phenobarbital), p-glycoprotein inducers (P-gp), immunosuppressants, antiarrhythmics (e.g., digoxin, ganciclovir, or valganciclovir)). In some embodiments, the amount of maribavir is increased to about 800 mg or about 1200 mg orally twice daily). In some embodiments, the amount of maribavir is increased to about 800 mg orally twice daily. In some embodiments, the amount of maribavir is increased to about 1200 mg orally twice daily.

[0024] In some embodiments, when used in combination with a particular drug (e.g., a CYP3A4 inducer (e.g., carbamazepine, phenytoin, or phenobarbital), a p-glycoprotein inducer (P-gp), an immunosuppressant, an antiarrhythmic (e.g., digoxin, ganciclovir, or valganciclovir)), the dosage of the concomitant drug is altered (e.g., increased or decreased) from the recommended amount provided on the label. In some embodiments, the dose of the concomitant drug is decreased compared to its standard dosing regimen. In some embodiments, a method is provided that further comprises monitoring the level of the concomitant drug (e.g., compared to a reference level or standard level) after discontinuing administration of maribavir. In some embodiments, a method is provided that further comprises increasing the amount of the concomitant drug administered to the patient (e.g., the amount of the concomitant drug administered prior to initiating administration of maribavir).

[0025] a. Maribavir and CYP3A4 inducers In some embodiments, the disclosure provides the recognition that maribavir is primarily metabolized by CYP3A4. Additionally or alternatively, the disclosure provides the recognition that drugs that are CYP3A4 inducers may decrease the plasma concentration of maribavir and reduce the virologic response. In some embodiments, coadministration of maribavir with certain CYP3A4 inducers is not recommended and / or the dosing regimen of one or both drugs should be modified.

[0026] In some embodiments, the disclosure provides a method of treating a CMV infection in a patient suffering from a CMV infection, the method comprising administering a therapeutically effective amount of maribavir to the patient, wherein the patient is administering or has been administered a CYP3A4 inducer prior to administration of the maribavir. In some embodiments, the method further comprises discontinuing administration of the CYP3A4 inducer prior to administration of the maribavir. In some embodiments, the method further comprises increasing the amount of maribavir administered to the patient.

[0027] In some embodiments, the CYP3A4 inducer is selected from the group consisting of rifampin, avasimibe, carbamazepine, phenytoin, rifabutin, phenobarbital, and St. John's wort. In some embodiments, the CYP3A4 inducer is selected from the group consisting of rifampin, carbamazepine, 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 carbamazepine, 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 can be administered according to a dosing regimen approved for the patient to be treated (eg, a US FDA approved dosage for a given indication).

[0028] In some embodiments, the CYP3A4 inducer is also a p-Gp inducer. In some embodiments, the CYP3A4 inducer also reduces the exposure of maribavir.

[0029] In some embodiments, the disclosure provides a method of treating a CMV infection in a patient suffering from a CMV infection, the method comprising: administering a therapeutically effective amount of maribavir (e.g., 400 mg orally twice daily) to a patient, who is receiving or has been receiving a cytochrome P450 3A4 (CYP3A4) inducer prior to administration of maribavir; and Discontinue CYP3A4 inducers prior to administration of maribavir.

[0030] In some embodiments, the disclosure provides a method of treating a CMV infection in a patient suffering from a CMV infection, the method comprising: administering an initial therapeutically effective dose of maribavir (e.g., 400 mg orally twice daily) to the patient (the patient is receiving a cytochrome P450 3A4 (CYP3A4) inducer); and Increasing the amount of maribavir administered to patients.

[0031] In some embodiments, the initial therapeutically effective amount of maribavir is a standard dose (400 mg orally twice a day). In some embodiments, the amount of maribavir is increased to about 800 mg or about 1200 mg orally twice a day. In some embodiments, the amount of maribavir is increased to about 800 mg orally twice a day. In some embodiments, the amount of maribavir is increased to about 1200 mg orally twice a day. In some embodiments, when the CYP3A4 inducer is carbamazepine, the amount of maribavir is increased to about 800 mg orally twice a day. In some embodiments, when the CYP3A4 inducer is phenytoin or phenobarbital, the amount of maribavir is increased to about 1200 mg orally twice a day.

[0032] In some embodiments, the disclosure provides a method of treating a CMV infection in a patient suffering from a CMV infection, the method comprising: Administering a therapeutically effective amount of maribavir (e.g., 800 mg or about 1200 mg orally twice daily) to the patient (the patient is receiving a cytochrome P450 3A4 (CYP3A4) inducer prior to administration of maribavir).

[0033] In some embodiments, if the patient is administered a CYP3A4 inducer prior to administration of maribavir, the therapeutically effective amount of maribavir is about 800 mg or about 1200 mg (oral twice daily). In some embodiments, if the CYP3A4 inducer is carbamazepine, the amount of maribavir administered is about 800 mg (oral twice daily). In some embodiments, if the CYP3A4 inducer is phenytoin or phenobarbital, the amount of maribavir administered is about 1200 mg (oral twice daily).

[0034] The potential drug-drug interactions of maribavir with cytochrome P450 enzymes and P-glycoprotein (P-gp) were thoroughly characterized. Reversible inhibition, time-dependent inhibition, and induction of CYPs were assessed using human cells or human-derived cell lines in the presence of maribavir. Inhibition of P-gp was also assessed.

[0035] Maribavir was not a reversible inhibitor of CYP2A6, CYP2B6, CYP2C8, CYP2D6, CYP2E1, or CYP3A4, but was a weak inhibitor of CYP1A2, CYP2C9, and CYP2C19 (half maximal inhibitory concentration, or IC 50 were 40, 18, and 35 μM, respectively).

[0036] Maribavir was not a time-dependent inhibitor of CYP1A2, CYP2C8, CYP2C9, CYP2C19, or CYP2D6. However, it was a time-dependent inhibitor of CYP3A4, with IC values ​​presented in Figure 1. 50 The IC value of maribavir was 1.21, 1.22, 1.06, 1.05, 1.04, 1.05, 1.08, 1.09, 1.27, 1.09, 1.28, 1.07, 1.09, 1.29, 1.40, 1.41, 1.42, 1.43, 1.44, 1.4 50 The values ​​exceeded 1.9 μM and 3.2 μM, respectively. As shown in Figure 2, the concentration of maribavir at half-maximal enzyme inactivation of CYP3A, or K I were 41.2 μM and 167 μM with midazolam and testosterone, respectively.

[0037] Maribavir was not an inducer of CYP1A2 or CYP2B6 mRNA, but was a weak in vitro inducer of CYP3A4 mRNA, showing a greater than 14-fold increase in mRNA induction and a greater than 30% increase in positive control levels. However, as shown in Figure 3, the effect varied from donor to donor. The half-maximal effective concentration or EC 50 was greater than 5 μM for all donors.

[0038] As shown in Figure 4, maribavir exhibited concentration-dependent inhibition of P-gp-mediated digoxin efflux. The IC 50 was 33.8 μM.

[0039] The data presented herein, specifically in Example 1, demonstrates the concentrations of maribavir required for observed levels of in vitro inhibition or induction of P-gp and / or several CYPs.

[0040] b. Maribavir and immunosuppressants In some embodiments, the present disclosure recognizes that maribavir has the potential to increase drug concentrations of certain immunosuppressants that are CYP3A4 and / or P-gp substrates, and that minimal concentration changes can lead to serious adverse events. Additionally or alternatively, immunosuppressant levels should be frequently monitored during treatment with maribavir, particularly after initiation and discontinuation of maribavir, and the dose of the immunosuppressant adjusted as needed.

[0041] In some embodiments, the disclosure provides a method of treating a CMV infection in a patient suffering from a CMV infection, the method comprising administering a therapeutically effective amount of maribavir (e.g., 400 mg orally twice daily) to the patient, where the patient is receiving or is receiving an immunosuppressant. In some embodiments, the method further comprises monitoring the level of the immunosuppressant (e.g., in whole blood or plasma). In some embodiments, the method further comprises reducing the amount of the immunosuppressant administered to the patient. In some embodiments, maribavir also increases the exposure of the immunosuppressant. In some embodiments, the provided method further comprises monitoring the level of the immunosuppressant (e.g., compared to a reference level or standard level) after ceasing administration of maribavir. In some embodiments, the provided method further comprises increasing the amount of the immunosuppressant administered to the patient (e.g., to the amount of the immunosuppressant administered before starting administration of maribavir).

[0042] In some embodiments, the immunosuppressant is selected from the group consisting of tacrolimus, cyclosporine, everolimus, sirolimus, prednisone, and mycophenolate. 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, prednisone, and mycophenolate. 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.

[0043] In some embodiments, the immunosuppressant may be administered according to an approved dosing regimen for the patient to be treated (e.g., U.S. FDA approved doses of tacrolimus). In some embodiments, tacrolimus is administered twice daily as a stable dose, with a total dose of about 0.5 mg to about 16 mg for the entire daily dose.

[0044] 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 administered (e.g., prior to administration of maribavir or during co-administration of maribavir) is about 0.075 mg / kg / day to 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, respectively. In some embodiments, tacrolimus is administered by injection at a concentration of 5.0 mg / mL. In some embodiments, tacrolimus is administered in oral suspension in granule packets of 1 mg unit doses. In some embodiments, observed whole blood trough concentrations of tacrolimus are monitored over a period of about 0 months to about 12 months from the initial administration of tacrolimus. In some embodiments, observed whole blood trough concentrations of tacrolimus are monitored at the initiation of administration of maribavir, during co-administration, and upon discontinuation of administration of maribavir. In some embodiments, the observed whole blood trough concentration of tacrolimus is about 4 to about 20 ng / mL. In some embodiments, the initial dose of tacrolimus administered is about 0.03% to 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, propylene carbonate, white petrolatum, and white wax. In some embodiments, co-administration of maribavir increases exposure to tacrolimus by about 50%.

[0045] In some embodiments, the disclosure provides a method of administering a therapeutically effective amount of an immunosuppressant to a patient in need thereof for the prevention or treatment of organ rejection and / or graft-versus-host disease, the improvement comprising administering a therapeutically effective amount of maribavir to the patient. In some embodiments, the improvement further comprises reducing the amount of the immunosuppressant administered. In some embodiments, the improvement further comprises reducing the amount of the immunosuppressant administered, where the immunosuppressant is tacrolimus.

[0046] In some embodiments, the disclosure provides a method for the prevention or treatment of organ rejection and / or graft-versus-host disease in a patient in need thereof, where the patient is receiving or has been receiving a therapeutically effective amount of an immunosuppressant, and the improvement comprises administering to the patient a therapeutically effective amount of maribavir. In some embodiments, the improvement further comprises reducing the amount of the immunosuppressant administered. In some embodiments, the improvement further comprises reducing the amount of the immunosuppressant administered, where the immunosuppressant is tacrolimus.

[0047] In some embodiments, the disclosure provides a method for the prevention or treatment of organ rejection and / or graft versus host disease to a patient in need thereof, where the patient is receiving or has been receiving a therapeutically effective amount of maribavir, and the improvement comprises administering to the patient a therapeutically effective amount of an immunosuppressant. In some embodiments, the improvement further comprises reducing the amount of the immunosuppressant administered. In some embodiments, the improvement further comprises reducing the amount of the immunosuppressant administered, where the immunosuppressant is tacrolimus.

[0048] C. Maribavir and digoxin Digoxin is the most commonly used antiarrhythmic drug for atrial fibrillation, atrial flutter, and heart failure. In some embodiments, the present disclosure recognizes that maribavir may increase the drug concentration of digoxin, which is a P-gp substrate, and minimal changes in concentration may lead to serious adverse events. Additionally or alternatively, digoxin levels should be frequently monitored during treatment with maribavir, especially after initiation and discontinuation of maribavir, and the dose of the immunosuppressant should be adjusted as necessary.

[0049] In some embodiments, the present disclosure provides a method of treating a cytomegalovirus (CMV) infection in a patient suffering from CMV infection, the method comprising administering a therapeutically effective amount of maribavir to the patient, where the patient is receiving or has been receiving 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 reducing the amount of digoxin administered to the patient, e.g., compared to the amount before co-administration of maribavir, e.g., a U.S. FDA approved dosage. In some embodiments, digoxin is administered at 0.5 mg once daily.

[0050] D. Maribavir and ganciclovir or valganciclovir In some embodiments, the present disclosure recognizes that maribavir can antagonize the antiviral activity of ganciclovir and / or valganciclovir by inhibiting human CMV pUL97 kinase, which is required for the activation / phosphorylation of ganciclovir and valganciclovir.

[0051] In some embodiments, the present disclosure provides a method of treating a cytomegalovirus (CMV) infection in a patient suffering from CMV infection, the method comprising administering a therapeutically effective amount of maribavir to the patient, where the patient is receiving or has been receiving ganciclovir and / or valganciclovir. In some embodiments, the provided method further comprises discontinuing administration of ganciclovir and / or valganciclovir prior to administration of maribavir. In some embodiments, the provided method further comprises monitoring the level of ganciclovir and / or valganciclovir (e.g., in whole blood or plasma) (e.g., compared to a reference or standard level) after discontinuing administration of maribavir. In some embodiments, the provided method further comprises increasing the amount of ganciclovir and / or valganciclovir administered to the patient (e.g., to the amount of ganciclovir and / or valganciclovir administered prior to initiating administration of maribavir).

[0052] 3.Patient As described above and herein, the methods provide for administering maribavir and a concomitant medication (e.g., a CYP3A4 inducer (e.g., carbamazepine, phenytoin, or phenobarbital), a p-glycoprotein inducer (P-gp), an immunosuppressant, an antiarrhythmic (e.g., digoxin, ganciclovir, or valganciclovir)) to a patient in need thereof. In some embodiments, the patient is suffering from a CMV infection. In some embodiments, the patient is suffering from a 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).

[0053] In some embodiments, the patient is resistant to treatment with one or more other drugs to treat CMV infection. In some embodiments, the patient is resistant with genotypic resistance to treatment with one or more other drugs to treat CMV infection. In some embodiments, the patient is resistant without genotypic resistance to treatment with one or more other drugs to treat CMV infection. In some embodiments, the patient is resistant to treatment with one or more of ganciclovir, valganciclovir, cidofovir, or foscarnet. In some embodiments, the patient is resistant to treatment with ganciclovir or valganciclovir. In some embodiments, the patient is resistant to treatment with ganciclovir. In some embodiments, the patient is resistant to treatment with valganciclovir.

[0054] In some embodiments, the patient is an adult or a child over 12 years of age and over 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 over 12 years of age. In some embodiments, the patient is a child over 35 kg. In some embodiments, the patient is a child over 12 years of age and over 35 kg.

[0055] 4. Assessment of the potential drug-drug interactions of maribavir using data from Phase 1 clinical trials and nonclinical in vitro studies Potential drug-drug interactions for maribavir are described in Example 3.

[0056] Accumulating data indicate that maribavir is primarily metabolized in the liver, with renal clearance being a minor pathway (accounting for less than 5 percent). VP44469 (N-dealkylated maribavir) was the major metabolite of maribavir in both urine and feces. In plasma, unchanged maribavir and VP44469 accounted for approximately 69% and 9.8% of the total radioactivity, respectively. Hepatic metabolism of maribavir was primarily facilitated by cytochrome P450. CYP3A4 and CYP1A2 were involved in 70-85% and 15-30% of the CYP-driven pathway, respectively. Glucuronidation accounted for less than 20% of metabolism.

[0057] Clinically significant drug interactions are summarized in Table 1-A in Example 3. Strong inducers of CYP34A and P-gp may decrease maribavir exposure, necessitating a maribavir dose increase. Inhibitors of CYP3A4 and / or P-gp may increase maribavir exposure. However, previous safety and tolerability data indicate that dose reduction is not necessary with CYP3A4 and / or P-gp inhibitors. Maribavir may increase exposure to immunosuppressants, so monitoring of concomitant immunosuppressants should be considered.

[0058] 5. Clinical Pharmacology of Maribavir Following oral administration, maribavir was rapidly and well absorbed, with peak concentrations usually achieved within 1 to 3 hours; exposure was not affected by food; bioavailability was not affected by tablet crushing or when taken with an antacid.

[0059] Maribavir was metabolized in the liver via the cytochrome P450 3A4 and 1A2 pathways. Less than 5% of maribavir was excreted via the kidney. Maribavir exhibited a half-life of approximately 5 to 7 hours.

[0060] Maribavir was found to have a low risk of drug-drug interactions. Coadministration of strong CYP3A4 inducers was found to decrease maribavir exposure and require increased doses of maribavir. Some immunosuppressants, such as tacrolimus, can be affected by maribavir, which increased tacrolimus exposure by 51%.

[0061] In conclusion, maribavir is a suitable treatment for CMV infection in a wide range of transplant recipients. It can be administered 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, requires minimal dose adjustments (e.g., only when taken concomitantly with CYP3A4 inducers or certain immunosuppressants), and has no effect on the QT interval.

[0062] Exemplary embodiments The following numbered embodiments are non-limiting examples of certain aspects of the present disclosure. 1. A method for treating a cytomegalovirus (CMV) infection in a patient suffering from a CMV infection, comprising: administering a therapeutically effective amount of maribavir to a patient, the patient being or having been administered a cytochrome P450 3A4 (CYP3A4) inducer prior to administration of maribavir; and Discontinue administration of CYP3A4 inducers prior to administration of maribavir. A method comprising: 2. The method of embodiment 1, wherein the CYP3A4 inducer is selected from the group consisting of rifampin, avasimibe, carbamazepine, phenytoin, rifabutin, phenobarbital, and Hypericum perforatum. 3. The method of embodiment 1 or 2, wherein the CYP3A4 inducer is a strong CYP3A4 inducer. 4. The method of any one of embodiments 1-3, wherein the CYP3A4 inducer is selected from the group consisting of rifampin, rifabutin, and Hypericum perforatum. 5. The method of any one of embodiments 1-4, comprising orally administering to the patient about 400 mg of maribavir twice daily. 6. The method of any one of embodiments 1-5, comprising administering maribavir to the patient with or without food. 7. A method for treating a cytomegalovirus (CMV) infection in a patient suffering from a CMV infection, comprising: administering an initial therapeutically effective amount of maribavir to a patient, the patient being treated with a cytochrome P450 3A4 (CYP3A4) inducer; and Increasing the amount of maribavir administered to patients A method comprising: 8. The method of embodiment 7, wherein the CYP3A4 inducer is selected from the group consisting of rifampin, avasimibe, carbamazepine, phenytoin, rifabutin, phenobarbital, and Hypericum perforatum. 9. The method of embodiment 7 or 8, wherein the CYP3A4 inducer is selected from the group consisting of rifampin, carbamazepine, phenytoin, rifabutin, phenobarbital, and Hypericum perforatum. 10. The method of any one of embodiments 7-9, wherein the CYP3A4 inducer is selected from the group consisting of carbamazepine, phenytoin, and phenobarbital. 11. The method of any one of embodiments 7-10, wherein prior to administration of the CYP3A4 inducer of about 400 mg (orally twice daily) of maribavir (the "initial therapeutically effective amount"), the patient was administered a therapeutically effective amount of maribavir. 12. The method of any one of embodiments 7-11, wherein the amount of maribavir is increased to about 800 mg or about 1200 mg of maribavir (orally twice a day). 13. The method of any one of embodiments 7-12, wherein the CYP3A4 inducer is carbamazepine and the amount of maribavir is increased to about 800 mg of maribavir orally twice daily. 14. The method of any one of embodiments 7-12, wherein the CYP3A4 inducer is phenytoin or phenobarbital, and the amount of maribavir is increased to about 1200 mg of maribavir orally twice daily. 15. A method for treating a cytomegalovirus (CMV) infection in a patient suffering from a CMV infection, comprising: administering a therapeutically effective amount of maribavir to a patient, the patient having been administered a cytochrome P450 3A4 (CYP3A4) inducer prior to administration of maribavir; A method comprising: 16. The method of embodiment 15, wherein the CYP3A4 inducer is selected from the group consisting of rifampin, avasimibe, carbamazepine, phenytoin, rifabutin, phenobarbital, and Hypericum perforatum. 17. The method of embodiment 15 or 16, wherein the CYP3A4 inducer is selected from the group consisting of rifampin, carbamazepine, phenytoin, rifabutin, phenobarbital, and Hypericum perforatum. 18. The method of any one of embodiments 15-17, wherein the CYP3A4 inducer is selected from the group consisting of carbamazepine, phenytoin, and phenobarbital. 19. The method of any one of embodiments 15-18, wherein the amount of maribavir administered is about 800 or about 1200 mg (orally twice a day). 20. The method of any one of embodiments 15-19, wherein the CYP3A4 inducer is carbamazepine and the amount of maribavir administered is about 800 mg (orally twice daily). 21. The method of any one of embodiments 15-19, wherein the CYP3A4 inducer is phenytoin or phenobarbital and the amount of maribavir administered is about 1200 mg (orally twice daily). 22. The method of any one of embodiments 1-21, wherein the CYP3A4 inducer reduces the exposure of maribavir. 23. A method for treating cytomegalovirus (CMV) infection in a patient suffering from CMV infection, comprising administering to the patient a therapeutically effective amount of maribavir, wherein the patient is receiving or has been receiving an immunosuppressant drug. 24. The method of embodiment 23, further comprising monitoring the level of the immunosuppressant after initiating administration of maribavir (e.g., compared to a reference level or standard level). 25. The method of embodiment 23 or 24, further comprising reducing the amount of immunosuppressant administered to the patient. 26. The method of any one of embodiments 23 to 25, further comprising a step of monitoring levels of the immunosuppressant (e.g., compared to a reference level or standard level) after discontinuing administration of maribavir. 27. The method of embodiment 26, further comprising increasing the amount of immunosuppressant administered to the patient (e.g., the amount of immunosuppressant administered prior to initiating administration of maribavir). 28. The method of any one of embodiments 23-27, wherein the immunosuppressant is selected from the group consisting of tacrolimus, cyclosporine, everolimus, sirolimus, prednisone, and mycophenolate. 29. The method of any one of embodiments 23-28, wherein the immunosuppressant is selected from the group consisting of tacrolimus, cyclosporine, everolimus, and sirolimus. 30. A method for treating cytomegalovirus (CMV) infection in a patient suffering from CMV infection, comprising administering a therapeutically effective amount of maribavir to the patient, wherein the patient is receiving or has been receiving digoxin. 31. The method of embodiment 30, further comprising monitoring the level of digoxin. 32. The method of embodiment 30 or 31, further comprising reducing the amount of digoxin administered to the patient. 33. The method of any of embodiments 1-32, wherein the patient is refractory to treatment with one or more other drugs that treat the CMV infection. 34. The method of any of embodiments 1-33, wherein the patient is refractory to treatment with one or more of ganciclovir, valganciclovir, cidofovir, or foscarnet. 35. The method of any one of embodiments 1-34, wherein the patient is resistant to the treatment due to genotypic resistance. 36. The method of any one of embodiments 1-34, wherein the patient is resistant to the treatment without genotypic resistance. 37. A method for treating a cytomegalovirus (CMV) infection in a patient suffering from a CMV infection, comprising: administering a therapeutically effective amount of maribavir to a patient, the patient being or having been administered ganciclovir or valganciclovir prior to administration of maribavir; and Discontinue ganciclovir or valganciclovir before administering maribavir A method comprising: 38. The method of any one of embodiments 7-37, comprising administering maribavir to the patient with or without food. 39. The method of any one of embodiments 1-38, wherein the patient is a transplant recipient. 40. The method of any one of embodiments 1-39, wherein the patient is a hematopoietic stem cell transplant recipient. 41. The method of any one of embodiments 1-39, wherein the patient is a solid organ transplant recipient. 42. The method of any one of embodiments 1-41, wherein the patient is an adult or a child over 12 years of age and over 35 kg. EXAMPLES

[0063] Example 1 - In vitro profiling of potential cytochrome P450 drug-drug interactions with maribavir Inhibition or induction of cytochrome P450 enzymes (CYPs) is one of the most commonly observed mechanisms of drug-drug interactions.

[0064] In vitro systems, such as human liver microsomes (HLM), recombinant enzymes, human hepatocytes, and other human-derived cell lines, have long been used as validation systems to characterize potential drug-drug interactions prior to clinical trials.

[0065] Reversible CYP Inhibitor HLM was performed to determine the half-maximal inhibitory concentration (IC) of maribavir for inhibiting the activity of nine CYP isoforms. 50 ) was used to evaluate the activity of phenacetin (CYP1A2), coumarin (CYP2A6), bupropion (CYP2B6), paclitaxel (CYP2C8), tolbutamide (CYP2C9), (S)-mephenytoin (CYP2C19), dextromethorphan (CYP2D6), chlorzoxazone (CYP2E1), as well as midazolam and testosterone (CYP3A4).

[0066] CYP activity was evaluated at concentrations of maribavir 0, 0.1, 0.3, 1, 3, 10, 30, and 100 μM.

[0067] Incubation of maribavir up to 100 μM in HLM did not result in significant inhibition of CYP2A6, CYP2B6, CYP2C8, CYP2D6, CYP2E1, and CYP3A4. Maribavir is a weak inhibitor of CYP1A2, CYP2C9, and CYP2C19, with IC 50 are 40, 18, and 35 μM, respectively.

[0068] Time-dependent CYP inhibition The potential for time-dependent inhibition (TDI) of various CYP enzymes was assessed by preincubating maribavir with HLM for 30 min in the presence and absence of nicotinamide adenine dinucleotide diphosphate (NADPH) followed by CYP enzyme activity assays.

[0069] The enzyme inactivation kinetics of maribavir against TDI of CYP3A, using midazolam and testosterone as probe substrates, was evaluated by preincubating HLM with various concentrations of maribavir with NADPH for six different preincubation time windows. CYP3A activity was measured by determining the formation of CYP3A probe metabolites. Nonlinear least-squares regression was used to estimate the inhibitor concentration at half-maximal enzyme inactivation (K I ) and the maximum enzyme inactivation rate constant (k 不活化 ) was estimated.

[0070] Maribaville IC 50 The shift values ​​were less than 1 μM for CYP1A2, CYP2C8, CYP2C9, CYP2C19, and CYP2D6 in HLM. 50 The shift values ​​were greater than 1.9 μM and 3.2 μM using midazolam and testosterone as probe substrates, respectively (Figure 1). Thus, maribavir at concentrations up to 100 μM is unlikely to cause TDI of CYP1A2, CYP2C8, CYP2C9, CYP2C19, or CYP2D6, but likely to cause TDI of CYP3A.

[0071] K of maribavir against TDI of CYP3A using midazolam as a substrate I and k 不活化 (Figure 2A) were 41.2 μM and 0.0117 min, respectively. -1 The K value of maribavir against the TDI of CYP3A, which uses testosterone as a substrate, was I and k 不活化 (Figure 2B) were 167 μM and 0.0357 min, respectively. -1 It was.

[0072] CYP induction Fresh human hepatocytes were treated with maribavir concentrations of 36 μM, 144 μM, and 480 μM in culture medium.

[0073] Positive controls were 50 μM omeprazole (CYP1A2), 1 mM phenobarbital (CYP2B6), and 50 μM rifampicin (CYP3A).

[0074] Incubation was carried out at 37°C for 72 hours, with compound-containing medium being changed daily. Total RNA was isolated and cDNA was synthesized from up to 1 μg of total isolated RNA. Analysis of CYP expression was performed using qPCR with CYP-specific probes.

[0075] Furthermore, concentration-response curves in three donors using maribavir at concentrations ranging from 0 to 100 μM determined the half-maximal effective concentration (EC 50 ) and maximum effect (E 最大(max) ) values ​​were determined.

[0076] Maribavir showed variable 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 level. Thus, maribavir may not be an inducer of CYP1A2 or CYP2B6 mRNA at clinically relevant concentrations.

[0077] Maribavir demonstrated a 14-fold increase in CYP3A4 mRNA induction at 36 μM and 30% of the positive control (rifampicin) level. Concentration-response curves in three donors were then performed to determine the EC 50 Value and E 最大 The values ​​were further determined.

[0078] Maribavir is an induction 最大 and E.C. 50 During characterization, we also demonstrated donor-dependent induction of CYP3A4 mRNA (Figure 3).

[0079] Example 2 - Quantitative prediction of maribavir exposure using historical in vitro and in vivo data A physiologically based pharmacokinetic (PBPK) model was constructed based on previous in vitro and in vivo information on the metabolism and disposition of maribavir to predict the plasma concentration-time profile of maribavir and to evaluate the possible effects of coadministration of CYP3A4 inhibitors and inducers on the disposition of maribavir in healthy subjects.

[0080] Model Development A combination of in vitro and clinical pharmacokinetic data obtained after a single dose of 400 mg maribavir was used to develop the PBPK model. Mean concentrations for the entire hypothetical population (n=100) are displayed and associated mean C 最大(max) and AUC (0-∞) The values ​​are compared in Table 2A. In addition, the predicted mean maribavir AUC values ​​were within 1.25-fold of the observed data. 最大 was slightly below the predicted value, and C 12時間 This can be predicted since the PBPK model has been optimized for good prediction of [Table 1]

[0081] A renal clearance of 0.051 L / H was obtained after single oral doses of 50-1600 mg maribavir. In vitro human liver microsomal and recombinant CYP data combined with reported oral clearance values ​​from two studies (n=46 individuals, Ma et al., 2006) were used to assign the relative contribution of CYP3A4 to the clearance of maribavir. Distribution models evaluated included a full PBPK model and a minimal PBPK model, both of which take into account hepatic and intestinal metabolism.[ 14Mass balance data from the [C]ADME study demonstrated an absorption fraction of 0.83 or greater following oral administration of a 400 mg dose of maribavir. Absorption models evaluated included a simple first-order absorption model and a more mechanistic "advanced dissolution absorption and metabolism" (ADAM) model. Although maribavir has been shown to be a P-gp substrate in vitro, its relatively linear pharmacokinetics over the dose range of interest (400 mg to 1600 mg) informed the selection of the simpler first-order absorption model used in this PBPK study.

[0082] Model Validation Comparison of observed and predicted plasma concentrations of maribavir after single oral doses of 800 mg and 1600 mg of maribavir in healthy subjects. Mean concentrations for the entire hypothetical population (n=100) are shown, with associated mean C 最大 Value and AUC (0-∞) The values ​​are compared in Tables 3A and 4A. The simulated and observed maribavir concentrations were in good agreement. In addition, the predicted mean maribavir AUC values ​​were within 1.25-fold of the observed data. [Table 2] [Table 3]

[0083] A comparison was performed between observed and predicted plasma concentrations of maribavir after oral administration of maribavir 400 mg twice daily. Mean concentrations for the entire hypothetical population (n=150) are displayed, and associated mean C 最大 and AUC (0-∞) The values ​​are compared in Table 5 A. The simulated and observed maribavir concentrations were in good agreement. In addition, the predicted mean maribavir AUC values ​​were within 1.25-fold of the observed data. [Table 4]

[0084] Comparisons were performed between observed and predicted plasma concentrations of maribavir following a single oral dose of 400 mg administered in the absence of ketoconazole (a CYP3A4 inhibitor) and 1 hour after a single dose of 400 mg ketoconazole administered to healthy subjects. Mean simulated and observed plasma maribavir concentrations were compared, and the associated geometric mean C 最大 Value and AUC (0-∞) The values ​​are shown in Table 6A and are within a factor of 1.25 of the observed data. [Table 5]

[0085] A comparison was performed between observed and predicted plasma concentrations of maribavir 400 mg after multiple oral doses administered in the absence of rifampicin and during co-treatment with rifampicin. Subjects received maribavir 400 mg (twice daily for 5 doses) on days 1-3, followed by rifampicin 600 mg (once daily) on days 4-12, followed by both maribavir 400 mg (twice daily) and rifampicin 600 mg (once daily) on days 13 and 14, with a final dose of maribavir and rifampicin on the morning of day 15. The associated geometric mean C of maribavir in the presence or absence of rifampicin was 12時間 Value, C 最大 value, and AUC (0-12時間) The values ​​are shown in Table 7A. 最大 and the predicted values ​​of AUC are within 1.25 times the observed parameter values. [Table 6]

[0086] Model Validation Simulation of plasma concentration-time profiles of maribavir 800 mg (twice daily) in the presence and absence of rifampicin 600 mg (once daily) Predicted plasma concentration-time profiles of maribavir at 800 mg (twice daily) in the absence and presence of rifampicin at 600 mg (once daily) during a 3-day dosing period (five doses) were generated on days 1 through 12. Each simulation used the mean concentration-time profile for each trial for 20 subjects (a total hypothetical population of 200 subjects). Predicted PK parameters (C 最大 , AUC (0-12時間) , and C 12時間 ) are shown in Table 8A. The predicted PK parameters for this interaction (C 最大 , AUC (0-12時間) and C 12時間 ) are compared with the PK parameters for the 400 mg (bid) dose of maribavir in Table 9A.

[0087] C of maribavir 800 mg (twice daily) in the presence of rifampicin 600 mg (once daily) 最大 was equivalent to that of maribavir 400 mg (twice daily) alone, but AUC (0-12) is 23% lower, C 12時間 was 75% lower, indicating that increasing the maribavir dose from 400 mg (bid) to 800 mg (bid) could not counteract the effect of rifampicin in reducing the therapeutic exposure of maribavir. [Table 7] [Table 8]

[0088] Simulation of plasma concentration-time profiles of maribavir 1200 mg (twice daily) in the presence and absence of rifampicin 600 mg (once daily) Predicted plasma concentration-time profiles of maribavir during a 3-day dosing period (5 doses) at 1200 mg (twice daily) in the absence and presence of rifampicin 600 mg (once daily) were generated on days 1-12. Each simulation used the mean concentration-time profile from each trial for 20 subjects (total fictitious population of 200 subjects). Predicted PK parameters (C 最大 , AUC (0-12時間) , and C 12時間 ) are shown in Table 10A. The predicted PK parameters of maribavir 1200 mg (bid) in the presence of rifampicin 600 mg (qd) compared to the PK parameters of maribavir 400 mg (qd) are presented in Table 11A.

[0089] The AUC of maribavir 1200 mg (twice daily) in the presence of rifampicin 600 mg (once daily) was similar to that of maribavir 400 mg (twice daily) alone, but 最大 was slightly higher. However, the geometric mean C 12時間 was 86% lower. This was despite increasing the maribavir dose from 400 mg (twice daily) to 1200 mg (twice daily) (mainly C 12時間 This indicates that rifampicin cannot be counteracted in terms of efficacy (based on the efficacy of rifampicin). Even when the dose of maribavir was increased to 1600 mg (twice daily), the geometric mean C 12時間 had a minimal effect on , which was 81% lower than increasing the maribavir dose to 400 mg twice daily. [Table 9] [Table 10]

[0090] Simulation of plasma concentration-time profiles of maribavir 400 mg (twice daily) in the presence and absence of phenobarbital 100 mg (once daily) Predicted plasma concentration-time profiles of maribavir at 400 mg (twice daily) during a 3-day dosing period (5 doses) were generated in the absence and presence of phenobarbital 100 mg (once daily) on days 1-12. Each simulation used the mean concentration-time profile from each trial for 20 subjects (a total hypothetical population of 200 subjects). Predicted PK parameters (C 最大 , AUC (0-12時間) and C 12時間 ) are shown in Table 12A. Induction of CYP3A4 by phenobarbital increased AUC (0-12時間) , C 最大 , and C 12時間 decreased by an average of 39%, 27%, and 63%, respectively. [Table 11]

[0091] Simulation of plasma concentration-time profiles of maribavir 800 mg (twice daily) in the presence and absence of phenobarbital 100 mg (once daily) Predicted plasma concentration-time profiles of maribavir during a 3-day dosing period (5 doses) at 800 mg (twice daily) in the absence and presence of phenobarbital 100 mg (once daily) were generated on days 1-12. Each simulation used the mean concentration-time profile from each trial for 10 subjects (a total hypothetical population of 200 subjects). Predicted PK parameters (C 最大 , AUC (0-12時間) , and C 12時間 ) are shown in Table 13A. The predicted PK parameters of maribavir 800 mg (bid) in the presence of phenobarbital 100 mg (qd) compared to the PK parameters of maribavir 400 mg (bid) are presented in Table 14A.

[0092] AUC and C of maribavir 800 mg (twice daily) in the presence of phenobarbital 100 mg (once daily) 最大 was slightly lower than that of maribavir 800 mg (twice daily) alone. However, C 最小was 63% lower with maribavir 800 mg alone. Increasing the dose of maribavir in combination with phenobarbital from 400 mg (twice daily) to 800 mg (twice daily) resulted in a mean C that was 15% lower than with maribavir 400 mg (twice daily) alone. 最小 Thus, by increasing the dose of maribavir to 800 mg twice daily, the interaction was largely negated. [Table 12] [Table 13]

[0093] Simulation of plasma concentration-time profiles of maribavir 1200 mg (twice daily) in the presence and absence of phenobarbital 100 mg (once daily) Predicted plasma concentration-time profiles of maribavir during a 3-day dosing period (5 doses) at 1200 mg (twice daily) in the absence and presence of phenobarbital 100 mg (once daily) were generated on days 1-12. Each simulation used the mean concentration-time profile from each trial for 10 subjects (a total hypothetical population of 200 subjects). Predicted PK parameters (C 最大 , AUC (0-12時間) , and C 12時間 ) are shown in Table 15A. The predicted PK parameters of maribavir 1200 mg (bid) in the presence of phenobarbital 100 mg (qd) compared to the PK parameters of maribavir 400 mg (bid) are presented in Table 16A.

[0094] AUC and C of maribavir 1200 mg (twice daily) in the presence of phenobarbital 100 mg (once daily) 最大 is approximately twice as high as that of maribavir 400 mg (twice a day) alone, but C 最小 is about 28% higher. Increasing the dose of maribavir from 400 mg (twice daily) to 1200 mg (twice daily) can negate the effect of phenobarbital. (AUC and C最大 It can be concluded that if higher exposure (as seen in ) is not detrimental to the treatment, the dose of maribavir should be adjusted from 400 mg (bid) to 1200 mg (bid) when coadministration with phenovarital is required. [Table 14] [Table 15]

[0095] Simulation of plasma concentration-time profiles of maribavir 400 mg (twice daily) in the presence and absence of phenytoin 300 mg (once daily) Predicted plasma concentration-time profiles of maribavir at 400 mg (twice daily) in the absence and presence of phenytoin 300 mg (once daily) during a 3-day dosing period (5 doses) were generated on days 1-12. Each simulation used the mean concentration-time profile for each trial for 10 subjects (a total hypothetical population of 200 subjects). Predicted PK parameters (C 最大 , AUC (0-12時間) , and C 12時間 ) are shown in Table 17A.

[0096] Induction of CYP3A4 by phenobarbital increases the AUC (0-12) The average decrease in 最大 The average decrease in 12時間 The average decrease was 64%. [Table 16]

[0097] Simulation of plasma concentration-time profiles of maribavir 800 mg (twice daily) in the presence and absence of phenytoin 300 mg (once daily) Predicted plasma concentration-time profiles of maribavir during a 3-day dosing period (5 doses) at 800 mg (twice daily) in the absence and presence of phenytoin 300 mg (once daily) were generated on days 1 through 12. Each simulation used the mean concentration-time profile from each trial for 10 subjects (a total hypothetical population of 200 subjects). Predicted PK parameters (C 最大 , AUC (0-12時間) , and C 12時間 ) are shown in Table 18A. The predicted PK parameters of maribavir 800 mg (bid) in the presence of phenytoin 300 mg (qd) compared to the PK parameters of maribavir 400 mg (qd) are presented in Table 19A.

[0098] AUC and C of maribavir 800 mg (twice daily) in the presence of phenytoin 300 mg (once daily) 最大 was slightly higher than that of maribavir 400 mg (twice daily) alone, but C 最小 was 26% lower. Increasing the dose of maribavir from 400 mg (twice daily) to 800 mg (twice daily) did not reduce the incidence of bronchitis (mainly C 最小 (due to efficacy) cannot counteract the effects of phenytoin. [Table 17] [Table 18]

[0099] Simulation of plasma concentration-time profiles of maribavir 1200 mg (twice daily) in the presence and absence of phenytoin 300 mg (once daily) Predicted plasma concentration-time profiles of maribavir during a 3-day dosing period (5 doses) at 1200 mg (twice daily) in the absence and presence of phenytoin 300 mg (once daily) were generated on days 1 through 12. Each simulation used the mean concentration-time profile from each trial for 10 subjects (total fictitious population of 200 subjects). Predicted PK parameters (C最大 , AUC (0-24時間) , and C 12時間 ) are shown in Table 20A. The predicted PK parameters of maribavir 1200 mg (bid) in the presence of phenytoin 300 mg (qd) compared to the PK parameters of maribavir 400 mg (qd) are presented in Table 21A.

[0100] AUC and C of maribavir 1200 mg (twice daily) in the presence of phenytoin 300 mg (once daily) 最大 was approximately twice as high as that of maribavir 400 mg (twice daily) alone, but C 最小 was equivalent to maribavir 400 mg alone. This was because increasing the dose of maribavir from 400 mg (twice daily) to 1200 mg (twice daily) reduced the risk of side effects (mainly C 最小 These results suggest that the effect of phenytoin may be counteracted in terms of efficacy (AUC and C 最大 ) would have to be evaluated. [Table 19] [Table 20]

[0101] Simulation of plasma concentration-time profiles of maribavir 400 mg (twice daily) in the presence and absence of carbamazepine Predicted plasma concentration-time profiles of maribavir were generated during 3 days of dosing (5 doses, starting on day 15) at 400 mg (twice daily) in the absence and presence of once-daily carbamazepine (200 mg on days 1 and 2, 400 mg on days 3-17). Each simulation used the mean concentration-time profile from each trial for 10 subjects (a total hypothetical population of 200 subjects). Predicted PK parameters (C 最大 , AUC (0-12時間) , and C 12時間 ) are shown in Table 22A.

[0102] Due to CYP3A4 induction by carbamazepine, the C 12時間 (Efficacy marker) mean decrease 46%, AUC mean decrease 29%, C 最大 The average decline is expected to be 23%. [Table 21]

[0103] Simulation of plasma concentration-time profiles of maribavir 800 mg (twice daily) in the presence and absence of carbamazepine Predicted plasma concentration-time profiles of maribavir were generated during 3 days of dosing (5 doses, starting on day 15) at 400 mg (twice daily) in the absence and presence of once-daily carbamazepine (200 mg on days 1 and 2, 800 mg on days 3-17). Each simulation used the mean concentration-time profile from each trial for 10 subjects (a total hypothetical population of 200 subjects). Predicted PK parameters (C 最大 , AUC (0-12時間) , and C 12時間 ) are shown in Table 23A. The predicted PK parameters of maribavir 800 mg (bid) in the presence of carbamazepine compared to the PK parameters of maribavir 400 mg (bid) are presented in Table 24A.

[0104] AUC and C of maribavir 800 mg (twice daily) in the presence of carbamazepine 400 mg (once daily) 最大 was slightly higher than that of maribavir 400 mg (twice daily) alone, but C 最小 was similar to that of maribavir 400 mg alone. This was because increasing the dose of maribavir from 400 mg (twice daily) to 800 mg (twice daily) reduced the risk of cardiovascular disease (mainly C 最小 This suggests that the effects of carbamazepine may be countered in terms of efficacy. [Table 22] [Table 23]

[0105] Simulation of plasma concentration-time profiles of maribavir 1200 mg (twice daily) in the presence and absence of carbamazepine Predicted plasma concentration-time profiles of maribavir were generated during 3 days of dosing (5 doses, starting on day 15) at 400 mg (twice daily) in the absence and presence of once-daily carbamazepine (200 mg on days 1 and 2, 1200 mg on days 3-17). Each simulation used the mean concentration-time profile from each trial for 10 subjects (total fictitious population of 200 subjects). Predicted PK parameters (C 最大 , AUC (0-12時間) , and C 12時間 ) are shown in Table 25A. The predicted PK parameters of maribavir 1200 mg (bid) in the presence of carbamazepine compared to the PK parameters of maribavir 400 mg (bid) are presented in Table 26A.

[0106] AUC and C of maribavir 1200 mg (twice daily) in the presence of carbamazepine 400 mg (once daily) 最大 was significantly (approximately 2-fold) higher than that of maribavir 400 mg (twice daily) alone. 最小 was approximately 50% higher than maribavir 400 mg alone, suggesting that from an efficacy standpoint, increasing the maribavir dose from 400 mg (bid) to 800 mg (bid) may be preferable to increasing the maribavir dose to 1200 mg (bid) to counteract the effects of carbamazepine. [Table 24] [Table 25]

[0107] Consideration When the model was used prospectively to predict possible interaction outcomes with rifampicin (maribavir 800 mg and 1200 mg twice daily), phenobarbital (maribavir 400 mg, 800 mg, and 1200 mg twice daily), phenytoin (maribavir 400 mg, 800 mg, and 1200 mg twice daily), and carbamazepine (maribavir 400 mg, 800 mg, and 1200 mg twice daily), the geometric mean (arithmetic mean) C for maribavir was 0.54 (0.56), 0.72 (0.73), 0.68 (0.69), and 0.77 (0.77), respectively. 最大 Ratios are shown. Corresponding predicted geometric mean (arithmetic mean) AUC 0-12時間 The ratios were 0.35 (0.37), 0.60 (0.61), 0.57 (0.58), and 0.70 (0.71), respectively. The corresponding predicted geometric (arithmetic) means C 12時間 The ratios were 0.04 (0.10), 0.31 (0.37), 0.30 (0.36), and 0.53 (0.54), respectively. There was no nonlinearity in the PBPK model of maribavir, so changes in exposure as a result of subjective CYP3A4-mediated induction were independent of maribavir dose.

[0108] The efficacy of maribavir was determined by the trough concentration of the drug (C 12時間 ) when a standard dose of maribavir 400 mg (twice daily) was combined with CYP3A4 inducers such as rifampicin, phenobarbital, phenytoin, and carbamazepine, the C 12時間 Simulations using higher doses of maribavir (i.e., 800 mg bid, 1200 mg bid, and 1600 mg bid) were performed to predict a significant reduction in C 12時間 We determined whether the reduction in C (and therefore the efficacy of maribavir) due to rifampicin-induced CYP3A4 could be overcome by increasing the dose. 12時間The reduction in C was not correctable with the use of maribavir up to 1600 mg (twice daily). The use of a dose of 800 mg (twice daily) of maribavir with phenobarbital reduced C by 15% compared with 400 mg (twice daily) of maribavir alone. 12時間 However, at 1200 mg (twice a day), C 12時間 Administration of maribavir 1200 mg twice daily with phenytoin also reduced the C 12時間 It was predicted that the reduction in C by carbamazepine would be overcome. 12時間 To overcome the reduction in IL-1, an increase in the dose of maribavir to 800 or 1200 mg (bid) can be used. Maribavir has demonstrated an acceptable safety / tolerability profile with no limiting toxicity at doses up to 1200 mg (bid) in Phase 2 studies for the treatment of CMV infection / disease. For a dose of 1200 mg (bid), the predicted mean AUC (0~12時間) and C 最大 The values ​​are 292 mg / L × time and 43.4 mg / L, respectively. As mentioned above, the predicted AUC (0-12時間) and C 最大The values ​​are below the exposure predicted with maribavir alone at 1200 mg twice daily, therefore, there are no safety concerns with increasing the maribavir dose to 400 mg to 800 mg, or 1200 mg in the presence of inducers. Overall, CYP3A4 inducers significantly reduce the systemic exposure of maribavir, therefore, an increase in the maribavir dose is required if coadministration with a CYP3A4 inducer is required. If coadministration with carbamazepine or phenobarbital is required, an increase in the maribavir dose to 800 or 1200 mg twice daily is recommended. If coadministration with phenytoin is required, increase the maribavir dose to 1200 mg twice daily (recommended). Rifampicin significantly reduced the exposure of maribavir. This cannot be overcome by increasing the maribavir dose to 1600 mg twice daily, therefore coadministration with rifampicin should be prohibited or an alternative antibacterial therapy with less potential for CYP3A4 induction should be considered.

[0109] General note: The inducer dose recommendations were based on arithmetic mean ratios due to bias in geometric mean estimates caused by coadministration. However, geometric mean ratios were used for inhibitor dose recommendations.

[0110] Example 3 - Co-administration of Maribavir with other drugs Drug interaction studies were summarized based on Example 2 and other available data (e.g., in vitro and clinical data). Considerations for each concomitant medication are presented in Table 1-A, and the effects of coadministration of other drugs on the pharmacokinetics of maribavir are summarized in Tables 1-B and 1-C. [Table 26] [Table 27] [Table 28]

[0111] While the inventors have described multiple embodiments of the invention, it will be apparent that the inventors' basic examples can be modified to provide other embodiments that utilize the compounds and methods of the invention. It will therefore be understood that the scope of the invention is to be defined by the appended claims rather than the specific embodiments that have been represented by way of example.

Claims

1. 1. A pharmaceutical composition for treating cytomegalovirus (CMV) infection in a patient suffering from CMV infection, comprising maribavir, 800 mg or 1200 mg of maribavir is orally administered twice daily to a patient who is currently receiving carbamazepine, phenytoin, or phenobarbital or who has received carbamazepine, phenytoin, or phenobarbital prior to administration of maribavir; The medicine wherein the patient is a transplant recipient.

2. The pharmaceutical composition of claim 1, wherein the patient is currently receiving carbamazepine or has been receiving carbamazepine prior to administration of maribavir, and the amount of maribavir administered is 800 mg orally twice daily.

3. The pharmaceutical composition of claim 1, wherein the patient is currently receiving phenytoin or phenobarbital or has been receiving phenytoin or phenobarbital prior to administration of maribavir, and the amount of maribavir administered is 1200 mg orally twice daily.

4. The pharmaceutical described in claim 1, wherein 1200 mg of maribavir is administered orally to a patient twice daily.

5. The pharmaceutical described in claim 1, wherein maribavir is administered in combination with carbamazepine, phenytoin or phenobarbital.

6. A pharmaceutical described in any one of claims 1 to 5, wherein the patient is currently receiving or has been receiving an immunosuppressant drug.

7. The pharmaceutical described in claim 6, wherein the immunosuppressant is selected from the group consisting of tacrolimus, cyclosporine, everolimus, and sirolimus.

8. The pharmaceutical described in claim 7, wherein the immunosuppressant is tacrolimus.

9. The pharmaceutical described in claim 6, wherein maribavir and an immunosuppressant are administered in combination.

10. The pharmaceutical agent described in claim 1, wherein the patient is resistant to treatment with one or more of ganciclovir, valganciclovir, cidofovir, or foscarnet.

11. The pharmaceutical described in claim 1, wherein the patient is a hematopoietic stem cell transplant recipient.

12. The pharmaceutical described in claim 1, wherein the patient is a solid organ transplant recipient.

13. The pharmaceutical composition of claim 1, wherein the patient is an adult or a child over 12 years of age and weighing over 35 kg.

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