Methods for administering intravenous baclofen

Abstract

Disclosed is a method for administering a therapeutically effective amount of baclofen intravenously (IV) in a dosing regimen that mimics the oral pharmacokinetic profile of baclofen. The disclosed method provides improved systemic exposure (AUC) and maximum plasma concentration (C max ) meets the bioequivalence criteria for both

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 130,503, filed December 24, 2020. The entire contents of the above-referenced application are hereby incorporated by reference. [Background technology]

[0002] Baclofen (USP) is a skeletal muscle relaxant and antispasticity agent. Baclofen is a structural analogue of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) and acts by inhibiting the release of GABA at the spinal cord level. B It acts as an agonist. Baclofen is indicated for the relief of signs and symptoms of spasticity, particularly flexor spasticity and associated pain, clonus, and rigidity. Baclofen treatment can help restore remaining function after reversible spasticity. Intravenous (IV) baclofen can be used for short-term use in hospitalized patients where chronic oral or intrathecal baclofen therapy has been temporarily discontinued to maintain plasma concentrations of baclofen until the oral or intrathecal route is re-established. In April 2020, the FDA granted orphan drug designation for IV baclofen for the prevention of baclofen withdrawal syndrome.

[0003] Baclofen is a white to off-white, odorless crystalline powder. It is slightly soluble in water (2090 mg / L), very slightly soluble in methanol, and insoluble in chloroform. The molecular formula for baclofen is C. 10 H 12 It is ClNO2. The molecular weight of baclofen is 213.66 Da. The chemical name of baclofen is 4-amino-3-[4-chlorophenyl]butanoic acid (Baclofen Oral Tablets Package Insert, 2015). The chemical structure of baclofen is: [ka]

[0004] Baclofen is used to treat spasticity associated with numerous medical conditions, including cerebral palsy, multiple sclerosis, traumatic brain injury, spinal cord injury, stroke, and neurodegenerative diseases. Baclofen is currently available commercially as an oral tablet (10 mg or 20 mg tablet) and as an intrathecal formulation (0.05 mg / mL, 0.5 mg / mL, or 2.0 mg / mL). The intrathecal formulation is used in conjunction with an implanted programmable pump to provide a constant infusion of the drug. Baclofen is typically used long-term to maintain its therapeutic effect.

[0005] Baclofen is an important part of the therapeutic armamentarium for treating spasticity present in patients suffering from several neurological disorders. When administered chronically in an individualized dose range, baclofen is well absorbed orally and excreted largely unchanged by the kidney. However, there are times when interruption of oral or intrathecal therapy is either necessary or unintended. Interruption of oral baclofen therapy may be caused by intercurrent illness, surgery, noncompliance, or inability to maintain the oral route of administration due to poor gastrointestinal absorption. Examples of the latter include gastroenteritis, ileus, or postoperative ileus after continuous anesthesia. Interruption of intrathecal baclofen may occur when removing, refilling, or replacing the programmable pump and / or catheter used for intrathecal administration. Interruption of baclofen therapy is undesirable as it may result in worsening of spasticity symptoms or, in more severe cases, a severe, but uncommon, withdrawal syndrome. The withdrawal syndrome is a severe syndrome that may include: - Rebound increase in muscle tone and spasticity - Hallucinations - Serotonin syndrome - Status epilepticus - Malignant hyperthermia - Increased plasma creatine kinase, increased aminotransferases, hepatic and renal failure, and in some cases, generalized intravascular coagulation. - Ultimately, withdrawal can lead to rhabdomyolysis, multiple organ failure, or even death.

[0006] Baclofen inhibits GABA in the spinal cord. B Baclofen exerts its anticonvulsant effects by binding to GABA receptors. Prolonged exposure to baclofen increases the GABA receptors in rats. B GABA binding density may decrease. B Decreased receptor sensitivity could explain the rapid rebound in CNS excitability observed when baclofen is withdrawn. In summary, given the known pharmacology of baclofen, maintenance of baclofen concentrations, or rapid replacement, is an essential goal of treatment.

[0007] Although oral and intrathecal baclofen are approved for the treatment of spasticity, there are no approved alternative dosage forms to maintain therapy when these routes are not available. Patients who experience baclofen therapy discontinuation face a variety of clinical management issues, including worsening muscle tone, side effects of other adjunctive medications, the need for larger replacement doses when oral baclofen is resumed, and the potential for difficult-to-manage baclofen withdrawal syndrome. When baclofen therapy discontinuation occurs or is anticipated, the availability of bridging therapy with intravenous baclofen reduces the risk of these management issues. The challenge of treating the consequences of baclofen discontinuation indicates the need to utilize preventative measures when baclofen discontinuation occurs or is a possibility. Intravenous baclofen provides clinicians with a dosage form that is readily available in hospitalized patients that maintains or achieves a therapeutic response in the short term.

[0008] Currently, there are no FDA-approved pharmacological therapies for the prevention or treatment of baclofen withdrawal syndrome. However, warnings about baclofen withdrawal symptoms associated with abrupt discontinuation are included on the labeling of oral and intrathecal products. Preoperative preparation in one specialty hospital for children with disabilities includes tapering and discontinuing oral baclofen before surgery to avoid baclofen withdrawal. This allows the patient's muscle tone to be inappropriately managed by other replacements, often for a short period of time, plus increased sedation from the medication due to added stress and discomfort during the cyclical experience. If oral baclofen therapy is discontinued, it is usually necessary to replace oral baclofen as soon as oral administration is again possible, usually requiring a larger than usual dose. If withdrawal symptoms persist, a benzodiazepine is administered as well. The diagnosis of baclofen withdrawal syndrome is often delayed due to the complex clinical presentation of the patient.

[0009] The current standard of care for baclofen withdrawal syndrome does not prevent serious sequelae and, in a few cases, has resulted in death. Therefore, prophylaxis such as intravenous baclofen would be ideal to avoid the withdrawal symptoms, which are associated with significant morbidity and cost.

[0010] When interruption of baclofen therapy is anticipated, the availability of bridging therapies, such as intravenous baclofen, may reduce the risk of baclofen withdrawal. The difficulty of treating baclofen withdrawal indicates the need to use preventative measures when baclofen withdrawal is likely. Baclofen IV provides clinicians with a dosage form that is rapidly available in the hospital and can be administered to patients to maintain a therapeutic response for a short period of time.

[0011] The main hospital situations in which intravenous baclofen is recommended in patients requiring maintenance of oral baclofen steady-state plasma concentrations include the following: - Fasting (including oral medications) prior to surgery requiring general anesthesia due to the risk of intraoperative aspiration, plus the possibility of postoperative nausea and vomiting; - Patients with cerebral palsy and other physical disabilities undergo multiple surgical, orthopedic, and other procedures and may represent a significant proportion of patients taking oral baclofen; - Patients who are unconscious due to trauma, stroke, or other medical condition that prevents the patient from taking medication orally; - Difficulty swallowing after surgery due to the endotracheal tube; and -Discontinuation of oral baclofen therapy with planned baclofen pump insertion surgery.

[0012] Additionally, interruptions in intrathecal baclofen therapy may occur when the pump and / or catheter used for intrathecal administration is removed, refilled, or replaced.

[0013] In such circumstances, discontinuation of baclofen therapy may result in rebound spasticity symptoms and the potential for progression to a more severe withdrawal syndrome. The availability of an IV formulation of baclofen, administered at doses to achieve plasma concentrations comparable to those that patients have with oral or intrathecal maintenance therapy, is expected to maintain the therapeutic effect of the oral or intrathecal formulations and reduce the likelihood of rebound or withdrawal until the oral or intrathecal route can be re-established.

[0014] Currently, there is no established method to fill the gap in oral or intrathecal therapy until oral or intrathecal baclofen can be resumed.

[0015] If left untreated, discontinuation of oral or intrathecal baclofen therapy can result in baclofen withdrawal syndrome, as there are no pharmacological treatments approved or licensed to prevent or treat such withdrawal in the U.S. Thus, the availability of safe and effective therapeutic modalities to address this problem represents an important unmet clinical need. Summary of the Invention

[0016] Disclosed is a method for administering a therapeutically effective amount of baclofen intravenously (IV) in a dosing regimen that mimics the oral pharmacokinetic profile of baclofen. The disclosed method provides improved systemic exposure (AUC) and maximum plasma concentration (C max ) meets the bioequivalence criteria for both

[0017] In one embodiment, a method of administering baclofen to a subject comprises administering an intravenous baclofen infusion comprising about 75% to about 85% therapeutically effective amount of oral baclofen over a period of about 180 to about 240 minutes.

[0018] In another embodiment, the method of administering baclofen to a subject comprises administering an intravenous baclofen infusion comprising about 80% of a therapeutically effective amount of oral baclofen over a period of about 180 minutes.

[0019] These and other aspects and advantages of the present disclosure will become apparent from the following detailed description and the appended claims. It is understood that one, some, or all of the features of the various embodiments described herein may be combined to form other embodiments of the present invention.

[0020] Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below. The materials, methods, and examples are illustrative only and are not intended to be limiting. Other features of the present disclosure will be apparent from the following detailed description and claims.

[0021] The following figures are included to illustrate certain aspects of the invention and should not be construed as exclusive embodiments. The disclosed subject matter is capable of considerable modification, permutations, combinations, and equivalents in form and function, as will occur to those of ordinary skill in the art having the benefit of this disclosure. [Brief description of the drawings]

[0022] [Figure 1]Plasma concentration-time profiles of baclofen after intravenous (5 mg) (circles) and oral (10 mg) (triangles) administration are shown. [Diagram 2] 1 is a table showing the mean pharmacokinetic parameters of baclofen following oral (10 mg) and intravenous (5 mg) administration. [Diagram 3] 1 is a table showing the mean pharmacokinetic parameters of baclofen following oral and intravenous administration in a dose escalation study. [Figure 4] 1 is a table showing pharmacokinetic model estimates in the dose escalation study population using Cohort 3. [Diagram 5] 1 is a table showing pharmacokinetic model estimates in the dose escalation study population using cohorts 2 and 3. [Figure 6] Observed (DV) and predicted plasma baclofen concentrations are shown (Cohort 3 only, Ka=0.8 hr-1) (Ka=rate constant). [Figure 7] Observed (DV) and predicted plasma baclofen concentrations are shown (Cohort 3 only, Ka=0.6 hr-1). [Figure 8] Observed (DV) and predicted plasma baclofen concentrations are shown (Cohorts 2 and 3, Ka=0.8 hr-1). [Figure 9] Observed (DV) and predicted plasma baclofen concentrations are shown (Cohorts 2 and 3, Ka=0.6 hr-1). [Figure 10] 13 is a table summarizing bioequivalence results for various infusion lengths using a population model developed using Cohort 3 only. [Figure 11] 1 is a table summarizing bioequivalence results for various infusion lengths using the population model developed using cohorts 2 and 3. [Figure 12] 1 is a table showing individual pharmacokinetic model estimation using cohort 3. [Figure 13] Individual pharmacokinetic model fits are shown. [Figure 14]4 shows the mean concentration-time profile of 15 mg IV baclofen. [Figure 15] 4 shows the mean concentration-time profile of 16 mg IV baclofen. [Figure 16] 1 is a table showing the estimation of mean pharmacokinetic parameters using non-compartmental analysis. [Figure 17] 1 is a table showing expected bioequivalence for various infusion lengths when each subject in Cohort 3 was modeled individually (dose=15 mg). [Figure 18] 1 is a table showing expected bioequivalence for various infusion lengths when each subject in Cohort 3 was modeled individually (dose=16 mg). [Figure 19] Shown are simulated plasma baclofen concentrations following administration of 20 mg PO, 15 mg IV infused over 180 minutes, and 16 mg IV infused over 180-240 minutes. [Figure 20] 1 is a table showing simulation of baclofen bioequivalence for various infusion regimens (N=30) assuming 80% bioavailability. [Figure 21] 1 shows mean plasma baclofen concentration-time profiles following a 16 mg baclofen IV infusion (2 mg / mL) over 180 minutes (Treatment B) and a single oral dose of a 20 mg baclofen tablet (Treatment D). [Figure 22] FIG. 1 is a table summarizing mean plasma pharmacokinetic parameters of baclofen by treatment (A, B, C, and D). [Diagram 23] 1 is a table showing statistical analysis of natural log transformed systemic exposure to baclofen. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0023] Terms and Definitions Unless otherwise explained, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this disclosure belongs. All references herein are incorporated by reference. The following explanations of terms and abbreviations are provided to better describe the present disclosure and to guide those skilled in the art in practicing the present disclosure.

[0024] For the sake of more precise description, some of the quantitative expressions shown herein are not modified with the term "about". It should be understood that, regardless of whether the term "about" is explicitly used, all amounts shown herein refer to actual given values, and also refer to approximations to such given values ​​that can be reasonably inferred by those skilled in the art, including approximations based on experimental and / or measurement conditions for such given values.

[0025] The term "subject" as used herein refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.

[0026] The term "therapeutically effective amount," as used herein, means an amount of an active compound or pharmaceutical agent that elicits the biological or medical response desired by a researcher, veterinarian, physician, or other clinician in a tissue system, animal, or human, that includes alleviation of at least one symptom of the disease or disorder being treated and / or a reduction in the frequency and / or severity of at least one symptom of the disease or disorder being treated.

[0027] Clinical Pharmacology The present disclosure provides various methods of administering a therapeutically effective amount of baclofen intravenously in a dosing regimen that mimics the oral pharmacokinetic profile of a given baclofen dose. The disclosed methods provide improved systemic exposure (AUC) and maximum plasma concentration (C max ) meets bioequivalence criteria for both. The disclosed methods are directed to the use of a sterile Baclofen IV injection (e.g., 2 mg / mL) drug product.

[0028] Two pilot studies were conducted to characterize the pharmacokinetics and safety of baclofen following intravenous administration and to investigate the absolute bioavailability of IV and oral baclofen. These studies are A Pilot Study Assessing Pharmacokinetics and Tolerability of Oral and Intravenous Baclofen in Healthy Adult Volunteers,Suresh K.Agarwal,Robert L.Kriel,James C.Cloyd,Lisa D.Coles,Lisa A.Scherkenbach,Michael H.Tobin,and Linda E.Krach,Journal of Child Neurology 2014,30(1) 37-41; and A Randomized Dose Escalation Study of Intravenous Baclofen in Healthy Volunteers: Clinical Tolerance and Pharmacokinetics,Schmitz NS,Krach LE,Coles LD,Mishra U,Agarwal SK,Cloyd JC,Kriel RL.PM&R,2017,Volume 9(8), 743-750, both of which are incorporated by reference as if fully set forth herein. Based on the results of these two prospective pharmacokinetic studies, which included bolus infusions of IV baclofen over 10-60 minutes, the estimated mean oral baclofen bioavailability was approximately 74-85%, or approximately 80%. Although these initial studies showed similarities in AUC (AUC = area under the concentration-time curve) following oral and IV baclofen, the C max (C max = maximum plasma concentration) is C max The exposure (AUC) and peak concentration (C maxThey concluded that longer infusion times would be required to meet bioequivalence criteria for both AUC and C. max For both, IV baclofen dosing regimens were predicted to be bioequivalent to the 20 mg oral dose. These simulations formed the basis of a pivot bioequivalence study in which three different dosing regimens of baclofen IV (15 mg infused over 3 hours; 16 mg infused over 3 hours; and 16 mg infused over 4 hours) were compared to a single dose of 20 mg oral tablet. Each of these IV regimens was bioequivalent to the 20 mg oral dose, but the 16 mg / 3 hour dose best met bioequivalence criteria.

[0029] The results of the two pilot studies mentioned above are briefly summarized below:

[0030] Study 1: A two-way crossover study of oral and intravenous baclofen in healthy adult volunteers

[0031] The objectives of this study were to characterize baclofen pharmacokinetics following oral and IV administration according to low doses in healthy adult volunteers and to determine the safety profile of IV baclofen formulations.

[0032] The study was a randomized, open-label, balanced, two-treatment, single-dose crossover design in normal, healthy adult human subjects under fasting conditions.

[0033] Initially, three adult volunteers received a single 3 mg IV and 5 mg oral baclofen dose on separate study days. On the first day of study drug administration, one subject received baclofen intravenously and two subjects received baclofen orally. On the second day of study drug administration, the subject who received oral baclofen received the IV dose and the individual who received the IV dose received the oral dose. Plasma concentrations of baclofen were measured from the first three subjects before clinical tolerance was investigated and further subjects were enrolled in the study. Nine additional adults received a single 5 mg IV and 10 mg oral baclofen dose on separate days. Randomization occurred in a 1:1 ratio so that all subjects received IV and oral baclofen on separate study days, but not necessarily in the same order. A total of 12 subjects completed the clinical phase of the study. Plasma samples from the 12 subjects were analyzed. However, data from nine subjects receiving the 5 mg IV and 10 mg oral regimens were considered for the pharmacokinetic analysis and for calculation of within-subject variability. Three subjects receiving 3 mg IV / 5 mg oral baclofen were excluded from the pharmacokinetic analysis because more than half of the plasma concentrations were below the limit of quantification (BLQ). Therefore, a meaningful estimation of the AUC was not possible for these subjects.

[0034] The mean plasma concentration profiles and mean pharmacokinetic parameters are presented in Figures 1 and 2, respectively.

[0035] Based on the results presented above (small sample size, n=9), the estimated mean absolute bioavailability of oral baclofen was 74%, indicating that approximately 25% of a 10 mg dose was either not absorbed or was subject to first-pass metabolism before the drug reached the systemic circulation. An IV dose infused over 15 minutes yielded a similar AUC. However, C max is high, T maxThe time to maximum plasma concentration (time to maximum plasma concentration) was shorter than with oral dosing. It also suggests that a smaller intravenous baclofen dose would be necessary if replacing oral dosing. Between-subject variability in exposure (area under the curve) was similar in both the intravenous and oral groups (coefficient of variation: 18%-24%). Both 3 and 5 mg IV baclofen were well tolerated. Results indicate that additional studies with larger sample sizes are needed to accurately measure the population mean absolute bioavailability and adverse event profile.

[0036] Study 2: A dose-escalation study of IV baclofen in healthy adult volunteers

[0037] Following completion of the first-in-human study, a dose-escalation study of IV and oral baclofen was conducted in 36 healthy volunteers using a randomized crossover oral / IV dose design and incorporating an investigational IV baclofen injection. The objectives of the study were: 1) to characterize the pharmacokinetics of clinically relevant doses of oral and intravenous baclofen, 2) to determine the safety profile of oral and intravenous baclofen, and 3) to evaluate bioequivalence parameters (AUC and C) for 10 and 60 minute (15 mg dose only) baclofen infusions. max ) was measured.

[0038] The overall design of the study included three cohorts of 12 subjects. First, three subjects were randomized to receive the lowest dosing regimen. Three subjects received 7.5 mg IV infusion, followed by a washout period of at least 2 days, followed by 10 mg oral. Once these three subjects demonstrated that they tolerated the IV dose, the remaining nine subjects were randomized to receive it. Twelve subjects completed cohort 1 and received 7.5 mg IV and 10 mg oral. The dose of IV baclofen was based on 75% of the bioavailability observed in the pilot study. In cohort 2, 12 different subjects received 11.5 mg IV and 15 mg oral baclofen. In cohort 3, another 12 subjects received 20 mg oral and 15 mg IV baclofen. Once all subjects completed the 15 mg IV dose without complications, an additional dosing period was added to this cohort in which 15 mg baclofen was infused over 60 minutes in 12 subjects. Subjects were observed in the clinical research facility for 24 hours after all doses and were assessed for nystagmus, ataxia, and sedation (using the modified Sanford Sleepiness Scale). Blood samples were collected from 0 to 24 hours. Plasma baclofen concentrations were measured using a validated liquid chromatography-mass spectrometry assay.

[0039] Pharmacokinetic analysis was performed using the pharmacokinetic data analysis package Phoenix (Centara). max ), time to maximum observed concentration (T max ), area under the concentration-time curve (AUC), clearance (CL), and volume of distribution (V d Pharmacokinetic parameters, including AUC(0-t), AUC(0-∞), and C were analyzed using noncompartmental analysis. Absolute oral bioavailability was calculated by dividing the dose-normalized AUC after oral administration by the dose-normalized AUC after intravenous administration. For exploratory bioequivalence studies, the geometric mean AUC(0-t), 90% confidence intervals for AUC(0-∞), and C were calculated using the 60-min infusion as the test dose and the oral 15 mg dose as the reference. max Oral / IV ratios were determined.

[0040] The estimated mean bioavailability for all cohorts was 89%. However, because of baclofen concentration limits above the limit of quantification for cohort 1, we believe the bioavailability estimates for cohorts 2 and 3 (85.8 and 81.2, respectively) are more reflective of actual values. Given the mean bioavailability for these groups, an IV dose that is 15-20% less than the oral dose would likely provide equivalent total systemic exposure. Mean pharmacokinetic parameters are summarized in Figure 3.

[0041] Total systemic exposure, AUC 0-t , and AUC 0-inf When 15 mg was used in a 10-minute infusion at all dose levels, rather than 15 mg in a 60-minute infusion, bioequivalence of IV and oral baclofen was demonstrated. However, the mean C max The ratios were 263% and 149%, with confidence intervals (CI) of 247 to 281% and 135 to 165%, respectively, and were not bioequivalent.

[0042] Safety Results: Mild, self-limited side effects were observed following both oral and IV baclofen administration. Adverse events associated with the known pharmacological effects of baclofen included nystagmus, ataxia, and sedation. Regarding sedation, all subjects were awake 3.5 hours after receiving a 10 mg oral dose, regardless of route of administration or dose, except for one individual who took 20 seconds to awaken.

[0043] All subjects were able to walk unassisted. One subject experienced mild transient ataxia after oral administration of 20 mg baclofen. Of the 12 subjects in each dose group, 2, 6, and 6 subjects experienced asymptomatic nystagmus after 10-minute infusions of 7.5 mg, 11.5 mg, and 15 mg, respectively. After a 60-minute infusion of 15 mg, 2 subjects experienced mild transient ataxia and 2 subjects had nystagmus. Evidence from 2 prospective studies in healthy volunteers indicates that side effects after single intravenous injections of clinically relevant baclofen doses are generally mild, with an IV to oral dose ratio of approximately 80-85%.

[0044] Conclusions: Based on the results of two prospective pharmacokinetic studies in healthy volunteers, side effects after a single intravenous injection of clinically relevant baclofen doses were generally mild, the IV to oral dose ratio was approximately 80-85%, and exposure met bioequivalence criteria (AUC) but not peak concentration criteria (C max ) is not satisfied.

[0045] To meet bioequivalence criteria for both exposure and peak concentration, a longer infusion time was required, and modeling and simulation studies were performed to select an appropriate infusion rate and identify a dosing regimen that best mimicked the oral pharmacokinetic (PK) profile.

[0046] In order to facilitate a better understanding of the present disclosure, the following examples of preferred or representative embodiments are given. The following examples should not be read to limit or define the scope of the present invention. Many embodiments within the scope of the claims will be obvious to those skilled in the art. Therefore, the following non-limiting examples are only intended to describe specific embodiments of the present disclosure.

[0047] Example 1 - Modeling and Simulation Studies Population modelling approach Model Building Plasma concentrations from cohorts 2 and 3 of Study 2 described above were used to construct a two-compartment model simultaneously accounting for IV and PO routes of administration. Data from cohort 3, as well as data from cohorts 2 and 3 combined, were used to develop a population PK model (see Figures 4 and 5). It is noteworthy that PK parameter estimates from both study populations were similar. 0.6 and 0.8 hr -1 Two PK models with fixed absorption rate constants (Ka) were used. These were determined from population pharmacokinetic models and literature estimates. Visual prediction checks for these models are shown in Figures 6-9.

[0048] simulation C max Simulations were performed using population PK parameter estimates measured from a baclofen dose ranging study to explore the effect of infusion time on PK and AUC. Using the model described above, 30 subject simulations (n=10) were completed using a 20 mg oral dose and 15 and 16 mg IV doses infused over 120, 150, 180, and 210 minutes. Simulation data was then analyzed using noncompartmental analysis of maximum concentration to investigate bioequivalence and area under the curve of maximum concentration. Figures 10 and 11 summarize how many simulations out of 10 had infusion rates that met bioequivalence when using the 16 and 15 mg doses, respectively.

[0049] Individual modeling approaches Model Building As an alternative approach, individual PK models were developed using plasma concentrations from each subject in Cohort 3 who received the IV dose as described in the population modeling approach. It is noteworthy that the PK parameter estimates (Figure 12) were similar to those from the population model (Figures 4 and 5). Goodness-of-fit plots are shown in Figure 13.

[0050] simulation Using the model described above, various infusion durations were simulated for each subject using doses of 15 and 16 mg. The simulated IV data was then analyzed using non-compartmental analysis of maximum concentration to examine the area under the curve comparing the exposure parameters for IV administration with those calculated for oral administration. The mean concentration-time profiles are shown in Figures 14 and 15. The results of the bioequivalence study are summarized in Figure 16.

[0051] Based on the population and individual modeling approaches, simulations described above, and fitting these results to a hypothetical crossover study (see Figures 17 and 18), a pivot bioequivalence study was designed to investigate regimens consisting of baclofen IV injection in dose strengths of 15 mg and 16 mg, and infusion over 180 or 240 minutes.

[0052] Rationale for pivot bioequivalence studies An important objective of adjusting the dose and duration of baclofen infusion is to evaluate the bioequivalence of systemic exposure (C) between a single dose of IV baclofen infusion and a 20 mg oral baclofen tablet. max The objective of this study was to achieve a mean oral bioavailability of 86% after a single dose in 45 subjects, with a wide range of interpatient variability (%F ranged from 42 to 132%). When clinically relevant doses (11.5 and 15 mg) were selected, the mean oral bioavailability was 80 and 85%, respectively.

[0053] For the design of this study, IV doses of 75 and 80% (15 and 16 mg) of the standard oral dose (20 mg) were chosen, and the conclusions were consistent with previous initial results in human studies. In addition, the C max Results from 10 and 60 minute infusions suggested that the desired similarity of was achieved (see below).

[0054] Conclusion: After intravenous baclofen administration, C max Modeling and simulation to assess the effect of infusion duration on AUC and Results of the dose-ranging study revealed that baclofen bioavailability is variable among patients and may be dose dependent. Because bioavailability is excluded as a source of variability following IV administration, systemic exposure following IV administration of baclofen is less variable than oral administration. Adjusting the dose in patients receiving IV baclofen replacement therapy protects against either low plasma concentrations that may result in an increased risk of spasticity or high concentrations that may result in potential CNS-related side effects.

[0055] C max To investigate the effect of infusion time on baclofen, a population pharmacokinetic model was developed using plasma concentrations of baclofen observed after oral administration of 20 mg and IV administration of 15 mg infused over 10 and 60 minutes. Plasma concentrations of baclofen were best described by a two-compartment model exhibiting a very fast tissue distribution phase, representing highly perfused tissues such as liver, lung, and brain, and a longer elimination phase. The mean distribution t 1 / 2 Modeling results revealed that the increase in plasma concentration of baclofen was rapid (approximately 0.3 hours) after the infusion was stopped. This indicates that the increase in plasma concentration of baclofen was short-lived once the infusion was stopped. The mean terminal t 1 / 2 The mean bioavailability (β) was approximately 4.2 hours, which corresponds to a value based on noncompartmental analysis. A mean bioavailability value of 84% was estimated. The PK model was used to simulate baclofen concentrations for a 20 mg oral dose, a 15 mg IV dose infused over 180 minutes, and a 16 mg IV dose infused over 180 and 240 minutes. This resulted in a baclofen C max We were able to measure the effect of injection time on the flow rate. The simulation results are summarized in Figure 19.

[0056] A hypothetical bioequivalence study was conducted using simulated data, and as shown in Figure 20, the 180 and 240 minute infusion rates had similar C max and AUC. These results provided support for the selected infusion times of 180 and 240 minutes tested in this clinical trial.

[0057] Example 2 - Clinical Bioequivalence Study Overall research design and planning The study was designed as a two-part, single-dose bioequivalence study of baclofen injection (test formulation) compared with commercial baclofen tablets (reference product) in healthy adult volunteers under fasting conditions. Part 1 of the study was a single-dose, open-label, four-treatment, randomized crossover bioequivalence study of baclofen tablets and baclofen tablets in healthy adults under fasting conditions. If necessary, part 2 of the study was planned to be a single-dose, two-way crossover between the most promising infusions of baclofen injection and baclofen tablets from part 1. The planned second part was not conducted because the study objectives of bioequivalence between baclofen injection(s) and baclofen tablets were addressed in part 1 of the study.

[0058] Subjects were randomized in a randomized crossover fashion to receive one of four treatments: - 15 mg baclofen injection administered intravenously over 180 minutes - 16 mg baclofen injection administered intravenously over 180 minutes - 16 mg baclofen injection administered intravenously over 240 minutes - 20mg baclofen tablets administered orally

[0059] Main purpose To identify a dose (volume and rate of infusion) of baclofen injection in healthy subjects that results in a systemic exposure comparable to a single dose of a 20 mg baclofen tablet, as demonstrated by bioequivalence.

[0060] Secondary Objectives To determine the single-dose pharmacokinetics and absolute bioavailability of 20 mg baclofen tablets and 15 mg and 16 mg baclofen injections infused at different rates in healthy adults.

[0061] To assess the safety and tolerability of baclofen injections given as an infusion and baclofen tablets taken orally.

[0062] Discussion of study design, including choice of control group The study design was a single-dose, open-label, four-treatment randomized crossover. Using this design, each subject was able to serve as their own control, eliminating the need for a separate control group. The study design is common for bioavailability and bioequivalence studies.

[0063] Administration of each treatment was separated by a washout period of at least 3 days. Each dose was administered after a 10-hour overnight fast.

[0064] During each study period, 6 mL blood samples were obtained prior to administration of study drug and at selected times up to 48 hours after drug administration. In study periods in which subjects received IV infusions, PK sampling was timed relative to the start of the infusion. Plasma pharmacokinetic samples were analyzed for baclofen using a validated achiral bioanalytical method. Pertinent pharmacokinetic parameters were calculated for each formulation using noncompartmental methods.

[0065] Blood and urine were collected for clinical laboratory testing at screening and end / early termination of the study. Urine was collected for drug, alcohol, and cotinine testing at screening and check-in. Urine from female subjects was collected for pregnancy testing at screening, check-in, and end / early termination of the study.

[0066] Thirty-two subjects were planned for Part 1, replacing two subjects who dropped out of the study.

[0067] treatment Subjects received a single dose of each treatment in a randomized, sequenced fashion. Each dose of baclofen injection was given by IV infusion. Baclofen tablet doses were administered orally with 240 mL (8 fluid ounces) of room temperature water.

[0068] Identity of investigational product Test product: Baclofen injection 2mg / mL

[0069] Treatments A, B, and C: Treatment A dose = 15 mg baclofen injection administered intravenously over 180 minutes Treatment B dose = 16 mg baclofen injection administered intravenously over 180 minutes Treatment C dose = 16 mg baclofen injection administered intravenously over 240 minutes

[0070] Control product: Treatment D: -Baclofen tablets 20 mg, dose = 1 x 20 mg tablet

[0071] All safety and pharmacokinetic measurements obtained in this study are standard and widely used in bioavailability and bioequivalence studies.

[0072] Blood samples were obtained to determine the pharmacokinetic profile and exposure of baclofen after each treatment.

[0073] Baclofen concentration-time data were analyzed using noncompartmental methods described in Phoenix™ WinNonlin® (Version 6.3, Certara LP). During the pharmacokinetic analysis, concentrations below the limit of quantification (BLQ) up to the time of the first quantifiable concentration were treated as zero. Buried (values ​​between two quantifiable concentrations) and / or terminal BLQ concentrations were treated as "missing". Time versus administration was used in the pharmacokinetic analysis.

[0074] The following pharmacokinetic parameters were determined: [Table 1]

[0075] Blood (plasma) pharmacokinetic characteristics were investigated after each administration of the investigational product.

[0076] During the treatment period for each baclofen injection, samples were collected at 0 hours (pre-dose) and 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 6.0, 7, 8, 10, 12, 18, 24, 30, 36, and 48 hours after the start of the infusion.

[0077] During the baclofen tablet treatment period, samples were taken at 0 hours (pre-dose) and 0.25, 0.5, 0.75, 1.0, 1.5, 2.0 3.0, 3.5, 4.0, 5.0, 6.0, 7, 8, 10, 12, 18, 24, 30, 36, and 48 hours after oral administration.

[0078] Pre-dose blood samples obtained from back-up subjects randomized into the study may have exceeded the pre-dose collection window.

[0079] Blood samples taken within ±2 minutes of the scheduled time up to and including 12 hours after dosing and blood samples taken within ±2 hours of the scheduled time 12 hours after dosing were not considered deviations.

[0080] Target placement A total of 34 subjects participated in the study; 32 of these subjects completed the entire study period. Two patients discontinued the study early, as described below. Subject X (male, age 19) withdrew consent on day 2 after receiving Treatment D (baclofen tablets 20 mg) in Period 1 and was therefore not included in the PK analysis. Subject Y (female, age 29) withdrew consent on day 3 after receiving Treatment B (baclofen IV 16 mg infused over 180 minutes) in Period 1 and was therefore not included in the PK analysis.

[0081] result No clinical efficacy investigations were conducted in this study. A summary of pharmacokinetic analyses was conducted for use as surrogates of efficacy and is detailed below.

[0082] The mean concentration-time profiles for the proposed dosing regimens are shown in FIG.

[0083] The mean pharmacokinetic parameters for baclofen are summarized in FIG.

[0084] C for log-transformed exposure parameters max , AUC last , and AUC inf The results of the ANOVA for as well as the statistical analysis resulting in 90% confidence intervals for bioequivalence are shown in FIG.

[0085] Compared with IV infusion, central T max occurred approximately 2.0 to 3.0 hours earlier than the oral tablet (1.0 h). max Values ​​were similar throughout the IV infusion and ranged from 3.0 to 4.0 hours. 1 / 2 was similar for the IV infusion and oral tablet, ranging from 5.5 h to 5.8 h.

[0086] Mean total systemic clearance (CL Τ ), and volume of distribution (Vz) values ​​were similar throughout the IV infusion. Τ ranged from 8.8 L / h to 8.9 L / h, and mean Vz ranged from 69.8 L to 71.4 L.

[0087] All three baclofen IV infusions (15 mg baclofen administered intravenously over 180 minutes; 16 mg baclofen administered intravenously over 180 minutes; and 16 mg baclofen administered intravenously over 240 minutes) were bioequivalent to the 20 mg baclofen oral tablet. Therefore, the study was terminated after Part 1.

[0088] Furthermore, 16 mg of baclofen administered intravenously over 180 minutes was max Regarding the AUC, it was 97.3% (93.7-101.0%). last 92.1% (89.7-94.6%) for inf Baclofen, 16 mg administered over 180 minutes, was selected as the dosing regimen for enrollment because it had a geometric mean ratio (90% confidence interval) for treatment D (20 mg oral tablet) of 92.2% (89.8-94.6%) for baclofen, and consistently demonstrated ratios greater than 90% for each critical parameter.

[0089] Based on the demonstrated bioequivalence, a conversion factor of 0.8 for an oral regimen administered over 180 minutes would result in bioequivalent substitution for oral baclofen.

[0090] Although some embodiments have been described above with a certain degree of specificity, those skilled in the art may make numerous modifications to the disclosed embodiments without departing from the spirit of the present disclosure. It is intended that all subject matter contained in the above specification or shown in the accompanying drawings be interpreted as merely illustrative and not limiting. Changes in detail or structure may be made without departing from the present teachings. The foregoing specification and the following claims are intended to cover all such modifications and variations.

[0091] Any patent, publication, or other disclosure material referred to as being incorporated by reference in whole or in part into this application is incorporated herein only to the extent that it does not conflict with existing definitions, statements, or other disclosure material set forth in this disclosure. Thus, and to the extent necessary, the disclosure expressly set forth herein takes precedence over any conflicting material incorporated herein by reference. Any material, or portion thereof, referred to as being incorporated herein by reference that conflicts with existing definitions, statements, or other disclosure material set forth herein is incorporated only to the extent that it does not create a conflict between the incorporated material and the existing disclosure material.

Claims

1. 1. A baclofen injection for the treatment of spasticity and / or for the treatment of baclofen withdrawal syndrome, comprising: A baclofen injection containing baclofen, characterized in that 75% to 85% of the therapeutically effective amount of oral baclofen is administered intravenously to a patient over a period of 180 to 240 minutes.

2. 10. The baclofen injection of claim 1 comprising a sterile solution of baclofen at a concentration of 2 mg / mL.

3. 10. The baclofen injection of claim 1, containing 80% of the baclofen of the therapeutically effective amount of said oral baclofen.

4. 2. The baclofen injection of claim 1, wherein the therapeutically effective amount of oral baclofen is 20 mg.

5. 2. The baclofen injection of claim 1, wherein the administration period is 180 minutes.

6. 10. The baclofen infusion of claim 1, wherein 16 mg of baclofen is administered intravenously over 180 minutes.

7. 10. The baclofen infusion of claim 1, wherein 15 mg of baclofen is administered intravenously over 180 minutes.

8. 10. The baclofen infusion of claim 1, wherein 16 mg of baclofen is administered intravenously over 240 minutes.

9. 10. The baclofen infusion of claim 1, wherein 80% of the therapeutically effective amount of the oral baclofen is administered intravenously over a 180 minute period.

10. 2. The baclofen injection of claim 1, wherein 80% of the therapeutically effective amount of oral baclofen comprises 16 mg of baclofen.

11. Administered intravenously over a specified period of time to achieve a defined plasma baclofen delivery profile; 2. The baclofen infusion of claim 1, wherein the defined plasma baclofen delivery profile comprises a maximum plasma baclofen concentration of 250-350 ng / mL.

12. 12. The baclofen injection of claim 11, wherein said specified period of time is 180 to 240 minutes.

13. 10. The baclofen injection of claim 1 comprising 15-16 mg of baclofen.

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