Pharmacometrics of clobazam in pediatrics: Prediction of effective clobazam doses for Dravet syndrome.

OBJECTIVE: To describe the use of a population pharmacokinetic (PopPK) model incorporating weight and ontogeny to identify effective clobazam (CLB) dosing for use in a clinical trial in pediatric patients with Dravet syndrome. METHODS: Pharmacokinetic data were combined from 3 CLB trials (OV-1012, OV-1017, and study 301) and a simulated study (study 401) for a total of 1306 CLB and 1305 N-desmethyl clobazam (N-CLB) samples from 193 Lennox-Gastaut syndrome patients and healthy subjects aged 6 months to 45 years. A structured approach based on US Food and Drug Administration guidance and pharmacometric knowledge discovery was developed using a nonlinear mixed-effects approach. Graphing and fitting using logistical weight regression were used to identify covariates for inclusion in the final model, which was evaluated using goodness-of-fit criteria and validated using prediction-corrected visual predictive check (pcVPC). Using the final PopPK model, a simulation study determined CLB and N-CLB distributions after 4 weeks of 1.5 and 2.0 mg/kg CLB. RESULTS: The parameters of the final PopPK model were similar to previous reports. Fixed-effect parameters were precisely estimated, with no significant increase in NONMEM objective function value. Intersubject variability estimates were similar to previous reports, with <35% shrinkage associated with parameter variability, except for intercompartmental clearance and apparent volumes of distribution of peripheral compartments. Goodness-of-fit plots and pcVPC show that the model adequately described CLB and N-CLB data. The CLB/N-CLB ratio in virtual study subjects aged <3 years was 0.23 for 1.5 and 2.0 mg/kg and was 0.14 for subjects aged ≥3 years, which is 2 to 3 times those reported in a previous stiripentol/CLB/valproate study in which seizure improvement was reported. SIGNIFICANCE: The PopPK model dosing parameters of 1.5 and 2.0 mg/kg are likely to result in efficacious concentrations of CLB and N-CLB in pediatric patients as young as 16 months. Dosages exceeding 1.5 mg/kg should be monitored for tolerability, particularly in patients aged <2 years, as there may be a higher incidence of sedation.

Drug-drug interactions and pharmacodynamics of concomitant clobazam and cannabidiol or stiripentol in refractory seizures.

OBJECTIVE: The goal of this study was to characterize the drug-drug interactions between clobazam and 2 antiseizure drugs, cannabidiol and stiripentol, for treatment of refractory seizures through the use of pharmacokinetic modeling. METHODS: A population pharmacokinetic/pharmacodynamic model was developed to characterize the combined effect of clobazam and its active metabolite, N-desmethylclobazam (i.e., N-clobazam), on seizure protection in patients with Lennox-Gastaut syndrome using data from the phase 3 CONTAIN trial. Drug-drug interactions between clobazam and cannabidiol were examined by comparing model-generated data to data from a study of 13 patients taking concomitant clobazam and cannabidiol. Modeling data were also descriptively compared with studies of patients administered both clobazam and stiripentol. Sedation-related adverse events from CONTAIN were analyzed to determine the exposure-somnolence relationship of clobazam. RESULTS: Exposure-efficacy analysis from the pharmacokinetic/pharmacodynamic model using CONTAIN data indicated that clobazam (half-maximal effective concentration [EC50], 303 ng/mL) was 3 times more potent than N-clobazam (EC50, 899 ng/mL). After administration of clobazam, when both clobazam and N-clobazam concentrations were each 1 to 2 times the EC50 value (clobazam dose, 20 mg), 70.0%-74.9% seizure protection was predicted; when concentrations were >2 times the EC50 value (clobazam dose, 40 mg), 74.0%-96.9% seizure protection was predicted. Generalized additive model analyses demonstrated decreased seizure probability with higher plasma concentration of clobazam. Coadministration of stiripentol and clobazam resulted in increased respective median plasma concentrations of clobazam and N-clobazam (1.1-1.2 times and 5.2-8.2 times) compared with administration of placebo and clobazam. Probability of somnolence significantly increased with age and higher N-clobazam plasma concentration. SIGNIFICANCE: Awareness of drug-drug interactions between clobazam and cannabidiol is needed when adding cannabidiol or stiripentol to a regimen of clobazam or vice versa. Based upon our population pharmacokinetic/pharmacodynamic model, we predict that an increase in N-clobazam levels, which patient data show may enhance efficacy and/or make adverse events such as somnolence more likely.

A Comprehensive Overview of the Clinical Pharmacokinetics of Clobazam.

Clobazam (CLB) is a 1,5-benzodiazepine that has been widely used as an anxiolytic and antiseizure drug (ASD) since it was first synthesized over 50 years ago. CLB was approved in the United States in 2011 as adjunctive therapy for seizures in patients ≥2 years old with Lennox-Gastaut syndrome. CLB pharmacokinetics (PK) have been studied in single- and multiple-dose administrations in healthy subjects. Salient features include high bioavailability, linear PK, and negligible effects from coadministration of other ASDs. CLB is highly and extensively absorbed, with little effect from food; time to maximum plasma concentration is 0.5 to 4 hours following the dose. After CLB doses of 20 to 40 mg/day, the volume of distribution is 99 to 120 L, with oral clearance ranging from 1.9 to 2.3 L/h. CLB is lipophilic and distributes throughout the body after oral administration. It is metabolized in the liver by cytochrome P450 (CYP) isoenzymes CYP3A, CYP2C19, and CYP2B6, and its main active metabolite is N-desmethylclobazam. The half-life of CLB after a single oral dose ranges from 36 to 42 hours; the half-life of N-desmethylclobazam ranges from 59 to 74 hours. The metabolites of CLB are primarily excreted renally. Population PK modeling using data from healthy subjects and patients with Lennox-Gastaut syndrome indicates that race, sex, age, weight, and renal function do not influence CLB PK. As CLB has been extensively studied since the 1970s, this review is meant to provide a consolidated and comprehensive resource on CLB PK for both prescribers and scientists alike.

A Thorough QT/QTc Study of Clobazam in Healthy Volunteers.

PURPOSE: A thorough QT study was conducted to assess the proarrhythmic potential of clobazam and its active metabolite, N-desmethylclobazam (N-CLB). METHODS: In this Phase I, single-site, randomized, double-blind, double-dummy, parallel-group study, healthy participants were randomized to 1 of 4 treatment groups: clobazam 40 mg/d (maximum therapeutic dosage), clobazam 160 mg/d (supratherapeutic dosage), placebo, or moxifloxacin 400 mg (active control). FINDINGS: Of 280 enrolled participants (n = 70 per treatment arm), 250 (92%) completed the study; 194 were included in the pharmacokinetics population (clobazam 40 mg/d, n = 66; clobazam 160 mg/d, n = 62; and moxifloxacin, n = 66). Mean changes from baseline in QT interval placebo-corrected for heart rate using the Fridericia formula (primary end point), Bazett formula, and individual correction method (QTcF, QTcB, and QTcI, respectively) with clobazam 40 and 160 mg/d revealed no effect on QTc. No clinically relevant or treatment-related arrhythmias were observed, and there were no instances of second- or third-degree atrioventricular block. Given that clobazam is primarily demethylated to N-CLB by cytochrome P450 (CYP) enzyme, CYP3A4, the mean plasma time-concentration profile of clobazam was unchanged with the exclusion of CYP2C19 poor metabolizers. As N-CLB is metabolized by CYP2C19, the exclusion of CYP2C19 poor metabolizers resulted in slightly decreased mean plasma time-concentration profiles of N-CLB. Using a linear mixed-effects model, the effects of the clobazam and N-CLB Cmax values on the placebo-corrected changes from baseline in QTcF, QTcI, and QTcB were near zero or slightly negative, and are not considered clinically important. The incidence of treatment-emergent adverse events was greatest in the clobazam groups (number of moderate AEs experienced by patients: PBO, 3/70; MOXI, 5/70; CLB 40 mg/d, 18/70; CLB 160 mg/d, 21/70; severe AEs: PBO, MOXI, & CLB 160 mg/d, 0; CLB 40 mg/d, 2/70); there were no serious AEs in any treatment group. A total of 10% of participants experienced benzodiazepine-withdrawal symptoms (16%, 23%, and 3% in the clobazam 40 and 160 mg/d groups and the moxifloxacin group, respectively). IMPLICATIONS: The findings from this thorough QT study are consistent with existing clinical data and support the lack of proarrhythmic potential with clobazam.

Intravenous carbamazepine: a new formulation of a familiar drug.

INTRODUCTION: Oral carbamazepine (CBZ), a broad-spectrum antiseizure drug (ASD) widely used for over 50 years, remains an important treatment choice for focal (partial) epilepsy. Although CBZ is a known inducer of cytochrome P450 (CYP) isoenzymes, many prescribers fail to recognize the potential issues with CBZ induction and are therefore unaware of the risk of drug toxicity upon CBZ withdrawal. Areas covered: Managing concomitant medications in CBZ-treated patients can be difficult. Abruptly stopping CBZ treatment, as may occur when patients are unable to take oral medication, can affect plasma concentrations of other medications. An intravenous (IV) formulation of CBZ has been recently approved by the US FDA for short-term replacement therapy in patients with focal and generalized seizures. Use of IV CBZ allows maintenance of stable plasma concentrations in circumstances when oral administration is temporarily impractical. Expert commentary: CBZ remains a frequently used treatment for focal seizures. With knowledge of the potential issues related to de-induction upon CBZ withdrawal, continuity of care with IV CBZ is an important step in improving the overall care of CBZ-treated patients.

Vigabatrin Lacks Proarrhythmic Potential: Results from a Thorough QT/QTc Study in Healthy Volunteers.

PURPOSE: A thorough QT study was performed to assess the proarrhythmic potential of vigabatrin, an antiepileptic drug approved in the United States for the treatment of infantile spasms and refractory complex partial seizures. METHODS: In this Phase I, randomized, double-blind, placebo- and active-controlled (moxifloxacin), 4-sequence, crossover study conducted at a single center, healthy participants received 1 of 4 randomly assigned treatments: 3.0g vigabatrin solution (therapeutic dose) and 1 moxifloxacin placebo tablet; 6.0g vigabatrin solution (supratherapeutic dose) and 1 moxifloxacin placebo tablet; 400 mg moxifloxacin and vigabatrin placebo solution; moxifloxacin placebo tablet and vigabatrin placebo solution. FINDINGS: Mean changes from baseline in placebo-corrected QTcF, QTcB, and QTcI with vigabatrin 3.0 g and 6.0 g indicated no signal for any QTc effect relative to baseline. All 1-sided upper 95% confidence intervals for the differences between each vigabatrin dose and placebo were <10 ms at all time points. QTcF was unaffected by increasing plasma vigabatrin concentrations; no arrhythmias were observed in any treatment group. Low rates of first-degree atrioventricular block, sinus tachycardia, and sinus bradycardia occurred in all treatment groups. Most adverse events were mild. IMPLICATIONS: The findings from this thorough QT study are consistent with existing clinical data and confirm a lack of proarrhythmic potential of vigabatrin.

An integrative population pharmacokinetics approach to the characterization of the effect of hepatic impairment on clobazam pharmacokinetics.

An integrative population pharmacokinetics (PPK)-based approach was used to characterize the effect of hepatic impairment on clobazam PK and its major metabolite in systemic circulation, N-desmethylclobazam (N-CLB). At therapeutic clobazam dosages, N-CLB plasma concentrations are 3-5 times greater than the parent compound. PK data from clinical trials in patients with Lennox-Gastaut syndrome (LGS; OV-1002 and OV-1012), healthy participants (OV-1016), and participants with and without renal impairment (OV-1032), as well as those from a publication describing the effects of hepatic impairment on clobazam PK, were merged to create the PPK model. Individual patient clobazam PK parameters from the publication were used to generate patient plasma-concentration data. Clobazam PK was linear and the formation of N-CLB was elimination-rate limited. Hepatic impairment did not affect the total apparent clearance of clobazam but may affect the PK of N-CLB. Because the formation of N-CLB is elimination-rate limited and the total apparent clearance of clobazam is unaffected by hepatic impairment, the PPK model suggests that patients with LGS and hepatic impairment may not require clobazam dosage modification.

Drug-metabolism mechanism: Knowledge-based population pharmacokinetic approach for characterizing clobazam drug-drug interactions.

A metabolic mechanism-based characterization of antiepileptic drug-drug interactions (DDIs) with clobazam in patients with Lennox-Gastaut syndrome (LGS) was performed using a population pharmacokinetic (PPK) approach. To characterize potential DDIs with clobazam, pharmacokinetic (PK) data from 153 patients with LGS in study OV-1012 (NCT00518713) and 18 healthy participants in bioavailability study OV-1017 were pooled. Antiepileptic drugs (AEDs) were grouped based on their effects on the cytochrome P450 (CYP) isozymes responsible for the metabolism of clobazam and its metabolite, N-desmethylclobazam (N-CLB): CYP3A inducers (phenobarbital, phenytoin, and carbamazepine), CYP2C19 inducers (valproic acid, phenobarbital, phenytoin, and carbamazepine), or CYP2C19 inhibitors (felbamate, oxcarbazepine). CYP3A4 inducers-which did not affect the oral clearance of clobazam-significantly increased the formation of N-CLB by 9.4%, while CYP2C19 inducers significantly increased the apparent elimination rate of N-CLB by 10.5%, resulting in a negligible net change in the PK of the active metabolite. CYP2C19 inhibitors did not affect N-CLB elimination. Because concomitant use of AEDs that are either CYP450 inhibitors or inducers with clobazam in the treatment of LGS patients had negligible to no effect on clobazam PK in this study, dosage adjustments may not be required for clobazam in the presence of the AEDs investigated here.

Bioequivalence of oral and intravenous carbamazepine formulations in adult patients with epilepsy.

OBJECTIVE: To evaluate the safety, tolerability, and comparative pharmacokinetics (PK) of intravenous and oral carbamazepine. METHODS: In this phase 1, open-label study, adult patients with epilepsy on a stable oral carbamazepine dosage (400-2,000 mg/day) were converted to intravenous carbamazepine (administered at 70% of the oral dosage). A 28-day outpatient period preceded an up to 10-day inpatient period and a 30-day follow-up period. Intravenous carbamazepine was administered over 15 or 30 min every 6 h on days 1-7; some patients in the 15-min group were eligible to receive four 2- to 5-min (rapid) infusions on day 8. Patients underwent blood sampling to determine the area under the concentration-time curve (AUC) for carbamazepine and metabolite carbamazepine-10,11-epoxide following oral (day 0) and intravenous carbamazepine administration (days 1, 7, and 8). Bioequivalence was evaluated in patients with normal renal function (creatinine clearance >80 ml/min). Safety assessments were conducted through day 38. RESULTS: Ninety-eight patients enrolled and 77 completed the PK component. The mean daily oral and intravenous carbamazepine dosage for 64 PK-evaluable patients with normal renal function was 962.5 and 675.1 mg (70% of oral dosage), respectively. Steady-state minimum concentration (C(min)) and overall exposure (AUC0-24) for intravenous carbamazepine infused over 30, 15, or 2-5 min were similar to oral carbamazepine. The 90% confidence intervals (CIs) for the ratios of the adjusted means for AUC0-24, maximum concentration (Cmax), and C(min) were within the 80%-125% bioequivalence range for 30-min intravenous infusions versus oral administration, but exceeded the upper limit for Cmax for the 15-min and rapid infusions. All intravenous carbamazepine infusions were well tolerated. SIGNIFICANCE: Intravenous carbamazepine infusions (70% of oral daily dose) of 30-, 15-, and 2- to 5-min duration, given every 6 h, maintained patients' plasma carbamazepine concentrations. Intravenous carbamazepine 30-min infusions were bioequivalent to oral carbamazepine in patients with normal renal function; rapid infusions were well-tolerated in this study.

Intravenous carbamazepine as short-term replacement therapy for oral carbamazepine in adults with epilepsy: Pooled tolerability results from two open-label trials.

OBJECTIVE: To report tolerability findings and maintenance of seizure control from a pooled analysis of phase I open-label trial OV-1015 (NCT01079351) and phase III study 13181A (NCT01128959). METHODS: Patients receiving a stable oral dosage of carbamazepine were switched to an intravenous (IV) carbamazepine formulation solubilized in a cyclodextrin matrix (at a 70% dosage conversion) for either a 15- or a 30-min infusion every 6 h for up to 7 days and then switched back. A subset of patients who tolerated 15-min infusions also received 2- to 5-min (rapid) infusions. Assessments included physical and laboratory evaluations, electrocardiography (ECG) studies, as well as adverse event (AE) monitoring for tolerability. Convulsion/seizure AE terms and data from seizure diaries were used as proxies for the assessment of consistency of seizure control between formulations. RESULTS: Of the 203 patients exposed to IV carbamazepine (30 min, n = 43; 15 min, n = 160), 113 received 149 rapid infusions. During infusion, the most commonly reported AEs (≥ 5%) were dizziness (19%), somnolence (6%), headache (6%), and blurred vision (5%). IV carbamazepine was not associated with clinically relevant cardiac AEs. The tolerability profile appeared similar between patients who received <1,600 mg/day (n = 174) and ≥ 1,600 mg/day (n = 29) carbamazepine. Cyclodextrin exposure was not associated with clinically relevant changes in AEs or renal biomarkers. Seizure control was maintained as patients transitioned between oral and IV carbamazepine. SIGNIFICANCE: IV carbamazepine administered as multiple 30- or 15-min infusions every 6 h, and as a single rapid infusion, was well tolerated as a short-term replacement in adults with epilepsy receiving stable dosages of oral carbamazepine. Infusion site reactions, which were generally mild, were the only unique AEs identified; seizure control was generally unchanged when patients were switching between formulations.

Population dose-response analysis of daily seizure count following vigabatrin therapy in adult and pediatric patients with refractory complex partial seizures.

Vigabatrin is an irreversible inhibitor of γ-aminobutyric acid transaminase (GABA-T) and is used as an adjunctive therapy for adult patients with refractory complex partial seizures (rCPS). The purpose of this investigation was to describe the relationship between vigabatrin dosage and daily seizure rate for adults and children with rCPS and identify relevant covariates that might impact seizure frequency. This population dose-response analysis used seizure-count data from three pediatric and two adult randomized controlled studies of rCPS patients. A negative binomial distribution model adequately described daily seizure data. Mean seizure rate decreased with time after first dose and was described using an asymptotic model. Vigabatrin drug effects were best characterized by a quadratic model using normalized dosage as the exposure metric. Normalized dosage was an estimated parameter that allowed for individualized changes in vigabatrin exposure based on body weight. Baseline seizure rate increased with decreasing age, but age had no impact on vigabatrin drug effects after dosage was normalized for body weight differences. Posterior predictive checks indicated the final model was capable of simulating data consistent with observed daily seizure counts. Total normalized vigabatrin dosages of 1, 3, and 6 g/day were predicted to reduce seizure rates 23.2%, 45.6%, and 48.5%, respectively.

Vigabatrin pediatric dosing information for refractory complex partial seizures: results from a population dose-response analysis.

We predicted vigabatrin dosages for adjunctive therapy for pediatric patients with refractory complex partial seizures (rCPS) that would produce efficacy comparable to that observed for approved adult dosages. A dose-response model related seizure-count data to vigabatrin dosage to identify dosages for pediatric rCPS patients. Seizure-count data were obtained from three pediatric and two adult rCPS clinical trials. Dosages were predicted for oral solution and tablet formulations. Predicted oral solution dosages to achieve efficacy comparable to that of a 1 g/day adult dosage were 350 and 450 mg/day for patients with body weight ranges 10-15 and >15-20 kg, respectively. Predicted oral solution dosages for efficacy comparable to a 3 g/day adult dosage were 1,050 and 1,300 mg/day for weight ranges 10-15 and >15-20 kg, respectively. Predicted tablet dosage for efficacy comparable to a 1 g/day adult dosage was 500 mg/day for weight ranges 25-60 kg. Predicted tablet dosage for efficacy comparable to a 3 g/day adult dosage was 2,000 mg for weight ranges 25-60 kg. Vigabatrin dosages were identified for pediatric rCPS patients with body weights ≥10 kg.

Population pharmacokinetics analysis of vigabatrin in adults and children with epilepsy and children with infantile spasms.

BACKGROUND AND OBJECTIVES: Vigabatrin is an inhibitor of γ-aminobutyric acid transaminase. The purpose of these analyses was to develop a population pharmacokinetics model to characterize the vigabatrin concentration-time profile for adults and children with refractory complex partial seizures (rCPS) and for children with infantile spasms (IS); to identify covariates that affect its disposition, and to enable predictions of systemic vigabatrin exposure for patients 1-12 months of age. METHODS: Vigabatrin pharmacokinetic data from six randomized controlled clinical trials and one open-label study were analyzed using nonlinear mixed-effects modeling. Data collected from 349 adults with rCPS and 119 pediatric patients with rCPS or IS were used in the analyses. RESULTS: A two-compartment model with first-order elimination and transit-compartment absorption consisting of five transit compartments adequately described the vigabatrin concentration-time data for these adult and pediatric patient populations. An exponential error model was used to estimate inter-individual variability for the transit-rate constant (k tr) (24.2 %), elimination rate constant (k) (14.7 %) and apparent central volume of distribution (V c/F) (18 %). For the study of children with IS, inter-occasion variability was estimated for k tr (58.1 %) and relative bioavailability (F) (26.9 %). Covariate analysis indicated that age, creatinine clearance (CLCR), and body weight were important predictors of vigabatrin pharmacokinetic parameters. Vigabatrin apparent clearance increased with increasing CLCR, consistent with renal excretion (primary pathway of vigabatrin elimination). Rate of vigabatrin absorption was dependent on age. The rate was slower in younger patients, which resulted in a smaller predicted maximum concentration and longer predicted time to maximum concentrations. Vigabatrin V c/F, apparent inter-compartmental clearance between the central and peripheral compartment, and apparent peripheral volume of distribution were increased with greater patient body weights. Sex did not contribute significantly to vigabatrin pharmacokinetic variability. CONCLUSION: The model adequately described vigabatrin pharmacokinetic and enabled predictions of systemic exposures in pediatric patients 1-12 months of age.

Withdrawal-related adverse events from clinical trials of clobazam in Lennox-Gastaut syndrome.

To assess withdrawal-related adverse event (AE) rates following abrupt clobazam discontinuation in Phase I trials and gradual clobazam tapering (2-3 weeks) following discontinuation from III trials met the criteria for potential/III trials, we evaluated AE data from four multiple-dosage Phase I trials (duration: 8-34 days). Therapeutic (20 and 40 mg/day) and supratherapeutic clobazam dosages (120 and 160 mg/day) were administered. Adverse events (AEs) were also assessed for patients with Lennox-Gastaut syndrome enrolled in Phase II (OV-1002) and Phase III (OV-1012) studies (duration ≤15 weeks) and in the open-label extension (OLE) trial OV-1004 (≤5 years). Potential withdrawal-related AEs were identified by preferred terms, provided that the AEs occurred ≥1 day following and ≤30 days after the last clobazam doses, or were deemed withdrawal symptoms by investigators. Clinical Institute Withdrawal Assessment for Benzodiazepines (CIWA-B) scale was used to evaluate withdrawal intensity in three of the four Phase I trials. A total of 207 participants in Phase I trials received steady-state clobazam dosages of 20-160 mg/day, 182 received clobazam dosages of ≥40 mg/day, and 94 received clobazam dosages of ≥120 mg/day. Abrupt clobazam discontinuation led to 193 withdrawal-related AEs for 68 Phase I participants. Nearly 50% of AEs occurred after discontinuation of clobazam dosages of ≥120 mg/day. Adverse events were mild or moderate and included headache (14% of Phase I participants), insomnia (12.6%), tremor (10.1%), and anxiety (8.7%). The CIWA-B scores varied (range: 0-59). Most scores were <30, indicating possible mild benzodiazepine withdrawal. III trials met the criteria for potential/III patients received clobazam dosages of ≤40 mg/day, and those in the OLE trial received clobazam dosages of ≤80 mg/day. Eighty-seven patients discontinued clobazam and were gradually tapered. No withdrawal-related AEs or incidences of status epilepticus were reported. Withdrawal-related AEs observed in Phase I studies following abrupt clobazam discontinuation at therapeutic and supratherapeutic dosages were generally mild. No withdrawal-related AEs occurred when dosages were tapered over 3 weeks, after short- or long-term clobazam use (≤5 years).

Pharmacokinetic drug interactions between clobazam and drugs metabolized by cytochrome P450 isoenzymes.

STUDY OBJECTIVE: To investigate potential drug-drug interactions between clobazam and cytochrome P450 (CYP) isoenzyme substrates, inhibitors, and inducers. DESIGN: Two, prospective, open-label, single-center, drug-drug interaction (DDI) studies and a population pharmacokinetics analysis of seven multicenter phase II-III trials. SETTING: Clinical research unit. PARTICIPANTS: Fifty-four healthy adult volunteers were enrolled in the two drug-drug interaction studies; 53 completed the studies. The population pharmacokinetics analysis evaluated data from 171 participants from five studies with healthy volunteers and two studies with patients with Lennox-Gastaut syndrome. Participants in these studies received clobazam and stable dosages of the following antiepileptic drugs: phenobarbital, phenytoin, carbamazepine, valproic acid, lamotrigine, felbamate, or oxcarbazepine. INTERVENTION: In the first drug-drug interaction study, 36 participants received a single oral dose of clobazam 10 mg on day 1, followed by either ketoconazole 400 mg once/day or omeprazole 40 mg once/day on days 17-22, with a single dose of clobazam 10 mg coadministered on day 22, to study the effects of CYP3A4 or CYP2C19 inhibition, respectively, on clobazam and its active metabolite N-desmethylclobazam (N-CLB). In the second study, 18 participants received a drug cocktail consisting of caffeine 200 mg, tolbutamide 500 mg, dextromethorphan 30 mg, and midazolam 4 mg on days 1 and 19, and clobazam 40 mg/day on days 4-19, to study clobazam's effects on CYP1A2, CYP2C9, CYP2D6, and CYP3A4. MEASUREMENTS AND MAIN RESULTS: In the first DDI study, coadministration of ketoconazole (a CYP3A4 inhibitor) and clobazam increased clobazam's area under the concentration time curve from time zero extrapolated to infinity (AUC(0-∞) ) 54% and decreased clobazam's maximum plasma concentration (C(max) ) by 15% versus administration of clobazam alone, but the combination affected these pharmacokinetic parameters for N-CLB to a lesser degree. The CYP2C19 inhibitor omeprazole increased AUC(0-∞) and C(max) of N-CLB by 36% and 15%, respectively, but did not significantly affect the pharmacokinetics of clobazam. At steady state, N-CLB has 3-4 times greater exposure than clobazam. In the second DDI study, no clinically significant drug-drug interactions were observed between clobazam 40 mg and the CYP probe substrates caffeine or tolbutamide. Exposure to midazolam and its 1-hydroxymidazolam metabolite, however, decreased by 27% and increased 4-fold, respectively. Clobazam increased dextromethorphan (CYP2D6) AUC(0-∞) by 95% and C(max) by 59%. In the population pharmacokinetics analysis, stable dosages of common antiepileptic drugs that induce CYP3A4 or CYP2C19, or inhibit CYP2C19, had negligible effects on clobazam or N-CLB. Clobazam did not affect valproic acid or lamotrigine exposures. CONCLUSION: These findings suggest no clinically meaningful drug-drug interactions between clobazam and drugs metabolized by CYP3A4, CYP2C19, CYP1A2, or CYP2C9. Concomitant use of drugs metabolized by CYP2D6 may require dosage adjustment. Clobazam may be administered safely as adjunctive therapy in patients with Lennox-Gastaut syndrome, without meaningful changes in clobazam pharmacokinetics that would require dosage adjustment.

Oral toxicity of vigabatrin in immature rats: characterization of intramyelinic edema.

OBJECTIVES: Two toxicologic studies of vigabatrin were conducted with immature Sprague Dawley rats to characterize intramyelinic edema (IME) formation and assess potential impact on behavioral measures. Study 1 was a dosage-ranging characterization of overall toxicity of vigabatrin in young, developing rats. Study 2 evaluated vacuolar brain lesions found in Study 1. METHODS: During Study 1, immature Sprague Dawley rats were orally administered deionized water (vehicle control), or vigabatrin at 5, 15, or 50mg/kg/day for ≤ 9 weeks, beginning at postnatal day 4 (PND 4) and followed by a recovery period. Toxicologic observations were collected, including adverse clinical signs, body weight gains, food consumption, ophthalmoloscopy, electroretinograms, sexual maturation, motor activity, memory, and learning behaviors. At sacrifice, CNS tissues were examined by light microscopy for evidence of IME. In Study 2, immature Sprague Dawley rats were again orally administered vigabatrin (50mg/kg/day for ≤ 9 weeks, beginning at PND 4). At sacrifice, CNS tissues were examined by both light and transmission electron microscopy for evidence of IME. RESULTS: At 5-50mg/kg/day, dosage-related reduced food consumption, decreased body weight, and delayed sexual maturation were found. Persisting through recovery, effects were more pronounced in males. Increased degrees of vacuolation were observed on PND 67 only after a dosage of 50mg/kg/day, and were attenuated during recovery. Vacuolar-change morphology was characteristic of IME, with no evidence of cellular or neuritic degeneration. Ultrastructural analyses revealed brain vacuoles initiated as splits of myelin sheaths along intra-period lines. These splits expanded, evolving into large membrane-rich vacuoles, and were more prominent at later stages of myelin development. Hypomyelination and gliopathy were noted from PNDs 4-15, and were likely related to vigabatrin exposure during active myelination. A lesser degree of hypomyelination was observed from PNDs 4-46 and 4-65. Vacuolation was markedly attenuated in post-recovery-period rats. CONCLUSIONS: The present studies indicated toxicities in young rats at vigabatrin dosages lower than those reported for toxicities in older rats. Dosages <50mg/kg/day did not affect CNS, behavior, and reproductive development. However, at the greatest dosage, some retardation of physical growth, delay in sexual maturation, reduction in physical strength, and induction of CNS stimulation (handling-induced spasms) occurred. The key pathologic finding was vacuolar brain lesions in the white and gray matter, which generally reversed upon drug discontinuation. Vacuoles were confined to myelin sheaths, consistent with observations in adult rats. Vigabatrin delayed but did not eliminate myelination despite continued dosing, an effect greatest during active myelination.

Effect of the rate of niacin administration on the plasma and urine pharmacokinetics of niacin and its metabolites.

The metabolic profile of niacin is influenced by the rate of niacin administration. This study characterizes the effect of administration rate on the pharmacokinetics of niacin and its metabolites. Twelve healthy males were enrolled in an open-label, dose-rate escalation study and received 2000 mg niacin at 3 different dosing rates. Plasma was analyzed for niacin, nicotinuric acid, nicotinamide, and nicotinamide-N-oxide. Urine was analyzed for niacin and the metabolites nicotinuric acid, nicotinamide, nicotinamide-N-oxide, N-methylnicotinamide, and N-methyl-2-pyridone-5-carboxamide. C(max) and AUC(0-t) for niacin and nicotinuric acid increased with an increase in dosing rate. The changes observed in plasma nicotinamide and nicotinamide-N-oxide parameters, however, did not correlate to dosing rate. The total amount of niacin and metabolites excreted in urine was comparable for all 3 treatments. However, with the increase in dosing rate, urine recovery of niacin and nicotinuric acid showed a significant increase, whereas N-methyl-2-pyridone-5-carboxamide and N-methylnicotinamide showed a significant decrease.

Disposition kinetics and tolerance of escalating single doses of ramelteon, a high-affinity MT1 and MT2 melatonin receptor agonist indicated for treatment of insomnia.

Ramelteon is a selective MT(1)/MT(2) receptor agonist, indicated for insomnia treatment. Safety, tolerance, pharmacokinetics, and cognitive performance were evaluated following increasing ramelteon doses. Healthy adults (35-65 years) were randomly assigned to receive 1 of 5 oral ramelteon doses (4, 8, 16, 32, or 64 mg; n = 8 per group) or placebo (n = 20). C(max) and AUC(infinity) (mean [%CV]) increased with each dose: C(max) = 1.15 (109), 5.73 (97), 6.92 (77), 17.4 (76), and 25.9 (77) ng/mL, respectively, and AUC(infinity) = 1.71 (114), 6.95 (108), 9.88 (78), 22.5 (80), and 36.1 (71 n x h/mL), respectively. Mean T(max) values of 0.75 to 0.94 hours and mean elimination half-life of 0.83 to 1.90 hours remained relatively constant. Ramelteon was extensively metabolized. Besides ramelteon, 4 metabolites, M-I, M-II, M-III, and M-IV, were measured in serum. Metabolite M-II, which has shown weak ramelteon-like activity in vitro, was the major metabolite in serum. Digit Symbol Substitution Test and visual analog scale alertness scores were similar across all dose groups and did not differ from placebo. All adverse events were mild or moderate and resolved before study completion.

Pharmacokinetics of eplerenone after single and multiple dosing in subjects with and without renal impairment.

The influence of renal impairment on the pharmacokinetics of eplerenone following single and multiple dosing was evaluated. Subjects (n = 64) were stratified based on creatinine clearance values as follows: renal impairment (mild, moderate, severe), hemodialysis, and normal matches. Subjects received a single dose of eplerenone 100 mg on day 1 and then received 100 mg once daily on days 3 to 8. There were no statistically significant differences between any of the renal impairment groups and their matched-normal groups for area under the curve (AUC), C(max), or CL/F or CL/F/WT following either single or multiple dosing (P > or = .093). The inactive metabolite and inactive ring-opened form displayed greater AUCs in renal impairment. Hemodialysis removed approximately 10% of the eplerenone dose. Eplerenone 100 mg once daily was well tolerated in all groups. Considering that renal function had no significant effects on eplerenone CL/F and that eplerenone metabolites are inactive, no dose adjustment appears necessary in patients with renal dysfunction.

Safety and pharmacokinetic profile of multiple escalating doses of (+)-calanolide A, a naturally occurring nonnucleoside reverse transcriptase inhibitor, in healthy HIV-negative volunteers.

BACKGROUND: (+)-Calanolide A is a naturally occurring nonnucleoside reverse transciptase inhibitor (NNRTI) that exhibits enhanced activity against HIV-1 isolates with the Y181C mutation and retains activity against HIV-1 isolates with dual Y181C and K103N mutations. Previous studies have demonstrated that (+)-calanolide A has a favorable safety profile in both animal and human subjects. METHOD: In this study, the safety and pharmacokinetics of multiple escalating doses of (+)-calanolide A were evaluated in a total of 47 healthy, HIV-seronegative individuals. RESULTS: All adverse events seen in the study were mild to moderate in intensity and were transient. The most common adverse events seen were headache, dizziness, nausea, and taste perversion (oily aftertaste). Laboratory abnormalities were determined to be clinically insignificant or unrelated to (+)-calanolide A administration. No dose-related pattern in adverse event or laboratory abnormality incidence was apparent. In all cohorts examined, administration of (+)-calanolide A produced highly variable plasma levels and absorption profiles. No accumulation of parent compound was seen over the 5-day treatment course, with the day 5 area under the curve (AUC) being approximately one half of that seen on the first day of dosing. Steady-state trough plasma levels were determined in the two highest dose cohorts (600 mg and 800 mg bid for 5 days). Mean elimination half-life in the two highest dosing cohorts combined was 15.5 hours in men and 35.2 hours in women. CONCLUSION: These pharmacokinetic properties, together with the benign safety profile, and unique in vitro resistance pattern warrant the continued development of this potential new antiviral agent.