Debra J. Tompson

Lamotrigine does not prolong QTc in a thorough QT/QTc study in healthy subjects

AIM To characterize the effects of lamotrigine on QT interval in healthy subjects. METHODS Healthy subjects received a single oral dose of moxifloxacin (400 mg) or placebo in crossover design, followed by a dose-escalating regimen of lamotrigine (n = 76) over a 77-day period, or matched placebo (n = 76). Blood samples were taken for determination of moxifloxacin and lamotrigine concentrations and digital 12-lead ECGs were recorded. The relationships between individual QT values and respective individual moxifloxacin or lamotrigine concentrations were explored using population pharmacokinetic-pharmacodynamic (PK-PD) modelling. RESULTS Moxifloxacin was associated with a maximum mean increase from baseline in QTcF of 14.81 ms [90% confidence interval (CI) 13.50, 16.11] 2.5 h after dosing. Steady-state exposure to lamotrigine (50, 150 or 200 mg b.d.) was not associated with an increase in QTc interval. Small reductions in QTcF (maximum mean difference from placebo -7.48 ms, 90% CI -10.49, -4.46) and small increases in heart rate (maximum mean difference from placebo 5.94 bpm, 90% CI 3.81, 8.06) were observed with lamotrigine 200 mg b.d. vs. placebo. No effect of lamotrigine on QRS duration or blood pressure was observed. No outliers with QTcF > 450 ms, or with an increase from baseline of >60 ms were observed in the lamotrigine group. PK-PD modelling indicated statistically significant decreases in individually corrected QT intervals for lamotrigine and statistically significant increases in individually corrected QT intervals for moxifloxacin over the concentration ranges studied. CONCLUSIONS Therapeutic doses of lamotrigine (50-200 mg b.d.) were not associated with QT prolongation in healthy subjects.

Steady-state pharmacokinetic properties of a 24-hour prolonged-release formulation of ropinirole: Results of two randomized studies in patients with Parkinson's disease

BACKGROUND Ropinirole 24-hour prolonged release is a new once-daily formulation of ropinirole that provides continuous delivery of ropinirole over 24 hours. OBJECTIVE The studies described here were conducted to characterize the steady-state pharmacokinetics of ropinirole 24-hour prolonged release in patients with Parkinsons disease. METHODS Study 164 was a 2-part study; Part A employed a crossover design to assess the relative bioavailability of steady-state ropinirole 24-hour prolonged release 8 mg QD and ropinirole immediate release 2.5 mg TID, and Part B evaluated the effect of food intake on the rate and extent of ropinirole absorption from ropinirole 24-hour prolonged release 8 mg QD. Study 165 assessed the dose proportionality of ropinirole 24-hour prolonged release 2-, 4-, and 8-mg tablets and the dose-strength equivalence of four 2-mg tablets compared with one 8-mg tablet. Intensive pharmacokinetic blood sampling was performed over 24 hours. Steady-state C(max), C(min), AUC from time zero to 24 hours after dosing (AUC(0-24)), and T(max) were determined by noncompartmental methods. RESULTS Twenty-three patients (91% white; mean age, 67 years [range, 34-80 years] mean weight, 84.5 kg [range, 57-103 kg]) were randomized to treatment in Study 164. Twenty-eight patients (86% white; mean age, 67 years [range, 47-87 years] mean weight, 84.6 kg [range, 49-128 kg]) were randomized to treatment in Study 165. Compared with ropinirole immediate release, ropinirole 24-hour prolonged release had a smooth plasma concentration-time profile over 24 hours. AUC(0-24) and C(min) values, normalized to a 1-mg dose, were similar for ropinirole 24-hour prolonged release and ropinirole immediate release. Dose-normalized C(max) was slightly lower (approximately 12%) for ropinirole 24-hour prolonged release than for ropinirole immediate release. The AUC(0-24) and C(min) were similar in the fed and fasted states. The pharmacokinetics of ropinirole 24-hour prolonged release were dose proportional, as indicated by the estimated slopes for AUC(0-24) and C(max) being close to unity, along with the 90% CIs being contained within the predefined dose-range-adjusted limits. For C(min), the slope was close to unity (1.04), but the upper end of the 90% CI fell marginally outside the predefined range. Statistical analysis indicated that the dose strengths were equivalent when a single pharmacokinetic outlier was excluded from the analysis. CONCLUSIONS Ropinirole 24-hour prolonged release provided continuous delivery of ropinirole over 24 hours, resulting in a smooth plasma concentration-time profile, and food had no significant effect on absorption. Dose-normalized AUC(0-24) and C(min) were similar for both formulations, and dose-normalized C(max) was slightly lower for ropinirole 24-hour prolonged release. These relative bioavailability data indicated that patients may switch overnight from ropinirole immediate release to ropinirole 24-hour prolonged release while maintaining similar daily exposure. The pharmacokinetics of ropinirole were dose proportional over the range from 2 to 8 mg. The dose strengths of four 2-mg tablets and one 8-mg tablet of ropinirole 24-hour prolonged release were found to be equivalent.

Steady-state pharmacokinetics of lamotrigine when converting from a twice-daily immediate-release to a once-daily extended-release formulation in subjects with epilepsy (The COMPASS Study).

Purpose: To compare the pharmacokinetics (PK) of lamotrigine (LTG) when converting from twice‐daily immediate‐release (LTG‐IR) to once‐daily extended‐release (LTG‐XR) in subjects with epilepsy.

Pharmacokinetic and pharmacodynamic comparison of ropinirole 24-hour prolonged release and ropinirole immediate release in patients with Parkinson's disease.

Objectives:To explore the pharmacokinetic-pharmacodynamic relationship between systemic exposure to ropinirole and the primary efficacy end points from two phase 3 studies. Methods:Efficacy and Safety Evaluation in Parkinsons Disease (EASE-PD) Monotherapy (101468/168) compared ropinirole 24-hour prolonged release with ropinirole immediate release in patients with early Parkinsons disease (PD). Efficacy and Safety Evaluation in Parkinsons Disease Adjunct (101468/169) compared ropinirole 24-hour prolonged release or placebo in patients with advanced PD not optimally controlled with l-dopa. Sparse blood samples were collected for pharmacokinetic evaluations through population analysis. The relationship between ropinirole systemic exposure [steady-state area under the curve between time zero and 24 hours after dose, AUC(0-24,ss)] and change from baseline in Unified Parkinsons Disease Rating Scale (UPDRS) total motor score, and awake time spent off was investigated. Results:In EASE-PD Monotherapy, the relationship between the decrease in UPDRS motor score and AUC(0-24,ss) was similar for both formulations, with a 60% to 80% probability of response for the exposure range studied. In patients with early PD, similar clinical benefit was achieved at AUC(0-24,ss) values associated with doses of 8 to 12 mg and higher doses (up to 24 mg). In EASE-PD Adjunct, the predicted probability of an off-time response for a patient on placebo was approximately 0.4, increasing to a near total probability of response rate (approximately 0.9) at higher systemic exposures of ropinirole 24-hour prolonged release. Conclusions:Characterization of the exposure-response relationship has identified that a dose range of 8 to 12 mg provides clinical benefit for the improvement in UPDRS total motor score in patients with early PD. Similarly, pharmacokinetic-pharmacodynamic analysis showed that, in patients with advanced PD, the probability of response increased with increasing exposures to ropinirole, indicating that doses more than 8 to 12 mg may lead to an improved benefit in parallel with reductions in l-dopa dose.

Clinical pharmacokinetics of retigabine/ezogabine.

BACKGROUND Retigabine is an antiepileptic drug that reduces neuronal excitability by enhancing potassium channel activity. METHODS This manuscript summarizes the pharmacokinetic and biopharmaceutical properties of retigabine collated from published and unpublished in vitro and clinical phase I-III studies in healthy volunteers or patients with partial-onset seizures. RESULTS Retigabine is rapidly absorbed with a median time to C(max) of 0.5-2.0 hours. Thereafter, plasma concentrations decline in a mono-exponential manner, with a median half-life of 6-8 hours. The absolute oral bioavailability of retigabine is ~60%. Retigabine is metabolized extensively by N-acetylation and subsequent N-glucuronidation. In vitro and in vivo studies have shown that the drug-interaction potential of retigabine is low. The pharmacokinetics of retigabine are linear over the dose range 200-400mg three times daily (tid), with ~ 35-50% between-subject variability. Systemic exposure was not affected by a high fat meal, but C(max) was, ~14% and ~38% higher in the fed versus fasted state for the 200 and 400mg tablets, respectively. Retigabine drug-related material is primarily eliminated renally with unchanged retigabine accounting for ~36%. Retigabine plasma clearance decreased as severity of renal or hepatic impairment increased. Systemic exposure to retigabine is unaffected by gender when normalized for body weight. In elderly patients, retigabine systemic exposure was higher, and half-life was longer than in younger patients. CONCLUSIONS Retigabine should be administered tid without regard to food. No adjustments required for gender, race, or genetic/polymorphisms. Dosage adjustments are recommended in elderly patients and those with moderate and severe renal or moderate hepatic impairment.

The effects of ethanol on the pharmacokinetics, pharmacodynamics, safety, and tolerability of ezogabine (retigabine).

BACKGROUND The antiepileptic drug ezogabine (EZG; US adopted name for retigabine [the international nonproprietary name]) reduces neuronal excitability by enhancing potassium channel activity. EZG has been approved as adjunctive treatment for adults with partial-onset seizures. OBJECTIVE The goal of this study was to examine the impact of coadministration of ethanol 1 g/kg on the safety and tolerability of EZG and the consequences of coadministration on pharmacokinetic (PK) and pharmacodynamic (PD) parameters in healthy volunteers. METHODS In a randomized, 4-way crossover, partially double-blind study, volunteers received 4 oral treatments (EZG 200 mg + ethanol placebo [light apple juice]; placebo + ethanol 1 g/kg; EZG 200 mg + ethanol 1 g/kg; or placebo + ethanol placebo) separated by 5 to 21 days. RESULTS PK and PD parameters were evaluated in 17 healthy volunteers (19 to 55 years) who were currently moderate alcohol drinkers. Ethanol coadministration increased EZG AUC(0-∞) and C(max) by 36% and 23%, respectively. EZG had no impact on ethanol PK. Ethanol alone impaired balance, blurred vision, and increased intoxication and dizziness. Objective tests (reaction times, response accuracy, attention, and manual tracking) were also impaired by ethanol. EZG treatment alone had no impact on PD measures other than a variable, transient increase in blurred vision (vision clear-crisp visual analog scale scores). Treatments were generally tolerated, with no serious adverse events or discontinuations owing to adverse events. CONCLUSIONS Ethanol increased EZG exposure, which did not seem to be clinically relevant. Except for an increase in blurred vision, impairment effects observed were related primarily to ethanol and were not exacerbated by the addition of EZG, which was generally tolerated with or without ethanol.

The interaction potential of retigabine (ezogabine) with other antiepileptic drugs.

BACKGROUND Retigabine is an antiepileptic drug (AED) that reduces neuronal excitability by enhancing neuronal KCNQ (Kv7) potassium channel activity. METHODS This manuscript provides an overview of the drug-drug interaction potential of retigabine with other AEDs, using data collated from both in vitro work and clinical studies, either previously published or from relevant information collated during the development of retigabine. RESULTS Retigabine is not a substrate for the major CYP enzymes and at clinically relevant concentrations there is little or no potential for retigabine to inhibit or induce the CYP enzymes or to inhibit the major renal drug transporters. The addition of retigabine to a range of existing AEDs showed little or no effect on the AED trough concentrations apart from a 20% decrease in lamotrigine concentrations. Results from a small phase II study showed that co-administration of valproic acid and topiramate had no impact on the PK of retigabine whereas carbamazepine and phenytoin increased the clearance of retigabine by approximately 27% and 36%, respectively. Conversely, a population PK analysis of combined data from phase I, II and III studies showed that none of the coadministered AEDs affected retigabine clearance apart from lamotrigine which lowered retigabine clearance by 6.7%. CONCLUSION Retigabine is not metabolized by CYP isozymes and does not induce or inhibit these isozymes at clinically relevant concentrations. Therefore, retigabine is associated with a low potential for PK interactions with other drugs via CYP450. Overall, there was little or no potential for retigabine to interact with other available AEDs. Although some PK interactions were observed with lamotrigine, these are unlikely to be clinically relevant.

Efficacy and Tolerability Exposure–Response Relationship of Retigabine (Ezogabine) Immediate-Release Tablets in Patients With Partial-Onset Seizures

BACKGROUND Retigabine (international nonproprietary name)/ezogabine (United States adopted name) is an antiepileptic drug (AED) that enhances KCNQ (Kv7) potassium channel activity. OBJECTIVES The aim of this study was to explore the relationship between retigabine/ezogabine systemic exposure and efficacy and adverse events (AEs) of retigabine/ezogabine from Phase III clinical trials. METHODS Data were combined from Studies 301 and 302, which were both randomized, double-blind, placebo-controlled, multicenter, parallel-group studies with similar inclusion and exclusion criteria. All patients had partial-onset seizures and were receiving 1 to 3 concomitant AEDs. Systemic exposure was predicted for each patient as the average steady-state AUC0-τ during the 12-week maintenance phase, based on a population pharmacokinetic model developed for retigabine/ezogabine. Efficacy end points included reduction in total partial-seizure frequency from baseline and probability of ≥50% reduction from baseline in seizure frequency. The probabilities of occurrence of 6 AEs were also evaluated. RESULTS AUC0-τ values increased linearly over the 600- to 1200-mg/d dose range. Over the entire AUC0-τ range, the probability of efficacy was greater than that for any AE. The slopes of the exposure-response relationship for probability of dizziness and abnormal coordination were similar to that for efficacy, whereas the slopes for dysarthria, somnolence, tremor, and blurred vision were shallower, indicating that the probability of these events occurring was less affected than the probability of efficacy by increases in retigabine/ezogabine AUC0-τ. CONCLUSIONS Based on the summary statistics of pharmacokinetic parameters, systemic exposure to retigabine/ezogabine increased linearly with dose (600-1200 mg/d). Population pharmacokinetics and pharmacodynamics showed that the probability of efficacy and AEs increased with increasing systemic retigabine/ezogabine exposure, and the probability of efficacy was higher than the probability of any of the AEs. The 35%-50% between-patient variability and overlap between retigabine/ezogabine dose levels in AUC0-τ values indicate that, as with other AEDs, doses should be individually titrated based on a balance between efficacy and tolerability.

Effect of hemodialysis on pharmacokinetics of ezogabine/retigabine and its N-acetyl metabolite in patients with end stage renal disease.

Ezogabine (EZG)/retigabine (RTG) and its metabolites are mainly eliminated renally. This Phase I study assessed the effect of hemodialysis on the pharmacokinetics of EZG/RTG and its N-acetyl metabolite (NAMR) in patients with end-stage renal disease; tolerability of EZG/RTG was a secondary endpoint. Patients (N=8) received EZG/RTG 100 mg orally 4 hours before (Period 1) or following (Period 2) dialysis. Blood (both periods) and dialysate (Period 1) samples were taken up to 68 hours post dose. Tolerability was assessed throughout both periods. The area under the concentration- time curve (0-68 hours) for EZG/RTG was 33% lower (geometric mean ratio [90% confidence interval]: 0.67 [0.61, 0.73]) on dialysis versus off dialysis and 43% lower for NAMR (0.57 [0.53, 0.62]). Median (range) reductions in plasma concentrations from dialysis start to end were 52% (17-59%) for EZG/RTG and 51% (27-72%) for NAMR. EZG/RTG 100 mg was generally tolerated.

The effect of ezogabine on the pharmacokinetics of an oral contraceptive agent.

OBJECTIVES Ezogabine (EZG) is a potassium-channel opener that has been approved as adjunctive treatment for partial-onset seizures in adults with epilepsy. This Phase I clinical study evaluated the pharmacokinetics (PK), safety, and tolerability of coadministration of EZG and a combined oral contraceptive (OC). METHODS An open-label drug-interaction study was conducted in healthy, female volunteers aged 18 - 55 years with regular menstrual cycles. The effects of steady-state 750 mg EZG on the PK of a combined OC agent containing 1 mg norethindrone and 0.035 mg ethinyl estradiol were evaluated, along with the effect of the contraceptive hormones on EZG PK. Safety was evaluated by clinical laboratory, vital sign, electrocardiogram, physical examination, and adverse event (AE) assessments. RESULTS Of 30 enrolled volunteers, 25 completed all treatments. OC did not affect the PK of EZG. EZG increased norethindrone area under the concentration-time curve (AUC) by 28%, with no change in the maximum plasma concentration (Cmax). Ethinyl estradiol Cmax was 21% lower with no change in AUC. The majority of AEs were mild in severity, with the most commonly reported being gastrointestinal disorders and nervous system disorders. No deaths or serious AEs were reported in this study. Five volunteers discontinued treatment due to AEs. CONCLUSIONS EZG did not have any clinically relevant impact on exposure of OC hormones in this study, and the OC hormones did not alter EZG PK parameters. This study provides PK evidence that doses of EZG and OCs do not need to be altered when co-administered.