Longitudinal modeling of efficacy response in patients with lupus nephritis receiving belimumab.

Belimumab was approved for active lupus nephritis (LN) in adults in the European Union and patients ≥ 5 years of age in the USA based on a Phase 3, double-blind, placebo-controlled, 104-week study. The study evaluated the efficacy of belimumab plus background standard therapy in adults with active LN using an intravenous (IV) dose of 10 mg/kg. A longitudinal analysis of Primary Efficacy Renal Response (PERR) and Complete Renal Response (CRR) was performed to assess whether patients with high proteinuria at the start of belimumab treatment would benefit from a higher dose. Responder probability was modeled as a logistic regression with probability a function of time and treatment (belimumab or placebo). Dropout risk at each visit was incorporated into a joint model of efficacy response; only efficacy data prior to dropout events (belimumab discontinuation, treatment failure, or withdrawal) were included. Average belimumab concentration over the first 4 and 12 weeks and baseline proteinuria were considered as continuous covariates. In general, renal response (PERR and CRR) over time was higher in patients receiving belimumab than in those receiving placebo. Baseline proteinuria was considered the most relevant predictor of renal response, with reduced efficacy in patients with increased proteinuria for both belimumab or placebo treatment. For belimumab-treated patients, belimumab exposure was not found to be an important predictor of renal response. In conclusion, the 10 mg/kg IV dose was considered appropriate in all patients and there was no evidence to suggest a higher response would be achieved by increasing the dose.

A randomised, placebo-controlled study of RIPK1 inhibitor GSK2982772 in patients with active ulcerative colitis.

OBJECTIVE: Tumour necrosis factor signalling via the receptor-interacting protein kinase 1 (RIPK1) pathway regulates colonic inflammation suggesting that RIPK1 inhibition may be a potential therapeutic target in ulcerative colitis (UC). This phase IIa, randomised, double-blind experimental medicine study investigated the safety, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary efficacy of the RIPK1 inhibitor GSK2982772 in patients with active UC. DESIGN: In part A, prior to a protocol amendment, one patient was randomised to receive GSK2982772 60 mg twice daily for 42 days. After the amendment, patients were randomised 2:1 to receive GSK2982772 60 mg or placebo three times daily for 42 days. In part B, all patients switched to open-label GSK2982772 60 mg three times daily for 42 days. Safety, PK, PD biomarkers, histological disease activity, clinical efficacy and quality of life were assessed at days 43 and 85. RESULTS: Thirty-six patients were randomised (n=12, placebo/open-label GSK2982772; n=24, GSK2982772/open-label GSK2982772). Most adverse events were mild, with headache reported the most frequently across groups (placebo/open-label GSK2982772, n=2 (17%); GSK2982772/open-label GSK2982772, n=8 (33%)). GSK2982772 was well distributed into colonic tissue, with generally higher concentrations in colonic biopsy samples versus plasma. No apparent differences between treatment groups were observed for PD, histological disease activity, clinical disease activity or quality-of-life measures. At screening, all patients had Mayo endoscopic scores of 2 or 3. At day 43, no patients in the placebo/open-label GSK2982772 group achieved Mayo endoscopic scores of 0 or 1 vs 3/24 (13%) for GSK2982772/open-label GSK2982772. At day 85, 1/9 (11%) achieved scores of 0 or one for placebo/open-label GSK2982772 vs 3/22 (14%) for GSK2982772/open-label GSK2982772. CONCLUSION: GSK2982772 was generally well tolerated, with no treatment-related safety concerns identified. However, no significant differences in efficacy were observed between treatment groups, suggesting that GSK2982772 as monotherapy is not a promising treatment for patients with active UC. TRIAL REGISTRATION NUMBER: NCT02903966.

Development of a Prototype, Once-Daily, Modified-Release Formulation for the Short Half-Life RIPK1 Inhibitor GSK2982772.

PURPOSE: GSK2982772 is a selective inhibitor of receptor-interacting protein kinase-1, with a 2-3 h half-life. This study evaluated if a once-daily modified-release formulation of GSK2982772 could be developed with no significant food effect. METHODS: Part A evaluated the pharmacokinetics of GSK2982772 following fasted single-dose (120 mg) administration of two matrix minitab formulations (MT-8 h and MT-12 h) vs 120 mg immediate release (IR) and MT-12 h with a high-fat meal. Part B evaluated once-daily MT-12 h for 3 days at three dose levels. Part C evaluated a matrix monolithic (MM-12 h) formulation at two dose levels in different prandial states. RESULTS: All modified-release formulations dosed in the fasted state reduced maximum plasma concentration (Cmax), delayed time to Cmax, and decreased area under the curve (AUC) vs IR. When MT-12 h or MM-12 h were co-administered with a meal (standard or high-fat) Cmax and AUC increased. Dosing MM-12 h 1 h before a standard or high-fat meal had minimal impact on exposure vs fasted. CONCLUSIONS: MT-12 h and MM-12 h provided a QD pharmacokinetic profile in the fasted state, however when MT-12 h was dosed with a high-fat meal a QD profile was not maintained. ( ClinicalTrials.gov Identifier: NCT03266172).

Comparison of the Pharmacokinetics of RIPK1 Inhibitor GSK2982772 in Healthy Western and Japanese Subjects.

BACKGROUND AND OBJECTIVES: GSK2982772 is an oral small-molecule RIPK1 inhibitor with potential therapeutic efficacy in immune-mediated inflammatory diseases (IMIDs). An inter-ethnic comparison of GSK2982772 pharmacokinetics was conducted based on data from Western (Study 1) and Japanese subjects (Study 2). METHODS: Both studies were single-centre, randomised, double-blind, placebo-controlled studies with objectives to assess the safety and characterise the pharmacokinetics of GSK2982772. Western subjects in Study 1 (NCT03305419), Part A (N = 15), were randomly assigned to receive 120 mg three times daily (TID), 240 mg TID, or 360 mg twice daily (BID) doses of GSK2982772, or placebo (TID or BID) for 1 day. Part B subjects (N = 47) received GSK2982772 120 mg TID, 240 mg TID, or placebo TID for 14 days. Japanese subjects in Study 2 (N = 13) (NCT03590613) were randomly assigned to receive TID doses of GSK2982772 60, 120, 240 mg TID or placebo TID for 1 day. RESULTS: GSK2982772 was well tolerated and adverse events were generally mild. Maximum observed plasma drug concentration (Cmax), time to reach Cmax (Tmax), area under the plasma drug concentration versus time curve after the first GSK2982772 dose (AUC(0-7)) of 120 and 240 mg, and (AUC(0-24)) values for the 120 and 240 mg TID doses over a single day were similar in Japanese and Western subjects. CONCLUSIONS: The pharmacokinetics and tolerability of GSK2982772 were similar between Western and Japanese subjects, justifying inclusion of Japanese subjects in future global clinical studies to assess the therapeutic potential of RIPK1 inhibition for the treatment of IMIDs. Clinical Trials: NCT03305419 and NCT03590613 available from http://www.clinicaltrials.gov .

Randomized clinical study of safety, pharmacokinetics, and pharmacodynamics of RIPK1 inhibitor GSK2982772 in healthy volunteers.

GSK2982772 is a highly selective inhibitor of receptor-interacting protein kinase 1 (RIPK1) being developed to treat chronic inflammatory diseases. This first-in-human study evaluated safety, tolerability, pharmacokinetics (PK), and exploratory pharmacodynamics (PD) of GSK2982772 administered orally to healthy male volunteers. This was a Phase I, randomized, placebo-controlled, double-blind study. In Part A, subjects received single ascending doses of GSK2982772 (0.1-120 mg) or placebo in a crossover design during each of 4 treatment periods. In Part B, subjects received repeat doses of GSK2982772 (20 mg once daily [QD] to up to 120 mg twice daily [BID]) or placebo for 14 days. Part C was an open-label relative bioavailability study comparing 20-mg tablets vs capsules. Safety, tolerability, pharmacokinetics (PK), RIPK1 target engagement (TE), and pharmacodynamics (PD) were assessed. The most common adverse events (AEs) were contact dermatitis and headache. Most AEs were mild in intensity, and there were no deaths or serious AEs. The PK of GSK2982772 was approximately linear over the dose range studied (up to 120 mg BID). There was no evidence of drug accumulation upon repeat dosing. Greater than 90% RIPK1 TE was achieved over a 24-hour period for the 60-mg and 120-mg BID dosing regimens. Single and repeat doses of GSK2982772 were safe and well tolerated. PK profiles showed dose linearity. The high levels of RIPK1 TE support progression into Phase II clinical trials for further clinical development.

Adolescent Clinical Development of Ezogabine/Retigabine as Adjunctive Therapy for Partial-Onset Seizures: Pharmacokinetics and Tolerability.

OBJECTIVES: To explore the pharmacokinetic (PK) profile and safety of ezogabine (EZG)/retigabine (RTG) as adjunctive therapy for uncontrolled partial-onset seizures (POS) in adolescents. METHODS: In this multiple-dose study (NCT01494584), adolescents with POS received EZG/RTG immediate-release tablets three times daily (TID) as adjunctive therapy to 1 to 3 concurrent antiepileptic drugs. The study comprised a screening phase, and a 5- to 8-week treatment phase starting with 100 mg TID up-titrated once weekly by ≤50 mg TID to a maximum dosage of 300 mg TID. There were 8 venous blood samples and 2 finger-prick blood samples collected for PK analysis during 8-hour time periods at the target dosages of 100, 200, and 300 mg TID. RESULTS: This study was terminated prematurely on US Food and Drug Administration advice due to pigmentation/discoloration findings in long-term, open-label extension studies in adults. Five participants (ages 13-16 years) had enrolled in the study. For the EZG/RTG 100-, 200-, and 300-mg doses, the area under the concentration-time curve during the dosage intervals was 1680, 2559, and 3784 ng/hr/mL; maximum plasma concentrations were 370, 536, and 751 ng/mL, and minimum plasma concentrations were 105, 200, and 287 ng/mL, respectively. Venous and finger-prick concentrations of EZG/RTG were similar. No significant adverse events were observed during treatment (133-213 days). CONCLUSIONS: EZG/RTG PK appeared linear across the dosage range of 100 to 300 mg TID in adolescents with POS, and were consistent with adult observations. The small sample size and short study duration preclude conclusions regarding the safety and efficacy of EZG/RTG.

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.

Lack of effect of ezogabine/retigabine on the pharmacokinetics of digoxin in healthy individuals: results from a drug-drug interaction study.

INTRODUCTION: The potential for ezogabine/retigabine (EZG/RTG) and its N-acetyl metabolite (NAMR) to inhibit the transporter protein P-glycoprotein-(P-gp)-mediated digoxin transport was tested in vitro. EZG/RTG did not inhibit P-gp. However, NAMR inhibited P-gp in a concentration-dependent manner. Based on these in vitro results, NAMR had the potential to inhibit P-gp at therapeutic doses of EZG/RTG (600-1,200 mg/day). As digoxin has a narrow therapeutic index, inhibition of digoxin clearance may have an impact on its safety. METHODS: An open-label, single-center, two session, fixed-sequence study was conducted to assess the effect of co-administration of therapeutic doses of EZG/RTG on digoxin pharmacokinetics in healthy adults. In session 1, subjects received a single dose of digoxin 0.25 mg. In session 2, EZG/RTG was up-titrated over 6 weeks. Digoxin 0.25 mg was co-administered at EZG/RTG steady-state doses of 600, 900, and, based on tolerability, 1,050/1,200 mg/day. Blood samples were collected over 144 hours for determination of digoxin, EZG/RTG, and NAMR concentrations. Urine samples were collected over 48 hours for determination of digoxin concentrations. RESULTS: Of 30 subjects enrolled, 29 were included in the pharmacokinetic analysis. Compared with digoxin alone, co-administration with EZG/RTG led to small increases in the digoxin plasma area under the concentration-time curve (AUC)0-120 at doses of 600, 900, and 1,050/1,200 mg (geometric mean ratio 1.08, 90% confidence interval [CI] 1.01-1.15; 1.18, 90% CI 1.10-1.27; 1.13, 90% CI 1.05-1.21, respectively). Safety was consistent with previous repeat-dose studies of EZG/RTG in healthy subjects. CONCLUSION: Co-administration of EZG/RTG across the therapeutic range resulted in small, non-dose-dependent and non-clinically relevant increases in digoxin systemic exposure, suggesting that digoxin dose adjustment is not necessary.

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.

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.

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.

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.

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.

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. METHODS: An open-label, conversion study was conducted, consisting of a 2-week LTG-IR Baseline Phase, followed by a 2-week LTG-XR Treatment Phase and a 1-week LTG-IR Phase. Forty-four subjects (> or =13 years of age) were enrolled and grouped as metabolically neutral (15), induced (15), or inhibited (14) based on the effects of the concomitant antiepileptic drugs (AEDs) on the clearance of LTG. The primary outcome was LTG PK parameters upon conversion. Secondary outcomes included seizure frequency, adverse events, and subject's preference. RESULTS: LTG-XR and LTG-IR regimens were similar with respect to area under curve from 0 to 24 h (AUC (0-24)), apart from the induced group, where the AUC (0-24) of LTG-XR was on average 21% lower than for LTG-IR. A reduction in the LTG Cmax was observed for LTG-XR compared to LTG-IR resulting in a decrease in the peak-to-trough fluctuation in serum LTG concentrations. The steady-state, dose-normalized, trough concentrations for LTG-XR were similar to those of LTG-IR. The median time to peak concentration (Tmax) following administration of LTG-XR ranged from 4 to 6 h, 6 to 10 h, and 9 to 11 h in the induced, neutral, and inhibited groups, respectively. In comparison, the median Tmax following administration of LTG-IR was between 1 and 1.5 h. CONCLUSIONS: Trough concentrations of LTG can be maintained on conversion from twice-daily LTG-IR to once-daily LTG-XR at the same total daily dose.

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 Parkinson's 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.