Pharmacokinetic interaction between retigabine and lamotrigine in healthy subjects.

PURPOSE: The antiepileptic drugs (AEDs) retigabine (RGB) and lamotrigine (LTG) undergo predominantly N-glucuronidation and renal excretion. This study was performed to evaluate potential pharmacokinetic interactions between both AEDs. METHODS: Twenty-nine healthy male subjects participated in the study. Group A ( n=14) received single oral 200-mg RGB doses on day 1 and day 7, and 25 mg o.i.d. LTG on days 3-8. Group B ( n=15) received single oral 200-mg LTG doses on day 1 and day 17, and was up-titrated to 300 mg RGB b.i.d. on days 6-20. Blood samples were collected to compare the pharmacokinetics of both AEDs and the N-acetyl metabolite of RGB (AWD21-360) after single and concomitant treatments. RESULTS: RGB was rapidly absorbed and eliminated with a mean half-life (t(1/2)) of 6.3+/-1.1 h and an apparent clearance (CL/F) of 0.69+/-1.4 l/h/kg. Under co-administration of LTG, mean RGB t(1/2) and area under the plasma concentration-time curve (AUC) were increased by 7.5% ( P=0.045) and 15% ( P=0.006), respectively, while CL/F was decreased by 13% ( P=0.06). Consistent results were obtained for AWD21-360. LTG was moderately rapidly absorbed, eliminated with a mean t(1/2) of 37+/-10.4 h and a CL/F of 0.028+/-0.007 l/h/kg. Under co-administration of RGB, mean LTG t(1/2) and AUC decreased by 15% and 18%, respectively, while CL/F increased by 22% (all parameters, P=0.001). CONCLUSIONS: RGB and LTG exhibit a modest pharmacokinetic interaction on each other. The slight decline in RGB clearance due to LTG is believed to result from competition for renal elimination rather than competition for glucuronidation. The induction of LTG clearance due to retigabine was unexpected since RGB did not show enzyme induction in various other drug-drug interaction studies. Further studies in patients are needed to assess the clinical relevance of these findings for concomitant treatment with both drugs in the upper recommended dose range.

Effects of age and sex on the disposition of retigabine.

BACKGROUND: The novel antiepileptic drug retigabine is the first selective M-current potassium channel opener for KCNQ2/3 and KCNQ3/5 channels. Retigabine undergoes phase II metabolism (N-glucuronidation, acetylation) exclusively and renal excretion. OBJECTIVE: Our objective was to evaluate the effects of age and sex on the pharmacokinetics of retigabine. METHODS: Healthy young (age range, 18-40 years) and elderly (age range, 66-81 years) white subjects (12 men and 12 women in each group) received a single 200-mg oral dose of retigabine. After dosing, blood was collected over a 72-hour period to determine plasma concentrations of retigabine and its acetylated metabolite, AWD21-360. Pharmacokinetics was compared for age group and sex by ANOVA. RESULTS: In young men, retigabine was rapidly absorbed, with the maximum concentration occurring within 2 hours, and was eliminated with an apparent clearance of 0.67 L x h(-1) x kg(-1) and a mean terminal half-life of 8.5 hours. Subjects were similarly exposed to AWD21-360. Compared with young men, young women had higher retigabine maximum concentration (56%) and exposure (20%) but similar clearance (0.68 L x h(-1) x kg(-1)); these differences were related to differences in body weight. Although maximum concentration was similar in elderly subjects, retigabine elimination was slower (30% lower apparent clearance normalized for weight), resulting in higher exposure (42%) and a longer half-life (30%). Because phase II metabolism is scarcely affected by age, these differences may be related to the known decline of renal function with age. CONCLUSIONS: Although there are no substantial sex-related differences in the disposition of retigabine, a relevant decrease in clearance resulting in higher exposure occurs in elderly patients. The results suggest that decline of renal function with age may account for some of the observed changes.

Multiple-dose, linear, dose-proportional pharmacokinetics of retigabine in healthy volunteers.

Retigabine, a first-in-class selective M-current potassium channel opener, is a novel antiepileptic compound currently in clinical development. The purpose of this randomized placebo-controlled study was to assess retigabine oral safety and pharmacokinetics in healthy male volunteers (N = 45). Subjects received one dose on day 1 and doses every 12 hours for the next 14 days. Fixed doses were given to the first four groups (200, 400, 500, and 600 mg per day). Titrated doses were given to group 5 in 100 mg increases every 4 days, achieving 700 mg per day on day 15. Serial blood samples were collected on days 1 and 15. Pharmacokinetic parameters were compared between days and among dose groups. After administration of a single dose, retigabine was rapidly absorbed, with maximum concentrations of 387 ng/ml (normalized to a 100 mg dose) occurring within 1.5 hours. Retigabine was eliminated with a mean terminal half-life of 8.0 hours and an apparent oral clearance of 0.70 L/h/kg in white subjects. In black subjects, retigabine clearance and volume of distribution were 25% and 30% lower, respectively, after normalizing by body weight, leading to higher exposure in this population. Retigabine's pharmocokinetics was linearly dose proportional. Steady-state pharmacokinetics was in agreement with single-dose pharmacokinetics, and the accumulation ratio was about 1.5. Retigabine and AWD21-360 trough evening concentrations were significantly lower (about 30% to 35%) than morning values. The titration regimen allowed for higher doses to be tolerated compared to the fixed-dose regimen. In conclusion, the pharmacokinetics of retigabine is linearly dose proportional for daily doses of 100 to 700 mg and is not modified on multiple administrations.