Population pharmacokinetic analysis in healthy volunteers treated with different oral formulations of riluzole.
F. Del Bene(1), M. Germani(1), F. Fiorentini(1), M. Rocchetti(2), P. Bettica(3)
(1) ACCELERA Srl , Nerviano, Milan, Italy; (2) external consultant; (3) Italfarmaco S.p.A., Cinisello Balsamo, Milan, Italy.
Objectives: The aim of the current study was to develop a population model to assess the PKs of riluzole administered orally as a suspension (50 mg/10 mL oral suspension, Italfarmaco S.p.A., Italy; test compound ) and as tablets (Rilutek® 50 mg film coated tablets; reference compound) in healthy subjects (HS). Once the population PK model was established, it was used to simulate 50 mg/10 mL oral suspension of riluzole and 50 and 100 mg oral treatment of Rilutek® at steady-state following a twice a day administration in order to characterize the population exposure-response relationships on tolerability endpoints in humans.
Methods: 53 HS in three clinical studies were treated with both riluzole as oral suspension and as tablets. The different formulations of riluzole were simultaneously analyzed using a two-compartment model (ADVAN4 TRANS4 subroutines in NONMEM) with sequential zero/first-order absorption. Parameters related with the absorption process (ALAG1, ka) were assumed to be different for test and reference. The effect of covariates (body weight, height, BMI, age and gender) on PK parameters was assessed using a stepwise regression model with a forward additive and a backward elimination step.
Providing the final model, 1000 concentration profiles were generated for each simulation scenario. Cmax and AUC0-12, were computed and summarized with descriptive statistics (i.e. median, quartiles, 5th, 95th and 99th percentiles).
Results: The final riluzole model, including body weight on CL/F, V2/F and V3/F as covariate, minimized successfully with the covariance step. Typical parameter estimates were: CL/F=55.5 L/h, Q/F=42.5 L/h, V2/F=154 L, V3/F=208 L, D1= 0.269 h, ka,test=18.5 h-1, ka,ref=8.22 h-1, ALAG1test=0.0650 h, ALAG1ref=0.134 h.
Following 50 mg/10 mL riluzole oral suspension, a median Cmax value of 303 ng/mL (5th-95th percentile interval: 130-637 ng/mL) was obtained The corresponding median values for 50 mg and 100 mg Rilutek® were 266 ng/mL (88.3-642 ng/mL) and 532 ng/mL (177-1284 ng/mL), respectively.
Conclusions: The results of the present investigation are in agreement with previous ones reported in [1,2]. The simulated results show that the expected distribution of Cmax and AUC of 50mg riluzole oral suspension and of 50 mg Rilutek® film coated tablets in the patient population are fully overlapping. Moreover, the distribution of Cmax and AUC of 50mg riluzole oral suspension are far below those of 100 mg Rilutek® film coated tablets.
References:
[1] Bruno R, Vivier N, et al. Population pharmacokinetics of riluzole in patients with amyothrophic lateral sclerosis. Clin Pharmacol & Ther 62 (5): 518-526, 1997.
[2] Le Liboux A, Cachia JP et al. A comparison of the pharmacokinetics and tolerability of riluzole after repeat dose administration in healthy elderly and young volunteers. J Clin Pharmacol 39: 480-486, 1999.