Alejandra Schiavo (1), Pietro Fagiolino (1), Iñaki F. Trocóniz (2,3), Manuel Ibarra (1)
(1) Department of Pharmaceutical Sciences. Faculty of Chemistry. Universidad de la República. Montevideo, Uruguay. (2) Pharmacometrics and Systems Pharmacology Research Unit, Department of Pharmaceutical Technology and Chemistry, School of Pharmacy and Nutrition, University of Navarra. Pamplona, Spain. (3) IdiSNA; Navarra Institute for Health Research, Pamplona, Spain.
Introduction: Valproic acid (VPA) is a narrow therapeutic index drug widely prescribed for the treatment of epilepsy, psychiatric disorders and migraine. First available as an enteric-coated immediate release formulation (IR), its fast absorption profile and short half-life motivated the development of extended-release formulations (ER) to reduce both daily administrations and pharmacokinetic peak-to-trough fluctuation. An ER product (Test) developed in collaboration between our group and a local laboratory has been available in Uruguay since 2010 after proving bioequivalence (BE) versus Depakote® IR (Abbot, Reference) in single dose fasting conditions. However, regulator authorities have required the current producer a multiple dose BE study in healthy subjects to hold the marketing approval, a clinical trial that was not allowed by the Ethics Committee on Human Experimentation due to safety concerns.
Objectives:
- Evaluate two methods for BE endpoint estimation using a non-linear mixed effects (NLME) model developed with single dose data.
- Predict the BE outcome in a multiple-dose scenario.
Methods: Observations from a standard single-dose average BE study conducted in 14 healthy subjects under fasting conditions of 500 mg were used to develop a NLME model in NONMEM 7.4 [1]. Model building was performed under the PsN-Pirana-Xpose platform [2]. Model selection was based on Akaike Information Criteria (AIC), parameter uncertainty and goodness of fit plots including estimation-based and simulation-based diagnostics. Secondary pharmacokinetic metrics, AUC and Cmax, were obtained from model simulations using the ncappc package in the R environment [3]. Two methods were evaluated for estimation of BE metrics: A) 90% non-parametric confidence intervals (CIs) were obtained for the AUC and Cmax Test/Reference ratios (T/R) after simulating 1000 studies using the developed NLME model and taking out the median T/R of each study; B) 90% parametric CIs were obtained for the AUC and Cmax T/R using the geometric means and median residual variances computed from the ANOVA analysis of 1000 simulated BE studies using the developed NLME model. The metrics obtained with the described methods were compared with the result reported for the single-dose study after traditional average BE analysis.
The performance of the NLME model at steady state was validated versus reported data for Depakote® in healthy subjects [4] based on the MPE for the mean and the standard deviation of AUC and Cmax. Finally, the BE outcome of a simulated multiple-dose study with fasting administration of 500 mg q12 for 5 days was assessed with methods A and B.
Results: A 2-compartment pharmacokinetic NLME model with first-order lagged absorption and linear elimination was developed from the single dose bioequivalence data. Estimated parameters and covariate analysis were in accordance with previous reports. Confidence intervals obtained for the T/R AUC and Cmax ratios with simulation-based methods were: [0.91-1.02] and [0.72-0.88] respectively for method A; [0.90-1.03] and [0.70-0.92] respectively for method B. These results were considered accurate regarding the reported BE 90%CI T/R: [0.91-1.03] for AUC and [0.72-0.87] for Cmax. MPE for the model steady-state predictions of AUC and Cmax were below 10% for 500 mg q12. The 90%CI predicted for the T/R AUC and Cmax ratios in a multiple-dose BE study were: [0.88-1.00] and [0.79-0.94] respectively for method A; [0.87-0.99] and [0.77-0.95] respectively for method B.
Conclusions: We present two alternative ways of assessing bioequivalence from a model-based approach. Results of both methods indicate that BE conclusions obtained in the single-dose study would hold under multiple-dose administration of 500 mg twice daily.
References:
[1] Beal SL et al. 1989-2011. NONMEM Users Guides. Icon Development Solutions, Ellicott City, Maryland, USA.
[2] Keizer R et al. 2013. Modeling and Simulation Workbench for NONMEM: Tutorial on Pirana, PsN, and Xpose. CPT Pharmacometrics Syst Pharmacol. Jun 26;2:e50.
[3] Acharya C et al. 2016. A diagnostic tool for population models using non-compartmental analysis: the ncappc package for R. Comput. Methods Programs. Biomed. 127: 83-93.
[4] Dutta S, Zhang Y. 2004. Bioavailability of divalproex extended-release formulation relative to the divalproex delayed-release formulation. Biopharm. Drug. Dispos. 25:345-352.
Reference: PAGE () Abstr 9533 [www.page-meeting.org/?abstract=9533]
Poster: Drug/Disease Modelling - Absorption & PBPK