A new model for the population pharmacokinetics of didanosine in healthy subjects

L.S Velasque,G Suarez-Kurtz,R.C.E Estrela,C.J Struchiner

doi:10.1590/s0100-879x2006005000048

Abstract

Didanosine (ddI) is a component of highly active antiretroviral therapy drug combinations, used especially in resource-limited settings and in zidovudine-resistant patients. The population pharmacokinetics of ddI was evaluated in 48 healthy volunteers enrolled in two bioequivalence studies. These data, along with a set of co-variates, were the subject of a nonlinear mixed-effect modeling analysis using the NONMEM program. A two-compartment model with first order absorption (ADVAN3 TRANS3) was fitted to the serum ddI concentration data. Final pharmacokinetic parameters, expressed as functions of the co-variates gender and creatinine clearance (CL CR), were: oral clearance (CL = 55.1 + 240 x CL CR + 16.6 L/h for males and CL = 55.1 + 240 x CL CR for females), central volume (V2 = 9.8 L), intercompartmental clearance (Q = 40.9 L/h), peripheral volume (V3 = 62.7 + 22.9 L for males and V3 = 62.7 L for females), absorption rate constant (Ka = 1.51/h), and dissolution time of the tablet (D = 0.43 h). The intraindividual (residual) variability expressed as coefficient of variation was 13.0%, whereas the interindividual variability of CL, Q, V3, Ka, and D was 20.1, 75.8, 20.6, 18.9, and 38.2%, respectively. The relatively high (>30%) interindividual variability for some of these parameters, observed under the controlled experimental settings of bioequivalence trials in healthy volunteers, may result from genetic variability of the processes involved in ddI absorption and disposition.

Highlights

Didanosine is a nucleoside analog of adenosine, which prevents replication of human immunodeficiency virus (HIV) by inhibiting HIV reverse transcriptase [1]. ddI is a component of highly active antiretroviral therapy drug combinations, used especially in resource-limited settings and among zidovudine-resistant patients [1,2]
No significant differences in Cmax, AUC0-∞, Tmax, t1/2, or CL/F were observed between the reference and the generic formulations tested in each bioequivalence trial
This is the first study of the population pharmacokinetics of ddI in healthy adults

Summary

Introduction

Didanosine (ddI) is a nucleoside analog of adenosine, which prevents replication of human immunodeficiency virus (HIV) by inhibiting HIV reverse transcriptase [1]. ddI is a component of highly active antiretroviral therapy drug combinations, used especially in resource-limited settings and among zidovudine-resistant patients [1,2]. DdI is a component of highly active antiretroviral therapy drug combinations, used especially in resource-limited settings and among zidovudine-resistant patients [1,2]. Regarding the pharmacokinetics of ddI, which is the focus of the present study, important interindividual variability has been reported for several parameters [3,4,5,6,7]. We used a broad range of serum ddI concentrations obtained from two bioequivalence trials to develop a new model for this antiretroviral drug in healthy volunteers. Bioequivalence trials are conducted in controlled settings and minimize various sources of variability, such as diet, timing of dosing, physical activity, etc. The pharmacokinetics of highly active antiretroviral therapy components among healthy volunteers may better describe the behavior of these drugs among infected individuals who start therapy early during the course of the infection

Methods

Results

Conclusion