97 Braz J Med Biol Res 40(1) 2007 Population pharmacokinetics of didanosine Brazilian Journal of Medical and Biological Research (2007) 40: 97-104 ISSN 0100-879X A new model for the population pharmacokinetics of didanosine in healthy subjects 1 Programa de Computação Científica, Fundação Oswaldo Cruz, 2 Coordenação de Pesquisa, Instituto Nacional de Câncer, Rio de Janeiro, RJ, Brasil L.S. Velasque 1 , R.C.E. Estrela 2 , G. Suarez-Kurtz 2 and C.J. Struchiner 1 Abstract Didanosine (ddI) is a component of highly active antiretroviral thera- py drug combinations, used especially in resource-limited settings and in zidovudine-resistant patients. The population pharmacokinet- ics 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 concen- tration data. Final pharmacokinetic parameters, expressed as func- tions 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 (V 2 = 9.8 L), intercompartmental clearance (Q = 40.9 L/h), peripheral volume (V 3 = 62.7 + 22.9 L for males and V 3 = 62.7 L for females), absorption rate constant (K a = 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, V 3 , K a , 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. Correspondence L.S. Velasque Programa de Computação Científica Fundação Oswaldo Cruz Av. Brasil, 4365 21045-900 Rio de Janeiro, RJ Brasil Fax: +55-21-2270-5141 E-mail: velasque@fiocruz.br Research supported by CNPq, Fundação Ary Frauzino, and FAPERJ. G. Suarez-Kurtz and C.J. Struchiner are Senior Investigators of CNPq. L.S. Velasque and R.C.E. Estrela were supported by post-graduate fellowships from FAPERJ and Ministério da Saúde, Brazil, respectively. Received June 14, 2005 Accepted March 9, 2006 Key words • Didanosine • Pharmacokinetics • NONMEM 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 antiretrovi- ral therapy drug combinations, used espe- cially in resource-limited settings and among zidovudine-resistant patients (1,2). The phar- macodynamic and pharmacokinetic proper- ties of ddI in HIV-infected individuals and in AIDS patients have been the subject of sev- eral reviews (3-6). Regarding the pharmaco- kinetics of ddI, which is the focus of the present study, important interindividual vari- ability has been reported for several param- eters (3-7). Uncontrolled experimental con-