Markov model for characterizing neuropsychologic impairment and Monte Carlo simulation for optimizing efavirenz therapy.
The study was undertaken to develop a pharmacokinetic-pharmacodynamic model to characterize efavirenz-induced neuropsychologic impairment, given preexistent impairment, which can be used for the optimization of efavirenz therapy via Monte Carlo simulations. The modeling was performed with NONMEM 7.2. A 1-compartment pharmacokinetic model was fitted to efavirenz concentration data from 196 Ugandan patients treated with a 600-mg daily efavirenz dose. Pharmacokinetic parameters and area under the curve (AUC) were derived. Neuropsychologic evaluation of the patients was done at baseline and in week 2 of antiretroviral therapy. A discrete-time 2-state first-order Markov model was developed to describe neuropsychologic impairment. Efavirenz AUC, day 3 efavirenz trough concentration, and female sex increased the probability (P01) of neuropsychologic impairment. Efavirenz oral clearance (CL/F) increased the probability (P10) of resolution of preexistent neuropsychologic impairment. The predictive performance of the reduced (final) model, given the data, incorporating AUC on P01and CL /F on P10, showed that the model adequately characterized the neuropsychologic impairment observed with efavirenz therapy. Simulations with the developed model predicted a 7% overall reduction in neuropsychologic impairment probability at 450 mg of efavirenz. We recommend a reduction in efavirenz dose from 600 to 450 mg, because the 450-mg dose has been shown to produce sustained antiretroviral efficacy.
['Bisaso|Kuteesa R|KR|', 'Mukonzo|Jackson K|JK|', 'Ette|Ene I|EI|']
D000328:Adult D000480:Alkynes D019380:Anti-HIV Agents D048588:Benzoxazines D003521:Cyclopropanes D004305:Dose-Response Relationship, Drug D005260:Female D015658:HIV Infections D006801:Humans D008297:Male D008390:Markov Chains D008954:Models, Biological D009010:Monte Carlo Method D009483:Neuropsychological Tests D020258:Neurotoxicity Syndromes D018894:Reverse Transcriptase Inhibitors
Markov model neuropsychologic impairment Monte Carlo simulation efavirenz NONMEM