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.
Department of Pharmacology and Therapeutics, College of Health Sciences, Makerere University, Kampala, Uganda.|Breakthrough Analytics Ltd, Kampala, Uganda.
Kuteesa R
KR
Bisaso
Department of Pharmacology and Therapeutics, College of Health Sciences, Makerere University, Kampala, Uganda.|Center for Operations Research in Africa, Kampala, Uganda.
Jackson K
JK
Mukonzo
Anoixis Corporation, Natick, MA, USA.
Ene I
EI
Ette
D000328:Adult; D000480:Alkynes; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D048588:Benzoxazines / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D003521:Cyclopropanes; D004305:Dose-Response Relationship, Drug; D005260:Female; D015658:HIV Infections / Q000188:drug therapy / Q000523:psychology; D006801:Humans; D008297:Male; D008390:Markov Chains; D008954:Models, Biological; D009010:Monte Carlo Method; D009483:Neuropsychological Tests; D020258:Neurotoxicity Syndromes / Q000209:etiology*; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use
D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D018894:Reverse Transcriptase Inhibitors; C098320:efavirenz
Markov model; Monte Carlo simulation; NONMEM; efavirenz; neuropsychologic impairment