Compartmental pharmacokinetic modeling of lopinavir in humans

Background: Lopinavir is a highly potent protease inhibitors commonly used in treatment of HIV infection. The drug has a very low bioavailability due to a rapid metabolism by cytochrome P450 3A (CYP3A) isoenzyme. We aimed to develop a biologically relevant pharmacokinetic model of lopinavir with a description of a CYP3A4-mediated first pass metabolism and enterohepatic circulation (EHC). Methods: A theoretical model of lopinavir was developed using the classical pharmacokinetic modeling concept. The model consisted of one compartment with first-order absorption from gastrointestinal (GI) depot and first-order clearance into recycling depot which incorporated into the model structure using ACSLX. Results: Lopinavir plasma concentration-time course was successfully simulated against a dataset from the literature. The model had an absorption rate constant (K_a) of 0.991 h^-1, a reabsorption rate constant (K_reabsorb) of 0.171 h^-1, and a volume of distribution (V/F) of 54.7 L. The 12 hours area under the concentration-time curve (AUC_0-12h) values from our model simulation compares to the experimental data were 0.8141 μg/ml.h and 0.7058 μg/ml.h, respectively. Maximum plasma concentration of the drug (C_max) predicted from our model compare to the experimental data were 0.273 μg/ml and 0.442 μg/ml, respectively. While, minimum plasma concentration of the drug (C_trough) predicted from our model compare to the experimental data were similar at 0.0015 μg/ml. Conclusions: Modified one compartment with first-order absorption from gastrointestinal (GI) depot and first-order clearance into recycling depot describes a pharmacokinetic of oral single dose of lopinavir 400 mg. The model can also simulate a concentration-time course with a difference dosing and variable which can be used for further describing the pharmacology of the drug interaction when combine with the- other drugs.