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Population pharmacokinetics of lopinavir in combination with ritonavir in HIV‐1‐infected patients
Author(s) -
Crommentuyn K. M. L.,
Kappelhoff B. S.,
Mulder J. W.,
Mairuhu A. T. A.,
Van Gorp E. C. M.,
Meenhorst P. L.,
Huitema A. D. R.,
Beijnen J. H.
Publication year - 2005
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/j.1365-2125.2005.02455.x
Subject(s) - lopinavir , ritonavir , lopinavir/ritonavir , pharmacokinetics , nonmem , pharmacology , population , medicine , reverse transcriptase inhibitor , nevirapine , virology , human immunodeficiency virus (hiv) , sida , antiretroviral therapy , viral load , viral disease , environmental health
Aims To develop a population pharmacokinetic model for lopinavir in combination with ritonavir, in which the interaction between both drugs was characterized, and in which relationships between patient characteristics and pharmacokinetics were identified. Methods The pharmacokinetics of lopinavir in combination with ritonavir were described using NONMEM (version V, level 1.1). First, ritonavir data were fitted to a previously developed model to obtain individual Bayesian estimates of pharmacokinetic parameters. Hereafter, an integrated model for the description of the pharmacokinetics of lopinavir with ritonavir was designed. Results From 122 outpatients 748 lopinavir and 748 ritonavir plasma concentrations were available for analysis. The interaction between the drugs was described by a time‐independent inverse relationship between the exposure to ritonavir over a dosing‐interval and the apparent clearance (CL/ F ) of lopinavir. The model parameters volume of distribution and absorption rate constant were 61.6 l (95% prediction interval (PI) 22.4, 83.7) and 0.564 h −1 (95% PI 0.208, 0.947), respectively. The model yielded a theoretical value for the CL/ F of lopinavir without ritonavir of 14.8 l h −1 (95%PI 12.1, 20.1), which translates to a value of 5.73 l h −1 in the presence of ritonavir. The only factor with significant effect on the pharmacokinetics was concurrent use of non‐nucleoside reverse transcriptase inhibitors (NNRTI), which increased the CL/ F of lopinavir by 39% ( P < 0.001). Conclusions We have developed a model that has defined a time‐independent inverse relationship between the exposure to ritonavir and the CL/ F of lopinavir, and provided an adequate description of the pharmacokinetic parameters for the latter. Concomitant use of the NNRTIs efavirenz and nevirapine increased the CL/ F of lopinavir.