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- Mukonzo, Jackson K, et al.
(författare)
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A novel polymorphism in ABCB1 gene, CYP2B6*6 and sex predict single-dose efavirenz population pharmacokinetics in Ugandans.
- 2009
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Ingår i: British journal of clinical pharmacology. - : Wiley. - 1365-2125 .- 0306-5251. ; 68:5, s. 690-9
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: Efavirenz exhibits pharmacokinetic variability causing varied clinical response. The aim was to develop an integrated population pharmacokinetic/pharmacogenetic model and investigate the impact of genetic variations, sex, demographic and biochemical variables on single-dose efavirenz pharmacokinetics among Ugandan subjects, using NONMEM. METHODS: Efavirenz plasma concentrations (n = 402) from 121 healthy subjects were quantified by high-performance liquid chromatography. Subjects were genotyped for 30 single nucleotide polymorphisms (SNPs), of which six were novel SNPs in CYP2B6, CYP3A5 and ABCB1. The efavirenz pharmacokinetics was described by a two-compartment model with zero- followed by first-order absorption. RESULTS: Apparent oral clearance (95% confidence interval) was 4 l h l(-1) (3.5, 4.5) in extensive metabolizers. In the final model, incorporating multiple covariates, statistical significance was found only for CYP2B6*6 and CYP2B6*11 on apparent oral clearance as well as ABCB1 (rs3842) on the relative bioavailability. Subjects homozygous for CYP2B6*6 (G516T, A785G) and *11 displayed 21 and 20% lower apparent oral clearance, respectively. Efavirenz relative bioavailability was 26% higher in subjects homozygous for ABCB1 (rs3842). The apparent peripheral volume of distribution was twofold higher in women compared with men. CONCLUSIONS: The model identified the four factors CYP2B6*6, CYP2B6*11, a novel variant allele in ABCB1 (rs3842) and sex as major predictors of efavirenz plasma exposure in a healthy Ugandan population after single-dose administration. Use of mixed-effects modelling allowed the analysis and integration of multiple pharmacogenetic and demographic covariates in a pharmacokinetic population model.
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| 2. |
- Röshammar, Daniel, 1979
(författare)
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Applied Population Pharmacokinetic/ Pharmacodynamic Modeling of Antiretroviral and Antimalarial Drug Therapy
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- HIV/AIDS and malaria are two major global infectious diseases. Although better drugs against these conditions are becoming more available, dosages may not always be optimal with respect to effectiveness, safety, cost or convenience of administration. This thesis aims to quantitate the pharmacological relationship between dosing history, sources of variation between individuals, drug exposure and response to selected antiretroviral and antimalarial regimens. Pharmacometric, i.e. pharmaco-statistical, models were fitted to observed data from five clinical studies, using the nonmem software. Several polymorphic genes coding for drug metabolizing enzymes and transporters were found to have impact on the disposition of the non-nucleoside reverse transcriptase inhibitor efavirenz in healthy Ugandan subjects after single dose administration. Moreover, using simulation it was demonstrated that a 200 mg dose reduction in Zimbabwean HIV-patients with genetically decreased metabolic capacity would maintain efavirenz exposure within the therapeutic range during repeated administration. In a typical clinical trial large amounts of drug response data are collected. However, usually only limited amounts of the recorded data are actually used for investigating differences between regimens. Herein, a drug-disease model was developed to describe the time-course of repeatedly measured HIV-RNA levels in Scandinavian patients randomized to one of three commonly prescribed antiretroviral regimens. The initial analysis showed that an efavirenz-containing regimen appeared to be more efficacious compared to two protease inhibitor-containing regimens. Antimalarial artemisinin-based combination therapy bears many resemblances to antiretroviral treatment. The drugs exhibit variable and complex pharmacokinetics and the diseases themselves bring reasonable possibilities for pharmacodynamic assessment. Auto-induction of drug metabolism was described after multiple dosing with artemisinin in Vietnamese patients. The frequency of recrudescent malaria infection was as high as 37% but could not directly be linked to low artemisinin exposure. The elimination half-life of piperaquine, a suitable partner drug for artemisinin-based combination treatment, was estimated to 12 days with large between-subject variability. The thesis demonstrates the utility of pharmacometric methodology in the analysis of clinical data originating from high-income countries as well as resource-limited settings. Ultimately it can be a tool for decision analysis and policy making.
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