Genetic determinants of the pharmacokinetic variability of rifampin in Malawian adults with pulmonary tuberculosis
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Variable exposure to antituberculosis (TB) drugs, partially driven by genetic factors, may be associated with poor clinical outcomes. Previous studies have suggested an influence of the SLCO1B1 locus on the plasma area under the concentration-time curve (AUC) of rifampin. We evaluated the contribution of single nucleotide polymorphisms (SNPs) in SLCO1B1 and other candidate genes (AADAC and CES-1) to interindividual pharmacokinetic variability in Malawi. A total of 174 adults with pulmonary TB underwent sampling of plasma rifampin concentrations at 2 and 6 h postdose. Data from a prior cohort of 47 intensively sampled, similar patients from the same setting were available to support population pharmacokinetic model development in NONMEM v7.2, using a two-stage strategy to improve information during the absorption phase. In contrast to recent studies in South Africa and Uganda, SNPs in SLCO1B1 did not explain variability in AUC0-∞ of rifampin. No pharmacokinetic associations were identified with AADAC or CES-1 SNPs, which were rare in the Malawian population. Pharmacogenetic determinants of rifampin exposure may vary between African populations. SLCO1B1 and other novel candidate genes, as well as nongenetic sources of interindividual variability, should be further explored in geographically diverse, adequately powered cohorts.
Sloan , D J , McCallum , A D , Schipani , A , Egan , D , Mwandumba , H C , Ward , S A , Waterhouse , D , Banda , G , Allain , T J , Owen , A , Khoo , S H & Davies , G R 2017 , ' Genetic determinants of the pharmacokinetic variability of rifampin in Malawian adults with pulmonary tuberculosis ' , Antimicrobial Agents and Chemotherapy , vol. 61 , no. 7 , e00210-17 . https://doi.org/10.1128/AAC.00210-17
Antimicrobial Agents and Chemotherapy
© 2017 Sloan et al. This is an Open Access article distributed under the terms of the Creative Commons Attribution 4.0 International license.
DescriptionD.J.S. was supported by a Wellcome Trust Clinical PhD Fellowship (086757/Z/08/A to D.J.S.). A.D.M. was supported by a National Institute for Health Research Integrated Clinical Academic Training Fellowship and a Wellcome Trust Clinical PhD Fellowship (105/392/B/14/Z). The Malawi Liverpool Wellcome Trust Clinical Research Programme is supported by a strategic award from the Wellcome Trust.
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