Sloan, Derek J, McCallum, Andrew D, Schipani, Alessandro, Egan, Deirdre, Mwandumba, Henry C, Ward, Steve A, Waterhouse, David, Banda, Gertrude, Allain, Theresa J, Owen, Andrew 
ORCID: 0000-0002-9819-7651 et al (show 2 more authors)
(2017)
Genetic Determinants of the Pharmacokinetic Variability of Rifampin in Malawian Adults with Pulmonary Tuberculosis.
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 61 (7).
e00210-e00217.
Abstract
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 <i>SLCO1B1</i> locus on the plasma area under the concentration-time curve (AUC) of rifampin. We evaluated the contribution of single nucleotide polymorphisms (SNPs) in <i>SLCO1B1</i> and other candidate genes (<i>AADAC</i> and <i>CES-1</i>) 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 <i>SLCO1B1</i> did not explain variability in AUC<sub>0-∞</sub> of rifampin. No pharmacokinetic associations were identified with <i>AADAC</i> or <i>CES-1</i> SNPs, which were rare in the Malawian population. Pharmacogenetic determinants of rifampin exposure may vary between African populations. <i>SLCO1B1</i> and other novel candidate genes, as well as nongenetic sources of interindividual variability, should be further explored in geographically diverse, adequately powered cohorts.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | tuberculosis, pharmacokinetics, single nucleotide polymorphism, SLCO1B1, AADAC, CES-1 |
| Depositing User: | Symplectic Admin |
| Date Deposited: | 17 May 2017 06:33 |
| Last Modified: | 13 Feb 2024 14:55 |
| DOI: | 10.1128/AAC.00210-17 |
| Open Access URL: | http://aac.asm.org/content/early/2017/04/26/AAC.00... |
| Related URLs: | |
| URI: | https://livrepository.liverpool.ac.uk/id/eprint/3007493 |
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