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Genetic determinants of the pharmacokinetic variability of rifampicin in Malawian adults with pulmonary tuberculosis

Sloan, Derek, McCallum, Andrew, Schipani, Alessandro, Egan, Deirdre, Mwandumba, Henry ORCID:, Ward, Steve ORCID:, Waterhouse, David, Banda, Gertrude, Allain, Theresa J, Owen, Andrew, Khoo, Saye H and Davies, Geraint R (2017) 'Genetic determinants of the pharmacokinetic variability of rifampicin in Malawian adults with pulmonary tuberculosis'. Antimicrobial Agents and Chemotherapy, Vol 61, Issue 7, e00210-e00217.

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Variable exposure to anti-tuberculosis (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 rifampicin. We evaluated the contribution of Single Nucleotide Polymorphisms (SNPs) in SLCO1B1 and other candidate genes (AADAC, CES-1) to inter-individual pharmacokinetic variability in Malawi. 174 adults with pulmonary TB underwent sampling of plasma rifampicin concentrations at 2- and 6-hours post-dose. 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. Contrary to recent studies in South Africa and Uganda, SNPs in SLCO1B1 did not explain variability in AUC0-∞ of rifampicin. No pharmacokinetic associations were identified with AADAC or CES-1 SNPs, which were rare in the Malawian population. Pharmacogenetic determinants of rifampicin exposure may vary between African populations. SLCO1B1 and other novel candidate genes, as well as non-genetic sources of inter-individual variability, should be further explored in geographically diverse, adequately powered cohorts.

Item Type: Article
Subjects: QU Biochemistry > Genetics > QU 475 Genetic processes
QV Pharmacology > QV 38 Drug action.
WA Public Health > Health Problems of Special Population Groups > WA 395 Health in developing countries
WF Respiratory System > Tuberculosis > WF 300 Pulmonary tuberculosis
Faculty: Department: Clinical Sciences & International Health > Clinical Sciences Department
Digital Object Identifer (DOI):
Depositing User: Mary Creegan
Date Deposited: 19 May 2017 10:01
Last Modified: 12 Sep 2019 14:16


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