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

Derek J. Sloan; Andrew D. McCallum; Alessandro Schipani; Deirdre Egan; Henry C. Mwandumba; Steve A. Ward; David Waterhouse; Gertrude Banda; Theresa J. Allain; Andrew Owen; Saye H. Khoo; Geraint R. Davies

doi:10.1128/AAC.00210-17

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

Derek J. Sloan^*, Andrew D. McCallum, Alessandro Schipani, Deirdre Egan, Henry C. Mwandumba, Steve A. Ward, David Waterhouse, Gertrude Banda, Theresa J. Allain, Andrew Owen, Saye H. Khoo, Geraint R. Davies

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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 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 AUC_0-∞ 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.

Original language	English
Article number	e00210-17
Number of pages	9
Journal	Antimicrobial Agents and Chemotherapy
Volume	61
Issue number	7
Early online date	27 Jun 2017
DOIs	https://doi.org/10.1128/AAC.00210-17
Publication status	Published - Jul 2017

Keywords

AADAC
CES-1
Pharmacokinetics
Single nucleotide polymorphism
SLCO1B1
Tuberculosis

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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© 2017 Sloan et al. This is an Open Access article distributed under the terms of the Creative Commons Attribution 4.0 International license.
Final published version, 276 KBLicence: CC BY

Derek James Sloan
- djs26st-andrews.acuk
- School of Medicine - Reader/Consultant in Infectious Diseases
- Infection and Global Health Division
Person: Academic

Cite this

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, 61(7), Article e00210-17. https://doi.org/10.1128/AAC.00210-17

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title = "Genetic determinants of the pharmacokinetic variability of rifampin in Malawian adults with pulmonary tuberculosis",

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 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.",

keywords = "AADAC, CES-1, Pharmacokinetics, Single nucleotide polymorphism, SLCO1B1, Tuberculosis",

author = "Sloan, {Derek J.} and McCallum, {Andrew D.} and Alessandro Schipani and Deirdre Egan and Mwandumba, {Henry C.} and Ward, {Steve A.} and David Waterhouse and Gertrude Banda and Allain, {Theresa J.} and Andrew Owen and Khoo, {Saye H.} and Davies, {Geraint R.}",

note = "D.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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AU - Sloan, Derek J.

AU - McCallum, Andrew D.

AU - Schipani, Alessandro

AU - Egan, Deirdre

AU - Mwandumba, Henry C.

AU - Ward, Steve A.

AU - Waterhouse, David

AU - Banda, Gertrude

AU - Allain, Theresa J.

AU - Owen, Andrew

AU - Khoo, Saye H.

AU - Davies, Geraint R.

N1 - D.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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N2 - 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.

AB - 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.

KW - AADAC

KW - CES-1

KW - Pharmacokinetics

KW - Single nucleotide polymorphism

KW - SLCO1B1

KW - Tuberculosis

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DO - 10.1128/AAC.00210-17

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AN - SCOPUS:85022015785

SN - 0066-4804

VL - 61

JO - Antimicrobial Agents and Chemotherapy

JF - Antimicrobial Agents and Chemotherapy

IS - 7

M1 - e00210-17

ER -

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

Abstract

Keywords

UN SDGs

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Derek James Sloan

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