Effect of SLCO1B1 Polymorphisms on Rifabutin Pharmacokinetics in African HIV-Infected Patients with Tuberculosis.
Rifabutin, used to treat HIV-infected tuberculosis, shows highly variable drug exposure, complicating dosing. Effects of SLCO1B1 polymorphisms on rifabutin pharmacokinetics were investigated in 35 African HIV-infected tuberculosis patients after multiple doses. Nonlinear mixed-effects modeling found that influential covariates for the pharmacokinetics were weight, sex, and a 30% increased bioavailability among heterozygous carriers of SLCO1B1 rs1104581 (previously associated with low rifampin concentrations). Larger studies are needed to understand the complex interactions of host genetics in HIV-infected tuberculosis patients. (This study has been registered at ClinicalTrials.gov under registration no. NCT00640887.).
School of Pharmacy, The University of Queensland, Woolloongabba, Australia s.hennig@uq.edu.au.
Stefanie
S
Hennig
TB Research Unit, Medical Research Council, Durban, South Africa.
Suhashni
S
Naiker
Biostatistics Unit, Medical Research Council, Durban, South Africa.
Tarylee
T
Reddy
Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, United Kingdom.
Deirdre
D
Egan
Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa.
Tracy
T
Kellerman
Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa.
Lubbe
L
Wiesner
Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, United Kingdom.
Andrew
A
Owen
Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa.
Helen
H
McIlleron
TB Research Unit, Medical Research Council, Durban, South Africa KwaZulu-Natal Research Institute for Tuberculosis & HIV (K-RITH), Nelson Mandela School of Medicine, Durban, South Africa.
Alexander
A
Pym
D000328:Adult; D000995:Antitubercular Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D018791:CD4 Lymphocyte Count; D060085:Coinfection; D004977:Ethambutol / Q000008:administration & dosage; D005260:Female; D015870:Gene Expression; D015658:HIV Infections / Q000473:pathology / Q000821:virology; D006801:Humans; D007538:Isoniazid / Q000008:administration & dosage; D027381:Liver-Specific Organic Anion Transporter 1; D008297:Male; D009010:Monte Carlo Method; D027361:Organic Anion Transporters / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D011718:Pyrazinamide / Q000008:administration & dosage; D017828:Rifabutin / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D012293:Rifampin / Q000008:administration & dosage; D012737:Sex Factors; D014397:Tuberculosis, Pulmonary / Q000097:blood / Q000188:drug therapy* / Q000382:microbiology / Q000473:pathology
D000995:Antitubercular Agents; D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; C503999:SLCO1B1 protein, human; D017828:Rifabutin; D011718:Pyrazinamide; D004977:Ethambutol; D007538:Isoniazid; D012293:Rifampin