Effects of Tuberculosis, Race, and Human Gene SLCO1B1 Polymorphisms on Rifampin Concentrations

Abstract

Rifampin has concentration-dependent activity against Mycobacterium tuberculosis. However, marked intersubject variation of rifampin concentrations occurs. In this study, we evaluated rifampin pharmacokinetics in relation to tuberculosis, geographic region, race, and single nucleotide polymorphisms of the human transporter genes SLCO1B1, SLCO1B3, and MDR1. Seventy-two adults with pulmonary tuberculosis from Africa, North America, and Spain were evaluated during multidrug intensive-phase therapy, and their results were compared to those from 16 healthy controls from North America. Rifampin pharmacokinetic values were similar between tuberculosis patients and controls (geometric mean [GM] area under the concentration-time curve from 0 to 24 h [AUC 0-24 ] of 40.2 versus 40.9 g ⅐ h/ml; P ‫؍‬ 0.9). However, in multivariable analyses, the rifampin AUC 0-24 was significantly affected by rifampin dosage (in mg/kg of body weight), polymorphisms in the SLCO1B1 gene, and the presence of tuberculosis by geographic region. The adjusted rifampin AUC 0-24 was lowest in patients with tuberculosis from Africa compared to that in non-African patients or control subjects. The adjusted rifampin AUC 0-24 was also 36% lower among participants with SLCO1B1 genotype c.463CA than that among participants with SLCO1B1 genotype c.463CC (adjusted GM, 29.8 versus 46.7 g ⅐ h/ml; P ‫؍‬ 0.001). Polymorphisms in the SLCO1B1 gene associated with lower rifampin exposure were more frequent among black subjects. In conclusion, marked intersubject variation of the rifampin AUC 0-24 values was observed, but the mean values of the AUC 0-24 did not significantly vary between patients with tuberculosis and healthy controls. Lower rifampin exposure was associated with the polymorphism of the SLCO1B1 c.463C>A gene. When adjusted for the patient mg/kg dosage and transporter gene polymorphisms, rifampin exposure was lower in patients with tuberculosis, which suggests that additional absorption or metabolic processes affect rifampin exposure with tuberculosis disease.

Nutritional Supplementation Increases Rifampin Exposure among Tuberculosis Patients Coinfected with HIV

“…Surprisingly, SLCO1B1 genotypes were not found to affect drug exposure in our study population. These results are in contrast to those reported by Weiner et al and Chigutsa et al, who have reported that SLCO1B1 rs4149032 was associated with substantially reduced rifampin exposure (37,38). However, our results are in line with those from a Chinese study (39).…”

Phase I Safety, Pharmacokinetics, and Pharmacogenetics Study of the Antituberculosis Drug PA-824 with Concomitant Lopinavir-Ritonavir, Efavirenz, or Rifampin

“…An association has been reported between an SLCO1B1 polymorphism and rifampin PK (20,21). It is important to consider whether these polymorphisms affect drug interactions.…”

“…Genetic polymorphisms reported to predict plasma PK of efavirenz (11)(12)(13)(14)(15), rifampin (20,21), and lopinavir (17,18) were genotyped in duplicate. For efavirenz, CYP2B6 516 G¡T (rs3745274), 983 T¡C (rs28399499), and 15582 C¡T (rs4803419) were assayed using MassARRAY iPLEX Gold (Sequenom Inc., San Diego, CA, USA).…”

The SLCO1B1*15 haplotype associated with lower clinical outcome in Indonesian tuberculosis patients

“…3 Despite this concern, there is limited RIF dosing information to ensure optimal outcome. A number of studies have shown interindividual RIF pharmacokinetic variability [4][5][6] and this genetic diversity may support the need to increase RIF dosage in Indonesian TB patients. 7 Recent research has explored a link between genetics and treatment efficacy 4,8 and the present study is the first to assess genetic diversity in Indonesian patients with confirmed diagnosis of pulmonary TB (PTB) and extrapulmonary TB (EPTB).…”