The SLCO1B1 rs4149032 polymorphism is highly prevalent in South Africans and is associated with reduced rifampin concentrations: dosing implications

Abstract

Among patients with tuberculosis, rifampin plasma concentrations and sputum conversion rates have been reported to be lower in Africans. Rifampin is a substrate of P-glycoprotein (coded for by the ABCB1 gene) and organic anion-transporting polypeptide 1B1 (coded for by SLCO1B1). The objectives were to identify genetic polymorphisms of drug transporters and the transcriptional regulators pregnane X receptor (PXR) and constitutive androstane receptor (CAR) with an impact on rifampin pharmacokinetics in South Africans. Fifty-seven patients with tuberculosis from Cape Town underwent pharmacokinetic sampling during treatment with rifampin, pyrazinamide, isoniazid, and ethambutol. DNA was genotyped for ABCB1, SLCO1B1, PXR, and CAR polymorphisms by using real-time PCR. NONMEM was used for data analysis. The allele frequency of the SLCO1B1 rs4149032 polymorphism was 0.70. Patients heterozygous and homozygous for this polymorphism had reductions in the bioavailability (and, thus, the area under the curve [AUC]) of rifampin of 18% and 28%, respectively. Simulations showed that increasing the daily rifampin dose by 150 mg in patients with the polymorphism would result in plasma concentrations similar to those of wild-type individuals and reduce the percentage of patients with peak plasma concentrations (C(max)) below 8 mg/liter from 63% to 31%. ABCB1, PXR, and CAR polymorphisms were not associated with differences in rifampin pharmacokinetics. SLCO1B1 rs4149032 was present in most patients and was associated with substantially reduced rifampin exposure. These data suggest that the standard recommended dose of rifampin should be reconsidered for South Africans.

Figures

Fig. 1.

Linkage disequilibrium (LD) plots for the assessed SNPs in SLCO1B1. The shading within the boxes indicates the extent of LD between respective single-nucleotide polymorphisms, with white indicating a weaker LD than gray.

Fig. 2.

Visual predictive check of the final model. The open circles indicate the observations. The upper dotted line represents the 95th percentile of the observation. The continuous line represents the median of the observations. The lower dotted line represents the 5th percentile of the observations. The shaded areas are the simulated confidence intervals for the corresponding percentiles. For a clearer picture of the low concentrations, a log-transformed visual predictive check of the same model is shown on the right. The VPC is truncated at the LLOQ for both predictions and observations.

Fig. 3.

Predicted rifampin plasma concentration-time profiles for typical individuals weighing 46 and 62.5 kg homozygous for the common allele and minor alleles, respectively, with standard weight-based dosing (A) and after an additional 150 mg for those homozygous for the common allele (B).

Fig. 4.

Box (interquartile range)-and-whisker (95th percentiles) plot of simulated variation in the Cmax based on the final model, with weight, sex, and genotype distributions in our data set. Simulations were performed by using the currently recommended doses (dose 1), and a genotype-based dose whereby SLCO1B1 rs41490932 carriers received an additional 150 mg of rifampin daily (dose 2).