1991. Rifampin Target Attainment During Treatment of Tuberculosis Meningitis: The Role of Pharmacogenetics
Session: Poster Abstract Session: Antimicrobial Pharmacokinetics and Pharmacodynamics
Saturday, October 29, 2016
Room: Poster Hall

Background: Tuberculosis (TB) patients with a single nucleotide polymorphism (SNP) of the drug transporter gene SLCO1B1 (C463A) have reduced oral bioavailability (F) of rifampin. The impact of this pharmacogenetic variability on TB treatment outcomes is uncertain. A recent rifampin population PK model for TB meningitis (TBM) by Savic et al. (2015) provided the opportunity to examine the effect of pharmacogenetics on rifampin concentrations in CSF.

Methods: We evaluated the population PK model for rifampin during TBM treatment with published CSF rifampin data that had not been used in model development (D'Oliveira et al. 1972), with a two-compartment distribution model, first-order absorption and clearance, and a CSF effect compartment. We performed a Monte Carlo simulation of rifampin CSF concentrations in TBM patients (n=10,000), with rifampin dose by weight bands based on WHO guidelines, and minimum inhibitory concentrations (MICs) sampled from the wild-type distribution. Based on published data, we introduced the SLCO1B1 SNP into the model as a 36% reduction in oral bioavailability. We calculated the AUC0-24/MIC ratio on the 7th day of treatment, with a target AUC0-24/MIC of 271.

Results: We observed agreement between predicted and observed rifampin CSF concentrations (Figure 1). Across all TBM patients with the high-F SLCO1B1 genotype, a mean of 77% reached the target, compared with 50% among patients with low-F genotype. At an MIC of 0.25 mg/L, the AUC target in CSF was reached in 79% of patients with high-F genotype, compared with 15% of patients with low-F genotype (Figure 2).

Conclusion: We observed a difference in target attainment by SLCO1B1 genotype across a range of MICs below the breakpoint of 1.0 ug/mL. Next, we will simulate rifampin dosing strategies for TBM treatment, to inform clinical trial design.

Figure 1. Evaluation of Savic et al population PK model with previously published rifampin CSF data.

Legend: Triangle = Observations; Dash = 95th percentile predicted conc; Solid = 50th percentile predicted conc; Dot = 5th percentile predicted conc.

Figure 2. Probability of target attainment based on pharmacogenetics variability in SLCO1B1.

Legend: Solid = Low F genotype; Dash = High F genotype

Alyssa Mezochow, MSc1, Tao Liu, BSc2, Kiran Thakur, MD3, Vijay Ivaturi, PhD2 and Christopher Vinnard, MD4, (1)Drexel University College of Medicine, Philadelphia, PA, (2)University of Maryland School of Pharmacy, Baltimore, MD, (3)Department of Neurology, Columbia University, New York, NY, (4)Public Health Research Institute, Rutgers University, Newark, NJ

Disclosures:

A. Mezochow, None

T. Liu, None

K. Thakur, None

V. Ivaturi, None

C. Vinnard, None

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