Evaluation of pharmacokinetic interaction between tenofovir and para-aminosalicylic acid in healthy volunteers

Tuberculosis has an annual incidence rate of 10 million globally. One million of these new patients are expected to be HIV(+). Tenofovir is a widely used drug in HIV treatment. para-Aminosalicylic acid is a second line drug for treatment of drug resistant tuberculosis. Tenofovir is mainly excreted in urine via glomerular filtration and Organic Anion Transporter 1 (OAT1) and OAT3 mediated tubular secretion. It has been shown that PAS inhibits OAT1 and OAT3 mediated transport of tenofovir, in vitro. The aim of this study was to investigate if there is a drug-drug interction between PAS and tenofovir in healthy human subjects. For this purpose, we designed an open-label, randomised, two-period and two-sequence, crossover clinical study. Twenty healthy Korean volunteers were included into the study. The drugs have been administered as single dose tenofovir (300 mg) in the reference group and simultaneous single oral dose of tenofovir (300 mg) and 7 oral doses of PAS (5.28 g, BID) in the test group. Since PAS is a substrate of organic cation transporter 2 (OCT2), effect of OCT2 genetic polymorphisms (c.808G>T, c.602C>T, c.596C>T) on PAS pharmacokinetics was evaluated. Plasma and urine samples of the volunteers were collected and tenofovir and PAS concentrations were analysed. Plasma tenofovir concentrations significantly decreased when it was administered concomitantly with PAS. Maximum plasma concentration (Cmax) values (mean ± SD) were 245.2 ± 78.1 and 86.5 ± 39.7 ng/mL; area under the curve (AUC) values were 2205.9 ± 426.0 and 789.3 ± 253.2 ng·h/mL in the reference and test groups, respectively. The geometric mean ratios (test/reference) and 90% CIs of the Cmax and AUC were 0.33 (0.28-0.38) and 0.29 (0.26-0.33), respectively. These values were beyonf the range of 0.80-1.25 "no effect boundaries" suggested by the FDA. Therefore the interaction was significant. OCT2 haplotypes did not affect PAS pharmacokinetics. In conclusion, concomitant administration of PAS significantly decreased plasma tenofovir concentration in healthy human subjects. Other clinical studies are warranted to support the clinical significance of this interaction.