Probability of mycobactericidal activity of para-aminosalicylic acid with novel dosing regimens.

Abstract

Para-aminosalicylic acid (PAS) is currently one of the add-on group C medicines recommended by the World Health Organization for multidrug-resistant tuberculosis treatment. At the recommended doses (8-12g per day in two to three divided doses) of the widely available slow-release PAS formulation, studies suggest PAS exposures are lower than those reached with older PAS salt formulations and do not generate bactericidal activity. Understanding the PASER dose-exposure-response relationship is crucial for dose optimization. The objective of our study was to establish a representative population pharmacokinetics model for PASER and evaluate the probability of bactericidal and bacteriostatic target attainment with different dosing regimens. To this end, we validated and optimized a previously published population pharmacokinetic model on an extended dataset. The probability of target attainment was evaluated for once-daily doses of 12g, 14g, 16g and 20g PASER. The final optimized model included the addition of variability in bioavailability and allometric scaling with body weight on disposition parameters. Peak PAS concentrations over minimum inhibitory concentration of 100, which is required for bactericidal activity are achieved in 53%, 65%, 72% and 84% of patients administered 12, 14, 16 and 20g once-daily PASER, respectively, when MIC is 1mg/L. For the typical individual, the exposure remained above 1mg/L for ≥ 98% of the dosing interval in all the evaluated PASER regimens. The pharmacokinetic/pharmacodynamic parameters linked to bactericidal activity should be determined for 14g, 16g and 20g once-daily doses of PASER.