The Pharmacokinetics of Para - Aminosalicylic Acid in HIV - 1 uninfected and HIV Co - Infected Tuberculosis Patients 2 receiving antiretroviral therapy , managed for Multidrug - 3 resistant and Extensively Drug - Resistant Tuberculosis 4

19 The emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) 20 Mycobacterium tuberculosis prompted the reintroduction of para-aminosalicylic acid 21 (PAS) to protect companion anti-tuberculosis drugs from additional acquired resistance. 22 In sub-Saharan Africa, MDR/XDR tuberculosis with HIV co-infection is common and 23 concurrent treatment of HIV-infection and MDR/XDR tuberculosis is required. Out of 24 necessity, patients receive multiple drugs and PAS therapy is frequent; however neither 25 potential drug interactions nor the effect of HIV-infection are known. Potential drug-drug 26 interaction with PAS and the effect of HIV-infection was examined in 73 pulmonary 27 tuberculosis patients; 22 (30.1%) were HIV co-infected. 41 pulmonary MDR or XDR 28 tuberculosis patients received 4g PAS twice-daily or, in a second cross-over study, 29 another 32 patients were randomized receiving 4g PAS twice-daily or 8g PAS once30 daily. A PAS population pharmacokinetic model in two dosing regimens was developed; 31 potential covariates affecting its pharmacokinetics were examined; and Monte Carlo 32 simulations were conducted evaluating the pharmacokinetic-pharmacodynamic index. 33 The probability of target attainment (PTA) to maintain PAS levels above minimal 34 inhibitory concentration (MIC) during the dosing interval was estimated by simulation of 35 once-, twice-, and thrice-daily dosing regimens not exceeding 12g daily. Efavirenz 36 (EFV) concurrent medication or possibly HIV-seropositive status resulted in a 52% 37 increase in PAS clearance and a corresponding >30% reduction in mean PAS area 38 under the concentration curve in 19 of 22 HIV-TB co-infected patients. Current practice 39 recommends maintenance of PAS concentrations > 1 μg/mL (the MIC of M. 40 tuberculosis), but the model predicts that at only a minimum dose of 4g twice-daily 41 on S etem er 2, 2017 by gest httpaac.asm .rg/ D ow nladed fom dosing can this PTA be achieved in at least 90% of the population whether or not EFV 42 was concomitantly administered. Once-daily dosing of 12g PAS will not provide PAS 43 concentrations exceeding MIC over the entire dosing interval if co-administered with 44 EFV, while 4g twice-daily ensures concentrations exceeding MIC over the entire dosing 45 interval, even in HIV-infected patients who received EFV. 46 on S etem er 2, 2017 by gest httpaac.asm .rg/ D ow nladed fom