Peter Donald
Stellenbosch University ,Cape Town, South Africa
Title: The influence of NAT-1 genotype on Para-aminosalicylic acid (PAS) pharmacokinetics and intolerance following once daily or twice daily PAS dosing
Biography
Biography: Peter Donald
Abstract
Para-aminosalicylic acid (PAS) is still used for extensively- or multidrug- resistant tuberculosis (TB) (XDR or MDR). Despite relatively good survival (81% 5-years) when used with streptomycin, current XDR TB mortality using PAS with remaining drugs is poor (30%-90%). We reviewed PAS literature concluding that PAS accompanied by weak drugs should be dosed 20 g daily; intolerance did not increase with once daily-dosing. Early bactericidal activity studies found PAS moderately bactericidal. We studied pharmacokinetics and tolerance over 8-days post-administration of granular slow-release PAS (PASER) 8 g once daily or 2x4 g in 32 patients with MDR or XDR TB using a randomized, two-period, cross-over design; NAT1 and NAT2 genotypes were determined and tolerability assessed by visual-analog scales. Median Cmax following PAS once daily and twice daily was 80 and 61 μg/mL and AUC0-12 652 and 428 μg.h/mL respectively (p<0.001 for both comparisons). The commonest NAT1 genotype was *4/*10 found in 45% of patients. The *14A allele was present in two patients (6.3%) and NAT1*3 in one patient all three had higher PAS Cmax (p=0.007). Intolerance was similar between regimens; VAS scores for intolerance were low and more than 50% of scores were 0. Neither Cmax nor AUC was associated with intolerance; occurrence of intolerance differed little between regimens. Women had higher Cmax (p=0.003), but less intolerance. PAS could be dosed once daily without increased intolerance; this might improve efficacy. The slow acetylator status of NAT1*4/*10 genotypes is confirmed and for the first time the NAT1*3 allele associated with high PAS concentrations.