Pharmacokinetics and dosing rationale of Para-Aminosalicylic acid in children and the evaluation of the in vitro metabolism of Ethionamide, Terizidone and Para-aminosalicylic acid

[摘要] ENGLISH ABSTRACT:BACKGROUND: The emergence of mycobacterium tuberculosis resistance to first linedrugs has renewed interest in second-line anti-tuberculosis drugs. Generally, Paraaminosalicylicacid (PAS) is less potent and frequently more toxic than the first linedrugs. Furthermore, the pharmacokinetics of PAS in children has not been wellcharacterized.AIMS: The aims of the present study were (1) to determine the pharmacokinetics ofPAS in pediatric patients, (2) to describe the discrepancy between children and adultpharmacokinetics and the appropriate dosing regimen of PAS and (3) to investigate thepotential of the second-line anti-tuberculosis drugs PAS, terizidone and ethionamide(often used as first-line drug in children) to inhibit the catalytic activities of CYP450 1A2and 2C9.PATIENTS: Twenty two patients with drug resistant tuberculosis were included in thestudy. Ten patients were children with mean age of 4.2 years (range: 1 to 12 years).Twelve patients were adults with mean age of 31.3 years (range: 18 to 53). 4 children(40%) and 4 adults (33.3%) were HIV positive and were on ART.METHODS: Children received 75 mg/kg twice daily on the first visit and after two weeksthey received 150 mg/kg once. Adults received a standard 4 g twice daily. Bloodsamples were taken at different time points after the dose. In the additional study, theinhibitory effects of PAS, ethionamide and terizidone on phenacetin O-deethylation, amarker substrate of CYP1A2 and diclofenac 4'-hydroxylation, a marker substrate ofCYP2C9, were studied using human liver microsomes.RESULTS: For the 75 mg/kg dose, the mean AUC was 233.3 =g•h/ml and the mean CLwas 10.4 l/h/kg. The mean of the observed Cmax of the drug was 45.4 =g/ml and themean Tmax was 4.8 hrs. For the 150 mg/kg dose, the mean AUC of PAS was 277.9=g•h/ml and the mean CL was 47.1 l/h/kg. The mean of the observed Cmax of the drugwas 56.5 =g/ml and the mean Tmax was 4.8 hrs. On the first visit the mean AUC was 368=g•h/ml and the mean CL was 13.2 l/h/kg. The mean of the observed Cmax of PAS was51.3 =g/ml and the mean Tmax was 5.2 hrs. On the second visit the mean AUC was 230 =g•h/ml and the mean CL was 23.9 l/h/kg. The mean of the observed Cmax of PAS was37.6 =g/ml and the mean Tmax was 5.2 hrs. The comparisons between pharmacokineticsprofile of PAS and patients characteristics e.g. age, indicated no statistically significantdifferences between children (both treatment regimens) and adult patients as well asHIV positive and negative patients. In the in vitro study, all drugs demonstrated noinhibition potency towards the investigated CYP450 enzymes.CONCLUSIONS:The dose of 75 mg/kg twice daily in children appears to be appropriateto achieve serum concentration above the PAS minimum inhibitory concentration ofapproximately 1 =g/ml. PAS, ethionamide and terizidone are unlikely to affect themetabolism of concomitantly administered medications that are metabolized by eitherCYP450 1A2 and/or 2C9 isoenzymes.

[发布机构] Stellenbosch University