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
2012
ENGLISH ABSTRACT: BACKGROUND: The emergence of mycobacterium tuberculosis resistance to first line
drugs has renewed interest in second-line anti-tuberculosis drugs. Generally, Paraaminosalicylic
acid (PAS) is less potent and frequently more toxic than the first line
drugs. Furthermore, the pharmacokinetics of PAS in children has not been well
characterized.
AIMS: The aims of the present study were (1) to determine the pharmacokinetics of
PAS in pediatric patients, (2) to describe the discrepancy between children and adult
pharmacokinetics and the appropriate dosing regimen of PAS and (3) to investigate the
potential 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 1A2
and 2C9.
PATIENTS: Twenty two patients with drug resistant tuberculosis were included in the
study. 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 weeks
they received 150 mg/kg once. Adults received a standard 4 g twice daily. Blood
samples were taken at different time points after the dose. In the additional study, the
inhibitory effects of PAS, ethionamide and terizidone on phenacetin O-deethylation, a
marker substrate of CYP1A2 and diclofenac 4’-hydroxylation, a marker substrate of
CYP2C9, 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 CL
was 10.4 l/h/kg. The mean of the observed Cmax of the drug was 45.4 =g/ml and the
mean 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 drug
was 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 was
51.3 =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 was
37.6 =g/ml and the mean Tmax was 5.2 hrs. The comparisons between pharmacokinetics
profile of PAS and patients characteristics e.g. age, indicated no statistically significant
differences between children (both treatment regimens) and adult patients as well as
HIV positive and negative patients. In the in vitro study, all drugs demonstrated no
inhibition potency towards the investigated CYP450 enzymes.
CONCLUSIONS:The dose of 75 mg/kg twice daily in children appears to be appropriate
to achieve serum concentration above the PAS minimum inhibitory concentration of
approximately 1 =g/ml. PAS, ethionamide and terizidone are unlikely to affect the
metabolism of concomitantly administered medications that are metabolized by either
CYP450 1A2 and/or 2C9 isoenzymes.%%%%AFRIKAANSE…
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