Claire Pressiat
University Paris 5
Objectives: The aims of this study were to describe the pharmacokinetics of the cotrimoxazole (CTX : association of sulfamethoxazole (SMX) and trimethoprim (TMP)) in a large population of children, to identify factors influencing the pharmacokinetics of TMP and SMX, and to evaluate the doses recommended by the World Health Organization during childhood.
Methods: All HIV-infected children diagnosed before two years of age, and confirmed by DNA-PCR were enrolled in an initial therapeutic cohort offering a cART with cotrimoxazole prophylaxis (TMP/SMX: 200/40/day once daily) in Ouagadougou (Burkina Faso) and Abidjan (Ivory Coast). Quantification of TMP and SMX in human plasma collected 6 months, 19 months and 25 months after cART initiation was performed using a validated liquid chromatography method with UV-detector. Plasma concentrations collected from HIV-infected children aged from 6 months to 4 years were analyzed using a nonlinear mixed effects modeling, with NONMEM software. Estimated individual PK parameters were used to calculated individual exposures to TMP and SMX. Moreover, pharmacogenetics studies were carried out on the enzymes involved in the metabolism of SMX.
Results: Overall, 114 children with a median age of 1.8 years, a median weight of 8.9 kg, and a sex ratio (M/F) of 1.15 were analysed. TMP’s and SMX’s PK were described by a one-compartment model with first-order absorption and elimination. The effect on body weight on the apparent volume of distribution was significant for SMX and TMP. For the SMX, the effect of polymorphism of the enzyme NAT 1, involved in the metabolism of SMX, affects the clearance of the drug.
Conclusions: A very large interindividual variability in cotrimoxazole concentrations was pointed out. With the dosing regimen currently recommended, exposures are much lower of the children than those found in adults. In order to maintain a comparable exposure as in adults in this population, an increase of the dose should be considered.
Reference: PAGE 25 (2016) Abstr 5781 [www.page-meeting.org/?abstract=5781]
Poster: Drug/Disease modeling - Paediatrics