Suboptimal cotrimoxazole prophylactic concentrations in HIV-infected children according to the WHO guidelines

Abstract

Aims: A clinical study was conduct in HIV-infected children to evaluate the prophylactic doses of cotrimoxazole [sulfamethoxazole (SMX) and trimethoprim (TMP)] advised by the WHO.

Methods: Children received lopinavir-based antiretroviral therapy with cotrimoxazole prophylaxis (200 mg of SMX/40 mg of TMP once daily). A nonlinear mixed effects modelling approach was used to analyse plasma concentrations. Factors that could impact the pharmacokinetic profile were investigated. The model was subsequently used to simulate individual exposure and evaluate different administration schemes.

Results: The cohort comprised 136 children [average age: 1.9 years (range: [0.7-4]), average weight: 9.5 kg (range: [6-16.3])]. A dose per kg was justified by the significant influence of implementing an allometrically scaled body size covariate on SMX and TMP pharmacokinetics. SMX and TPM clearance were estimated at 0.49 l h^-1 /9.5 kg and 3.06 l h^-1 /9.5 kg, respectively. The simulated exposures obtained after administration of oral dosing recommended by the WHO for children from 10 to 15 kg were significantly lower than in adults for SMX and TMP. This could induce a reduction of effectiveness of cotrimoxazole. Simulations show that regimens of 30 mg kg^-1 of SMX and 6 mg kg^-1 of TMP in the 5-10 kg group and 25 mg kg^-1 of SMX and 5 mg kg^-1 of TMP in the 10-15 kg group are more suitable doses.

Conclusions: In this context of high prevalence of opportunistic infections, a lower exposure to cotrimoxazole in children than adults was noted. To achieve comparable exposure to adults, a dosing scheme per kg was proposed.

Trial registration: ClinicalTrials.gov NCT01127204.

Keywords: HIV; children; pharmacokinetics; sulfamethoxazole; trimethoprim.

Figure 1

SMX (on the left) and TMP (on the right) prediction‐corrected visual predictive check: comparison between the 5th (lower dashed line), 50th (solid line) and 95th (upper dashed line) percentiles obtained from 1000 simulations and the observed data (points) for SMX or TMP concentrations

Figure 2

SMX (at the top) and TMP (at the bottom) NPDE

Figure 3

AUC_0–24 SMX and AUC_0–24 TMP for different dose regimens [median (black lines) and 5th and 95th percentiles (black dashed lines)]. The grey lines represent the recommended preventive AUC_0–24 in adults (mean ± 2SD)