Claire Pressiat1, Veronique Mea-Assande2, Caroline Yonaba3, Jean-Marc Treluyer1,4, Désiré-Lucien Dahourou5,6,7, Madeleine Amorissani-Folquet8, Stéphane Blanche1,9, François Eboua10, Diarra Ye11, Gabrielle Lui1, Karen Malateste7, Yi Zheng1,4, Valeriane Leroy12, Déborah Hirt1,4. 1. Paris Descartes University, EA 7323, Paris, France. 2. PACCI Programme, Site ANRS, MONOD Project, Abidjan, Côte d'Ivoire. 3. Pediatric Department, Centre Hospitalier Universitaire Yalgado Ouédraogo, Ouagadougou, Burkina Faso. 4. Clinical Pharmacology Department, AP-HP, Paris Centre Hospital Group, Paris, France. 5. MONOD Project, ANRS 12206, Centre de Recherche Internationale pour la Santé, Ouagadougou, Burkina Faso. 6. Centre Muraz, Bobo-Dioulasso, Burkina Faso. 7. Inserm, Unité U1219, Université Bordeaux, Bordeaux, France. 8. Pediatric Department, Centre Hospitalier Universitaire of Cocody, Abidjan, Côte d'Ivoire. 9. Immunology Hematology Pediatric Unit, AP-HP, Necker Hospital, Paris, France. 10. Pediatric Department, Centre Hospitalier Universitaire de Yopougon, Abidjan, Côte d'Ivoire. 11. Department of Paediatrics, CHU Charles de Gaulle, Université de Ouagadougou, Ouagadougou, Burkina Faso. 12. Inserm, Unité U1027, Université Paul Sabatier of Toulouse 3, Toulouse, France.
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.
RCT Entities:
AIMS: A clinical study was conduct in HIV-infectedchildren 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.
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