Population Pharmacokinetics and Pharmacodynamics of Piperaquine, as chemoprevention, in Young Children with Uncomplicated Malaria
Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
Introduction: Malaria is a longstanding problem among African children. A promising prevention strategy is the drug combination dihydroartemisinin-piperaquine (DHA-PQ). However, the pharmacokinetic (PK) properties of PQ and the knowledge about the relationship between drug level and clinical efficacy for prevention is limited. Aim: Primary objectives were to (i) describe the PK of PQ in children less than two years old, (ii) to assess non-adherence behavior and (iii) to quantify the relationship between adherence, PQ PK and the hazard of getting a malaria infection in order to determine the effective PQ exposure in children. Method: Data was compiled from a prospective clinical trail conducted in 187 Ugandan children (median age 17.2 months), receiving either no chemoprevention, or active treatment of 160 or 240 mg of PQ, based on their weight. Dosing was for three consecutive days each month, for 18 months. Non-linear mixed effects- and parametric survival analysis methodology were used to characterize population PK- and PD relationships. Result: PQ PK in children was best described by a two-transit compartment absorption model and three-compartment disposition model. The typical values of clearance (CL/F) and volume of distribution (Vc/F) were 10.0 L/h and 1290 L, respectively. On average, estimated patient adherence was 77.4%. PQ plasma concentration was found to be significant predictor of risk of malaria infection with estimated IC50 of 8.9 ng/ml. Conclusion: Major determinants of unsatisfactory malaria protection were low PQ plasma levels driven by non-adherence and/or insufficient dosing. Current dosing regimens in pediatrics should be revised and adherence reinforced in order to provide sustained protection from malaria.
Place, publisher, year, edition, pages
2015. , 21 p.
IdentifiersURN: urn:nbn:se:uu:diva-259074OAI: oai:DiVA.org:uu-259074DiVA: diva2:843106
University of California, San Francisco
Subject / course
Master of Science Programme in Pharmacy
Savic, Rada, Assistant Professor
Hammarlund-Udenaes, Margareta, Professor