Background: Population pharmacokinetics (PK) of azithromycin (AZ) and chloroquine (CQ) following administration\r\nof fixed-dose combination tablet formulations of AZ and CQ (AZCQ) was evaluated using data from two studies:\r\n1) in children with symptomatic uncomplicated falciparum malaria in sub-Saharan Africa; and 2) in healthy adults in\r\nthe United States.\r\nMethods: Study 1 included paediatric subjects randomized to either AZCQ or artemether-lumefantrine treatment in\r\nCohort 1 (age 5ââ?¬â??12 years) and Cohort 2 (age 6ââ?¬â??59 months). Dosing of AZCQ was approximately 30 mg/kg AZ and\r\n10 mg/kg CQ once daily for 3 days (for =20 kg weight: AZ/CQ 300/100 mg per tablet; 5 to <20 kg weight: AZ/CQ\r\n150/50 mg per tablet). Study 2 included adults randomized to receive either two AZCQ tablets (AZ/CQ 250/155 mg\r\nper tablet) or individual commercial tablets of AZ 500 mg and CQ 300 mg. Serum AZ and plasma CQ concentrations\r\nfrom both studies were pooled. Population PK models were constructed using standard approaches to evaluate the\r\nconcentration-time data for AZ and CQ and to identify any covariates predictive of PK behaviour.\r\nResults: A three-compartment PK model with linear clearance and absorption adequately described AZ data, while a\r\ntwo-compartment model with linear clearance and absorption and an absorption lag adequately described CQ\r\ndata. No overall bias or substantial model misspecification was evident using diagnostic plots and visual predictive\r\nchecks. Body weight as an allometric function was the only covariate in the final AZ and CQ PK models. There were\r\nsignificantly lower AZ (0.488 vs 0.745 [mgââ?¬Â¢h/L]/[mg/kg], p < 0.00001) and CQ (0.836 vs 1.27 [mgââ?¬Â¢h/L]/[mg/kg],\r\np < 0.00001) exposures (AUCinf) normalized by dose (mg/kg) in children compared with the adults.\r\nConclusions: The PK of AZ and CQ following administration of AZCQ was well described using a three- and twocompartment\r\nmodel, respectively. AZ and CQ exhibited linear absorption and clearance; the model for CQ included\r\nan absorption lag. Weight was predictive of exposure for both AZ and CQ. Assuming equivalent dosing (mg/kg), AZ\r\nand CQ exposure in children would be expected to be lower than that in adults, suggesting that children may\r\nrequire a higher dose (mg/kg) than adults to achieve the same AZ and CQ exposure.
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