Population pharmacokinetics of azithromycin and chloroquine in healthy adults and paediatric malaria subjects following oral administration of fixed-dose azithromycin and chloroquine combination tablets

Zhao et al. Malaria Journal 2014, 13:36 http://www.malariajournal.com/content/13/1/36 RESEARCH Open Access Population pharmacokinetics of azithromycin and chloroquine in healthy adults and paediatric malaria subjects following oral administration of fixed-dose azithromycin and chloroquine combination tablets Qinying Zhao1*, Thomas G Tensfeldt1, Richa Chandra2 and Diane R Mould3 Abstract Background: Population pharmacokinetics (PK) of azithromycin (AZ) and chloroquine (CQ) following administration of fixed-dose combination tablet formulations of AZ and CQ (AZCQ) was evaluated using data from two studies: 1) in children with symptomatic uncomplicated falciparum malaria in sub-Saharan Africa; and 2) in healthy adults in the United States. Methods: Study 1 included paediatric subjects randomized to either AZCQ or artemether-lumefantrine treatment in Cohort 1 (age 5–12 years) and Cohort 2 (age 6–59 months). Dosing of AZCQ was approximately 30 mg/kg AZ and 10 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 150/50 mg per tablet). Study 2 included adults randomized to receive either two AZCQ tablets (AZ/CQ 250/155 mg per tablet) or individual commercial tablets of AZ 500 mg and CQ 300 mg. Serum AZ and plasma CQ concentrations from both studies were pooled. Population PK models were constructed using standard approaches to evaluate the concentration-time data for AZ and CQ and to identify any covariates predictive of PK behaviour. Results: A three-compartment PK model with linear clearance and absorption adequately described AZ data, while a two-compartment model with linear clearance and absorption and an absorption lag adequately described CQ data. No overall bias or substantial model misspecification was evident using diagnostic plots and visual predictive checks. Body weight as an allometric function was the only covariate in the final AZ and CQ PK models. There were significantly lower AZ (0.488 vs 0.745 [mg•h/L]/[mg/kg], p < 0.00001) and CQ (0.836 vs 1.27 [mg•h/L]/[mg/kg], p < 0.00001) exposures (AUCinf) normalized by dose (mg/kg) in children compared with the adults. Conclusions: The PK of AZ and CQ following administration of AZCQ was well described using a three- and twocompartment model, respectively. AZ and CQ exhibited linear absorption and clearance; the model for CQ included an absorption lag. Weight was predictive of exposure for both AZ and CQ. Assuming equivalent dosing (mg/kg), AZ and CQ exposure in children would be expected to be lower than that in adults, suggesting that children may require a higher dose (mg/kg) than adults to achieve the same AZ and CQ exposure. Keywords: Population pharmacokinetics, Malaria, Azithromycin, Chloroquine * Correspondence: 1 Pfizer Inc, 445 Eastern Point Road, MS8260-2112, Groton CT 06340, USA Full list of author information is available at the end of the article © 2014 Zhao et al.; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Zhao et al. Malaria Journal 2014, 13:36 http://www.malariajournal.com/content/13/1/36 Background Worldwide, malaria remains a burden to global health. The World Health Organization reports that approximately 3.3 billion people were at risk of malaria in 2010, with the population of sub-Saharan Africa at the highest risk [1]. The combination of AZ and CQ exhibits synergistic activity against CQ-resistant strains of Plasmodium falciparum in vitro and in vivo [2-4]. Results from Phase 2 and 3 studies demonstrated that the combination of AZ and CQ had ~95% or more efficacy against symptomatic uncomplicated P. falciparum malaria in various geographic areas [3,5,6]. To be useful in combination, anti-malarial agents must not have clinically significant pharmacokinetic (PK) interactions. A lack of a PK interaction between AZ and CQ has been demonstrated [7]. In healthy adults, CQ did not have any clinically relevant effect on the PK of AZ; AZ also did not have any clinically relevant effect on either the PK of CQ or its active metabolite, desethylchloroquine (DECQ). For adults, an investigational AZCQ tablet formulation has been developed containing AZ 250 mg and CQ 155 mg and has been evaluated in a bioavailability study in healthy adult volunteers with intensive PK sampling [8]. In this study, the AZCQ tablet was shown to be bioequivalent to the AZ 500 mg (Zithromax®, Pfizer Inc, New York, NY, USA) and CQ 300 mg (Aralen®, Sanofi Aventis, Bridgewater, NJ, USA) tablets taken individually in healthy adults using area under the concentrationtime curve (AUC) as the criterion of exposure. Two additional paediatric AZCQ tablet formulations (AZ 300 mg/CQ 150 mg per tablet and AZ 150 mg/CQ 50 mg per tablet) were developed and evaluated in paediatric patients with malaria in Africa using sparse PK sampling. The population PK analysis approach can be helpful in characterizing drug concentration-time profiles and between-subject variability in the PK. In addition, these analyses are useful to identify factors that are predictive of PK variability. Therefore, this population PK analysis was performed by combining the data from the bioavailability and paediatric treatment studies to evaluate the population PK of AZ and CQ in healthy adults from US and paediatric malaria subjects from sub-Saharan Africa. Methods Study design PK data from two studies were pooled and analysed. The first study was an open-label efficacy study that compared the efficacy of AZCQ versus artemether-lumefantrine (AL) for the treatment of uncomplicated P. falciparum malaria in children in sub-Saharan Africa. In this study, patients were enrolled in two cohorts by age (Cohort 1 Page 2 of 8 [5–12 years] and Cohort 2 [6–59 months]) and randomized to either AZCQ or AL treatment. This analysis only includes data from AZCQ-treated patients. In AZCQtreated patients, dosing of AZCQ was based on weight, with patients receiving approximately 30 mg/kg of AZ and 10 mg/kg of CQ. AZCQ tablets were given once daily for three days based on weight (≥20 kg weight: AZ/CQ 300/100 mg strength tablet; 5 to <20 kg weight: AZ/CQ 150/50 mg strength tablet). The second study was an open-label, randomized, single dose study to estimate the bioavailability of AZCQ tablets in healthy adult volunteers in the US. Subjects in this study were randomized to receive either two AZCQ tablets (AZ/CQ 250/155 mg strength tablet; test treatment) or co-administration of individual commercial tablets of AZ 500 mg and CQ 300 mg (reference treatment). Blood sampling and analysis In the paediatric study, sparse blood samples were collected from both cohorts to determine AZ concentration in serum and CQ/desethylchloroquine (DECQ) concentration in plasma prior to AZCQ dosin (...truncated)