生物等效性和生物利用度杂志

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Relative Bioavailability of a Fixed-Combination Tablet Formulation of Azithromycin and Chloroquine in Healthy Adult Subjects

Qinying Zhao, Vivek Purohit, Jenny Cai, Robert R. LaBadie and Richa Chandra

A fixed-dose combination of azithromycin and chloroquine (AZCQ) is in development for intermittent preventive treatment of malaria in pregnant women (IPTp). The combination has demonstrated synergistic activity against chloroquine-resistant strains of Plasmodium falciparum in vitro and in vivo and efficacy in Phase 2 and 3 treatment studies in patients with symptomatic uncomplicated P. falciparum malaria. This was an open-label, randomized, single-dose, parallel-group study to estimate the relative bioavailability of two AZCQ tablets, each containing azithromycin base 250 mg and chloroquine base 155 mg (test treatment), compared with the coadministration of commercially available individual tablets of azithromycin base 500 mg and chloroquine base 300 mg (reference treatment) in 40 healthy male and female subjects (aged 18-55 years; body weight >50.0 kg). Fasting subjects were randomized 1:1 to receive either test or reference treatment. Blood samples for the determination of serum azithromycin and plasma chloroquine concentrations were collected at specified time points pre- and post-dose for noncompartmental pharmacokinetic analyses. Safety evaluations included monitoring adverse events and vital signs as well as performing clinical laboratory tests. All subjects completed the study. Area under the concentration– time curve from time zero to time of last measurable concentration (AUClast) of azithromycin and chloroquine for the two AZCQ tablets was comparable to the reference treatment. The relative bioavailability as measured by AUClast ratio of adjusted geometric means (90% confidence interval) for the two AZCQ tablets was 101% (85.4%, 119%) for azithromycin and 99.1% (84.0%, 117%) for chloroquine compared with the reference treatment. Maximum concentration values for the two AZCQ tablets were approximately 13.0% higher for azithromycin and 11.0% lower for chloroquine compared with reference treatment. Both treatments were well tolerated. This AZCQ tablet formulation is currently being evaluated in Phase 3 clinical trials for IPTp.