LACK OF A PHARMACOKINETIC INTERACTION BETWEEN AZITHROMYCIN AND CHLOROQUINE

JACK A. COOK 0 EDWARD J. RANDINITIS 0 CANDACE R. BRAMSON 0 DAVID L. WESCHE 0 Pfizer Global Research 0 Development 0 Pfizer Incorporated 0 Ann Arbor 0 Michigan 0 0 search and Development , Michigan Laboratories , Pfizer Inc. , 2800 Plymouth Road, Ann Arbor, MI 48105 A study was conducted to investigate a possible pharmacokinetic interaction between azithromycin and chloroquine. Twenty-four subjects received azithromycin, 1,000 mg a day for three days, followed by a washout period, then azithromycin, 1,000 mg plus chloroquine 600 mg base on days 1 and 2, and azithromycin, 1,000 mg plus chloroquine 300 mg base on day 3 of the final period. A second group of 16 subjects received chloroquine, 600 mg base on days 1 and 2, then 300 mg base on day 3. Blood samples were obtained serially up to 624 hours after the day 3 dose in each period. Log transformed maximum concentration and area under the curve values of azithromycin and chloroquine were compared using 90% confidence intervals calculated from appropriate analysis of variance models. Ninety percent confidence intervals for all pharmacokinetic parameters were contained within the interval 80-125%, which indicates the absence of a clinically relevant pharmacokinetic interaction. - A combination azithromycin/chloroquine regimen is currently being developed for the treatment of chloroquineresistant malaria. Synergy of antimalarial effect has been reported with chloroquine in combination with azithromycin in vitro.1 A pilot clinical trial showed promising results in the treatment of Plasmodium falciparum malaria in India: 28 days after taking chloroquine or azithromycin, clinical success was observed in only 27% and 33% of patients, respectively, but when the two drugs were taken in combination, clinical success was achieved in 97% of patients.2 The mechanism of synergy between these two agents is not understood. Chloroquine resistance has been reversed by co-administration of agents, such as verapamil, with the ability to inhibit pglycoprotein-mediated efflux.3 It is not known whether azithromycin is such an inhibitor; however, azithromycin has been shown to be a p-glycoprotein substrate.4 Thus, we investigated whether alterations in human pharmacokinetics of either compound could be responsible for at least part of the increased effectiveness of these compounds when given together. MATERIALS AND METHODS Study design. This was a single-center, phase 1, open-label, randomized, multiple-dose (three days) study conducted in two groups of healthy volunteers. Forty subjects who fulfilled the entry criteria were randomly assigned to one of two groups (group 1, 24 subjects; group 2, 16 subjects). The threeday regimens of azithromycin and chloroquine were identical to regimens studied in the pilot clinical trial and the chloroquine regimen was consistent with the standard World Health Organization three-day chloroquine treatment regimen.5 Group 1 received azithromycin (Zithromax ; Pfizer Inc., Ann Arbor, MI), 1,000 mg every day for three days during the first period. After a 35-week washout, group 1 participants received azithromycin, 1,000 mg plus chloroquine (Aralen ; Bayer, Myerstown, PA), 1,000 mg (600 mg base) on days 1 and 2, and azithromycin, 1,000 mg plus chloroquine 500 mg (300 mg base) on day 3. Group 2 subjects received chloroquine, 1,000 mg (600 mg base) on days 1 and 2 and 500 mg (300 mg base) on day 3. The effect of chloroquine on azithromycin pharmacokinetics was to be examined by withinsubject comparisons of azithromycin data obtained during the two regimens received by group 1. However, because of the long half-life of chloroquine, between-group comparisons were used to investigate the effect of azithromycin on chloroquine pharmacokinetics. Subjects of any race that met the following criteria were eligible to participate in the study: good health as determined by medical history, physical examination, clinical laboratory measurements, and electrocardiogram (ECG); age 1860 years inclusive; either male or female of nonchild-bearing potential; and with a body weight 50 kg. Subjects could not participate in the study if any of the following conditions existed: history of retinopathy, liver disease, or alcoholism; retinal or visual changes attributable to either 4-aminoquinoline compounds or any other etiology; psoriasis or porphyria; hypersensitivity to azithromycin, any other macrolide antibiotics, or 4-aminoquinoline compounds; use of any medication not considered acceptable by the clinical investigators during the 14-day period before the start of the study; donation of a unit of blood or participation in a study of investigational or marketed drugs during the 30-day period before initiation of treatment with study drug; or significant urine concentration of any drug that could interfere with the study. All doses were taken between 7:00 AM and 11:00 AM, after an overnight fast, with 240 mL of tap water. Food was restricted for at least one hour after each dose on days 1 and 2, and for at least four hours after dosing on day 3. Safety assessments consisted of clinical observation, physical examination, vital signs measurement, clinical laboratory measurements, and adverse events. Twelve-lead ECGs were recorded at screening and closeout for all subjects. In addition, for subjects in the chloroquine alone and chloroquine plus azithromycin treatment groups, ECGs were recorded predose on day 1 and 35 hours postdose on days 1 and 3. In each study period, blood samples were drawn before dosing on day 3 and at 1, 2, 3, 4, 6, 12, 24, 48, 72, 96, 120, 168, 240, and 624 hours, except that 240- and 624-hour samples were not obtained when azithromycin was dosed alone. Samples of venous blood (5 mL for azithromycin and/or 7 mL for chloroquine) were withdrawn into vacuum blood collection tubes containing either no anticoagulant (for azithromycin) or sodium heparin (for chloroquine). After each collection, blood samples were centrifuged and plasma was separated. Plasma samples were stored frozen in polyethylene tubes at 20C until analyzed for azithromycin or chloroquine and desethylchloroquine (its major and active metabolite) concentrations. Ethical approval. The protocol and consent documents were reviewed and approved by the Institutional Review Board of the Pfizer Research Clinic. The study was conducted in accordance with the International Conference on Harmonization Guidelines for Good Clinical Practice, the Declaration of Helsinki, and in compliance with United States Food and Drug Administration regulations for informed consent and protection of subject rights as described in 21 Code of Federal Regulations 50, 56, and 312. Written informed consent was obtained from all participants. Subjects were told that they were free to withdraw from the study at any time. Bioanalytical methods. Serum concentrations for azithromycin were measured by a validated liquid chromatography/ electron capture method at BAS Analytics (We (...truncated)