Pharmacokinetics and Ex Vivo Antimalarial Activity of Artesunate-Azithromycin in Healthy Volunteers

Abstract

In 18 male healthy subjects, artesunate (200 mg)-azithromycin (1,500 mg) daily for 3 days was found to be well tolerated, with only mild gastrointestinal disturbances reported. The pharmacokinetic properties of artesunate-azithromycin given in combination are comparable to those of the drugs given alone. Artesunate and its major active metabolite, dihydroartemisinin, are responsible for most of the ex vivo antimalarial activity, with a delayed contribution by azithromycin.Artemisinin-based combination therapies (ACTs) are currently recommended for the first-line treatment of uncomplicated Plasmodium falciparum malaria, worldwide (25). The two risk groups most vulnerable to malaria are young children and pregnant women, who are immunosuppressed and particularly at risk for severe disease (26). In pregnant women, limited safety and pharmacological data are available on the use of ACTs, particularly during the first trimester. The World Health Organization (WHO) recommends that quinine combined with the antibiotic clindamycin be given for 7 days during the first trimester and, if quinine-clindamycin is either unavailable or fails, an ACT is indicated (25). Historically, 7-day daily regimens are limited by poor compliance in an outpatient setting (9). For the second and third trimesters, WHO recommends artesunate (AS)-clindamycin.However, a drawback in using clindamycin is its short halflife of 2.4 h (10), which necessitates repeated dosing every 12 h, which may affect compliance and thus effectiveness (20). Unlike clindamycin, the antibiotic azithromycin (AZ) possesses wider therapeutic applications (8) and has pharmacokinetic properties that are characterized by more extensive tissue distribution, prolonged phagocyte concentrations, and a longer elimination half-life of about 50 h (1, 14). These favorable features allow once-daily dosing with AZ compared with multiple daily dosing with clindamycin. Recently, 3-day courses of quinine with either 1,000 or 1,500 mg AZ were shown to be well tolerated and effective in curing multidrug-resistant P. falciparum malaria in adults (12). AZ also has a good safety profile in children and pregnant women (6, 21).Because of AZ's favorable pharmacokinetic properties, artesunate (AS) plus AZ may be a suitable ACT during pregnancy. In vitro studies have shown dihydroartemisinin (DHA), the active metabolite of the prodrug AS, combined with AZ to be additive (17) tending to synergistic (16) against multidrugresistant P. falciparum strains. Recent studies of AS-AZ have shown good efficacy in the treatment of uncomplicated falciparum malaria using 3-day regimens of 200 mg AS daily with either 1,000 mg AZ (cure rate, 89%) (15) or 1,500 mg AZ (cure rates, Ͼ92%) (15, 24). The AS-AZ combinations are far more effective than monotherapy, with recrudescence rates of between 10% and 80% with 3-to 5-day courses of AS alone (4) and 67% with 1,000 mg/day AZ for 3 days (7). Similarly, the addition of AZ (1,000 mg daily for 2 days) to 1,500 mg sulfadoxine and 75 mg pyrimethamine for the treatment o...

Pharmacokinetics and Ex Vivo Antimalarial Activity of Artesunate-Amodiaquine plus Methylene Blue in Healthy Volunteers

“…The PK properties of AS, DHA, AQ, and DAQ with and without MB are summarized in Table 1. Overall, the PK properties of AS, DHA, AQ, and DAQ obtained in this study are in broad agreement with those obtained in other studies in healthy volunteers given either AS or AQ alone or in combination with a longer-acting antimalarial drug (27)(28)(29)(30).…”

In Vivo Efficacy and Tolerability of Artesunate–Azithromycin for the Treatment of Falciparum Malaria in Vietnam

“…The gastrointestinal disturbances were probably azithromycin related as these adverse events were also experienced in healthy Vietnamese volunteers administered the same 3-day ASAZ regimen. 19 The high efficacy and good tolerability of ASAZ reported in the present study further supports earlier studies in Bangladesh 20 and Thailand 21 that showed a 3-day course of azithromycin (30 mg/kg/day)-artesunate (4 mg/kg/day) to be effective (PCR-corrected cure rate > 92%) in curing uncomplicated P. falciparum malaria in adults and children. However, a lower dosage of azithromycin (20 mg/kg) coadministered with artesunate (4 mg/kg) given daily for 3 days in Tanzania 22 and Thailand 21 was less efficacious (PCR-corrected cure rate < 89%), emphasizing the importance of adequate azithromycin dosing.…”

“…The azithromycin dose of 25 mg/kg/day selected in the present study was considered the maximum acceptable dose based on our previous study in healthy Vietnamese volunteers. 19 Prolongation of parasite clearance times (> 72 hours) reported in studies from western Cambodia 23 and south Vietnam 24 with artesunate alone was not evident in the present study, with no patients having parasites present on day 3 after starting treatment, suggesting that the parasite populations were susceptible to artesunate at the time of the study. This was further confirmed with a lack of polymorphism in the PfKelch 13 gene of falciparum parasites sampled from the patients.…”

Targeting nasopharyngeal carcinoma by artesunate through inhibiting Akt/mTOR and inducing oxidative stress

“…The ED 50 of artesunate in inhibiting proliferation in multiple NPC cell lines is 16–22 μ m ( Figure ). In the treatment of mild–moderate falciparum malaria, patients receive a single dose of up to 200 mg oral artesunate and serum concentrations of artesunate are less than 10 μ m . However, for severe malaria, intravenous artesunate is recommended in adults .…”