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ClinicalTrials.gov identifier NCT00479206.

The pharmacokinetic properties of oral and intravenous artesunate (2 mg/kg of body weight) were studied in 19 adult patients with acute uncomplicated Plasmodium falciparum malaria by using a randomized crossover design. A sensitive bioassay was used to measure the antimalarial activity in plasma which results from artesunate and its principal metabolite, dihydroartemisinin. The oral study was repeated with 15 patients during convalescence. The mean absolute oral bioavailability of the antimalarial agent in patients with acute malaria was 61% (95% confidence interval [CI], 52 to 70%). The absorption and elimination of oral artesunate were rapid, with a mean elimination half-life of antimalarial activity of 43 min (95% CI, 33 to 53 min). Following oral administration to patients with acute falciparum malaria, peak antimalarial activity in plasma and the area under the plasma concentration-time curve were approximately double those during convalescence and the apparent volume of distribution and clearance were approximately half those during convalescence (P < 0.005). Acute malaria is associated with a significant reduction in the clearance of artesunateassociated antimalarial activity.Artemisinin (qinghaosu) and its derivatives are a major advance in antimalarial treatment (8). These drugs are increasingly used in southeast Asia for the treatment of multidrugresistant Plasmodium falciparum malaria (2,8,15,22). Artesunate, the most widely available of the artemisinin-related compounds, is a hemisuccinate derivative of dihydroartemisinin (DHA). It may be given parenterally, intravenously, intramuscularly, orally, or rectally. Oral artesunate is used either alone or in combination, usually with mefloquine (15). Despite considerable use in areas where malaria is endemic, there are relatively few data on the pharmacokinetics of artesunate in the treatment of malaria (2-4, 6, 9, 13, 21, 27). There are concerns that the various artesunate formulations may have different bioavailabilities and that the development of resistance will be accelerated if suboptimal doses are used (13,24). Optimization of dosing recommendations is also important because of evidence that high doses of parenteral artemisinin derivatives (artemether, arteether) are neurotoxic in experimental mammals (16).Oral artesunate and artemether, but not artemisinin, are hydrolyzed rapidly back to the common metabolite DHA, which is intrinsically more active as an antimalarial agent. Oral artesunate may be considered mainly a prodrug for DHA, as the metabolite is the main contributor to overall antimalarial activity (2, 6). Thus, in order to compare different formulations of these drugs accurately and to guide the accurate choice of compound, the bioavailability of the antimalarial agent must be assessed.Chemical methods for the assay of DHA and the related derivatives have a limit of accurate quantitation above the range of concentrations which provide significant antimalarial effect. High-performance liquid chromatography (HPLC) with electrochemical detect...

Cambodia's first-line artemisinin combination therapy, dihydroartemisinin-piperaquine (DHA-PPQ), is no longer sufficiently curative against multidrug-resistant Plasmodium falciparum malaria at some Thai-Cambodian border regions. We report recent (2008 to 2013) drug resistance trends in 753 isolates from northern, western, and southern Cambodia by surveying for ex vivo drug susceptibility and molecular drug resistance markers to guide the selection of an effective alternative to DHA-PPQ. Over the last 3 study years, PPQ susceptibility declined dramatically (geomean 50% inhibitory concentration [IC 50 ] increased from 12.8 to 29.6 nM), while mefloquine (MQ) sensitivity doubled (67.1 to 26 nM) in northern Cambodia. These changes in drug susceptibility were significantly associated with a decreased prevalence of P. falciparum multidrug resistance 1 gene (Pfmdr1) multiple copy isolates and coincided with the timing of replacing artesunate-mefloquine (AS-MQ) with DHA-PPQ as the first-line therapy. Widespread chloroquine resistance was suggested by all isolates being of the P. falciparum chloroquine resistance transporter gene CVIET haplotype. Nearly all isolates collected from the most recent years had P. falciparum kelch13 mutations, indicative of artemisinin resistance. Ex vivo bioassay measurements of antimalarial activity in plasma indicated 20% of patients recently took antimalarials, and their plasma had activity (median of 49.8 nM DHA equivalents) suggestive of substantial in vivo drug pressure. Overall, our findings suggest DHA-PPQ failures are associated with emerging PPQ resistance in a background of artemisinin resistance. The observed connection between drug policy changes and significant reduction in PPQ susceptibility with mitigation of MQ resistance supports reintroduction of AS-MQ, in conjunction with monitoring of the P. falciparum mdr1 copy number, as a stop-gap measure in areas of DHA-PPQ failure.

BackgroundThe emergence of artemisinin resistance has raised concerns that the most potent antimalarial drug may be under threat. The currently recommended daily dose of artesunate (AS) is 4 mg/kg, and is administered for 3 days together with a partner antimalarial drug. This study investigated the impact of different AS doses on clinical and parasitological responses in malaria patients from an area of known artemisinin resistance in western Cambodia.MethodsAdult patients with uncomplicated P. falciparum malaria were randomized into one of three 7-day AS monotherapy regimens: 2, 4 or 6 mg/kg/day (total dose 14, 28 and 42 mg/kg). Clinical, parasitological, pharmacokinetic and in vitro drug sensitivity data was collected over a 7-day inpatient period and during weekly follow-up to 42 days.Results143 patients were enrolled (n = 75, 40 and 28 to receive AS 2, 4 and 6 mg/kg/day respectively). Cure rates were high in all treatment groups at 42 days despite almost half the patients remaining parasitemic on Day 3. There was no impact of increasing AS dose on median parasite clearance times, median parasite clearance rates or on the proportion of patients remaining parasitemic on Day 3. However at the lowest dose used (2 mg/kg/d) patients with parasitemia >10,000/µL had longer median (IQR) parasite clearance times than those with parasitemia <10,000/µL (63 (48–75) vs. 84 (66–96) hours, p<0.0001). 19% of patients in the high-dose arm developed neutropenia (absolute neutrophil count <1.0×109/L) by Day 14 and resulted in the arm being halted early.ConclusionThere is no pharmacodynamic benefit of increasing the daily dose of AS (4mg/kg) currently recommended for short-course combination treatment of uncomplicated malaria, even in regions with emerging artemisinin resistance, as long as the partner drug retains high efficacy.Trial RegistrationClinicalTrials.gov NCT00722150.

1 The pharmacokinetic and effect kinetic properties of oral (p.o.), intramuscular (i.m.), and intrarectal (i.r.) artemether (5 mg kg‐1) were compared in a crossover study in eight healthy adult volunteers. Plasma concentrations of artemether (AM) and its active metabolite dihydroartemisinin (DHA) were measured by high performance liquid chromatography with reductive mode electrochemical detection (h.p.l.c.‐ECD), and plasma antimalarial activity in vitro (effect) was assessed on the same samples by a sensitive bioassay (BA). 2 Artemether was absorbed rapidly after oral administration with a mean (95% CI) Cmax for the parent compound of 406 (249 to 561) nmol l‐1 and for DHA of 1009 (639 to 1379) nmol l‐1 with tmax values of 1.7 (1.2 to 2.2) and 1.8 (1.4 to 2.2) h respectively. The mean (95% CI) elimination half‐life of AM was 2.6 (1.8 to 3.4) h and for DHA was 1.9 (1.4 to 2.4) h. Plasma concentration and effect profiles with h.p.l.c.‐ECD and BA were similar suggesting that other unidentified bioactive metabolites contributed little to antimalarial activity in vivo. 3 Absorption was slower, more variable, and DHA concentrations were lower following the i.m. and i.r. routes of administration. The mean (95% CI) relative bioavailability compared with oral artemether in the 6 h following administration AUC(0,6h) was 25 (9 to 41)% following i.m. and 35 (10 to 60)% following i.r. artemether. 4 These data demonstrate that oral artemether undergoes extensive first pass metabolism to the more active metabolite DHA. Plasma antimalarial activity following oral administration is significantly greater than following i.m. administration. The i.r. route of administration provided similar bioavailability to i.m. injection but there was considerable variability in absorption following both routes. Further studies are needed to determine whether i.r. artemether would be an effective treatment of severe malaria in the rural tropics in situations where oral or parenteral administration is not possible.

Abstract. The single-dose pharmacokinetics of 100 mg of orally administered artesunate (AS) were studied in 6 patient volunteers with uncomplicated falciparum malaria and in 6 healthy volunteers. Plasma concentrations of both the parent drug, AS, and its major metabolite, dihydroartemisinin (DHA), were measured simultaneously by highperformance liquid chromatography (HPLC) with electrochemical detection (ECD). The antimalarial activity of each plasma sample measured by an in vitro bioassay (BA) was used to derive activity concentrations. Artesunate was absorbed rapidly and then almost completely hydrolyzed to DHA in patients, whereas hydrolysis was incomplete in healthy volunteers. The mean Ϯ standard deviation (SD) maximum concentration (C max ) of AS was 296 Ϯ 110 nmol/ L, the time to peak blood level (t max ) was 0.71 Ϯ 0.66 hr, the half-life (t 1/2,z ) was 0.41 Ϯ 0.34 hr, and the bioavailability over 12 hr (area under the curve [AUC] (0-12) ) was 253 Ϯ 185 nmol hr/L. Measured by HPLC, the C max and AUC (0)(1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12) values of DHA in patients with malaria were significantly greater than in volunteers (1,948 Ϯ 772 and 1,192 Ϯ 315 nmol/L; 4,024 Ϯ 1,585 and 1,763 Ϯ 607 nmol hr/L, respectively; P Յ 0.05). These differences were even greater when measured by BA. The C max for patients with malaria was 2,894 Ϯ 2,497 and 795 Ϯ 455 nmol/L for volunteers, and AUC (0-12) was 5,970 Ϯ 3,625 and 1,307 Ϯ 391 nmol hr/L, respectively (P Յ 0.05). In contrast, DHA parameter estimates for t 1/2,z and t max were similar between patients and healthy volunteers, with values of 0.80 Ϯ 0.30 versus 0.87 Ϯ 0.06 hr and 1.50 Ϯ 0.55 versus 1.13 Ϯ 0.52 hr, respectively (P Ͼ 0.5). Both drug metabolism and tissue protein binding could contribute to the differences between the antimalarial activity of artemisinin drugs in healthy volunteers and malaria infected patients.