Artesunate and Dihydroartemisinin (DHA): Unusual Decomposition Products Formed under Mild Conditions and Comments on the Fitness of DHA as an Antimalarial Drug

Dihydroartemisinin-piperaquine (DHP) is an important new treatment for drug-resistant malaria, although pharmacokinetic studies on the combination are limited. In Papua, Indonesia, we assessed determinants of the therapeutic efficacy of DHP for uncomplicated malaria. Plasma piperaquine concentrations were measured on day 7 and day 28, and the cumulative risk of parasitological failure at day 42 was calculated using survival analysis. Of the 598 patients in the evaluable population 342 had infections with Plasmodium falciparum, 83 with Plasmodium vivax, and 173 with a mixture of both species. The unadjusted cumulative risks of recurrence were 7.0% (95% confidence interval [CI]: 4.6 to 9.4%) for P. falciparum and 8.9% (95% CI: 6.0 to 12%) for P. vivax. After correcting for reinfections the risk of recrudescence with P. falciparum was 1.1% (95% CI: 0.1 to 2.1%). The major determinant of parasitological failure was the plasma piperaquine concentration. A concentration below 30 ng/ml on day 7 was observed in 38% (21/56) of children less than 15 years old and 22% (31/140) of adults (P ‫؍‬ 0.04), even though the overall dose (mg per kg of body weight) in children was 9% higher than that in adults (P < 0.001). Patients with piperaquine levels below 30 ng/ml were more likely to have a recurrence with P. falciparum (hazard ratio [HR] ‫؍‬ 6.6 [95% CI: 1.9 to 23]; P ‫؍‬ 0.003) or P. vivax (HR ‫؍‬ 9.0 [95% CI: 2.3 to 35]; P ‫؍‬ 0.001). The plasma concentration of piperaquine on day 7 was the major determinant of the therapeutic response to DHP. Lower plasma piperaquine concentrations and higher failure rates in children suggest that dose revision may be warranted in this age group.

Section: Discussionmentioning

confidence: 99%

Clinical and Pharmacological Determinants of the Therapeutic Response to Dihydroartemisinin-Piperaquine for Drug-Resistant Malaria

Price

Hasugian

Ratcliff

et al. 2007

“…5). Dihydroartemisinin is unstable in acidic pH, and a prolonged gastric retention in pregnant women might result in an increased presystemic decomposition of dihydroartemisinin and a reduction in relative bioavailability compared to nonpregnant women (12,18). The metabolism of drugs catalyzed by UDP glucuronosyltransferase (UGT) isoenzymes (UGT1A4 and UGT2B7) is increased during pregnancy (2).…”

Section: Figmentioning

confidence: 99%

Population Pharmacokinetics of Dihydroartemisinin and Piperaquine in Pregnant and Nonpregnant Women with Uncomplicated Malaria

Tärning

Rijken

McGready

et al. 2012

140

c Pregnant women are particularly vulnerable to malaria. The pharmacokinetic properties of antimalarial drugs are often affected by pregnancy, resulting in lower drug concentrations and a consequently higher risk of treatment failure. The objective of this study was to evaluate the population pharmacokinetic properties of piperaquine and dihydroartemisinin in pregnant and nonpregnant women with uncomplicated malaria. Twenty-four pregnant and 24 matched nonpregnant women on the Thai-Myanmar boarder were treated with a standard fixed oral 3-day treatment, and venous plasma concentrations of both drugs were measured frequently for pharmacokinetic evaluation. Population pharmacokinetics were evaluated with nonlinear mixed-effects modeling. The main pharmacokinetic finding was an unaltered total exposure to piperaquine but reduced exposure to dihydroartemisinin in pregnant compared to nonpregnant women with uncomplicated malaria. Piperaquine was best described by a three-compartment disposition model with a 45% higher elimination clearance and a 47% increase in relative bioavailability in pregnant women compared with nonpregnant women. The resulting net effect of pregnancy was an unaltered total exposure to piperaquine but a shorter terminal elimination half-life. Dihydroartemisinin was best described by a one-compartment disposition model with a 38% lower relative bioavailability in pregnant women than nonpregnant women. The resulting net effect of pregnancy was a decreased total exposure to dihydroartemisinin. The shorter terminal elimination half-life of piperaquine and lower exposure to dihydroartemisinin will shorten the posttreatment prophylactic effect and might affect cure rates. The clinical impact of these pharmacokinetic findings in pregnant women with uncomplicated malaria needs to be evaluated in larger series. Children under the age of 5 years and pregnant women are especially vulnerable to malaria. An estimated 85 million pregnancies occurred in areas with falciparum malaria transmission during 2007 (13). Malaria during pregnancy is responsible for maternal and fetal mortality (42,43). Both falciparum malaria and vivax malaria during pregnancy are associated with low birth weight resulting from intrauterine growth restriction (8, 9, 48). Effective treatment and prophylaxis of malaria in pregnancy rely on the use of efficacious antimalarial drugs.Pregnancy has substantial effects on the pharmacokinetic characteristics of many antimalarial drugs. Previous studies report artesunate, artemether, dihydroartemisinin, sulfadoxine, atovaquone, proguanil, cycloguanil, pyrimethamine, and lumefantrine concentrations to be reduced in pregnant women (25,33,34,36,44,58). This may contribute to lower antimalarial cure rates in pregnant than nonpregnant adults (58). Other studies report no pharmacokinetic differences in pregnant women compared to nonpregnant women (e.g., pyrimethamine and amodiaquine/desethylamodiaquine) or even a higher drug exposure during pregnancy (pyrimethamine) (15,25,46).Artemisinin-based combi...

“…Of the various artemisinin-type compounds in use, dihydroartemisinin (DHA), the reduced lactol derivative of artemisinin, is an antimalarial compound on its own (currently coformulated with piperaquine) and the main bioactive metabolite of artesunate and artemether. DHA itself is chemically fragile and displays a marked propensity to undergo ring opening of the lactol and rearrangement under neutral conditions, leading to a new, biologically active peroxide, which in turn rapidly decays to the inert end product deoxyartemisinin (6). Under aqueous conditions, artemisinins tend to react with labile ferrous iron and heme-Fe(II), and in certain organic solvents, such as dimethyl sulfoxide (DMSO), they degrade very quickly (7).…”

mentioning

confidence: 99%

Stability of the Antimalarial Drug Dihydroartemisinin under Physiologically Relevant Conditions: Implications for Clinical Treatment and Pharmacokinetic and In Vitro Assays

Parapini

Olliaro

Navaratnam

et al. 2015

f Artemisinins are peroxidic antimalarial drugs known to be very potent but highly chemically unstable; they degrade in the presence of ferrous iron, Fe(II)-heme, or biological reductants. Less documented is how this translates into chemical stability and antimalarial activity across a range of conditions applying to in vitro testing and clinical situations. Dihydroartemisinin (DHA) is studied here because it is an antimalarial drug on its own and the main metabolite of other artemisinins. The behaviors of DHA in phosphate-buffered saline, plasma, or erythrocyte lysate at different temperatures and pH ranges were examined. The antimalarial activity of the residual drug was evaluated using the chemosensitivity assay on Plasmodium falciparum, and the extent of decomposition of DHA was established through use of high-performance liquid chromatography with electrochemical detection analysis. The role of the Fe(II)-heme was investigated by blocking its reactivity using carbon monoxide (CO). A significant reduction in the antimalarial activity of DHA was seen after incubation in plasma and to a lesser extent in erythrocyte lysate. Activity was reduced by half after 3 h and almost completely abolished after 24 h. Serum-enriched media also affected DHA activity. Effects were temperature and pH dependent and paralleled the increased rate of decomposition of DHA from pH 7 upwards and in plasma. These results suggest that particular care should be taken in conducting and interpreting in vitro studies, prone as their results are to experimental and drug storage conditions. Disorders such as fever, hemolysis, or acidosis associated with malaria severity may contribute to artemisinin instability and reduce their clinical efficacy.A rtemisinin derivatives have been the most potent antimalarials available to date; they are highly active against all Plasmodium species and parasite stages, including young gametocytes, and constitute the backbone of malaria case management for severe and uncomplicated malaria (as a component of artemisinin combination therapy [ACT]) (1). The emergence and spread of artemisinin resistance in Southeast Asia is, therefore, a serious threat to malaria control (2, 3).All artemisinin derivatives share a distinctive 1,2,4-trioxane pharmacophore, which confers their antimalarial activity (the corresponding acyclic analogues lacking the endoperoxide bridge are inactive) (4, 5) but also makes these molecules particularly highly reactive and thus difficult to quantify in plasma or blood. Of the various artemisinin-type compounds in use, dihydroartemisinin (DHA), the reduced lactol derivative of artemisinin, is an antimalarial compound on its own (currently coformulated with piperaquine) and the main bioactive metabolite of artesunate and artemether. DHA itself is chemically fragile and displays a marked propensity to undergo ring opening of the lactol and rearrangement under neutral conditions, leading to a new, biologically active peroxide, which in turn rapidly decays to the inert end product deoxyartemisi...