Pharmacokinetics of dihydroartemisinin in Artekin tablets for single and repeated dosing in Chinese healthy volunteers

Hong, Xia; Liu, Changhui; Huang, Xuan; Huang, Tian-lai; Ye, Shao-mei; Wei-ping, OU; Ning-sheng, Wang; Mi, Suiqing

doi:10.1002/bdd.607

Cited by 19 publications

(26 citation statements)

References 29 publications

(29 reference statements)

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“…The pharmacokinetic properties of dihydroartemisinin in healthy volunteers and nonpregnant patients with malaria have been well characterized with noncompartmental analysis, but no data on the population pharmacokinetics of dihydroartemisinin when administered as the fixed dihydroartemisinin-piperaquine combination are available (7,11,19,27,40,54). Results presented in this study for nonpregnant women with malaria are in agreement with previously published results for nonpregnant patients with uncomplicated malaria.…”

Section: Figsupporting

confidence: 89%

“…Not enough data were collected in the absorption phase to support both an estimation of the drug transit rate and the absorption rate from the last transit compartment to the central compartment, and the two rate constants were therefore set to be identical. Dihydroartemisinin has previously been described by one-and two-compartment models, when modeled as individual concentration-time data in nonpregnant healthy volunteers and patients with malaria, which supports the structural model result in this study (19,26,38,39). Caution should be exerted when modeling artemisinin compounds since censoring of data (a high proportion of data below the limit of quantification at later time points) can lead to inappropriate structural models if model selection is based on statistical criterion alone (OFV) and not confirmed by simulation-based diagnostics (Fig.…”

Section: Figsupporting

confidence: 87%

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

Tärning

Rijken

McGready

et al. 2012

Antimicrob Agents Chemother

140

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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...

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Section: Figsupporting

confidence: 89%

Section: Figsupporting

confidence: 87%

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

Tärning

Rijken

McGready

et al. 2012

Antimicrob Agents Chemother

140

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“…The half-life of only 18 days in pregnant women and the low day 28 concentrations of PPQ suggest that at least monthly doses would be required when DHA-PPQ is considered for intermittent preventive treatment in pregnancy or chemoprophylaxis. Pharmacokinetic parameter estimates (clearance and apparent volume of distribution) for DHA were slightly higher than those previously reported in nonpregnant adult patients but lower than those reported in healthy volunteers (6,9,12,18,20). DHA exposure after the first dose was significantly lower in pregnant women; however, the differences were relatively small and may be explained by the high interindividual variability.…”

Section: Discussioncontrasting

confidence: 66%

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

Rijken

McGready

Phyo

et al. 2011

Antimicrob Agents Chemother

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Dihydroartemisinin-piperaquine is a fixed-dose artemisinin-based combination treatment. Some antimalarials have altered pharmacokinetics in pregnancy. Pregnant women in the 2nd or 3rd trimester and matched nonpregnant women with uncomplicated falciparum malaria were treated with a total of 6.4 mg/kg of body weight dihydroartemisinin and 51.2 mg/kg piperaquine once daily for 3 days. Venous blood samples were drawn at prespecified time points over 9 weeks. Plasma dihydroartemisinin and piperaquine concentrations were analyzed by liquid chromatography-mass spectrometry. Piperaquine and dihydroartemisinin pharmacokinetics were well described. There were no significant differences in total piperaquine exposure (P ‫؍‬ 0.80) or drug exposure during the terminal elimination phase (72 h to infinity) (P ‫؍‬ 0.64) between the two groups. The apparent volume of distribution of piperaquine was significantly smaller (602 liters/kg versus 877 liters/kg) in pregnant women than in nonpregnant women (P ‫؍‬ 0.0057), and the terminal elimination half-life was significantly shorter (17.8 days versus 25.6 days; P ‫؍‬ 0.0023). Dihydroartemisinin exposure after the first dose was significantly lower (844 h ؋ ng/ml versus 1,220 h ؋ ng/ml, P ‫؍‬ 0.0021) in pregnant women, but there were no significant differences in total dihydroartemisinin exposure or maximum concentrations between the two groups. There were no significant differences in any pharmacokinetic parameters between the second and third trimester. These results obtained through noncompartmental analysis suggest that in the treatment of falciparum malaria, there are no clinically important differences in the pharmacokinetics of dihydroartemisinin or piperaquine between pregnant and nonpregnant women. However, a more detailed analysis using population pharmacokinetic modeling is needed to fully investigate the differences found for some of the pharmacokinetic parameters, such as the terminal half-life.In the eastern and western border areas of Thailand, Plasmodium falciparum has developed resistance to almost every antimalarial drug (5). This poses particular problems for the treatment of pregnant women, a group especially vulnerable to P. falciparum infections. The World Health Organization (WHO) recommends the use of artemisinin combination therapy (ACT) (short-course, 3-day treatments) in the second and third trimester of pregnancy (37). However, pregnant women often have lower antimalarial blood concentrations than nonpregnant women and are therefore at risk of undertreatment (13-16, 34, 36). Dihydroartemisinin-piperaquine (DHA-PPQ) is one of the most promising ACTs. It is a coformulation of dihydroartemisinin and piperaquine. Randomized clinical trials in Asia, Africa, and South America indicate excellent tolerability and high cure rates in nonpregnant populations (2-4, 8, 25, 31, 35, 38). Recently, DHA-PPQ was found to be well tolerated and effective in the treatment of multiple recrudescent P. falciparum infections in 50 pregnant women in Thailand (27) and in 104 pregnan...

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“…However, previous detailed PK studies of oral and parenteral administration of ARS have demonstrated a clear malaria effect on the relative bioavailability thought to result from reduced first pass metabolism (40,41). The decreased absorption rate with increasing parasite density was unexpected and opposite to previous observations (39,(42)(43)(44)(45)(46)(47)(48). The underlying mechanism of this effect cannot be elucidated from data collected in this study.…”

Section: Population Pharmacokineticscontrasting

confidence: 85%

Population Pharmacokinetic and Pharmacodynamic Modeling of Artemisinin Resistance in Southeast Asia

Das

Dondorp

Nosten

et al. 2017

AAPS J

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Abstract.Orally administered artemisinin-based combination therapy is the first-line treatment against uncomplicated P. falciparum malaria worldwide. However, the increasing prevalence of artemisinin resistance is threatening efforts to treat and eliminate malaria in Southeast Asia. This study aimed to characterize the exposure-response relationship of artesunate in patients with artemisinin sensitive and resistant malaria infections. Patients were recruited in Pailin, Cambodia (n = 39), and Wang Pha, Thailand (n = 40), and received either 2 mg/kg/day of artesunate mono-therapy for 7 consecutive days or 4 mg/kg/day of artesunate monotherapy for 3 consecutive days followed by mefloquine 15 and 10 mg/kg for 2 consecutive days. Plasma concentrations of artesunate and its active metabolite, dihydroartemisinin, and microscopy-based parasite densities were measured and evaluated using nonlinear mixed-effects modeling. All treatments were well tolerated with minor and transient adverse reactions. Patients in Cambodia had substantially slower parasite clearance compared to patients in Thailand. The pharmacokinetic properties of artesunate and dihydroartemisinin were well described by transit-compartment absorption followed by one-compartment disposition models. Parasite density was a significant covariate, and higher parasite densities were associated with increased absorption. Dihydroartemisinin-dependent parasite killing was described by a delayed sigmoidal Emax model, and a mixture function was implemented to differentiate between sensitive and resistant infections. This predicted that 84% and 16% of infections in Cambodia and Thailand, respectively, were artemisinin resistant. The final model was used to develop a simple diagnostic nomogram to identify patients with artemisinin-resistant infections. The nomogram showed > 80% specificity and sensitivity, and outperformed the current practice of day 3 positivity testing.

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Pharmacokinetics of dihydroartemisinin in Artekin tablets for single and repeated dosing in Chinese healthy volunteers

Cited by 19 publications

References 29 publications

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

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

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

Population Pharmacokinetic and Pharmacodynamic Modeling of Artemisinin Resistance in Southeast Asia

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