Evaluation of the safety and relative bioavailability of a new dihydroartemisinin tablet formulation in healthy Thai volunteers

Kongpatanakul, Supornchai; Chatsiricharoenkul, Somruedee; Sathirakul, Korbtham; Suputtamongkol, Yupin; Atipas, Suvajana; Watnasirichaikul, Suchat; Pongnarin, Piyapat; Sangvanich, Polkit

doi:10.1016/j.trstmh.2007.05.010

Cited by 7 publications

(3 citation statements)

References 21 publications

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“…A formulation of up to 5.3 mg/kg was well tolerated when administered as a single dose to Thai volunteers but resulted in a significant but transient decrease in hemoglobin and hematocrit. 33,34 The safety and tolerability of higher doses of dihydroartemisinin and piperaquine must be thoroughly evaluated to support revision in dose recommendations in children. An extrapolation of the model simulations to infants (5–7 kg of body weight) suggests an even greater need for dose adjustment in patients of this body weight group.…”

Section: Discussionmentioning

confidence: 99%

Population Pharmacokinetics and Pharmacodynamics of Piperaquine in Children With Uncomplicated Falciparum Malaria

Tärning

Zongo

Somé

et al. 2012

Clin Pharmacol Ther

161

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Dihydroartemisinin-piperaquine is being increasingly used as a first-line artemisinin combination treatment for malaria. The aim of this study was to describe the pharmacokinetic and pharmacodynamic properties of piperaquine in 236 children with uncomplicated falciparum malaria in Burkina Faso. They received a standard body weight-based oral 3-day fixed-dose dihydroartemisinin-piperaquine regimen. Capillary plasma concentration-time profiles were characterized using nonlinear mixed-effects modeling. The population pharmacokinetics of piperaquine were described accurately by a two-transit-compartment absorption model and a three-compartment distribution model. Body weight was a significant covariate affecting clearance and volume parameters. The individually predicted day 7 capillary plasma concentration of piperaquine was an important predictor (P < 0.0001) of recurrent malaria infection after treatment. Young children (2-5 years of age) received a significantly higher body weight-normalized dose than older children (P = 0.025) but had significantly lower day 7 piperaquine concentrations (P = 0.024) and total piperaquine exposures (P = 0.021), suggesting that an increased dose regimen for young children should be evaluated.

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Section: Discussionmentioning

confidence: 99%

Population Pharmacokinetics and Pharmacodynamics of Piperaquine in Children With Uncomplicated Falciparum Malaria

Tärning

Zongo

Somé

et al. 2012

Clin Pharmacol Ther

161

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“…[3][4][5][6] DHA is well-tolerated in human and animals with only mild adverse effects. 7 In recent years, studies have shown that ART derivatives including DHA also have profound effect against human tumors including cancers of cervix, pancreas, prostate, liver and neuroblastoma. [8][9][10][11][12] However, the exact molecular mechanisms by which ART and DHA exert their anticancer effect remain to be fully investigated.…”

Section: Introductionmentioning

confidence: 99%

Dihydroartemisinin upregulates death receptor 5 expression and cooperates with TRAIL to induce apoptosis in human prostate cancer cells

Shi²,

Shen³

et al. 2010

Cancer Biology & Therapy

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Dihydroartemisinin (DHA) is a derivative of artemisinin and is an effective anti-malaria therapeutic used worldwide. In this paper, we report that DHA is as a potential anticancer drug for prostate cancer. Our data indicate that DHA suppresses the PI3-K/Akt and ERK cell survival pathways and triggers the induction of death receptor DR5 and activation of extrinsic and intrinsic cell death signaling. DHA-mediated DR5 induction appears to occur via increased transcriptional activity of DR5 promoter. Our data also show that, while DHA has strong cytotoxicity in tumor cells, it exhibits minimal cytotoxic effects on normal prostate epithelial cells. Our studies also demonstrate that DHA worked cooperatively with death ligand TRAIL. Combination of DHA and TRAIL significantly enhanced cell killing above that noted with a single agent alone. Based on these results, we propose a novel idea of developing DHA alone and/or in combination with TRAIL for the treatment of prostate cancer.

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“…Many clinical trials involving artemisinins have been conducted in different populations and in various parts of the world (36)(37)(38)(39)(40)(41)(42)(43). All studies have indicated that artemisinins are generally well tolerated with minimal adverse drug reactions.…”

Section: Clinical Toxicology and Safetymentioning

confidence: 99%

Population pharmacokinetics of artesunate and its active metabolite dihydroartemisinin

Tan¹

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Artemisinin compounds are the most potent anti-malarial drugs available in the market. Today, malaria treatment is largely relies on the artemisinin-based combination therapies. Artesunate (AS) is the most widely used artemisinin derivative. In this thesis, we characterized the population pharmacokinetics of AS and its active metabolite dihydroartemisinin (DHA) following oral administration of AS in different populations. In Chapter II, we developed a population pharmacokinetic model of AS and DHA in healthy subjects. These subjects received either single-or multipledosing of oral AS, as a monotherapy regimen or in combination with pyronaridine, with or without food. In Chapter III, we developed a population pharmacokinetic model of AS and DHA in adult and pediatric patients with uncomplicated falciparum and vivax malaria who were administered oral pyronaridine/artesunate combination once daily for 3 days. We modeled the AS and DHA data simultaneously using a parent-metabolite model that assumed complete conversion of AS to DHA. Following oral administration, AS is rapidly absorbed with maximum concentrations reached at about 0.5 hours postdose. AS is rapidly converted to DHA. DHA then undergoes rapid metabolism, with an elimination half-life of about 0.8 hours in malarial patients. Inter-individual variability for almost all pharmacokinetic parameters and residual variability for both compounds were estimated by the models. Substantial variability was seen in the pharmacokinetic parameters between the subjects. In healthy subjects, intake of food with the dose was found to delay the absorption of AS significantly, but not the extent of absorption. Weight was also included in this model as a determinant of DHA clearance. When modeling the data from patients, we included weight as part of the model a priori using an established allometric function. No other covariates examined in the analysis were statistically significant. ACKNOWLEDGMENTS This work would never have been completed without the labor and support of many hands and minds, and thus my deepest gratitude goes to them: My mentor Dr. Larry Fleckenstein for his insightful discussion, inspiring work attitude and his ever open door. Drs. Erika Ernst, Lee Kirsch, Dawei Liu, and DJ Murry for being my committee members and for the comments and suggestions. Dr. Peter Veng-Pedersen for changing my perspective on pharmacokinetics and letting me sit in his class every year. My friends and colleagues Thitima Wattanavitjitkul for her support, motivation and the precious discussion, Dr. Himanshu Naik for his advice and encouragement, Denise Morris and Dr. Amal Al Omari for the powwows , Paul Imming and Mark Schmidt for the hard work in analyzing the samples, Grace Kim for checking the data, and Drs. Sherry Wei and George Lien for their kind assistance. My many friends in Iowa City who have extended their helping hands and kind words. The list is long, but you know who you are. Dr. Jitkang Lim for being a true friend of life. My family, both the Tan's and Larese-Casanov...

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Evaluation of the safety and relative bioavailability of a new dihydroartemisinin tablet formulation in healthy Thai volunteers

Cited by 7 publications

References 21 publications

Population Pharmacokinetics and Pharmacodynamics of Piperaquine in Children With Uncomplicated Falciparum Malaria

Population Pharmacokinetics and Pharmacodynamics of Piperaquine in Children With Uncomplicated Falciparum Malaria

Dihydroartemisinin upregulates death receptor 5 expression and cooperates with TRAIL to induce apoptosis in human prostate cancer cells

Population pharmacokinetics of artesunate and its active metabolite dihydroartemisinin

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