Single dose pharmacokinetics of oral artemether in healthy Malaysian volunteers

Mordi, Mohd Nizam; Mansor, S.M.; Navaratnam, V.; Wernsdorfer, W. H.

doi:10.1046/j.1365-2125.1997.00573.x

Cited by 36 publications

(29 citation statements)

References 3 publications

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“…All subjects had plasma concentration profiles of both ARM and DHA that exhibited the same pattern as observed in healthy subjects (9), with t max values all close to 4 h, and concentrations in plasma that fell progressively thereafter to levels that were below, or close to, the limit of detection at 24 h (10). These findings are in marked contrast to those in our patients and the other reported studies with ARM (13,19) and the closely related compound arteether (11), which suggests that the absorption of the oil based drugs from an i.m. depot is prolonged and erratic, and biotransformation to DHA much reduced compared to that after oral dosing.…”

Section: Discussioncontrasting

confidence: 57%

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Comparative Pharmacokinetics of Intramuscular Artesunate and Artemether in Patients with Severe Falciparum Malaria

Hien

Davis

Chuong

et al. 2004

Antimicrob Agents Chemother

108

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The first-dose pharmacokinetic properties of intramuscular (i.m.) artesunate (ARTS; 2.4 mg/kg immediately [stat], followed by 1.2 mg/kg i.m. daily) and artemether (ARM; 3.2 mg/kg i.m. stat, followed by 1.6 mg/kg i.m. daily) were compared in Vietnamese adults with severe falciparum malaria. A total of 19 patients were studied; 9 received ARTS, and 10 received ARM. ARTS was absorbed very rapidly; concentrations in plasma peaked between 1,362 and 8,388 nmol/liter (median, 5,710 nmol/liter) within 20 min of injection and then declined with a median (range) half-life (t 1/2 ) of 30 (3 to 67) min. ARTS was hydrolyzed rapidly and completely to the biologically active metabolite dihydroartemisinin (DHA). Peak DHA concentrations in plasma ranged between 1,718 and 7,080 nmol/liter (median, 3,060 nmol/liter) and declined with a t 1/2 of 52 (26 to 69) min. In contrast, ARM was slowly and erratically absorbed. The absorption profile appeared biphasic. Maximum ARM concentrations in plasma ranged between 67 nmol/liter (a value close to the 50% inhibitory concentration for some Plasmodium falciparum isolates) and 1,631 nmol/liter (median, 574 nmol/liter) and occurred at a median (range) of 10 (1.5 to 24) h. There was relatively little conversion to DHA. After i.m. injection in cases of severe malaria, absorption of the water-soluble ARTS is rapid and extensive, whereas the oil-based ARM is slowly and erratically absorbed, with relatively little conversion to the more active DHA. On the basis of this pharmacological study, parenteral ARTS is preferable to ARM as an initial antimalarial therapy, particularly in the most seriously ill patients. These findings should be formally assessed by a randomized clinical trial.Severe malaria kills between one and two million people each year. The qinghaosu derivatives artesunate (ARTS) and artemether (ARM) are being used increasingly for the parenteral treatment of severe falciparum malaria (23,24). They are intrinsically more potent as antimalarials, have a broader stage specificity of action against the malaria parasite (20), and are simpler to administer and safer than parenteral quinine (1,6,25). ARM has been more intensively evaluated, although ARTS is more widely used. ARM is formulated in an oil base because of its poor water solubility and can only be injected by the intramuscular (i.m.) route. There is evidence that i.m.

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Section: Discussioncontrasting

confidence: 57%

“…There is evidence that i.m. ARM may not be absorbed adequately in severely ill children with falciparum malaria who are hypotensive or acidotic (13). Nevertheless, i.m.…”

mentioning

confidence: 99%

Comparative Pharmacokinetics of Intramuscular Artesunate and Artemether in Patients with Severe Falciparum Malaria

Hien

Davis

Chuong

et al. 2004

Antimicrob Agents Chemother

108

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“…The conversion of AM to DHA is catalyzed by cytochrome P450 (P450) (van Agtmael et al, 1999b,c;Navaratnam et al, 2000). However, the elimination half-life of AM is very short, and it shows large interindividual variability in pharmacokinetic parameters (Na Bangchang et al, 1994;Mordi et al, 1997;van Agtmael et al, 1999a;Lefèvre et al, 2002;Ali et al, 2010;Mwesigwa et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Functional Characterization of CYP2B6 Allelic Variants in Demethylation of Antimalarial Artemether

Honda¹,

Muroi²,

Tamaki³

et al. 2011

Drug Metab Dispos

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ABSTRACT:Artemether (AM) is one of the most effective antimalarial drugs. The elimination half-life of AM is very short, and it shows large interindividual variability in pharmacokinetic parameters. The aim of this study was to identify cytochrome P450 (P450) isozymes responsible for the demethylation of AM and to evaluate functional differences between 26 CYP2B6 allelic variants in vitro. Of 14 recombinant P450s examined in this study, CYP2B6 and CYP3A4 were primarily responsible for production of the desmethyl metabolite dihydroartemisinin. The intrinsic clearance (V max /K m ) of CYP2B6 was 6-fold higher than that of CYP3A4. AM demethylation activity was correlated with CYP2B6 protein levels (P ‫؍‬ 0.004); however, it was not correlated with CYP3A4 protein levels (P ‫؍‬

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“…DHA is formed through cytochrome P450-mediated demethylation (25). The metabolite reaches C max in plasma at approximately the same time as ARM, within 2 h of ARM administration (6,20,24). The reported elimination half-life of DHA ranges from 0.4 to 12.5 h (6,24).…”

mentioning

confidence: 99%

“…It is rapidly absorbed from the gastrointestinal tract, reaching maximum concentrations (C max ) within 2 h of administration (6,20,24). ARM is metabolized to DHA with a reported half-life of 0.8 to 4 h (6,20,24). DHA is formed through cytochrome P450-mediated demethylation (25).…”

mentioning

confidence: 99%

Population Pharmacokinetics and Pharmacodynamics of Artemether and Lumefantrine during Combination Treatment in Children with Uncomplicated Falciparum Malaria in Tanzania

Hietala

Mårtensson

Ngasala

et al. 2010

Antimicrob Agents Chemother

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The combination of artemether (ARM) and lumefantrine is currently the first-line treatment of uncomplicated falciparum malaria in mainland Tanzania. While the exposure to lumefantrine has been associated with the probability of adequate clinical and parasitological cure, increasing exposure to artemether and the active metabolite dihydroartemisinin (DHA) has been shown to decrease the parasite clearance time. The aim of this analysis was to describe the pharmacokinetics and pharmacodynamics of artemether, dihydroartemisinin, and lumefantrine in African children with uncomplicated malaria. In addition to drug concentrations and parasitemias from 50 Tanzanian children with falciparum malaria, peripheral parasite densities from 11 asymptomatic children were included in the model of the parasite dynamics. The population pharmacokinetics and pharmacodynamics of artemether, dihydroartemisinin, and lumefantrine were modeled in NONMEM. The distribution of artemether was described by a two-compartment model with a rapid absorption and elimination through metabolism to dihydroartemisinin. Dihydroartemisinin concentrations were adequately illustrated by a one-compartment model. The pharmacokinetics of artemether was time dependent, with typical oral clearance increasing from 2.6 liters/h/kg on day 1 to 10 liters/h/kg on day 3. The pharmacokinetics of lumefantrine was sufficiently described by a one-compartment model with an absorption lag time. The typical value of oral clearance was estimated to 77 ml/h/kg. The proposed semimechanistic model of parasite dynamics, while a rough approximation of the complex interplay between malaria parasite and the human host, adequately described the early effect of ARM and DHA concentrations on the parasite density in malaria patients. However, the poor precision in some parameters illustrates the need for further data to support and refine this model.Artemisinin-based combination therapy is generally accepted as treatment of choice for acute uncomplicated Plasmodium falciparum malaria (31). A fixed-dose combination containing artemether (ARM) and lumefantrine (LUM) is currently the first-line treatment of uncomplicated falciparum malaria in mainland Tanzania. The rationale behind combining ARM with LUM is to make use of the disparate pharmacokinetic profiles of the two drugs and thereby improve treatment efficacy and delay development of drug resistance. While ARM and its primary active metabolite dihydroartemisinin (DHA) are rapidly eliminated, LUM is slowly cleared from the body.

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Single dose pharmacokinetics of oral artemether in healthy Malaysian volunteers

Cited by 36 publications

References 3 publications

Comparative Pharmacokinetics of Intramuscular Artesunate and Artemether in Patients with Severe Falciparum Malaria

Comparative Pharmacokinetics of Intramuscular Artesunate and Artemether in Patients with Severe Falciparum Malaria

Functional Characterization of CYP2B6 Allelic Variants in Demethylation of Antimalarial Artemether

Population Pharmacokinetics and Pharmacodynamics of Artemether and Lumefantrine during Combination Treatment in Children with Uncomplicated Falciparum Malaria in Tanzania

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