Arteether administration in humans: preliminary studies of pharmacokinetics, safety and tolerance

Kager, Piet A.; Schultz, MJ; Zijlstra, E.E.; Berg, Benno van den; Boxtel, C. J. Van

doi:10.1016/0035-9203(94)90475-8

Cited by 44 publications

(27 citation statements)

References 3 publications

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“…Phase I studies of the drug in healthy adult volunteers in The Netherlands documented its tolerability, safety, and pharmacokinetics (Jonkman JHG and others, unpublished data). 10 Phase II studies in Thai adults with uncomplicated and severe malaria showed safety and efficacy when used over a five-day period with an initial loading dose (Peeters PAM and others, unpublished data). Subsequently, a Phase III, multicenter, open label, randomized comparative efficacy study was proposed in African children with cerebral malaria.…”

Section: Introductionmentioning

confidence: 99%

A randomized controlled trial of artemotil (beta-arteether) in Zambian children with cerebral malaria.

Thuma¹,

Bhat²,

Mabeza³

et al. 2000

The American Journal of Tropical Medicine and Hygiene

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Abstract. The efficacy and safety of intramuscular artemotil (ARTECEF ) was compared to intravenous quinine in African children with cerebral malaria. This prospective block randomized open-label study was conducted at two centers in Zambia. Subjects were children aged 0 to 10 years of age with cerebral malaria and a Blantyre Coma Score of 2 or less. Ninety two children were studied; 48 received artemotil and 44 quinine. No significant differences in survival, coma resolution time, neurologic sequelae, parasite clearance time, and fever resolution time were seen between the two regimens. Rates for negative malaria smears one month after therapy were similar in both groups. Artemotil was a well-tolerated drug in the 48 patients in this study. It appears to be at least therapeutically equivalent to quinine for the treatment of pediatric cerebral malaria. It has the advantage of being able to be given intramuscularly once daily for only five days.

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Section: Introductionmentioning

confidence: 99%

A randomized controlled trial of artemotil (beta-arteether) in Zambian children with cerebral malaria.

Thuma¹,

Bhat²,

Mabeza³

et al. 2000

The American Journal of Tropical Medicine and Hygiene

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“…Pharmacokinetic data demonstrated that accumulation of AE and AM was observed in the plasma of rats, 6 beagle dogs, 7 rhesus monkeys (Q. G. Li, unpublished data), and humans 8,9 following multiple intramuscular (im) injections. The rat data demonstrated that the accumulation of AE in plasma was due to a slow and prolonged absorption from the injection sites.…”

Section: Introductionmentioning

confidence: 99%

Neurotoxicity and efficacy of arteether related to its exposure times and exposure levels in rodents.

Mog²,

Z³

et al. 2002

The American Journal of Tropical Medicine and Hygiene

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Abstract. The neurotoxicity of ␤-arteether (AE) is related to drug accumulation in blood due to slow and prolonged absorption from the intramuscular injection sites. In this efficacy and toxicity study of AE, the traditional sesame oil vehicle was replaced with cremophore to decrease the accumulation and toxicity of AE. Dihydroartemisinin (DQHS), a more toxic and active metabolite of AE, was also analyzed. When administered at a daily dosage of 25 mg/kg for seven days, blood accumulation of AE with sesame oil (AESO) was used had a 7.5-fold higher area under the curve (AUC) (on last versus first day dosing), while AE with cremophore (AECM) had only a 1.8-fold higher AUC. Although the accumulation of AECM was greatly reduced, its total exposure level (46.29 g и h/ml) was 2.7-fold higher than with AESO (16.92 gиh/ml) due to a higher bioavailability of AECM (74.5%) compared with AESO (20.3%). Total exposure time (calculated at over the minimal detected neurotoxicity level of 41.32 ng/ml) of AECM was 103 hours during the whole treatment period (192 hours), which was more than one-third (37%) less than with AESO (162 hours). Similar pharmacokinetic results were also shown with the active metabolite, DQHS. Anorexia and gastrointestinal toxicity with AESO were significantly more severe than with AECM (P < 0.001). Histopathologic examination of the brain demonstrated neurotoxic changes; the AESO rat group was significantly more severe than the AECM rat group. The brain injury scores with AECM were mild to moderate (2.3-3.0), and with AESO they were moderate to severe (3.0-4.7) on day 7 and day 10, respectively. In addition, the results of a 50% cure dose (CD 50 ) against Plasmodium berghei in mice were 34.1 mg/kg for AESO and 14.2 mg/kg for AECM, indicating a significant higher efficacy was found in the AECM animals. Toxicity and efficacy of DQHS were also dependent on its exposure time and level, which was the same as its parent drug (AE). In conclusion, following the seven-day treatment in rats, AE and DQHS exposure time and level varied based on the vehicle used. The extension of drug exposure time and the low peak level of AE and DQHS were more associated with severe neurotoxicity and lower antimalarial efficacy, whereas the high level and short exposure time of AE and DQHS resulted in higher efficacy and milder toxicity.

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“…PK data from various animal studies have shown that AE and AM will accumulate in the plasma of rats (Li et al, 1999b), beagle dogs (Classen et al, 1999), rhesus monkeys (Li et al, 2007a), and humans (Kager et al, 1994) following multiple intramuscular injections. Data collected from rat studies showed that the accumulation of AE in the plasma is due to a slow and prolonged absorption from the injection sites.…”

Section: Cause Of Am and Ae Accumulation After Intramuscular Injectionmentioning

confidence: 99%

“…The intramuscular administration of AM and AE was associated with slow absorption because the drugs were dissolved in sesame oil or peanut oil that, when injected, formed a depot from which the drug was slowly released (Kager et al, 1994: Li et al, 2004. The slow elimination of AE was recently demonstrated in a rat study, which also found significant accumulation of AE in the plasma from injection sites (Li et al, 1999b).…”

Section: Cause Of Am and Ae Accumulation After Intramuscular Injectionmentioning

confidence: 99%

Pharmacokinetic (PK) and Pharmacodynamic Profiles of Artemisinin Derivatives Influence Drug Neurotoxicity in Animals

Li¹,

Hickman²

2012

Readings in Advanced Pharmacokinetics - Theory, Methods and Applications

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Arteether administration in humans: preliminary studies of pharmacokinetics, safety and tolerance

Cited by 44 publications

References 3 publications

A randomized controlled trial of artemotil (beta-arteether) in Zambian children with cerebral malaria.

A randomized controlled trial of artemotil (beta-arteether) in Zambian children with cerebral malaria.

Neurotoxicity and efficacy of arteether related to its exposure times and exposure levels in rodents.

Pharmacokinetic (PK) and Pharmacodynamic Profiles of Artemisinin Derivatives Influence Drug Neurotoxicity in Animals

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