Pharmacokinetic profiles of artesunate following multiple intravenous doses of 2, 4, and 8 mg/kg in healthy volunteers: Phase 1b study
Abstract Background Severe malaria results in over a million deaths every year, most of them in children aged less than five years and living in sub-Saharan Africa. Injectable artesunate (AS) was recommended as initial treatment for severe malaria by WHO in 2006. The Walter Reed Army Institute of Re...
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ftdoajarticles:oai:doaj.org/article:7077ea5a3c3249a0b36763023b007194 2023-05-15T15:13:18+02:00 Pharmacokinetic profiles of artesunate following multiple intravenous doses of 2, 4, and 8 mg/kg in healthy volunteers: Phase 1b study Miller Robert Li Qigui Cantilena Louis R Leary Kevin J Saviolakis George A Melendez Victor Smith Bryan Weina Peter J 2012-08-01T00:00:00Z https://doi.org/10.1186/1475-2875-11-255 https://doaj.org/article/7077ea5a3c3249a0b36763023b007194 EN eng BMC http://www.malariajournal.com/content/11/1/255 https://doaj.org/toc/1475-2875 doi:10.1186/1475-2875-11-255 1475-2875 https://doaj.org/article/7077ea5a3c3249a0b36763023b007194 Malaria Journal, Vol 11, Iss 1, p 255 (2012) Artesunate injection Severe malaria Pharmacokinetics Healthy volunteers Tolerability Multiple doses Arctic medicine. Tropical medicine RC955-962 Infectious and parasitic diseases RC109-216 article 2012 ftdoajarticles https://doi.org/10.1186/1475-2875-11-255 2022-12-31T08:51:12Z Abstract Background Severe malaria results in over a million deaths every year, most of them in children aged less than five years and living in sub-Saharan Africa. Injectable artesunate (AS) was recommended as initial treatment for severe malaria by WHO in 2006. The Walter Reed Army Institute of Research (WRAIR) has been developing a novel good manufacturing practice (GMP) injection of AS, which was approved by the US FDA for investigational drug use and distribution by the CDC. Methods Tolerability and pharmacokinetics of current GMP intravenous AS, as an anti-malarial agent, were evaluated after ascending multiple doses of 2, 4, and 8 mg/kg daily for three days with 2-minute infusion in 24 healthy subjects (divided into three groups) in the Phase 1 clinical trial study. Results Results showed that there were no dose-dependent increases in any adverse events. Drug concentrations showed no accumulation and no decline of the drug during the three days of treatment. After intravenous injection, parent drug rapidly declined and was converted to dihydroartemisinin (DHA) with overall mean elimination half-lives ranging 0.15-0.23 hr for AS and 1.23-1.63 hr for DHA, but the peak concentration (C max ) of AS was much higher than that of DHA with a range of 3.08-3.78-folds. In addition, the AUC and C max values of AS and DHA were increased proportionally to the AS climbing multiple doses. Discussion The safety of injectable AS, even at the highest dose of 8 mg/kg increases the probability of therapeutic success of the drug even in patients with large variability of parasitaemia. Article in Journal/Newspaper Arctic Directory of Open Access Journals: DOAJ Articles Arctic Malaria Journal 11 1 255 |
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Directory of Open Access Journals: DOAJ Articles |
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ftdoajarticles |
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English |
topic |
Artesunate injection Severe malaria Pharmacokinetics Healthy volunteers Tolerability Multiple doses Arctic medicine. Tropical medicine RC955-962 Infectious and parasitic diseases RC109-216 |
spellingShingle |
Artesunate injection Severe malaria Pharmacokinetics Healthy volunteers Tolerability Multiple doses Arctic medicine. Tropical medicine RC955-962 Infectious and parasitic diseases RC109-216 Miller Robert Li Qigui Cantilena Louis R Leary Kevin J Saviolakis George A Melendez Victor Smith Bryan Weina Peter J Pharmacokinetic profiles of artesunate following multiple intravenous doses of 2, 4, and 8 mg/kg in healthy volunteers: Phase 1b study |
topic_facet |
Artesunate injection Severe malaria Pharmacokinetics Healthy volunteers Tolerability Multiple doses Arctic medicine. Tropical medicine RC955-962 Infectious and parasitic diseases RC109-216 |
description |
Abstract Background Severe malaria results in over a million deaths every year, most of them in children aged less than five years and living in sub-Saharan Africa. Injectable artesunate (AS) was recommended as initial treatment for severe malaria by WHO in 2006. The Walter Reed Army Institute of Research (WRAIR) has been developing a novel good manufacturing practice (GMP) injection of AS, which was approved by the US FDA for investigational drug use and distribution by the CDC. Methods Tolerability and pharmacokinetics of current GMP intravenous AS, as an anti-malarial agent, were evaluated after ascending multiple doses of 2, 4, and 8 mg/kg daily for three days with 2-minute infusion in 24 healthy subjects (divided into three groups) in the Phase 1 clinical trial study. Results Results showed that there were no dose-dependent increases in any adverse events. Drug concentrations showed no accumulation and no decline of the drug during the three days of treatment. After intravenous injection, parent drug rapidly declined and was converted to dihydroartemisinin (DHA) with overall mean elimination half-lives ranging 0.15-0.23 hr for AS and 1.23-1.63 hr for DHA, but the peak concentration (C max ) of AS was much higher than that of DHA with a range of 3.08-3.78-folds. In addition, the AUC and C max values of AS and DHA were increased proportionally to the AS climbing multiple doses. Discussion The safety of injectable AS, even at the highest dose of 8 mg/kg increases the probability of therapeutic success of the drug even in patients with large variability of parasitaemia. |
format |
Article in Journal/Newspaper |
author |
Miller Robert Li Qigui Cantilena Louis R Leary Kevin J Saviolakis George A Melendez Victor Smith Bryan Weina Peter J |
author_facet |
Miller Robert Li Qigui Cantilena Louis R Leary Kevin J Saviolakis George A Melendez Victor Smith Bryan Weina Peter J |
author_sort |
Miller Robert |
title |
Pharmacokinetic profiles of artesunate following multiple intravenous doses of 2, 4, and 8 mg/kg in healthy volunteers: Phase 1b study |
title_short |
Pharmacokinetic profiles of artesunate following multiple intravenous doses of 2, 4, and 8 mg/kg in healthy volunteers: Phase 1b study |
title_full |
Pharmacokinetic profiles of artesunate following multiple intravenous doses of 2, 4, and 8 mg/kg in healthy volunteers: Phase 1b study |
title_fullStr |
Pharmacokinetic profiles of artesunate following multiple intravenous doses of 2, 4, and 8 mg/kg in healthy volunteers: Phase 1b study |
title_full_unstemmed |
Pharmacokinetic profiles of artesunate following multiple intravenous doses of 2, 4, and 8 mg/kg in healthy volunteers: Phase 1b study |
title_sort |
pharmacokinetic profiles of artesunate following multiple intravenous doses of 2, 4, and 8 mg/kg in healthy volunteers: phase 1b study |
publisher |
BMC |
publishDate |
2012 |
url |
https://doi.org/10.1186/1475-2875-11-255 https://doaj.org/article/7077ea5a3c3249a0b36763023b007194 |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
Malaria Journal, Vol 11, Iss 1, p 255 (2012) |
op_relation |
http://www.malariajournal.com/content/11/1/255 https://doaj.org/toc/1475-2875 doi:10.1186/1475-2875-11-255 1475-2875 https://doaj.org/article/7077ea5a3c3249a0b36763023b007194 |
op_doi |
https://doi.org/10.1186/1475-2875-11-255 |
container_title |
Malaria Journal |
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11 |
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1 |
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255 |
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1766343868940288000 |