Population pharmacokinetics of halofantrine in healthy volunteers and patients with symptomatic falciparum malaria

Klein, Kerenaftali, Aarons, Leon, ter Kuile, Feiko. O., Nosten, Francois, White, Nick. J., Edstein, Michael. D. and Teja-Isavadharm, Paktiya (2012) Population pharmacokinetics of halofantrine in healthy volunteers and patients with symptomatic falciparum malaria. Journal of Pharmacy and Pharmacology, 64 11: 1603-1613. doi:10.1111/j.2042-7158.2012.01554.x


Author Klein, Kerenaftali
Aarons, Leon
ter Kuile, Feiko. O.
Nosten, Francois
White, Nick. J.
Edstein, Michael. D.
Teja-Isavadharm, Paktiya
Title Population pharmacokinetics of halofantrine in healthy volunteers and patients with symptomatic falciparum malaria
Journal name Journal of Pharmacy and Pharmacology   Check publisher's open access policy
ISSN 0022-3573
0373-1022
Publication date 2012-05-13
Sub-type Article (original research)
DOI 10.1111/j.2042-7158.2012.01554.x
Open Access Status Not Open Access
Volume 64
Issue 11
Start page 1603
End page 1613
Total pages 11
Place of publication West Sussex, United Kingdom
Publisher John Wiley & Sons
Language eng
Abstract To investigate the population pharmacokinetics of the antimalarial halofantrine (HF) in healthy volunteers and patients with symptomatic falciparum malaria.
Formatted abstract
Aims  To investigate the population pharmacokinetics of the antimalarial halofantrine (HF) in healthy volunteers and patients with symptomatic falciparum malaria.

Methods  Healthy volunteer data were obtained from six volunteers who received three different doses of HF (250, 500 and 1000 mg) after an overnight fast with a washout period of at least 6 weeks between doses. Patient data (n = 188) were obtained from randomised controlled trials conducted on the Thai–Burmese border in the early 1990s. They were either assigned to receive a total HF dose of 24 mg/kg (8 mg/kg every 6 h for 24 h) or 72 mg/kg (8 mg/kg every 6 to 10 h for 3 days). The population pharmacokinetics of HF were evaluated using non-linear mixed effects modelling with a two-compartment model with first-order absorption.

Key findings 
The population estimates of apparent clearance (CL), volume of compartment one (V1), distributional clearance (CLD) and volume of compartment two (V2) of HF in healthy volunteers were 2453 l/day (102 l/h), 2386 l, 716 l/day (29.8 l/h) and 2641 l, respectively. The population estimates of the PK parameters in patients were 429 l/day (17.9 l/h), 729 l, 178 l/day (7.42 l/h) and 1351 l, respectively. All PK parameters were significantly related to body weight and some were related to sex, sampling method, pre-treatment parasite density and whether patients vomited or not. When the two datasets were analysed jointly using a maximum likelihood method, the population estimates in patients were 196 l/day (8.17 l/h), 161 l, 65 l/day (2.71 l/h) and 89 l, respectively, and the parameters were significantly related to body weight and sex. Bayesian analysis of the patient data, with a diffuse prior based on the healthy volunteer data analysis results, yielded the population estimates 354 l/day (14.8 l/h), 728 l, 162 l/day (6.75 l/h) and 1939 l, respectively.

Conclusions  The pharmacokinetic properties of HF in patients with malaria are affected by several demographic variables as well as other relevant covariates. Apparent differences between the healthy volunteer and the patient data analysis results are not entirely due to differences in bioavailability. For the patient data analysis, the Bayesian method was preferred, as the fitting procedure was more stable, allowing random effects to be estimated for all four dispositional parameters.
Keyword Bayesian modelling
Halofantrine
Malaria
Non-linear mixed effects modelling
Population pharmacokinetics
Q-Index Code C1
Q-Index Status Confirmed Code
Grant ID 089275
093956
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2013 Collection
School of Public Health Publications
 
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Created: Wed, 23 May 2012, 02:43:03 EST by Kere Klein on behalf of School of Public Health