Population pharmacokinetics of tafenoquine during malaria prophylaxis in healthy subjects

Charles, B. G., Miller, A. K., Nasveld, P. E., Reid, M. G., Harris, I. E. and Edstein, M. D. (2007) Population pharmacokinetics of tafenoquine during malaria prophylaxis in healthy subjects. Antimicrobial Agents And Chemotherapy, 51 8: 2709-2715. doi:10.1128/AAC.01183-06

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Author Charles, B. G.
Miller, A. K.
Nasveld, P. E.
Reid, M. G.
Harris, I. E.
Edstein, M. D.
Title Population pharmacokinetics of tafenoquine during malaria prophylaxis in healthy subjects
Journal name Antimicrobial Agents And Chemotherapy   Check publisher's open access policy
ISSN 0066-4804
Publication date 2007
Sub-type Article (original research)
DOI 10.1128/AAC.01183-06
Open Access Status File (Publisher version)
Volume 51
Issue 8
Start page 2709
End page 2715
Total pages 7
Place of publication Washington, DC, United States
Publisher Amer Soc Microbiology
Collection year 2008
Language eng
Subject C1
320503 Clinical Pharmacology and Therapeutics
730101 Infectious diseases
Abstract The population pharmacokinetics of tafenoquine were studied in Australian soldiers taking tafenoquine for malarial prophylaxis. The subjects (476 males and 14 females) received a loading dose of 200 mg tafenoquine base daily for 3 days, followed by a weekly dose of 200 mg tafenoquine for 6 months. Blood samples were collected from each subject after the last loading dose and then at weeks 4, 8, and 16. Plasma tafenoquine concentrations were determined by liquid chromatography-tandem mass spectrometry. Population modeling was performed with NONMEM, using a one-compartment model. Typical values of the first-order absorption rate constant (K.), clearance (CL/F), and volume of distribution (V/F) were 0.243 h(-1), 0.056 liters/h/kg, and 23.7 liters/kg, respectively. The intersubject variability (coefficient of variation) in CL/F and V/F was 18% and 22%, respectively. The interoccasion variability in CL/F was 18%, and the mean elimination half-life was 12.7 days. A positive linear association between weight and both CL/F and V/F was found, but this had insufficient impact to warrant dosage adjustments. Model robustness was assessed by a nonparametric bootstrap (200 samples). A degenerate visual predictive check indicated that the raw data mirrored the postdose concentration-time profiles simulated (n = 1,000) from the final model. Individual pharmacokinetic estimates for tafenoquine did not predict the prophylactic outcome with the drug for four subjects who relapsed with Plasmodium vivax malaria, as they had similar pharmacokinetics to those who were free of malaria infection. No obvious pattern existed between the plasma tafenoquine concentration and the pharmacokinetic parameter values for subjects with and without drug-associated moderate or severe adverse events. This validated population pharmacokinetic model satisfactorily describes the disposition and variability of tafenoquine used for long-term malaria prophylaxis in a large cohort of soldiers on military deployment.
Keyword Microbiology
Pharmacology & Pharmacy
Plasmodium-falciparum
Mefloquine
Chemoprophylaxis
Antimalarial
Primaquine
Vivax
Model
Q-Index Code C1
Q-Index Status Confirmed Code

 
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Created: Mon, 18 Feb 2008, 14:36:32 EST