Population pharmacokinetics of artesunate and dihydroartemisinin following single- and multiple-dosing of oral artesunate in healthy subjects.
BACKGROUND
The population pharmacokinetics of artesunate (AS) and its active metabolite dihydroartemisinin (DHA) were studied in healthy subjects receiving single- or multiple-dosing of AS orally either in combination with pyronaridine (PYR) or as a monotherapy with or without food.


METHODS
Data from 118 concentration-time profiles arising from 91 healthy Korean subjects were pooled from four Phase I clinical studies. Subjects received 2-5 mg/kg of single- and multiple-dosing of oral AS either in combination with PYR or as a monotherapy with or without food. Plasma AS and DHA were measured simultaneously using a validated liquid chromatography- mass spectrometric method with a lower limit of quantification of 1 ng/mL for both AS and DHA. Nonlinear mixed-effect modelling was used to obtain the pharmacokinetic and variability (inter-individual and residual variability) parameter estimates.


RESULTS
A novel parent-metabolite pharmacokinetic model consisting of a dosing compartment, a central compartment for AS, a central compartment and a peripheral compartment for DHA was developed. AS and DHA data were modelled simultaneously assuming stoichiometric conversion to DHA. AS was rapidly absorbed with a population estimate of absorption rate constant (Ka) of 3.85 h-1. The population estimates of apparent clearance (CL/F) and volume of distribution (V2/F) for AS were 1190 L/h with 36.2% inter-individual variability (IIV) and 1210 L with 57.4% IIV, respectively. For DHA, the population estimates of apparent clearance (CLM/F) and central volume of distribution (V3/F) were 93.7 L/h with 28% IIV and 97.1 L with 30% IIV, respectively. The population estimates of apparent inter-compartmental clearance (Q/F) and peripheral volume of distribution (V4/F) for DHA were 5.74 L/h and 18.5 L, respectively. Intake of high-fat and high-caloric meal prior to the drug administration resulted in 84% reduction in Ka. Body weight impacted CLM/F, such that a unit change in weight resulted in 1.9-unit change in CLM/F in the same direction.


CONCLUSIONS
A novel simultaneous parent-metabolite pharmacokinetic model with good predictive power was developed to study the population pharmacokinetics of AS and DHA in healthy subjects following single- and multiple-dosing of AS with or without the presence of food. Food intake and weight were significant covariates for Ka and CLM/F, respectively.
Tan
Beesan
B
College of Pharmacy, University of Iowa, Iowa City, IA, USA.
Naik
Himanshu
H
Jang
In-Jin
IJ
Yu
Kyung-Sang
KS
Kirsch
Lee E
LE
Shin
Chang-Sik
CS
Craft
J Carl
JC
Fleckenstein
Lawrence
L
D000284:Administration, Oral; D000328:Adult; D000962:Antimalarials / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D037621:Artemisinins / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D000077332:Artesunate; D002853:Chromatography, Liquid / Q000379:methods; D004435:Eating; D005260:Female; D006801:Humans; D008297:Male; D013058:Mass Spectrometry / Q000379:methods; D015233:Models, Statistical; D009287:Naphthyridines / Q000008:administration & dosage; D010949:Plasma / Q000737:chemistry; D056910:Republic of Korea; D055815:Young Adult
D000962:Antimalarials; D037621:Artemisinins; D009287:Naphthyridines; D000077332:Artesunate; C039060:artenimol; C027871:pyronaridine