Artesunate (AS) is a clinically versatile artemisinin derivative utilized for the treatment of mild to severe malaria infection. Given the therapeutic significance of AS and the necessity of appropriate AS dosing, substantial research has been performed investigating the pharmacokinetics of AS and its active metabolite dihydroartemisinin (DHA). In this article, a comprehensive review is presented of AS clinical pharmacokinetics following administration of AS by the intravenous (IV), intramuscular (IM), oral or rectal routes. Intravenous AS is associated with high initial AS concentrations which subsequently decline rapidly, with typical AS half-life estimates of less than 15 minutes. AS clearance and volume estimates average 2 - 3 L/kg/hr and 0.1 - 0.3 L/kg, respectively. DHA concentrations peak within 25 minutes post-dose, and DHA is eliminated with a half-life of 30 - 60 minutes. DHA clearance and volume average between 0.5 - 1.5 L/kg/hr and 0.5 - 1.0 L/kg, respectively. Compared to IV administration, IM administration produces lower peaks, longer half-life values, and higher volumes of distribution for AS, as well as delayed peaks for DHA; other parameters are generally similar due to the high bioavailability, assessed by exposure to DHA, associated with IM AS administration (> 86%). Similarly high bioavailability of DHA (> 80%) is associated with oral administration. Following oral AS, peak AS concentrations (Cmax) are achieved within one hour, and AS is eliminated with a half-life of 20 - 45 minutes. DHA Cmax values are observed within two hours post-dose; DHA half-life values average 0.5 - 1.5 hours. AUC values reported for AS are often substantially lower than those reported for DHA following oral AS administration. Rectal AS administration yields pharmacokinetic results similar to those obtained from oral administration, with the exceptions of delayed AS Cmax and longer AS half-life. Drug interaction studies conducted with oral AS suggest that AS does not appreciably alter the pharmacokinetics of atovaquone/proguanil, chlorproguanil/dapsone, or sulphadoxine/pyrimethamine, and mefloquine and pyronaridine do not alter the pharmacokinetics of DHA. Finally, there is evidence suggesting that the pharmacokinetics of AS and/or DHA following AS administration may be altered by pregnancy and by acute malaria infection, but further investigation would be required to define those alterations precisely.

Although widely recognized as a comprehensive framework for representing score reliability, generalizability theory (G-theory), despite its potential benefits, has been used sparingly in reporting of results for measures of individual differences. In this article, we highlight many valuable ways that G-theory can be used to quantify, evaluate, and improve psychometric properties of scores. Our illustrations encompass assessment of overall reliability, percentages of score variation accounted for by individual sources of measurement error, dependability of cut-scores for decision making, estimation of reliability and dependability for changes made to measurement procedures, disattenuation of validity coefficients for measurement error, and linkages of G-theory with classical test theory and structural equation modeling. We also identify computer packages for performing G-theory analyses, most of which can be obtained free of charge, and describe how they compare with regard to data input requirements, ease of use, complexity of designs supported, and output produced. (PsycINFO Database Record

In this article, we illustrate ways in which generalizability theory (G-theory) can be used with continuous latent response variables (CLRVs) to address problems of scale coarseness resulting from categorization errors caused by representing ranges of continuous variables by discrete data points and transformation errors caused by unequal interval widths between those data points. The mechanism to address these problems is applying structural equation modeling (SEM) as a tool in deriving variance components needed to estimate indices of score consistency and validity. Illustrations include quantification of multiple sources of measurement error, use of non-nested and nested designs, derivation of indices of consistency for norm- and criterion-referenced interpretation of scores, estimation of effects when changing measurement procedures and designs, and disattenuation of correlation coefficients for measurement error. These illustrations underscore the effectiveness of G-theory with continuous latent response variables in providing stable indices of reliability and validity that are reasonably independent of the number of original scale points used, unevenness of scale intervals, and average degree of item skewness. We discuss general distinctions in reliability estimation within G-theory, SEM, and classical test theory; make specific recommendations for using G-theory on raw score and CLRV metrics; and provide computer code in an online supplement for doing all key analyses demonstrated in the article using R and M (PsycINFO Database Record

In this article, we illustrate how generalizability theory (G-theory) can extend traditional assessment methods for designing, improving, and evaluating results from both objectively and subjectively scored measures of individual differences. Our illustrations include quantification of multiple sources of measurement error, derivation of unique indexes of consistency for norm- and criterion-referenced interpretations of scores, estimation of score consistency when changing a measurement procedure, and disattenuation of correlation coefficients for measurement error. We also expand G-theory analyses beyond the item level to include parcels and split measures and highlight linkages among G-theory, classical test theory, and structural equation modeling. Computer code and sample data are provided in online supplements to help readers apply the demonstrated techniques to their own assessments.

BackgroundThe World Health Organization endorses the use of artemisinin-based combination therapy for treatment of acute uncomplicated falciparum malaria in the second and third trimesters of pregnancy. However, the effects of pregnancy on the pharmacokinetics of artemisinin derivatives, such as artesunate (AS), are poorly understood. In this analysis, the population pharmacokinetics of oral AS, and its active metabolite dihydroartemisinin (DHA), were studied in pregnant and non-pregnant women at the Kingasani Maternity Clinic in the DRC.MethodsData were obtained from 26 pregnant women in the second (22 - 26 weeks) or the third (32 - 36 weeks) trimester of pregnancy and from 25 non-pregnant female controls. All subjects received 200 mg AS. Plasma AS and DHA were measured using a validated LC-MS method. Estimates for pharmacokinetic and variability parameters were obtained through nonlinear mixed effects modelling.ResultsA simultaneous parent-metabolite model was developed consisting of mixed zero-order, lagged first-order absorption of AS, a one-compartment model for AS, and a one-compartment model for DHA. Complete conversion of AS to DHA was assumed. The model displayed satisfactory goodness-of-fit, stability, and predictive ability. Apparent clearance (CL/F) and volume of distribution (V/F) estimates, with 95% bootstrap confidence intervals, were as follows: 195 L (139-285 L) for AS V/F, 895 L/h (788-1045 L/h) for AS CL/F, 91.4 L (78.5-109 L) for DHA V/F, and 64.0 L/h (55.1-75.2 L/h) for DHA CL/F. The effect of pregnancy on DHA CL/F was determined to be significant, with a pregnancy-associated increase in DHA CL/F of 42.3% (19.7 - 72.3%).ConclusionsIn this analysis, pharmacokinetic modelling suggests that pregnant women have accelerated DHA clearance compared to non-pregnant women receiving orally administered AS. These findings, in conjunction with a previous non-compartmental analysis of the modelled data, provide further evidence that higher AS doses would be required to maintain similar DHA levels in pregnant women as achieved in non-pregnant controls.