METHODS: Malaysian adults presenting with uncomplicated P. knowlesi infections received six doses of artemether (1.7 mg/kg) plus lumefantrine (10 mg/kg) over 3 days. Venous blood and dried blood spot (DBS) samples were taken at predetermined time-points over 28 days. Plasma and DBS artemether, dihydroartemisinin, lumefantrine and desbutyl-lumefantrine were measured using liquid chromatography-mass spectrometry. Multi-compartmental population pharmacokinetic models were developed using plasma with or without DBS drug concentrations.
RESULTS: Forty-one participants (mean age 45 years, 66% males) were recruited. Artemether-lumefantrine treatment was well tolerated and parasite clearance was prompt. Plasma and DBS lumefantrine concentrations were in close agreement and were used together in pharmacokinetic modelling, but only plasma concentrations of the other analytes were used because of poor correlation with DBS levels. The areas under the concentration-time curve (AUC0-∞ ) for artemether, dihydroartemisinin and lumefantrine (medians 1626, 1881 and 625 098 μg.h/L, respectively) were similar to those reported in previous pharmacokinetic studies in adults and children. There was evidence of auto-induction of artemether metabolism (mean increase in clearance relative to bioavailability 25.2% for each subsequent dose). The lumefantrine terminal elimination half-life (median 9.5 days) was longer than reported in healthy volunteers and adults with falciparum malaria.
CONCLUSION: The disposition of artemether, dihydroartemisinin and lumefantrine in knowlesi malaria largely parallels that in other human malarias. DBS lumefantrine concentrations can be used in pharmacokinetic studies but DBS technology is currently unreliable for the other analytes.
OBJECTIVES: This study aimed to explore factors associated with blood DHA and AA concentrations of very preterm infants receiving standard care, in the days following birth.
METHODS: We examined the fatty acid composition of whole blood samples collected on cards at 0-6 d after birth, from a cross-sectional study of 1174 infants born <29 weeks of gestation in Australia, New Zealand, and Singapore.
RESULTS: Considerable variation was observed in the proportions of blood AA (1.4%-18.0%) and DHA (0.4%-5.7%) concentrations. Infant blood DHA status was not associated with gestational age at birth, but AA was lower by 0.11% for each week of gestation (95% CI: -0.07%, 0.15%). There was an inverse relationship between age of sampling after birth and DHA (0.07% lower per day; 95% CI: 0.04%, 0.09%) and AA (0.09% lower; 95% CI: 0.04%, 0.14%). A concomitant positive relationship was observed between days after birth and the fatty acids present in the intravenous lipid emulsion administered: ω-6 linoleic acid (range: 2.1%-35.1%) and ω-9 oleic acid (range: 12.2%-52.9%).
CONCLUSIONS: Preterm infants whose blood was sampled later after birth have lower DHA and AA status relative to those sampled earlier after birth; samples taken at later timepoints are concurrently higher in the fatty acids of linoleic acid and oleic acid, which are the major compositional components of intravenous lipid emulsions routinely administered to preterm infants. The results support calls to develop intravenous feeds closely matching the fatty acid composition of infant blood at birth. The N3RO Trial is registered at the Australian New Zealand Clinical Trial Registry as ACTRN12612000503820 (https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=12612000503820).