A One-compartment Constant Rate Intravascular Infusion Model for the Evaluation of Increases in Hematocrit after Artemisinin-based Combination Treatments of Acute Falciparum Malaria in Children

Abstract

Increases in hematocrit frequently follow successful treatment of uncomplicated falciparum infections in children, but there is no pharmacokinetic model for the analyses of the increases in hematocrit following artemisinin-based combination treatments (ACTs) in malarious children. A one-compartment constant rate intravascular infusion model (CRIVIM), which employed the principles of constant rate intravenous infusion of drugs (CRIVID), was used to evaluate the kinetics of the increases in hematocrit after artesunate-amodiaquine (AA) or artemether-lumefantrine (AL) treatments in 112 malarious children. The model assumed baseline hematocrit was zero, a constant rate increase in hematocrit from baseline following treatment, and it involved semi-logarithm plots of the difference between hematocrit at plateau and that at earlier times, against the corresponding times. Hematocrit reached a plateau in a median time of 28 days after treatment started. Mean plateau hematocrit was 6.7% (95%CI 5.9.-7.5) and was similar in AA- and AL- treated children [6.8% (95%CI 6-7.7), n = 81 v 6.3% (95%CI 4.9-7.7), n = 31, P = 0.56]. Times to plateau were significantly shorter and plateau hematocrit significantly lower in non-anemic compared to anemic children. Overall, declines from semi-logarithmic plots were monoexponential with mean half-time of hematocrit of 2.5 days (95%CI 2.2-2.8). Half-times were similar in AA and AL-treated children [2.4 days (95%CI 2.1-2.8) v 2.7 days (95%CI 2-3.3), P = 0.46], and were significantly shorter in anemic compared to non-anemic children [2.1 days (95%CI 1.8-2.4, n = 57) v 2.9 days (95%CI 2.4-3.5, n = 55), P = 0.01). Mean anemia recovery time was 13.8 days (95%CI 11.9 – 15.7). Bland-Altman analysis of 7 or 8 multiples of anaemia half-time and anaemia recovery times showed narrow limit of agreement with insignificant biases (P = 0.17 or 0.68, respectively). Steady state parameters were independent of baseline parasitemias. The one-compartment CRIVIM permits evaluation of increases in hematocrit following ACTs and may be used in observational and clinical studies in uncomplicated falciparum malaria.