Comparative Plasmodium falciparum kinetics during treatment with amodiaquine and chloroquine in children

Objectives: To examine the kinetics of the disposition of Plasmodium falcip arum during treatment with amodiaquine, a Mannich base derivative of chloro quine and chloroquine. Additional aims were to compare P. falciparum kineti cs in children in whom initial treatment with chloroquine failed and follow ing re-treatment with amodiaquine, and in siblings in whom there was househ old clustering of falciparum infections. An important aim was to validate t he kinetic method of evaluating therapeutic efficacy in a randomised trial involving the antimalarial drugs amodiaquine and chloroquine. Design: Nonblind, randomised, controlled trial. Patients and Participants: 210 children aged 0.5 to 12 years who presented with acute, symptomatic, uncomplicated I;I falciparum malaria between Septe mber and December 2000. Methods: Children were randomised to receive amodiaquine 30 mg/kg given ove r 3 days (n = 104) or chloroquine base 30 mg/kg given over 3 days (n = 106) . Clinical and parasitological assessments were done pretreatment and 24-ho urly for 168 hours and at 336, 504 and 672h. Parasite disposition kinetics were estimated from parasite concentrations by using a noncompartmental met hod. Results: Following treatment, the areas under the parasite density versus t ime curve (AUC(pd)) and the half-life of parasitaemia (t1/2,(pd)) were sign ificantly lower with amodiaquine than with chloroquine [518.7 +/- 47.5 (sta ndard error) vs 810.7 +/- 101.3 asexual forms/mul.h, p = 0.01, and 3.5 +/- 0.1 (class IIb) vs 4.5 +/- 0.3h (class IV), p = 0.001, respectively]. The v olume of blood completely cleared of parasites per unit time (CLBpd) was hi gher (not significant) with amodiaquine than with chloroquine. Fractional r eduction of AUC(pd) at 24 and 48h was significantly higher (0.87 +/- 0.01 v s 0.8 +/- 0.02, p = 0.001; 0.98 +/- 0.001 vs 0.93 +/- 0.02, p = 0.02, respe ctively) and the t1/2,(pd) index was significantly lower (1.9 +/- 0.05 vs 2 .5 +/- 0.2, p = 0.0035) with amodiaquine than with chloroquine. In children where initial treatment with chloroquine failed (n = 20), t1/2,(pd) and t1 /2,(pd) index following re-treatment with amodiaquine were significantly lo wer [3.9 +/- 0.4 (class ma) vs 6.0 +/- 1.03h (class V), p = 0.047; 2.1 +/- 0.19 vs 4.3 +/- 0.9, p = 0.03, respectively] and the CLBpd was higher (not significant) than during initial treatment with chloraquine. In siblings in whom there was clustering of infections (amodiaquine n = 12; chloroquine n = 11), there was no difference in parasite kinetic profiles.. Both drugs w ere relatively well tolerated. Conclusions: These findings indicate that amodiaquine produces more favour- able P. falciparum disposition kinetic profiles than chloroquine, indicati ng a better efficacy, and may be used as an alternative to chloroquine in c hloroquine-resistant infections in endemic areas. The kinetic method of eva luating therapeutic efficacy can be employed in formal therapeutic trials o f antimalarial drugs.