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

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

Author by Prof. Christiana Sowunmi

Journal/Publisher: Clinical Drug Investigation

Volume/Edition: 21

Language: English

Pages: 371 - 381

Abstract

Objectives: To examine the kinetics of the disposition of Plasmodium falciparum during treatment with amodiaquine, a Mannich base derivative of chloroquine and chloroquine. Additional aims were to compare P. falciparum kinetics in children in whom initial treatment with chloroquine failed and following re-treatment with amodiaquine, and in siblings in whom there was household clustering of falciparum infections. An important aim was to validate the 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 P. falciparum malaria between September and December 2000.

Methods: Children were randomised to receive amodiaquine 30 mg/kg given over 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-hourly for 168 hours and at 336, 504 and 672h. Parasite disposition kinetics were estimated from parasite concentrations by using a noncompartmental method.

Results: Following treatment, the areas under the parasite density versus time curve (AUCpd) and the half-life of parasitaemia (t1/2pd) were significantly lower with amodiaquine than with chloroquine [518.7 ± 47.5 (standard error) vs 810.7 ± 101.3 asexual forms/?l · h, p = 0.01, and 3.5 ± 0.1 (class IIb) vs 4.5 ± 0.3h (class IV), p = 0.001, respectively]. The volume of blood completely cleared of parasites per unit time (CLBpd) was higher (not significant) with amodiaquine than with chloroquine. Fractional reduction of AUCpd at 24 and 48h was significantly higher (0.87 ± 0.01 vs 0.8 ± 0.02, p = 0.001; 0.98 ± 0.001 vs 0.93 ± 0.02, p = 0.02, respectively) 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 lower [3.9 ± 0.4 (class IIIa) 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 chloroquine. 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 were relatively well tolerated.

Conclusions: These findings indicate that amodiaquine produces more favourable P. falciparum disposition kinetic profiles than chloroquine, indicating a better efficacy, and may be used as an alternative to chloroquine in chloroquine-resistant infections in endemic areas. The kinetic method of evaluating therapeutic efficacy can be employed in formal therapeutic trials of antimalarial drugs.

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