Unanticipated CNS Safety Signal in a Placebo-Controlled, Randomized Trial of Co-Administered Atovaquone-Proguanil and Amodiaquine

Abstract

Atovaquone-proguanil (ATV-PG) plus amodiaquine (AQ) has been considered as a potential replacement for sulfadoxine-pyrimethamine plus AQ for seasonal malaria chemoprevention in African children. This randomized, double-blind, placebo-controlled, parallel group study assessed the safety, tolerability, and pharmacokinetics (PKs) of ATV-PG plus AQ in healthy adult males and females of Black sub-Saharan African origin. Participants were randomized to four treatment groups: ATV-PG/AQ (n = 8), ATV-PG/placebo (n = 12), AQ/placebo (n = 12), and placebo/placebo (n = 12). Treatments were administered orally once daily for 3 days (days 1-3) at daily doses of ATV-PQ 1000/400 mg and AQ 612 mg. Co-administration of ATV-PG/AQ had no clinically relevant effect on PK parameters for ATV, PG, the PG metabolite cycloguanil, AQ, or the AQ metabolite N-desethyl-amodiaquine. Adverse events occurred in 8 of 8 (100%) of participants receiving ATV-PG/AQ, 11 of 12 (91.7%) receiving ATV-PG, 11 of 12 (91.7%) receiving AQ, and 3 of 12 (25%) receiving placebo. The safety and tolerability profiles of ATV-PG and AQ were consistent with previous reports. In the ATV-PG/AQ group, 2 of 8 participants experienced extrapyramidal adverse effects (EPAEs) on day 3, both psychiatric and physical, which appeared unrelated to drug plasma PKs or cytochrome P450 2C8 phenotype. Although rare cases are reported with AQ administration, the high incidence of EPAE was unexpected in this small study. Owing to the unanticipated increased frequency of EPAE observed, the combination of ATV-PQ plus AQ is not recommended for further evaluation in prophylaxis of malaria in African children.

Figure 1

Frequency of adverse events following administration of atovaquone‐proguanil (ATV‐PG), amodiaquine (AQ) or ATV‐PG/AQ. Values are the percentage of participants experiencing the adverse event.

Figure 2

Individual participant values for maximum plasma concentration (C_max) and area under the concentration–time curve (AUC) for atovaquone (ATV), proguanil (PG), cycloguanil (CG), amodiaquine (AQ), and N‐desethyl‐amodiaquine (DEAQ) following administration of ATV‐PG/AQ. Participants that experienced extrapyramidal adverse effects (EPAEs) are shown with a black square (participant 11010) and a black triangle (participant 12013). Participants without EPAE are shown with black circles.

Figure 3

Plasma concentration–time profiles for atovaquone (ATV), proguanil (PG), and cycloguanil (CG) following administration of ATV‐PG or ATV‐PG/amodiaquine (AQ). See also Figure S2 for the extended plasma concentration–time profile for ATV up to day 22.

Figure 4

Plasma concentration–time profiles for amodiaquine (AQ) and N‐desethyl‐amodiaquine (DEAQ) following administration of AQ or atovaquone‐proguanil (ATV‐PG)/AQ.