Phase 1 Studies of a Candidate Aminoquinoline Antimalarial (Aq-13) in Humans

Our previous studies have developed a series of AQs which are active against multiply- resistant strains of Plasmodium falciparum in vitro. One candidate, AQ-13, was compared with chloroquine (CQ) in animals and found to have similar safety and pharmacology [1]. The objectives of the Phase 1 Study of AQ-13 reported here are to: 1) define the safety of AQ-13 in healthy, adult, human volunteers, and 2) define the pharmacokinetics of AQ-13. AQ-13 and CQ were compared at a series of incremental doses: 10, 100, 300, 600 and 1500 mg base. At the 600 mg dose, pharmacokinetic analysis indicated that an AQ-13 dose equivalent to 700 mg CQ was necessary to provide bioavailability of AQ-13 similar to that of 600 mg CQ. Therefore, volunteers in the final stage of the study were allocated randomly to receive 1750 mg AQ-13 or 1500 mg CQ. Continuous heart monitoring, drug/metabolite levels, and adverse events (AE) were recorded. The adjusted dose of 1750 mg AQ-13 produced similar bioavailability (area under the curve, AUC) to that of 1500 mg CQ (AQ-13 AUC [median, range] = 311.9 (119.2–440.3), CQ AUC = 226.3 (126.8–493.3); p= 0.31). There were no substantive differences in cardiac toxicity or other AEs between AQ-13 and CQ (p = 0.2–0.9 for different AEs reported). No serious AEs in both drug groups occurred [2]. These results suggest that AQ-13 has similar pharmacokinetic and safety profiles to CQ. Phase 2 (efficacy) trials of AQ-13 in patients with malaria are planned. References: [1] De D, et al. (1996) Am J Trop Med Hyg. 55: 579–583. [2] Mzayek F, et al. (2007) PLOS Clin Trial 2(1): e6.