Randomized dose-ranging controlled trial of AQ-13, a candidate antimalarial, and chloroquine in healthy volunteers

Abstract

Objectives: To determine: (1) the pharmacokinetics and safety of an investigational aminoquinoline active against multidrug-resistant malaria parasites (AQ-13), including its effects on the QT interval, and (2) whether it has pharmacokinetic and safety profiles similar to chloroquine (CQ) in humans.

Design: Phase I double-blind, randomized controlled trials to compare AQ-13 and CQ in healthy volunteers. Randomizations were performed at each step after completion of the previous dose.

Setting: Tulane-Louisiana State University-Charity Hospital General Clinical Research Center in New Orleans.

Participants: 126 healthy adults 21-45 years of age.

Interventions: 10, 100, 300, 600, and 1,500 mg oral doses of CQ base in comparison with equivalent doses of AQ-13.

Outcome measures: Clinical and laboratory adverse events (AEs), pharmacokinetic parameters, and QT prolongation.

Results: No hematologic, hepatic, renal, or other organ toxicity was observed with AQ-13 or CQ at any dose tested. Headache, lightheadedness/dizziness, and gastrointestinal (GI) tract-related symptoms were the most common AEs. Although symptoms were more frequent with AQ-13, the numbers of volunteers who experienced symptoms with AQ-13 and CQ were similar (for AQ-13 and CQ, respectively: headache, 17/63 and 10/63, p = 0.2; lightheadedness/dizziness, 11/63 and 8/63, p = 0.6; GI symptoms, 14/63 and 13/63; p = 0.9). Both AQ-13 and CQ exhibited linear pharmacokinetics. However, AQ-13 was cleared more rapidly than CQ (respectively, median oral clearance 14.0-14.7 l/h versus 9.5-11.3 l/h; p < or = 0.03). QTc prolongation was greater with CQ than AQ-13 (CQ: mean increase of 28 ms; 95% confidence interval [CI], 18 to 38 ms, versus AQ-13: mean increase of 10 ms; 95% CI, 2 to 17 ms; p = 0.01). There were no arrhythmias or other cardiac AEs with either AQ-13 or CQ.

Conclusions: These studies revealed minimal differences in toxicity between AQ-13 and CQ, and similar linear pharmacokinetics.

Figure 1. Phase 1 Randomized Clinical Trial of AQ-13 in Comparison with CQ

Designed as a series of double-blind RCTs at incremental oral doses of 10, 100, 300, 600, and 1,500 mg, with a 700 mg adjustment dose after 600 mg to ensure similar bioavailability for AQ-13 and CQ at the 1,500/1,750 mg dose (based on the area under the curve, AUC_τ, in h × μM, as in Figure 3). *AQ-13 dosages: 700 + 700 + 350 mg on days 1, 2, and 3, respectively; CQ dosages: 600 + 600 + 300 mg on days 1, 2, and 3, respectively.

Figure 2. Structures of AQ-13, CQ, and Their Metabolites

Two-dimensional structures are presented. Note that the AQ rings of AQ-13 and CQ are identical; the structural differences between AQ-13 and CQ are in their side chains: linear propyl side chain for AQ-13, branched isopentyl side chain for CQ. Therefore, the molecular weight (MW) of AQ-13 (292 Da) is 28 Da less than CQ (320 Da). Metabolism by N-dealkylation converts an ethyl group to a hydrogen (proton) at each step, resulting in stepwise MW differences of 28 Da.

Figure 3. Pharmacokinetics of AQ-13 and CQ at Doses Equivalent to 600 and 700 mg CQ Base

Charts of blood concentration data for individual volunteers during the first week (168 h) after: 600 mg dose of AQ-13 (A), 700 mg dose of AQ-13 (B), or 600 mg dose of CQ (C). Individual volunteers received single oral doses of 600 mg AQ-13 or CQ, or 700 mg AQ-13. Blood samples of 5 ml were then obtained at multiple points in time after drug administration (see Methods) and examined using a fluorescence HPLC assay for AQ-13, CQ, and their N-dealkylated metabolites [34]. Modeling was performed using the WinNonlin software (Pharsight).

Figure 4. Changes in the QTc Interval after 1,750 mg AQ-13 or 1,500 mg CQ

Changes in the QTc interval from baseline were determined using the Rozinn Electronics system software to evaluate the Holter recordings.

Figure 5. Modeled Concentration-Time Data (1,750 mg AQ-13 Therapeutic Dose)

Individual volunteers received daily oral doses of AQ-13 for 3 d (day 1, 700; day 2, 700; and day 3, 350 mg). Blood samples were then obtained, analyzed, and modeled (see Methods).

Figure 6. Modeled Concentration–Time Data (1,500 mg CQ Therapeutic Dose)

Individual volunteers received daily oral doses of CQ for 3 d (day 1, 600; day 2, 600; and day 3, 300 mg). Blood samples were then obtained, analyzed and modeled (see Methods).