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, AUCτ, 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).
Table 1.
Randomization of Volunteers to AQ-13 and CQ: Baseline Characteristics
Table 2.
Frequency of Related Adverse Events by Drug and Dose
Table 3.
Comparative Pharmacokinetics of AQ-13 and CQ at 600 and 700 mg Doses
Table 4.
Comparative Pharmacokinetics of AQ-13 and CQ at 1,750 and 1,500 mg Doses
Table 5.
Comparative Pharmacokinetics of AQ-72 and MDCQ at Different Doses of AQ-13 and CQ (median, range)
Table 6.
Effects of AQ-13 and CQ on the QTc Interval
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).