Pharmacokinetic interactions and safety evaluations of coadministered tafenoquine and chloroquine in healthy subjects

Abstract

Aims: The long-acting 8-aminoquinoline tafenoquine (TQ) coadministered with chloroquine (CQ) may radically cure Plasmodium vivax malaria. Coadministration therapy was evaluated for a pharmacokinetic interaction and for pharmacodynamic, safety and tolerability characteristics.

Methods: Healthy subjects, 18-55 years old, without documented glucose-6-phosphate dehydrogenase deficiency, received CQ alone (days 1-2, 600 mg; and day 3, 300 mg), TQ alone (days 2 and 3, 450 mg) or coadministration therapy (day 1, CQ 600 mg; day 2, CQ 600 mg + TQ 450 mg; and day 3, CQ 300 mg + TQ 450 mg) in a randomized, double-blind, parallel-group study. Blood samples for pharmacokinetic and pharmacodynamic analyses and safety data, including electrocardiograms, were collected for 56 days.

Results: The coadministration of CQ + TQ had no effect on TQ AUC0-t , AUC0-∞ , Tmax or t1/2 . The 90% confidence intervals of CQ + TQ vs. TQ for AUC0-t , AUC0-∞ and t1/2 indicated no drug interaction. On day 2 of CQ + TQ coadministration, TQ Cmax and AUC0-24 increased by 38% (90% confidence interval 1.27, 1.64) and 24% (90% confidence interval 1.04, 1.46), respectively. The pharmacokinetics of CQ and its primary metabolite desethylchloroquine were not affected by TQ. Coadministration had no clinically significant effect on QT intervals and was well tolerated.

Conclusions: No clinically significant safety or pharmacokinetic/pharmacodynamic interactions were observed with coadministered CQ and TQ in healthy subjects.

Trial registration: ClinicalTrials.gov NCT00871156.

Keywords: chloroquine; malaria; pharmacokinetics; radical cure; tafenoquine.

© 2013 The British Pharmacological Society.

Figures

Figure 1

Primaquine and tafenoquine structure

Figure 2

(A–C) Mean plasma concentration vs. time profiles for chloroquine (CQ), desethylchloroquine (DQ) and tafenoquine (TQ), during coadministration of tafenoquine and chloroquine. , CQ + TQ; , CQ alone (A,B); , TQ alone (C)

Figure 3

Mean (SD) percentage of methaemoglobin in blood following treatment with tafenoquine (—Δ—), chloroquine () and tafenoquine + chloroquine (—+—)

Figure 4

(A,B) Adjusted mean changes from baseline (95% confidence interval) in QTcF (A) and QTcB (B) during administration of tafenoquine (– – –), chloroquine (——) and tafenoquine + chloroquine