Effects of triclabendazole and its metabolite exposure on the heart-rate-corrected QT intervals: A randomized, placebo- and positive-controlled thorough QT study in healthy individuals

Abstract

Triclabendazole is an effective and well-tolerated treatment for human fascioliasis. A placebo- and positive-controlled, four-sequence by four-period crossover study was conducted in 45 healthy participants to assess the effect of therapeutic (10 mg/kg twice daily [b.i.d.] for 1 day) and supratherapeutic (10 mg/kg b.i.d. for 3 days) oral doses of triclabendazole on corrected QT (QTc) interval prolongation. Moxifloxacin (400 mg, oral) was used as a positive control. The highest mean placebo-corrected change from baseline in QTcF (ΔΔQTcF) on day 4 with triclabendazole was 9.2 at therapeutic dose ms and 21.7 ms at supratherapeutic dose, at 4 h postdose. The upper limit of the two-sided 90% confidence interval exceeded 10 ms across all timepoints, except at predose timepoint on day 4 in the therapeutic group indicating that an effect of triclabendazole on cardiac repolarization could not be excluded. However, triclabendazole had no clinically significant effects on heart rate and cardiac conduction at the studied doses. In the moxifloxacin group, the mean ΔΔQTcF peak value was 13.7 ms at 3 h on day 4. The assay sensitivity was confirmed. Maximum plasma concentration of triclabendazole, sulfoxide metabolite, and sulfone metabolite occurred at ~3-, 4-, and 6-h postdose, respectively. No deaths, serious adverse events, study discontinuations due to treatment-emergent adverse events, or clinically relevant abnormalities in laboratory evaluations and vital sign values were observed. This study showed that triclabendazole had no clinically relevant effects on heart rate and cardiac conduction; however, an effect on cardiac repolarization (ΔΔQTcF >10 ms) could not be excluded.

FIGURE 1

Study design. BL, baseline; EoP, end of phase; EoS, end of study; placebo, triclabendazole‐matched placebo; TBZL, triclabendazole. Treatment sequences: ABCD, BDAC, CADB, DCBA.

FIGURE 2

Placebo‐corrected mean change from baseline in (a) QTcF (ΔΔQTcF), (b) HR (ΔΔHR), (c) PR (ΔΔPR), and (d) QRS (ΔΔQRS) across timepoints on day 4 (PD analysis set). BID, twice daily; CI, confidence interval; HR, heart rate; LS, least squares; msec, millisecond; PD, pharmacodynamics; TBZL, triclabendazole.

FIGURE 3

Triclabendazole plasma concentration‐time profiles – combined analytes (PK analysis set). BID, twice daily; PK, pharmacokinetics; TBZL, triclabendazole.