AIMS: 1) To characterize the variability of multiple-dose halofantrine pharmacokinetics over time in healthy adults, 2) to correlate the pharmacodynamic measure electrocardiographic (ECG) QT interval with (+)- and (-)-halofantrine plasma concentration and 3) to evaluate the safety and tolerance of halofantrine hydrochloride given over time to healthy adults. METHODS:Twenty-one healthy subjects were enrolled and 13 completed the study (180 days). Subjects received either 500 mg of racemic halofantrine once daily in the fasted state for 42 days, or placebo, and then halofantrine washout was documented for the following 138 days. Pharmacokinetic and pharmacodynamic (ECG QTc) measurements were obtained. RESULTS: Mean accumulation half-times (days) for halofantrine were: 7.0 +/- 4.8 [(+)-halofantrine] and 7.3 +/- 4.8 [(-)-halofantrine]. Mean steady-state concentrations were: 97.6 +/- 52.0 ng ml(-1) [(+)-halofantrine] and 48.5 +/- 20.8 [(-)-halofantrine]. Steady-state oral clearance was: 139 +/- 73 l h(-1) [(+)-halofantrine] and 265 +/- 135 l h(-1) [(-)-halofantrine]. Peak plasma concentrations of both (+)- and (-)-halofantrine were attained at 6 h and maximal ECG QTc prolongation was at 4-8 h following drug administration. Fourteen of 16 subjects who received active drug had ECG QTc prolongation that was positively correlated with both (+)- and (-)-halofantrine concentration. The five subjects who received placebo had no demonstrable change in ECG QTc throughout the study. Conclusions Halofantrine accumulates extensively and shows high intersubject pharmacokinetic variability, is associated with concentration-related ECG QTc prolongation in healthy subjects, and is clinically well tolerated in this subject group.
RCT Entities:
AIMS: 1) To characterize the variability of multiple-dose halofantrine pharmacokinetics over time in healthy adults, 2) to correlate the pharmacodynamic measure electrocardiographic (ECG) QT interval with (+)- and (-)-halofantrine plasma concentration and 3) to evaluate the safety and tolerance of halofantrine hydrochloride given over time to healthy adults. METHODS: Twenty-one healthy subjects were enrolled and 13 completed the study (180 days). Subjects received either 500 mg of racemic halofantrine once daily in the fasted state for 42 days, or placebo, and then halofantrine washout was documented for the following 138 days. Pharmacokinetic and pharmacodynamic (ECG QTc) measurements were obtained. RESULTS: Mean accumulation half-times (days) for halofantrine were: 7.0 +/- 4.8 [(+)-halofantrine] and 7.3 +/- 4.8 [(-)-halofantrine]. Mean steady-state concentrations were: 97.6 +/- 52.0 ng ml(-1) [(+)-halofantrine] and 48.5 +/- 20.8 [(-)-halofantrine]. Steady-state oral clearance was: 139 +/- 73 l h(-1) [(+)-halofantrine] and 265 +/- 135 l h(-1) [(-)-halofantrine]. Peak plasma concentrations of both (+)- and (-)-halofantrine were attained at 6 h and maximal ECG QTc prolongation was at 4-8 h following drug administration. Fourteen of 16 subjects who received active drug had ECG QTc prolongation that was positively correlated with both (+)- and (-)-halofantrine concentration. The five subjects who received placebo had no demonstrable change in ECG QTc throughout the study. Conclusions Halofantrine accumulates extensively and shows high intersubject pharmacokinetic variability, is associated with concentration-related ECG QTc prolongation in healthy subjects, and is clinically well tolerated in this subject group.
Authors: F Nosten; F O ter Kuile; C Luxemburger; C Woodrow; D E Kyle; T Chongsuphajaisiddhi; N J White Journal: Lancet Date: 1993-04-24 Impact factor: 79.321
Authors: E F Boudreau; L W Pang; K E Dixon; H K Webster; K Pavanand; L Tosingha; P Somutsakorn; C J Canfield Journal: Bull World Health Organ Date: 1988 Impact factor: 9.408
Authors: T M Cosgriff; E F Boudreau; C L Pamplin; E B Doberstyn; R E Desjardins; C J Canfield Journal: Am J Trop Med Hyg Date: 1982-11 Impact factor: 2.345
Authors: Xin Hui S Chan; Yan Naung Win; Ilsa L Haeusler; Jireh Y Tan; Shanghavie Loganathan; Sompob Saralamba; Shu Kiat S Chan; Elizabeth A Ashley; Karen I Barnes; Rita Baiden; Peter U Bassi; Abdoulaye Djimde; Grant Dorsey; Stephan Duparc; Borimas Hanboonkunupakarn; Feiko O Ter Kuile; Marcus V G Lacerda; Amit Nasa; François H Nosten; Cyprian O Onyeji; Sasithon Pukrittayakamee; André M Siqueira; Joel Tarning; Walter R J Taylor; Giovanni Valentini; Michèle van Vugt; David Wesche; Nicholas P J Day; Christopher L-H Huang; Josep Brugada; Ric N Price; Nicholas J White Journal: PLoS Med Date: 2020-03-05 Impact factor: 11.069