Effect of a single supratherapeutic dose of dolutegravir on cardiac repolarization.

To assess the effect of a supratherapeutic dose of the integrase inhibitor dolutegravir on the QT and corrected QT (QTc) interval. Randomized, partial-blind, placebo-controlled, single-dose, 3-period, balanced crossover study. Clinical research unit. Forty-two healthy subjects were randomized; of these subjects, 38 completed the study, three withdrew early because of protocol violations, and one was lost to follow-up. Subjects were randomized to receive three single doses of the following treatments: dolutegravir 250-mg suspension, moxifloxacin 400-mg tablet, and placebo suspension; each treatment was separated by a 14-day washout period. Treatment with the dolutegravir and placebo suspension was blinded, whereas treatment with moxifloxacin was open label. The pharmacokinetic exposure at a supratherapeutic dose of dolutegravir 250 mg was 2-4 times higher than the pharmacokinetic exposure at clinically relevant dosages (50 mg once or twice/day). The upper limit of the 90% confidence interval (CI) for the placebo-adjusted mean change from baseline of the QTc interval (ΔΔQTcF) using Fridericia's formula was less than 10 msec at all time points. The sensitivity of the study to detect modest increases in QT interval was established with moxifloxacin, a positive control for QT-interval prolongation. The maximum ΔΔQTcF values for dolutegravir and moxifloxacin were observed at 4 hours: 1.99 msec (90% CI -0.55-4.53 msec) and 9.58 msec (90% CI 7.05-12.11 msec), respectively. This pharmacokinetic-pharmacodynamic model demonstrates no relationship between dolutegravir plasma concentration and ΔΔQTcF. Furthermore, a supratherapeutic dose of dolutegravir was generally well tolerated without any serious or severe adverse events. As such, dolutegravir does not affect cardiac repolarization.

Chen S ，Min SS ，Peppercorn A ，Borland J ，Lou Y ，Song I ，Fujiwara T ，Piscitelli SC ... -  《-》

Effect of intravenous zanamivir on cardiac repolarization.

To assess the effect of a therapeutic and supratherapeutic intravenous dose of the neuraminidase inhibitor zanamivir on QT and rate-corrected QT intervals. Randomized, placebo-controlled, single-dose, four-period, balanced crossover study. Clinical research unit. Forty healthy adults were randomized to receive intravenous zanamivir at two dose levels, oral moxifloxacin, and placebo; 38 subjects completed all four study treatments. Subjects were randomized to receive a single intravenous dose of zanamivir 600 mg (therapeutic dose) with oral moxifloxacin placebo, a single intravenous dose of zanamivir 1200 mg (supratherapeutic dose) with oral moxifloxacin placebo, oral moxifloxacin 400 mg (positive control) with intravenous zanamivir placebo, or intravenous zanamivir placebo with oral moxifloxacin placebo. Subjects crossed over to all other treatments, with each treatment separated by a 7-day washout period. Zanamivir pharmacokinetics were dose proportional; the pharmacokinetic exposure from zanamivir 1200 mg was 2 times higher than that from 600 mg, the maximum dose under clinical evaluation. For both 600-mg and 1200-mg doses of intravenous zanamivir, the upper limit of the 90% confidence interval (CI) for the placebo-adjusted mean change from baseline of the QT interval corrected for heart rate using Fridericia's formula (ΔΔQTcF) was less than 10 msec at all time points. The sensitivity of the study to detect modest increases in QT interval was established with the positive control, moxifloxacin. The maximum ΔΔQTcF value for zanamivir 1200 mg was 1.73 msec (90% CI -0.40 to 3.87 msec), which was observed within 30 minutes after dosing, and 11.21 msec (90% CI 8.81-13.60) for moxifloxacin, observed at 4 hours after dosing. No relationship was observed between zanamivir serum concentration and ΔΔQTcF. Zanamivir was generally well tolerated, with very few adverse events; none were serious or severe. Intravenous zanamivir does not affect cardiac repolarization. Accordingly, treatment with intravenous zanamivir does not require additional cardiac monitoring beyond the standard of care.

Lou Y ，Gan J ，Peppercorn A ，Gould E ，Weller S ，Piscitelli SC ，Patel P ... -  《-》

Sugammadex is not associated with QT/QTc prolongation: methodology aspects of an intravenous moxifloxacin-controlled thorough QT study.

de Kam PJ ，van Kuijk J ，Smeets J ，Thomsen T ，Peeters P ... -  《INTERNATIONAL JOURNAL OF CLINICAL PHARMACOLOGY AND THERAPEUTICS》

Etravirine has no effect on QT and corrected QT interval in HIV-negative volunteers.

Peeters M ，Janssen K ，Kakuda TN ，Schöller-Gyüre M ，Lachaert R ，Hoetelmans RM ，Woodfall B ，De Smedt G ... -  《-》

Effect of levetiracetam on cardiac repolarization in healthy subjects: a single-dose, randomized, placebo- and active-controlled, four-way crossover study.

Hulhoven R ，Rosillon D ，Bridson WE ，Meeus MA ，Salas E ，Stockis A ... -  《-》