naphthoquinones and Long-QT-Syndrome

This study examined the safety, tolerability, and pharmacokinetics (PK) of napabucasin in healthy Asian and non-Asian participants and investigated the potential for QT/QTc interval prolongation. This five-part (A-E) study proceeded in a stepwise manner, unless stopping criteria were met. Parts A-D were randomized, double-blind, placebo-controlled, and included healthy Asian male and female and non-Asian male participants. PK parameters were measured following single-dose napabucasin (80-1200 mg) in the fasted or fed state (Part D). Potential QT/QTc interval prolongation was assessed using digital 12-lead electrocardiogram (Parts B and C). Part E was open-label, and examined the PK of single-dose napabucasin (240-720 mg) in healthy non-Asian males. Safety and tolerability were measured in Parts A-E. Changes from baseline in the Fridericia-corrected QT interval (ΔQTcF) and other electrocardiogram parameters were analyzed using a linear mixed-effects model. Napabucasin was well-tolerated across the study (n = 70), and no serious adverse events or significant safety issues were reported when administered with or without food. The most frequent treatment-emergent adverse events were diarrhea and abdominal pain, and these were mild in severity. No prolongation of the QTcF interval was reported following single-dose napabucasin (240-1200 mg) and changes in other cardiac parameters were negligible. The PK profile of napabucasin was consistent with earlier studies. Single-dose napabucasin was tolerated in healthy male and female participants, and no significant safety (including no QTcF prolongation) or tolerability issues were identified, irrespective of food intake. Clinical studies of napabucasin in advanced cancers are ongoing.

Topics: Abdominal Pain; Antineoplastic Agents; Asian People; Benzofurans; Diarrhea; Double-Blind Method; Electrocardiography; Female; Healthy Volunteers; Heart Conduction System; Humans; Long QT Syndrome; Male; Naphthoquinones; Reactive Oxygen Species

Combinations are set to become the mainstay in treatment and prophylaxis of malaria due to Plasmodium falciparum. Various antimalarials have been implicated in cardiotoxicity via prolongation of the QTc interval. Atovaquone-proguanil is an effective and increasingly popular antimalarial choice when used alone or with artesunate in areas of drug resistance. We report the results of an investigation carried out on the Thai-Burmese border in 42 patients randomized to receive either atovaquone-proguanil or atovaquone-proguanil-artesunate for three days. Electrocardiographic recordings were made at baseline and one hour after each dose. There was no statistically significant change in QTc interval between baseline and any subsequent readings in either treatment group or the cohort as a whole. We conclude that atovaquone-proguanil shows no evidence of cardiotoxicity either alone or when combined with artesunate.

Topics: Adolescent; Adult; Animals; Antimalarials; Artemisinins; Artesunate; Atovaquone; Child; Drug Therapy, Combination; Electrocardiography; Female; Heart Diseases; Humans; Long QT Syndrome; Malaria, Falciparum; Male; Middle Aged; Myanmar; Myocardium; Naphthoquinones; Plasmodium falciparum; Proguanil; Sesquiterpenes; Thailand; Treatment Outcome