Effects of methylphenidate hydrochloride on the cardiovascular system in vivo and in vitro: A safety pharmacology study

Introduction:We examined the effects of methylphenidate hydrochloride (MPH) on the cardiovascular system using in vivo and in vitro study methods in accordance with the ICH-S7B guideline.MethodsMPH was orally administered at doses of 3, 10 and 30 mg/kg to unrestrained conscious dogs implanted with a telemetry transmitter and attached with body surface electrodes, and electrocardiogram (ECG) leads. The QTcF interval was determined while heart rate (HR), and blood pressure (BP) were measured. Action potentials in isolated guinea-pig papillary muscle and the rapid component of the delayed rectifier potassium current (IKr) in HEK-293 cells stably transfected with hERG were also investigated at concentrations of 0.1, 0.3 and 1 µg/mL (0.37, 1.1 and 3.7 µmol/L) of MPH.ResultsNo ECG changes were observed except for a shortening of the QT interval due to a shortening of the RR interval at the maximum dose tested, 30 mg/kg. The only observed change was an elevation of BP in dogs at the dose of 30 mg/kg, which is approximately 10 times higher than the maximum therapeutic dose for use in children with attention deficit hyperactivity disorder (ADHD). Neither APD prolongation nor IKr inhibition was observed by MPH in the in vitro studies up to the maximum concentration tested, 1 µg/mL (3.7 µmol/L), which is approximately 34 times higher than the clinically attainable unbound plasma MPH concentrations in children with ADHD.DiscussionThese results suggest that it is unlikely that MPH affects ventricular repolarization processes at the therapeutically recommended dose levels in patients with ADHD.