Pharmacokinetics of propranolol following single and multiple-dosing with Inderal-LA or a chrontherapeutic form of propranolol

Abstract

Blood pressure rises rapidly upon waking and may be responsible in part for the increased incidence of myocardial infarction and stroke during the morning hours. Current formulations and dosing of antihypertensive drugs do not provide maximum coverage during this vulnerable period. This study was performed to demonstrate that propranolol CR, a novel chronotherapeutic formulation of propranolol designed for nighttime dosing, had appropriate pharmacokinetics to provide maximum effect in the morning. Beta-blockers may be well-suited for the purpose of chronotherapy since they attenuate sympathetic activity and thereby decrease the increase in heart rate and contractility that are seen upon waking. Pharmacokinetics of propranolol CR and Inderal LA following single and multiple doses were determined in normal male volunteers in this open-label, two-period, crossover study. The drugs were dosed in the evening and serial blood samples were taken for determination of propranolol concentration the next 24 to 72 hours. Following a single 160 mg dose of propranolol CR administered at 10 PM, absorption was delayed by about 4 hrs, after which plasma concentration rose steadily, reaching a peak at about 10 AM. In contrast, after dosing with Inderal LA, plasma levels of propranolol began to rise almost immediately, reaching a plateau between 4 AM and 10 AM. During multiple dosing, steady-state trough plasma concentrations were achieved after 2 days with either drug. Following the final dose, the changes in plasma concentration were similar to those observed in the single dose study. Bioavailability was similar for both formulations of propranolol. In conclusion, Propranolol CR exhibited appropriate pharmacokinetics for the chronotherapeutic treatment of hypertension; moreover, the higher peak plasma levels and the slightly greater bioavailability observed after dosing with propranolol CR offer potential advantages over Inderal LA. See Figure 1.