Lack of interaction between lansoprazole and propranolol, a pharmacokinetic and safety assessment.
Due to the prevalence of both gastrointestinal and cardiovascular diseases, it is likely that patients may be coprescribed gastric parietal cell proton pump inhibitors and beta-adrenergic antagonists. Therefore, the objectives of this phase I study were to assess the potential effects of the coadministration of lansoprazole on the pharmacokinetics of propranolol and to evaluate the safety of propranolol with concomitant lansoprazole dosing. In a double-blind fashion, 18 healthy male nonsmokers were initially randomized to receive either 60 mg oral lansoprazole, each morning for 7 days, or an identical placebo (period 1). On day 7, all subjects were concomitantly administered oral propranolol, 80 mg. After a minimum of 1 week following the last dose of either lansoprazole or placebo, subjects were crossed over to the opposite treatment for another 7 days (period 2). Subjects were again administered oral propranolol on day 7. During both treatment periods, blood samples for the determination of plasma propranolol and 4-hydroxy-propranolol were obtained just before the dose and at 0.5, 1, 2, 3, 4, 6, 8 12, 16, 20, and 24 hours postdose. Plasma propranolol and 4-hydroxy-propranolol concentrations were determined by using HPLC with fluorescence detection. The Cmax, tmax, AUC0-infinity, and t1/2 values for propranolol, as well as the AUC0-infinity for 4-hydroxy-propranolol, were calculated and compared between the lansoprazole and placebo regimens. The mean age of the 15 subjects who successfully completed the study was 31 years (range: 24-38 years), and their average weight was 174.8 pounds (range: 145-203 pounds). There were no statistically significant differences between the lansoprazole and placebo regimens for the propranolol Cmax, tmax, AUC0-infinity, and t1/2 values. Also, there were no statistically significant differences between regimens for the 4-OH-propranolol AUC0-infinity. Safety evaluations, which included adverse events, vital signs, clinical laboratory determinations, ECG, and physical examinations, revealed no unexpected clinically significant findings and did not suggest a drug-drug interaction. In conclusion, lansoprazole does not significantly alter the pharmacokinetics of propranolol, suggesting that it does not interact with the CYP2D6- or CYP2C19-mediated metabolism of propranolol. Modification of a propranolol dosage regimen in the presence of lansoprazole is not indicated, based on the pharmacokinetic analysis and the lack of a clinically significant alteration in the pharmacodynamic response.
Karol
M D
MD
Abbott Laboratories, Abbott Park, Illinois 60064-6104, USA.
Locke
C S
CS
Cavanaugh
J H
JH
D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D000319:Adrenergic beta-Antagonists / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology; D000328:Adult; D000897:Anti-Ulcer Agents / Q000009:adverse effects / Q000494:pharmacology*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004347:Drug Interactions; D006801:Humans; D064747:Lansoprazole; D008297:Male; D009853:Omeprazole / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology; D011433:Propranolol / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology; D054328:Proton Pump Inhibitors
D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D000319:Adrenergic beta-Antagonists; D000897:Anti-Ulcer Agents; D054328:Proton Pump Inhibitors; D064747:Lansoprazole; D011433:Propranolol; D009853:Omeprazole