Population pharmacokinetic model of propranolol and its metabolite reflecting the first-pass effect in patients with hepatic impairment
Sunae Ryu(1), Sunny Park(1), Jong-Gu Lee(1), Ze-Won Park(1), Woo-Yong Oh(1), Seung-Eun Choi(1)
(1)Clinical Research Division, National Institute of Food and Drug Safety, Ministry of Food and Drug Safety, Republic of Korea
Objectives: Propranolol, a beta adrenergic receptor blocker, is routinely used for primary prophylaxis of variceal haemorrage in cirrhotic patients [1-2]. Since propranolol is highly hepatic extracted drug and subject to undergo alteration of first-pass effect according to hepatic function status, this study aimed to develop population pharmacokinetic models that described the first-pass effect of propranolol and simulate the optimal dosing regimen for patient with hepatic impairment in different degree of severity [3-4].
Methods: We developed a joint population pharmacokinetic model of propranolol and its active metabolite, 4-hydroxy propranolol, from phase I clinical study with 54 mild to moderate hepatic impaired patients and 24 healthy volunteers. Population PK analysis were performed via nonlinear mixed effects modeling using the software program NONMEM 7 (Version 7.3, ICON, LLC, Maryland, USA) using PREDPP Subroutine ADVAN6 and the first-order conditional estimation with interaction (FOCE-I) algorithms.
Results: The joint model with two central compartments for each compound and direct absorption of the metabolite into the systemic circulation reflecting hepatic first-pass effect described the data adequately. Platelet count and body weight were added in the model as significant covariates. In hepatic impaired patients, the increased systemic exposure of propranolol resulted in the decrease of volume of distribution (Vc) and clearance (CL) of propranolol, whereas clearance of metabolite (CLm) and metabolic rate constant (Km) were increased in association with decreased platelet count. Simulation in varying degree of severity of hepatic impairment revealed that the pharmacokinetic profiles of propranolol were affected by the hepatic impairment but not significant change was found according to the severity of the disease. Also the dosing simulation showed that 25 or 30mg twice a day of propranolol in hepatic impaired patients would give comparable systemic exposure to 40mg twice a day in patients with normal hepatic function.
Conclusions: The population pharmacokinetic model with hepatic first-pass effect adequately described the data for both propranolol and 4-hydroxy propranolol with a two central compartment model for each compound. The dosing simulation suggest a dose reduction in hepatic impaired patients to give similar exposure compared to healthy subjects but further study would be necessary to determine the clinical significance.
References:
[1] Mona A. Amin et al., The north Italia endoscopic club for the study and treatment oesophageal varices. Prediction of the first varicea hemorrhage in patients with cirrhosis of the live and esophageal varices. N England J Med 1988;319:983-9
[2] Dhiraj Tripathi et al., UK guidelines on the management of variceal haemorrhage in cirrhotic patients. Gut. 2015;0:1-25
[3] Inderal product information https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/018031s036lbl.pdf
[4] Julie Bertrand et al., Development of a complex parent-metabolite joint population pharmacokinetic model. The AAPS Journal. 2011;13:390-404.