Joo Young Na1, Jaeseong Oh1, Jae-Yong Chung2
1 Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea 2 Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Bundang Hospital, Seongnam, Gyeonggi-do, Korea
Objectives:
Omeprazole blocks the gastric H+/K+ adenosine triphosphatase, thus inhibiting gastric acid secretion. Omeprazole is extensively metabolized into 5-hydroxy omeprazole through the action of cytochrome P450 (CYP) 2C19 and into omeprazole sulfone through the action of CYP3A4. Previous studies showed that the CYP2C19 polymorphism has a significant impact on the pharmacokinetics (PK), pharmacodynamics and efficacy of omeprazole. Due to the physiological changes in the elderly, there are different PK consequences compared to young people and can show differences in the efficacy and safety of drugs. The objective of this study was to develop a PK model of omeprazole in elderly subjects and to evaluate the effect of CYP2C19 polymorphism on the PK of omeprazole.
Methods:
An open-label, single-dose, single-sequence study was conducted in 15 healthy elderly subjects (age range of 65-73 years, height of 147.8-175.8 cm, body weight of 51.3-85.7 kg, and BMI of 21.7-27.9 kg/m2). Among them, six, three, and six subjects were CYP2C19 extensive metabolizer (EM), intermediate metabolizer (IM), and poor metabolizer (PM), respectively. The subjects received a single oral dose of omeprazole 20 mg. A total of 146 plasma concentrations of omeprazole obtained from 15 elderly subjects were included for population PK analysis. A population PK model was developed using a non-linear mixed-effects method with NONMEM version 7.4.4. The First-Order Conditional Estimation with Interaction estimation method was used, and model qualifications were followed using a likelihood ratio test, goodness-of-fit (GOF) plots, and visual predictive checks (VPCs). Inter-individual variability (IIV) was modeled using an exponential error model and residual variability was modeled using a proportional random-effects model. Covariates including age, height, body weight, and CYP2C19 phenotype were tested through stepwise forward selection and backward elimination at significance levels of 0.05 (forward) and 0.001 (backward). Simulations were performed investigating the difference in omeprazole exposure among CYP2C19 phenotypes after multiple administrations of omeprazole.
Results:
The PK of omeprazole was well described by a one-compartment first-order elimination model with zero-order absorption with absorption lag time. The population typical estimates of the clearance (CL) (relative standard error, RSE) in EM, IM, and PM were 7.26 L/hr (19%), 6.06 L/hr (10%), and 3.79 L/hr (9%), respectively, and the volume of distribution was 15.7 L (6%). The estimate (RSE) of the duration of zero-order absorption (D1) was 1.75hr (10%) and the absorption lag time was fixed to 0.64 hr. CYP2C19 phenotype was the only selected covariate in the model and had a significant effect on the CL. The IIV (coefficient of variations, %) of CL was 31.3%. The model evaluation by GOF plot and VPC result suggested that the final PK model was robust and adequate with proper precision.
Conclusions:
The developed population PK model adequately described the observed plasma concentration of omeprazole in elderly subjects. The model can be applied to determine the optimal dosage regimens for elderly patients.
References:
[1] Na JY, Jeon I, Yoon J, Choi Y, Yoon SH, Yu KS, Chung JY. Influence of CYP2C19 Polymorphisms on the Pharmacokinetics of Omeprazole in Elderly Subjects. Clin Pharmacol Drug Dev. 2021 Dec;10(12):1469-1477. doi: 10.1002/cpdd.966. Epub 2021 Aug 2. PMID: 34337876.
[2] Greenblatt DJ, Sellers EM, Shader RI. Drug disposition in old age. N Engl J Med. 1982;306(18):1081-1088.
[3] Wynne HA, Cope LH, Mutch E, Rawlins MD, Woodhouse KW, James OF. The effect of age upon liver volume and apparent liver blood flow in healthy man. Hepatology. 1989;9(2):297-301.
[4] Klotz U. Pharmacokinetics and drug metabolism in the elderly. Drug Metab Rev. 2009;41(2):67-76.
Reference: PAGE 30 (2022) Abstr 10026 [www.page-meeting.org/?abstract=10026]
Poster: Drug/Disease Modelling - Other Topics