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Evaluation of Omeprazole Limited Sampling Strategies to Estimate Constitutive Cytochrome P450 2C19 Activity in Healthy Adults

Lin, Swan, PharmD*; Nikanjam, Mina, MD, PhD*; Capparelli, Edmund V., PharmD*; Allegrini, Alessandro, MS; Pavone, Daniele, MS; Yim, Dong-Seok, MD, PhD; Hammami, Muhammad M., MD, PhD§; Bertino, Joseph S. Jr, PharmD; Nafziger, Anne N., MD, PhD; Park, Yoo-Sin, PhD; Yin, Ophelia Q., PhD**; Ma, Joseph D., PharmD*

doi: 10.1097/FTD.0000000000000554
Short Communication

Background: Limited sampling strategy (LSS) is a validated method to estimate pharmacokinetic (PK) parameters from a reduced number of samples. Omeprazole is used to phenotype in vivo cytochrome P450 (CYP) 2C19 activity. This study examined an LSS using 2 estimation methods to determine apparent oral clearance (CL/F) and thus CYP2C19 activity.

Methods: Data from 7 previously published studies included healthy subjects receiving a single, oral dose of omeprazole with intensive PK sampling. CL/F was estimated using noncompartmental analysis (NCA) and population PK modeling. LSS was simulated by selecting the 1, 2, 4, and/or 6-hour postdose time points. Linear regression was performed to assess whether CL/F estimated from limited sampling could accurately predict CL/F from the full PK profile.

Results: Median CL/F was 23.7 L/h by NCA and 19.3 L/h by population PK modeling. In comparing the LSS NCA estimated versus observed CL/F, all evaluated linear regression models had unacceptable coefficients of determination (r 2, range: 0.14–0.81). With the population PK approach, 737 plasma concentrations (n = 71) and CYP2C19 genotype data were described with a 1-compartment structural model with mixed zero and first-order absorption and lag time. In comparing the population PK LSS estimated versus observed CL/F, all evaluated linear regression models had unacceptable r 2 (range: 0.02–0.74). Post hoc comparison of CYP2C19 poor metabolizers versus CYP2C19 extensive metabolizers resulted in significantly lower CL/F in poor metabolizers versus extensive metabolizers.

Conclusions: Omeprazole LSS performed poorly in estimating CL/F using 2 separate estimation approaches and does not seem to be a suitable method for determining CYP2C19 activity.

*University of California, San Diego, La Jolla, California;

FOURPHARMA C.R.O. srl, Rome, Italy;

Department of Pharmacology, Clinical Pharmacology Unit, Clinical Trial Center/Clinical Research Institute, Seoul National University College of Medicine and Hospital, Seoul, South Korea;

§King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia;

Bertino Consulting, Schenectady, New York

Shintong Rehabilitation Clinic, Suji-gu, Yongin-si, Gyeonggi-do, South Korea; and

**School of Pharmacy, Faculty of Medicine, the Chinese University of Hong Kong, Shatin, New Territories, Hong Kong.

Correspondence: Joseph D. Ma, PharmD, Skaggs School of Pharmacy and Pharmaceutical Sciences, 9500 Gilman Drive, MC 0714, La Jolla, CA 92093-0714 (e-mail: joema@ucsd.edu).

S. Lin was a post-doctoral fellow with funding supported by Pfizer Global Research and Development and the UCSD, Skaggs School of Pharmacy and Pharmaceutical Sciences, La Jolla, CA. Funding support was provided by a Research in Pediatric and Developmental Pharmacology NIH grant (1U54HD090259-01 to E.V.C.).

The authors declare no conflict of interest.

Presented in part at the 46th Annual Meeting of the American College of Clinical Pharmacology, September 17–19, 2017, San Diego, CA.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.drug-monitoring.com).

Received March 01, 2018

Accepted June 13, 2018

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