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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:

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.

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Received March 01, 2018

Accepted June 13, 2018

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