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.
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.
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.
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: email@example.com).
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