Swan Lin1, Mina Nikanjam1, Edmund V Capparelli1, Alessandro Allegrini2, Daniele Pavone2, Dong-Seok Yim3, Muhammad M Hammami4, Joseph S Bertino5, Anne N Nafziger5, Yoo-Sin Park6, Ju-Seop Kang7, Ophelia Q Yin8, Joseph D Ma1. 1. University of California, San Diego, La Jolla, California. 2. FOURPHARMA C.R.O. srl, Rome, Italy. 3. Department of Pharmacology, Clinical Pharmacology Unit, Clinical Trial Center/Clinical Research Institute, Seoul National University College of Medicine and Hospital, Seoul, South Korea. 4. King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia. 5. Bertino Consulting, Schenectady, New York. 6. Shintong Rehabilitation Clinic, Suji-gu, Yongin-si, Gyeonggi-do, South Korea. 7. Department of Pharmacology & Clinical Pharmacology Lab, College of Medicine, Hanyang University, Seoul, Republic of Korea 8. School of Pharmacy, Faculty of Medicine, the Chinese University of Hong Kong, Shatin, New Territories, Hong Kong.
Abstract
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, 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 (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.
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, 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 (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.
Authors: Eileen B Lawson; Jerry C Wu; R Michael Baldwin; Magnus Ingelman-Sundberg; Staffan Rosenborg; Dong-Seok Yim; Ophelia Q P Yin; Edmund V Capparelli; Joseph D Ma Journal: Eur J Clin Pharmacol Date: 2011-10-19 Impact factor: 2.953
Authors: Wei Tai; Sheryl L Gong; Shirley M Tsunoda; Howard E Greenberg; J Christopher Gorski; Scott R Penzak; S Aubrey Stoch; Joseph D Ma Journal: Drug Metabol Drug Interact Date: 2013