Tags

Type your tag names separated by a space and hit enter

Bottom-up modeling and simulation of tacrolimus clearance: prospective investigation of blood cell distribution, sex and CYP3A5 expression as covariates and assessment of study power.
Biopharm Drug Dispos. 2011 Dec; 32(9):498-506.BD

Abstract

The objectives were to investigate the ability of population-based in vitro-in vivo extrapolation (IVIVE) to reproduce the influence of haematocrit on the clearance of tacrolimus, observed previously, and to assess the power of clinical studies to detect the effects of covariates on the clearance of tacrolimus. A population-based pharmacokinetic simulator (Simcyp) was used to simulate tacrolimus clearance from in vitro metabolism data and demographic characteristics of Japanese liver transplant patients (JLTs). The relationship between haematocrit and dose-to-concentration (D/C) ratio was validated using seven JLTs, whose highly variable haematocrit and D/C ratio were previously analysed. This validation was used as a surrogate for establishing 'interindividual' variability and to assess the power of clinical studies to discern the effect of haematocrit, sex and CYP3A5 genotype on tacrolimus clearance in a virtual JLT population. The relationship between haematocrit and D/C ratio was reproducible by Simcyp and corresponded well to those observed in seven JLTs. The number of JLTs required to detect the influence of CYP3A5 genotype and sex were estimated to be about 50 and > 600, respectively, which was consistent with the results of previous population pharmacokinetic studies for tacrolimus. In conclusion, population-based IVIVE is considered to be a useful approach to assess the influence of covariates a priori before conducting clinical studies. This is also helpful with study design and assessment of the statistical power of clinical studies involving population-based pharmacokinetics to detect the effects of covariates.

Authors+Show Affiliations

Keio University Faculty of Pharmacy, 1-5-30 Shinakouen, Minato-ku, Tokyo 105-8512, Japan. ohtani-tky@umin.netNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Clinical Trial
Journal Article

Language

eng

PubMed ID

22028295

Citation

Ohtani, Hisakazu, et al. "Bottom-up Modeling and Simulation of Tacrolimus Clearance: Prospective Investigation of Blood Cell Distribution, Sex and CYP3A5 Expression as Covariates and Assessment of Study Power." Biopharmaceutics & Drug Disposition, vol. 32, no. 9, 2011, pp. 498-506.
Ohtani H, Barter Z, Minematsu T, et al. Bottom-up modeling and simulation of tacrolimus clearance: prospective investigation of blood cell distribution, sex and CYP3A5 expression as covariates and assessment of study power. Biopharm Drug Dispos. 2011;32(9):498-506.
Ohtani, H., Barter, Z., Minematsu, T., Makuuchi, M., Sawada, Y., & Rostami-Hodjegan, A. (2011). Bottom-up modeling and simulation of tacrolimus clearance: prospective investigation of blood cell distribution, sex and CYP3A5 expression as covariates and assessment of study power. Biopharmaceutics & Drug Disposition, 32(9), 498-506. https://doi.org/10.1002/bdd.777
Ohtani H, et al. Bottom-up Modeling and Simulation of Tacrolimus Clearance: Prospective Investigation of Blood Cell Distribution, Sex and CYP3A5 Expression as Covariates and Assessment of Study Power. Biopharm Drug Dispos. 2011;32(9):498-506. PubMed PMID: 22028295.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Bottom-up modeling and simulation of tacrolimus clearance: prospective investigation of blood cell distribution, sex and CYP3A5 expression as covariates and assessment of study power. AU - Ohtani,Hisakazu, AU - Barter,Zoe, AU - Minematsu,Tsuyoshi, AU - Makuuchi,Masatoshi, AU - Sawada,Yasufumi, AU - Rostami-Hodjegan,Amin, Y1 - 2011/11/08/ PY - 2011/06/28/received PY - 2011/09/28/revised PY - 2011/10/11/accepted PY - 2011/10/27/entrez PY - 2011/10/27/pubmed PY - 2012/5/11/medline SP - 498 EP - 506 JF - Biopharmaceutics & drug disposition JO - Biopharm Drug Dispos VL - 32 IS - 9 N2 - The objectives were to investigate the ability of population-based in vitro-in vivo extrapolation (IVIVE) to reproduce the influence of haematocrit on the clearance of tacrolimus, observed previously, and to assess the power of clinical studies to detect the effects of covariates on the clearance of tacrolimus. A population-based pharmacokinetic simulator (Simcyp) was used to simulate tacrolimus clearance from in vitro metabolism data and demographic characteristics of Japanese liver transplant patients (JLTs). The relationship between haematocrit and dose-to-concentration (D/C) ratio was validated using seven JLTs, whose highly variable haematocrit and D/C ratio were previously analysed. This validation was used as a surrogate for establishing 'interindividual' variability and to assess the power of clinical studies to discern the effect of haematocrit, sex and CYP3A5 genotype on tacrolimus clearance in a virtual JLT population. The relationship between haematocrit and D/C ratio was reproducible by Simcyp and corresponded well to those observed in seven JLTs. The number of JLTs required to detect the influence of CYP3A5 genotype and sex were estimated to be about 50 and > 600, respectively, which was consistent with the results of previous population pharmacokinetic studies for tacrolimus. In conclusion, population-based IVIVE is considered to be a useful approach to assess the influence of covariates a priori before conducting clinical studies. This is also helpful with study design and assessment of the statistical power of clinical studies involving population-based pharmacokinetics to detect the effects of covariates. SN - 1099-081X UR - https://www.unboundmedicine.com/medline/citation/22028295/Bottom_up_modeling_and_simulation_of_tacrolimus_clearance:_prospective_investigation_of_blood_cell_distribution_sex_and_CYP3A5_expression_as_covariates_and_assessment_of_study_power_ L2 - https://doi.org/10.1002/bdd.777 DB - PRIME DP - Unbound Medicine ER -