- Title
- Evaluation of pharmacogenomics and hepatic nuclear imaging–related covariates by population pharmacokinetic models of irinotecan and its metabolites
- Creator
- Liu, Zheng; Martin, Jennifer H.; Hatzimihalis, Athena; Campbell, Ian; Crowley, Simone; Beale, Phillip J.; Karapetis, Christos S.; Price, Timothy; Burge, Mathew E.; Michael, Michael; Liauw, Winston; Mclachlan, Sue-Anne; Link, Emma; Matera, Anetta; Thompson, Michael; Jefford, Michael; Hicks, Rod J.; Cullinane, Carleen
- Relation
- European Journal of Clinical Pharmacology Vol. 78, Issue 1, p. 53-64
- Publisher Link
- http://dx.doi.org/10.1007/s00228-021-03206-w
- Publisher
- Springer
- Resource Type
- journal article
- Date
- 2021
- Description
- Background: Body surface area (BSA)–based dosing of irinotecan (IR) does not account for its pharmacokinetic (PK) and pharmacodynamic (PD) variabilities. Functional hepatic nuclear imaging (HNI) and excretory/metabolic/PD pharmacogenomics have shown correlations with IR disposition and toxicity/efficacy. This study reports the development of a nonlinear mixed-effect population model to identify pharmacogenomic and HNI-related covariates that impact on IR disposition to support dosage optimization. Methods: Patients had advanced colorectal cancer treated with IR combination therapy. Baseline blood was analysed by Affymetrix DMET™ Plus Array and, for PD, single nucleotide polymorphisms (SNPs) by Sanger sequencing. For HNI, patients underwent 99mTc-IDA hepatic imaging, and data was analysed for hepatic extraction/excretion parameters. Blood was taken for IR and metabolite (SN38, SN38G) analysis on day 1 cycle 1. Population modelling utilised NONMEM version 7.2.0, with structural PK models developed for each moiety. Covariates include patient demographics, HNI parameters and pharmacogenomic variants. Results: Analysis included (i) PK data: 32 patients; (ii) pharmacogenomic data: 31 patients: 750 DMET and 22 PD variants; and (iii) HNI data: 32 patients. On initial analysis, overall five SNPs were identified as significant covariates for CLSN38. Only UGT1A3_c.31 T > C and ABCB1_c.3435C > T were included in the final model, whereby CLSN38 reduced from 76.8 to 55.1%. Conclusion: The identified UGT1A3_c.31 T > C and ABCB1_c.3435C > T variants, from wild type to homozygous, were included in the final model for SN38 clearance.
- Subject
- irinotecan; DMET; hepatic functional imaging; pharmacokinetics; pharmacodynamics; population model; SDG 3; Sustainable Development Goals
- Identifier
- http://hdl.handle.net/1959.13/1460560
- Identifier
- uon:46000
- Identifier
- ISSN:0031-6970
- Language
- eng
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