Evaluation of pharmacogenomics and hepatic nuclear imaging-related covariates by population pharmacokinetic models of irinotecan and its metabolites.
Eur J Clin Pharmacol
; 78(1): 53-64, 2022 Jan.
Article
in En
| MEDLINE
| ID: mdl-34480602
ABSTRACT
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.Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Colorectal Neoplasms
/
Glucuronosyltransferase
/
Topoisomerase I Inhibitors
/
Irinotecan
/
Liver
Type of study:
Observational_studies
/
Risk_factors_studies
Limits:
Humans
Country/Region as subject:
Oceania
Language:
En
Journal:
Eur J Clin Pharmacol
Year:
2022
Document type:
Article
Affiliation country:
Australia