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
en 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.Palabras clave
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Neoplasias Colorrectales
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Glucuronosiltransferasa
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Inhibidores de Topoisomerasa I
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Irinotecán
/
Hígado
Tipo de estudio:
Observational_studies
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Risk_factors_studies
Límite:
Humans
País/Región como asunto:
Oceania
Idioma:
En
Revista:
Eur J Clin Pharmacol
Año:
2022
Tipo del documento:
Article
País de afiliación:
Australia