TY - JOUR
T1 - Evaluation of pharmacogenomics and hepatic nuclear imaging–related covariates by population pharmacokinetic models of irinotecan and its metabolites
AU - Liu, Zheng
AU - Martin, Jennifer H
AU - Liauw, Winston
AU - McLachlan, Sue-Anne
AU - Link, Emma
AU - Matera, Anetta
AU - Thompson, Michael
AU - Jefford, Michael
AU - Hicks, Rod J
AU - Cullinane, Carleen
AU - Hatzimihalis, Athena
AU - Campbell, Ian
AU - Crowley, Simone
AU - Beale, Phillip J
AU - Karapetis, Christos S
AU - Price, Timothy
AU - Burge, Mathew E
AU - Michael, Michael
PY - 2022/1
Y1 - 2022/1
N2 - 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.
AB - 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.
KW - DMET
KW - Hepatic functional imaging
KW - Irinotecan
KW - Pharmacodynamics
KW - Pharmacokinetics
KW - Population model
UR - http://www.scopus.com/inward/record.url?scp=85114138200&partnerID=8YFLogxK
UR - http://purl.org/au-research/grants/NHMRC/628564
U2 - 10.1007/s00228-021-03206-w
DO - 10.1007/s00228-021-03206-w
M3 - Article
C2 - 34480602
AN - SCOPUS:85114138200
SN - 0031-6970
VL - 78
SP - 53
EP - 64
JO - European Journal of Clinical Pharmacology
JF - European Journal of Clinical Pharmacology
IS - 1
ER -