Integration of DNA sequencing with population pharmacokinetics to improve the prediction of irinotecan exposure in cancer patients

Abstract

BACKGROUND: Irinotecan (CPT-11) is an anticancer agent widely used to treat adult solid tumours. Large interindividual variability in the clearance of irinotecan and SN-38, its active and toxic metabolite, results in highly unpredictable toxicity. METHODS: In 217 cancer patients treated with intravenous irinotecan single agent or in combination, germline DNA was used to interrogate the variation in 84 genes by next-generation sequencing. A stepwise analytical framework including a population pharmacokinetic model with SNP-and gene-based testing was used to identify demographic/clinical/genetic factors that influence the clearance of irinotecan and SN-38. RESULTS: Irinotecan clearance was influenced by rs4149057 in SLCO1B1, body surface area, and co-administration of 5-fluorouracil/ leucovorin/bevacizumab. SN-38 clearance was influenced by rs887829 in UGT1A1, pre-treatment total bilirubin, and EGFR rare variant burden. Within each UGT1A1 genotype group, elevated pre-treatment total bilirubin and/or presence of at least one rare variant in EGFR resulted in significantly lower SN-38 clearance. The model reduced the interindividual variability in irinotecan clearance from 38 to 34% and SN-38 clearance from 49 to 32%. CONCLUSIONS: This new model significantly reduced the interindividual variability in the clearance of irinotecan and SN-38. New genetic factors of variability in clearance have been identified.

All You Need to Know About UGT1A1 Genetic Testing for Patients Treated With Irinotecan: A Practitioner-Friendly Guide

“…A pharmacokinetic study 62 suggests that potential demographic or clinical risk factors that interacted with UGT1A1 polymorphism may also need to be considered for UGT1A1 genotype-guided dosing. UGT1A1 polymorphism showed an additive effect with high pretreatment total bilirubin, but not with demographic risk factors (age > 65 years or female sex), on SN-38 clearance.…”

Model‐Based Prediction of Irinotecan‐Induced Grade 4 Neutropenia in Advanced Cancer Patients: Influence of Demographic and Clinical Factors

“…The population pharmacokinetic model of irinotecan and its three metabolites in the patients analyzed in this study was developed and described elsewhere. 28 Subsequently, a population pharmacodynamic model was developed using the individual pharmacokinetic parameter values obtained from the pharmacokinetic model as input. Briefly, the pharmacokinetic profile of irinotecan was described using a three-compartment model with two elimination processes (first-order elimination and transit processes) in parallel (Figure 1).…”

Facile construction of irinotecan loaded mesoporous nano-formulation with surface-initiated polymerization to improve stimuli-responsive drug delivery for breast cancer therapy

“…A metabolite 7-ethyl-10-hydroxy camptothecin (SN-38) is produced in vivo from IRT, and this metabolite is 2–3 times more cytotoxic than IRT in the presence of cancer cells. Only 2–8% of IRT supplied can be converted to SN-38; substantial dosages of IRT infusions are typically necessary for treatment regimens to achieve therapeutic advantages [ [12] , [13] , [14] ]. On the other hand, IRT is linked with severe gastrointestinal toxicity and myelosuppression due to its high dosage.…”