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The Precision Medicine Approach in Oncology
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Irinotecan is hydrolyzed in vivo by enzymes such as carboxyl esterase to 7-ethyl-10-hydroxycamptothecin (SN-38), an active metabolite (Figure 11.26) which is also a potent inhibitor of topoisomerase I and approximately 200- to 2000-fold more cytotoxic than irinotecan itself. SN-38 is inactivated through glucuronidation by Uridine Diphosphate Glucoronosyltransferase 1A1 (UGT1A1). The inhibition of topoisomerase I by SN-38 eventually leads to inhibition of both DNA replication and transcription. Structure of irinotecan (CamptoTM or CamptosarTM) and its metabolite SN-38.
UGT1A1 Polymorphisms and Mutations Affect Anticancer Drug Therapy
Published in Sherry X. Yang, Janet E. Dancey, Handbook of Therapeutic Biomarkers in Cancer, 2021
Tristan M. Sissung, Roberto Barbier, Lisa M. Cordes, William D. Figg
Severe irinotecan toxicity is associated with genetic variants in UGT1A1, particularly those that reduce function. Although more than 60 genetic variations in the promoter and coding regions ofthe UGT1A1 gene are currently known, the UGT1A1*28 polymorphism has been the most extensively evaluated in pharmacogenetic studies. It has a significant impact on irinotecan metabolism and therefore adverse effects [5, 6]. UGT1A1*28 results in reduced UGT1A1 expression and glucuronidation of SN-38, leading to increased toxicity from elevated levels of SN-38 in serum [4, 7, 70, 83]. The heterozygous UGT1A1*1/UGT1A1*28 allele results in a 25% decrease in enzyme activity, while the homozygous UGT1A1*28/UGT1A1*28 allele results in a greater reduction of 70% [6]. Thus, the UGT1A1*28 polymorphism is a compelling pharmacogenetic biomarker for the prediction of irinotecan toxicity, and the association between this genotype and irinotecan-related toxicity is now referenced in the US Food and Drug Administration (FDA)-approved prescribing information. Specifically, in July 2005, the US FDA approved irinotecan labeling changes to include consideration of a reduction by one dose level in patients homozygous for UGT1A1*28 and subsequently approved a genetic test to help clinicians identify these patients. Conversely, UGT1A1*1 genotyping has been used to identify individuals capable of sustaining larger dosage levels of irinotecan without experiencing toxicity, potentially increasing the effectiveness of the irinotecan therapy [84].
Drug Delivery
Published in David A. Walker, Giorgio Perilongo, Roger E. Taylor, Ian F. Pollack, Brain and Spinal Tumors of Childhood, 2020
Gudrun Fleischhack, Martin Garnett, Kévin Beccaria
Irinotecan acts by its active metabolite, SN-38, which is 100–1,000-fold more potent than the parent drug.85 With irinotecan as a weekly single-drug infusion for 4 weeks followed by a 2-week rest period an objective response rate of 15% and a disease stabilization of 55% have been documented in adult patients with a recurrent and refractory high-grade glioma.86 Using the same schedule a Children’s Oncology Group (COG) phase II study has shown promising disease-specific activity in children with malignant glioma, medulloblastoma, and ependymoma, with acceptable toxicity.87 As known for topotecan the patients who received irinotecan and concomitant enzyme-inducing anticonvulsants (EIAs) have an altered irinotecan pharmacokinetics and showed significantly increased clearance requiring a dose adjustment in order to reach the same drug exposure as without EIAs.88 Subsequent phase II studies of irinotecan in combination with TMZ have demonstrated relevant activity in patients with recurrent and refractory medulloblastoma (objective response rate of 33%) but not in newly diagnosed high-grade gliomas.70,71
Optimizing outcomes and managing adverse events in locally advanced or metastatic urothelial cancer: a clinical pharmacology perspective
Published in Expert Review of Clinical Pharmacology, 2023
Pratap Singh, Anand Rotte, Anthony A. Golsorkhi, Sandhya Girish
SN-38 (the small molecule moiety of sacituzumab govitecan-hziy) is metabolized via UGT1A1. The mean half-life of sacituzumab govitecan-hziy and free SN-38 is 15.3 and 19.7 hours, respectively. Based on population pharmacokinetic analysis, the clearance of the sacituzumab govitecan-hziy is 0.14 L/h, and the central volume distribution of sacituzumab govetican-hziy is 2.96 L. Pharmacokinetic analyses did not identify an effect of age, race, or mild renal impairment on the pharmacokinetics of sacituzumab govitecan-hziy. Renal elimination is known to contribute minimally to the excretion of SN-38, the small molecule moiety of sacituzumab govitecan-hziy. The exposure of sacituzumab govitecan-hziy is similar in patients with mild hepatic impairment to patients with normal hepatic function.
Potential application of mass spectrometry imaging in pharmacokinetic studies
Published in Xenobiotica, 2022
Chukwunonso K. Nwabufo, Omozojie P. Aigbogun
Irinotecan is a prodrug and topoisomerase 1 inhibitor often used as a chemotherapeutic for colorectal cancer. Although it has weak cytotoxicity, its active metabolite, SN-38 exerts the desired pharmacological effect (Buck et al. 2015; He et al. 2021). In 2015, Buck et al. utilised MALDI-MSI for quantitative analysis of irinotecan and SN-38 distribution in normal tissues and colon cancer murine model system. MALDI-MSI of irinotecan revealed a distribution of the drug in all normal tissues except the spinal cord and encephalon with the highest signals in the kidney (19.0 pmol/mm2), faeces (11.0 pmol/mm2), pancreas (7.0 pmol/mm2), liver (5.4 pmol/mm2), and lung (4.5 pmol/mm2) while MALDI-MSI of SN-38 revealed lower concentrations of the metabolite in normal tissues. Metabolism of irinotecan to SN-38 largely occurred in the liver. MALDI-MSI of drug distribution in tumours from Apc+/1638N revealed interindividual differences in drug concentrations and unexpected poor conversion of irinotecan to SN-38 within tumours (Buck et al. 2015).
Tackling metastatic triple-negative breast cancer with sacituzumab govitecan
Published in Expert Review of Anticancer Therapy, 2021
Anna R Schreiber, Michelle Andress, Jennifer R Diamond
Pharmacokinetics of sacituzumab govitecan were further assessed in the Phase II dose expansion trial [36]. Half-life of sacituzumab govitecan at a dose of 10 mg/kg was noted to be around 11.7 hours compared to 102.7 hours for unconjugated IgG. Less than 5% of SN-38 in the serum was free, with most bound to IgG. Amounts of free SN-38 and glucuronidated SN-38 (SN-38 G) were similar, indicating that the SN-38 which was attached to IgG, remained protected from glucuronidation. Higher levels of SN-38 G in the serum has been associated with worsened diarrhea [37]. The SN-38 payload is released gradually with around half of the payload released from the IgG conjugate every 24 hours [36]. Given this gradual release, and low level of SN-38 G detected in the serum, the amount of diarrhea could be lessened. In the Phase II dose expansion trial, there was not found to be a relationship between free SN-38 and neutropenia. In addition, no antibody response to sacituzumab govitecan was noted in the 167 patients that were sampled.