Effect of omeprazole on the pharmacokinetics and toxicities of irinotecan in cancer patients: A prospective cross-over drug–drug interaction study

Bol, Jessica M. van der; Loos, Walter J.; Jong, Floris A. de; Meerten, Esther van; Konings, Inge R.; Lam, Mei H.; Bruijn, Peter de; Wiemer, Erik A.C.; Verweij, Jaap; Mathijssen, Ron H.J.

doi:10.1016/j.ejca.2010.11.030

Cited by 20 publications

(14 citation statements)

References 37 publications

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“…(32) was used for observed AUC and blood concentration–time profiles of irinotecan, SN-38, SN-38G, NPC, and APC. 30 selected sets of parameters were used for VCS as described below and given in ascending order of WSS for IDs 1 to 30.…”

Section: Methodsmentioning

confidence: 99%

“…The variabilities (CV) and the shape of distribution are described in Supplementary Table 3B. Because the observed blood concentration–time profile of irinotecan and its metabolites (32) used by the CNM was obtained from patients recruiting the same number of UGT1A1 *1/*1 and *1/*28 patients, the value of metabolic clearance of SN-38 to SN-38G (CL SN-38G,h(SN-38) and CL SN-38G,ent(SN-38) ) was recalculated for UGT1A1 *1/*1 using values obtained from the CNM as an average value between UGT1A1 *1/*1 and *1/*28.…”

Section: Methodsmentioning

confidence: 99%

“…CVs estimated using the calculated and reported BSA distribution corresponded with each other. In this VCS, the average and CV of body weight distribution were also estimated to compare the calculated distribution of BSA with the distribution reported after clinical study of irinotecan (5,32).

Plasma and blood unbound fraction of compounds

…”

Section: Methodsmentioning

confidence: 99%

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Virtual Clinical Studies to Examine the Probability Distribution of the AUC at Target Tissues Using Physiologically-Based Pharmacokinetic Modeling: Application to Analyses of the Effect of Genetic Polymorphism of Enzymes and Transporters on Irinotecan Induced Side Effects

Toshimoto¹,

Tomaru²,

Hosokawa

et al. 2017

Pharm Res

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PurposeTo establish a physiologically-based pharmacokinetic (PBPK) model for analyzing the factors associated with side effects of irinotecan by using a computer-based virtual clinical study (VCS) because many controversial associations between various genetic polymorphisms and side effects of irinotecan have been reported.MethodsTo optimize biochemical parameters of irinotecan and its metabolites in the PBPK modeling, a Cluster Newton method was introduced. In the VCS, virtual patients were generated considering the inter-individual variability and genetic polymorphisms of enzymes and transporters.ResultsApproximately 30 sets of parameters of the PBPK model gave good reproduction of the pharmacokinetics of irinotecan and its metabolites. Of these, 19 sets gave relatively good description of the effect of UGT1A1 *28 and SLCO1B1 c.521T>C polymorphism on the SN-38 plasma concentration, neutropenia, and diarrhea observed in clinical studies reported mainly by Teft et al. (Br J Cancer. 112(5):857-65, 20). VCS also indicated that the frequency of significant association of biliary index with diarrhea was higher than that of UGT1A1 *28 polymorphism.ConclusionThe VCS confirmed the importance of genetic polymorphisms of UGT1A1 *28 and SLCO1B1 c.521T>C in the irinotecan induced side effects. The VCS also indicated that biliary index is a better biomarker of diarrhea than UGT1A1 *28 polymorphism.Electronic supplementary materialThe online version of this article (doi:10.1007/s11095-017-2153-z) contains supplementary material, which is available to authorized users.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Virtual Clinical Studies to Examine the Probability Distribution of the AUC at Target Tissues Using Physiologically-Based Pharmacokinetic Modeling: Application to Analyses of the Effect of Genetic Polymorphism of Enzymes and Transporters on Irinotecan Induced Side Effects

Toshimoto¹,

Tomaru²,

Hosokawa

et al. 2017

Pharm Res

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“…Irinotecan and SN-38 are substrates of various polymorphic enzymes and transporters leading to very complicated pharmacokinetics and thus have been the subject of intensive investigation in recent years [4][5][6]. Irinotecan is metabolized into SN-38 by carboxylesterases types 1 and 2.…”

Section: Introductionmentioning

confidence: 99%

“…SN-38 is further conjugated by UDP-glucuronosyltransferase isoforms to form an inactive b-glucuronic acid conjugate, SN-38G to be eliminated by biliary and renal excretion. In addition to the liver, activation of irinotecan into SN-38 could be done in intestines as b-glucuronidase and carboxylesterase activities were also observed in normal colorectal and tumour tissue [5,7]. Finally, elimination of irinotecan is dependent on drug-transporting proteins from the ATP-binding cassette drug transporters family, notably P-glycoprotein (P-gp), multidrug resistance-associated protein gene (MRP) and breast cancer resistance protein (BCRP) [8].…”

Section: Introductionmentioning

confidence: 99%

Cetuximab increases concentrations of irinotecan and of its active metabolite SN‐38 in plasma and tumour of human colorectal carcinoma‐bearing mice

Chu

Abbara

Tandia

et al. 2014

Fundamemntal Clinical Pharma

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In a previous study, we showed that cetuximab, a monoclonal antibody directed towards epidermal growth factor receptor, could inhibit P-glycoprotein (P-gp), an efflux protein of ATP-binding cassette family, and lead to an increased P-gp substrate intracellular concentration. Cetuximab is given with irinotecan to patients with metastasis colorectal cancer who did not respond to irinotecan-based therapy. The mechanism of this successful clinical reversion remains unknown. As irinotecan is a P-gp substrate, we tested here whether cetuximab could modify irinotecan concentration in mice. Therefore, concentrations of irinotecan and of its active metabolite SN-38 were measured by HPLC in plasma and tumour of mice bearing a human colorectal carcinoma xenograft when irinotecan is given orally alone or after a pretreatment with cetuximab. Pharmacokinetic analysis showed no significant modification of irinotecan concentrations but a significant increase (1.7-fold) in SN-38 AUCs in plasma and in tumour after a pretreatment with cetuximab. Those results suggest that cetuximab influence irinotecan distribution into tissues probably due to inhibition of P-gp. As SN-38 is 200-fold more potent than irinotecan, cetuximab could reverse irinotecan resistance by an effect on its active metabolite. Inhibiting SN-38 efflux by P-gp drug transporters in biliary system and tumour can lead to pharmacokinetic modification and a higher anticancer efficacy.

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Pharmacokinetic, Pharmacodynamic, Preclinical and Clinical Models for Evaluation of Nanoparticles

Gharat,

Momin,

Khan

2024

Pharmacokinetics and Pharmacodynamics of Novel Drug Delivery Systems: From Basic Concepts to Applications

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Effect of omeprazole on the pharmacokinetics and toxicities of irinotecan in cancer patients: A prospective cross-over drug–drug interaction study

Abstract: Omeprazole 40mg did not alter the pharmacokinetics and toxicities of irinotecan. This widely used drug can, therefore, be safely administered during a 3-weekly single agent irinotecan schedule.

Cited by 20 publications

References 37 publications

Virtual Clinical Studies to Examine the Probability Distribution of the AUC at Target Tissues Using Physiologically-Based Pharmacokinetic Modeling: Application to Analyses of the Effect of Genetic Polymorphism of Enzymes and Transporters on Irinotecan Induced Side Effects

Virtual Clinical Studies to Examine the Probability Distribution of the AUC at Target Tissues Using Physiologically-Based Pharmacokinetic Modeling: Application to Analyses of the Effect of Genetic Polymorphism of Enzymes and Transporters on Irinotecan Induced Side Effects

Cetuximab increases concentrations of irinotecan and of its active metabolite SN‐38 in plasma and tumour of human colorectal carcinoma‐bearing mice

Pharmacokinetic, Pharmacodynamic, Preclinical and Clinical Models for Evaluation of Nanoparticles

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