Effect of antacid on imatinib absorption

Sparano, Brian A.; Egorin, Merrill J.; Parise, Robert A.; Walters, Jennifer Hardison; Komazec, Kristin A.; Redner, Robert L.; Beumer, Jan H.

doi:10.1007/s00280-008-0778-7

Cited by 45 publications

(27 citation statements)

References 4 publications

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“…The results are similar to results obtained when imatinib was co-administered with a Mg 2+ -Al 3+ -based antacid [13], but are in contrast to data demon- …”

Section: Discussionsupporting

confidence: 83%

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Effect of a proton pump inhibitor on the pharmacokinetics of imatinib

Egorin

Shah

Christner

et al. 2009

Brit J Clinical Pharma

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WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Gastric upset is a side-effect of imatinib therapy and the concomitant use of proton pump inhibitors is common. With the increase in oral chemotherapy in cancer treatment, oral drug-drug interactions are becoming more relevant, as is exemplified by dasatinib which has already been shown to be absorbed to a much lesser extent when co-administered with antacids or proton-pump inhibitors. Because exposure to subtherapeutic concentrations of anticancer drugs such as imatinib and dasatinib may result in selection of resistant clones, and ultimately relapse, we studied the effect of the proton pump inhibitor omeprazole on the pharmacokinetics of imatinib. WHAT THIS STUDY ADDS• Omeprazole may be co-administered with imatinib to treat the gastric side-effects of the latter without affecting the pharmacokinetics of imatinib and risking tumour relapse. AIMSImatinib mesylate (Gleevec®/Glivec®), which has revolutionized the treatment of chronic myeloid leukemias (CML) and gastrointestinal stromal tumours (GIST), has been reported to cause gastric upset. Consequently, proton pump inhibitors (PPI) are frequently coadministered with imatinib. Because PPI can elevate gastric pH and delay gastric emptying or antagonize ATP-binding-cassette transporters, they could influence imatinib absorption and pharmacokinetics. We aimed to evaluate whether use of omeprazole has a significant effect on imatinib pharmacokinetics. METHODSTwelve healthy subjects were enrolled in a two-period, open-label, single-institution, randomized cross-over, fixed-schedule study. In one period, each subject received 400 mg imatinib orally. In the other period, 40 mg omeprazole (Prilosec®) was administered orally for 5 days, and on day 5 it was administered 15 min before 400 mg imatinib. Plasma concentrations of imatinib and its active N-desmethyl metabolite CGP74588 were assayed by LC-MS, and data were analyzed non-compartmentally. RESULTSPPI administration did not significantly affect the imatinib area under the plasma concentration vs time curve (AUC) (34.1 mg ml -1 h alone vs 33.1 mg ml -1 h with omeprazole, P = 0.64; 80% power), maximum plasma concentration (Cmax) (2.04 mg ml -1 alone vs 2.02 mg ml -1 with omeprazole, P = 0.97), or half-life (13.4 h alone vs 14.1 h with omeprazole, P = 0.13). CONCLUSIONSOur results indicate that the use of omeprazole does not significantly affect the pharmacokinetics of imatinib, as opposed to, for example, dasatinib where PPI decreased AUC and Cmax two-fold.

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“…The results are similar to results obtained when imatinib was co-administered with a Mg 2+ -Al 3+ -based antacid [13], but are in contrast to data demon- …”

Section: Discussionsupporting

confidence: 83%

“…Plasma samples were analyzed for imatinib and its active N-desmethyl metabolite (CGP74588) using an LC-MS method that was previously developed and validated in our laboratory [13,14]. The assay was linear over the range of 10-1000 ng ml …”

Section: Pharmacokinetic Sampling and Bioanalysismentioning

confidence: 99%

Effect of a proton pump inhibitor on the pharmacokinetics of imatinib

Egorin

Shah

Christner

et al. 2009

Brit J Clinical Pharma

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“…Imatinib absorption is not influenced by food [41] . The concomitant administration of an Mg 2+ -Al 3+ -based antacid is not associated with meaningful alterations in imatinib absorption either [41] .…”

Section: Influence Of Comedication On Imatinib Pharmacokineticsmentioning

confidence: 99%

Therapeutic Drug Monitoring of Imatinib for Chronic Myeloid Leukemia Patients in the Chronic Phase

Takahashi

Miura²

2011

Pharmacology

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Imatinib is approved as a first-line treatment for Philadelphia chromosome-positive chronic myeloid leukemia (CML). Because of the variability in imatinib exposure among patients, therapeutic drug monitoring to maintain a plasma threshold level of about 1,000 ng/ml would be beneficial during imatinib therapy. Imatinib pharmacokinetics are influenced by body weight, comedication and pharmacogenetic factors, and the drug is excreted into the bile by the breast cancer resistance protein (ABCG2 gene). To attain the plasma threshold of approximately 1,000 ng/ml, the daily dose for patients with the ABCG2 421C/C genotype should be 400 mg; for patients with the 421C/A or 421A/A genotype, the dose should be 300 mg. Knowledge of the ABCG2 421 genotype could be useful when making dosing decisions aimed at achieving the optimal imatinib exposure. A therapeutic drug monitoring service should be routinely provided to CML patients taking imatinib. For CML patients who have an imatinib trough level of 1,000 ng/ml but lack a sufficient clinical response, switching to another tyrosine kinase inhibitor is recommended.

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“…40 Conversely, another study reported that concomitant administration of a Mg 2ϩ -Al 3ϩ -based antacid is not associated with meaningful alterations in imatinib absorption. 41 Concomitant administration of CYP3A4 inducers such as rifampicin or certain antiepileptics may lead to a reduction of as much as 74% in imatinib exposure. 12,13,42 Moreover, the pharmacokinetic profile of imatinib was significantly altered by St John's wort, with reductions of 30% in the median area under the concentration-time curve (AUC).…”

Section: Rosiglitazonementioning

confidence: 99%

Drug interactions with the tyrosine kinase inhibitors imatinib, dasatinib, and nilotinib

Haouala¹,

Widmer²,

Duchosal³

et al. 2011

Blood

215

147

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Several cancer treatments are shifting from traditional, time-limited, nonspecific cytotoxic chemotherapy cycles to continuous oral treatment with specific proteintargeted therapies. In this line, imatinib mesylate, a selective tyrosine kinases inhibitor (TKI), has excellent efficacy in the treatment of chronic myeloid leukemia. It has opened the way to the development of additional TKIs against chronic myeloid leukemia, including nilotinib and dasatinib. TKIs are prescribed for prolonged periods, often in patients with comorbidities. Therefore, they are regularly co-administered along with treatments at risk of drug-drug interactions. This aspect has been partially addressed so far, calling for a comprehensive review of the published data. We review here the available evidence and pharmacologic mechanisms of interactions between imatinib, dasatinib, and nilotinib and widely prescribed co-medications, including known inhibitors or inducers of cytochromes P450 or drug transporters. Information is mostly available for imatinib mesylate, well introduced in clinical practice. Several pharmacokinetic aspects yet remain insufficiently investigated for these drugs. Regular updates will be mandatory and so is the prospective reporting of unexpected clinical observations. (Blood. 2011;117(8):e75-e87)

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Effect of antacid on imatinib absorption

Cited by 45 publications

References 4 publications

Effect of a proton pump inhibitor on the pharmacokinetics of imatinib

Effect of a proton pump inhibitor on the pharmacokinetics of imatinib

Therapeutic Drug Monitoring of Imatinib for Chronic Myeloid Leukemia Patients in the Chronic Phase

Drug interactions with the tyrosine kinase inhibitors imatinib, dasatinib, and nilotinib

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