Gastric Acid Suppression Is Associated With Decreased Erlotinib Efficacy in Non–Small-Cell Lung Cancer

Chu, Michael P.; Ghosh, Sunita; Chambers, Carole; Basappa, Naveen S.; Butts, Charles; Chu, Quincy S.; Fenton, David; Joy, Anil A.; Sangha, Randeep; Smylie, Michael; Sawyer, Michael B.

doi:10.1016/j.cllc.2014.07.005

Cited by 99 publications

(106 citation statements)

References 21 publications

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“…When treatment with a histamine-2 receptor antagonist (H 2 RA) is required, erlotinib must be taken 10 hours after H 2 RA dosing and at least two hours before the next dose of the H 2 RA [6]. These recommendations were based on a study done in healthy volunteers [7] and there is conflicting evidence on efficacy and safety outcomes in the cancer patient population [8,9]. Thus, the true effect of acid-suppression on survival and safety outcomes in oncology patients taking erlotinib is incompletely elucidated.…”

Section: Introductionmentioning

confidence: 99%

Association of concurrent acid-suppression therapy with survival outcomes and adverse event incidence in oncology patients receiving erlotinib

Lam

Capparelli

Kurzrock

2016

Cancer Chemother Pharmacol

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Purpose Acid-suppression therapy is known to decrease the systemic exposure of erlotinib. The erlotinib prescribing information also recommends staggering dosing with a histamine-2 receptor antagonist (H2RA) and avoiding concurrent use of a proton-pump inhibitor (PPI). This retrospective analysis evaluated the frequency of concurrent acid-suppression therapy in oncology patients receiving erlotinib and its association with outcomes. Methods All patients prescribed erlotinib within UC San Diego Health System between February 26, 2011 and February 28, 2014 were assessed for eligibility, and for survival outcomes and adverse events. Results Of the 76 patients in the analysis, 24 were prescribed both a PPI and an H2RA with erlotinib therapy (31.6%). The two patient groups, with (n=24) and without PPI/H2RA (n=52), were similar in clinical characteristics and erlotinib dose. One patient received an H2RA therapy alone and was excluded from the analysis; no one received PPI therapy alone. Patients receiving erlotinib alone had a longer median progression-free survival (PFS) compared to patients with concurrent PPI/H2RA therapy (11.0 months vs. 5.3 months; P=0.029). Overall survival (OS) and incidence of rash and/or diarrhea did not correlate with use of acid-suppression therapy. Conclusion Nearly one-third of subjects received acid-suppression therapy. Patients treated with erlotinib and PPI/H2RA therapy had shorter PFS, but similar OS and adverse event profile compared to those who did not receive acid-suppression.

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Section: Introductionmentioning

confidence: 99%

Association of concurrent acid-suppression therapy with survival outcomes and adverse event incidence in oncology patients receiving erlotinib

Lam

Capparelli

Kurzrock

2016

Cancer Chemother Pharmacol

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“…126 However, acidsuppressing agents are suspected to decrease absorption and hence its efficacy. 126,142 Food does not significantly influence sunitinib's bioavailability. 154 The effect of acid-reducing agents on the absorption of both vandetanib and venurafenib has not been studied, but based on solubility data is anticipated to be insignificant.…”

Section: Pharmacogenetic And/or Drug-induced Changes In Metabolizing mentioning

confidence: 99%

“…141 In a study comparing use of PPIs and H2RAs in patients taking erlotinib for advanced non-small cell lung cancer, results showed better progressionfree survival and overall survival in patients who did not take concomitant acid suppression therapy. 142 The bioavailability of erlotinib is significantly decreased by coadministration of proton pump inhibitors 143,144 or H2RAs, 143 with subsequent clinically significant adverse outcomes. 142 Coadministration of erlotinib with food significantly increases its bioavailability; hence, it should be taken under fasting conditions.…”

Section: Pharmacogenetic And/or Drug-induced Changes In Metabolizing mentioning

confidence: 99%

“…142 The bioavailability of erlotinib is significantly decreased by coadministration of proton pump inhibitors 143,144 or H2RAs, 143 with subsequent clinically significant adverse outcomes. 142 Coadministration of erlotinib with food significantly increases its bioavailability; hence, it should be taken under fasting conditions. 143 Gefitinib exposure is reduced by the administration of ranitidine.…”

Section: Pharmacogenetic And/or Drug-induced Changes In Metabolizing mentioning

confidence: 99%

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Pharmacokinetic‐Guided Dosing of New Oral Cancer Agents

Lucas

Martin

2017

The Journal of Clinical Pharma

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Generally, licensed drug-dosing recommendations for chemotherapy are based on results from clinical trials in which subjects are usually of relatively normal body size, middle-aged, and are relatively racially homogeneous, with minimal comorbidity and specific tumor characteristics. Very few nontrial patients meet these characteristics, resulting in clinical practice having to extrapolate dosing recommendations to the specific patient. There is insufficient research on the impact of obesity-associated physiological changes prevalent in patients with common cancers on standard pharmacokinetic and pharmacodynamic parameters. Yet quantifying the influence of obesity on the pharmacology of chemotherapy is vital, as dosing inappropriate for body composition (ie, flat dosing or mg/kg based on total body weight) may increase the risk of adverse events and reduce clinical effectiveness. Unfortunately, there are few cancer guidelines to aid clinicians in selecting the optimal dose in the obese-even recent guidelines are based predominantly on clinical opinion/current practice in treating obese patients, rather than evidence. Data in many other vulnerable groups, for example, those with significant comorbidity and older patients, are also scarce. Because of the known limitations of body surface area-guided dosing, therapeutic drug monitoring or pharmacokinetic-guided dosing, which predicts an individual's exposure, has increasingly been shown to be a powerful tool in cancer therapy. Used appropriately, it can adjust for differences in pharmacokinetic parameters not considered when body size-based dosing or "one dose fits all" is used. This review will focus predominantly on the rationale for pharmacokinetic-guided dosing of the newer oral molecularly targeted antineoplastics in people whose drug exposure is not predicted by their physiology or body composition.

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“…Erlotinib is metabolized primarily in the liver, where it undergoes oxidative metabolism, mediated by cytochrome P450 3A4 (CYP3A4), to yield the major active oxidative metabolite OSI-420 [6,7]. In clinical practice, erlotinib is frequently used in combination with other drugs, so adverse effects or therapeutic efficacy of erlotinib treatment could also be influenced by variations in erlotinib pharmacokinetics due to drug-drug interactions [8][9][10]. Therefore, in order to understand the correlation between the pharmacokinetics of erlotinib and its adverse effects and therapeutic efficacy, it is essential to assess the concentration-time profiles of both erlotinib and OSI-420.…”

Section: Introductionmentioning

confidence: 99%

A Rapid and Simple UHPLC-UV Method for Quantitative Determination of Erlotinib and Its Active Metabolite OSI-420 in Human Serum, and Its Application in a Non-Small Cell Lung Cancer Patient

et al. 2017

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We developed a rapid and simple UHPLC-UV method for quantitative determination of erlotinib and its metabolite, OSI-420, in order to monitor their serum levels in patients with non-small cell lung cancer (NSCLC). Erlotinib and OSI-420 were extracted from 100 μL of human serum by liquid-liquid extraction using t-butyl methyl ether. The analytes were separated on Inertsil ODS-3 (100 mm × 2.1 mm I.D., 2 μm) as an analytical column using 20 mM potassium phosphate buffer (pH 2.5)/acetonitrile (74:26, v/v) as the mobile phase at a flow rate of 0.6 mL/min, and monitored at a UV wavelength of 345 nm. This method covered a linear concentration range of 6-6000 ng/mL for erlotinib and 6-2000 ng/mL for OSI-420, respectively (r > 0.999). The intra-and inter-day precisions of the analysis were < 6.8%, and the accuracy was ± 7.4%. This method has been successfully applied to measure erlotinib and OSI-420 in the serum of an NSCLC patient.

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Gastric Acid Suppression Is Associated With Decreased Erlotinib Efficacy in Non–Small-Cell Lung Cancer

Cited by 99 publications

References 21 publications

Association of concurrent acid-suppression therapy with survival outcomes and adverse event incidence in oncology patients receiving erlotinib

Association of concurrent acid-suppression therapy with survival outcomes and adverse event incidence in oncology patients receiving erlotinib

Pharmacokinetic‐Guided Dosing of New Oral Cancer Agents

A Rapid and Simple UHPLC-UV Method for Quantitative Determination of Erlotinib and Its Active Metabolite OSI-420 in Human Serum, and Its Application in a Non-Small Cell Lung Cancer Patient

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