A phase I dose-escalation and bioavailability study of oral and intravenous formulations of erlotinib (Tarceva®, OSI-774) in patients with advanced solid tumors of epithelial origin

Ranson, Malcolm R; Shaw, Heather; Wolf, Julie; Hamilton, Marta; McCarthy, Sean P.; Dean, Emma; Reid, Alison; Judson, Ian

doi:10.1007/s00280-009-1133-3

Cited by 31 publications

(20 citation statements)

References 4 publications

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“…Prediction of Oral Clearance. Erlotinib has been reported to be wellabsorbed from the gastrointestinal tract (Ranson et al, 2010). Consequently, the intestinal clearance is assumed to be negligible for erlotinib, particularly in the presence of ritonavir or ketoconazole.…”

Section: Methodsmentioning

confidence: 99%

Ritonavir and Efavirenz Significantly Alter the Metabolism of Erlotinib—an Observation in Primary Cultures of Human Hepatocytes That Is Relevant to HIV Patients with Cancer

et al. 2013

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Erlotinib is approved for the treatment of non-small cell lung and pancreatic cancers, and is metabolized by CYP3A4. Inducers and inhibitors of CYP3A enzymes such as ritonavir and efavirenz, respectively, may be used as part of the highly active antiretroviral therapy drugs to treat patients with human immunodeficiency virus (HIV). When HIV patients with a malignancy need treatment with erlotinib, there is a potential of as-yet-undefined drug-drug interaction. We evaluated these interactions using human hepatocytes benchmarked against the interaction of erlotinib with ketoconazole and rifampin, the archetype cytochrome P450 inhibitor and inducer, respectively. Hepatocytes were treated with vehicle [0.1% dimethylsulfoxide, ritonavir (10 mM)], ketoconazole (10 mM), efavirenz (10 mM), or rifampin (10 mM) for 4 days. On day 5, erlotinib (5 mM) was incubated with the above agents for another 24-48 hours. Concentrations of erlotinib and O-desmethyl erlotinib were quantitated in collected samples (combined lysate and medium) using liquid chromatography and tandem mass spectrometry. The half-life (t 1/2 ) of erlotinib increased from 10.6 6 2.6 to 153 6 80 and 23.9 6 4.8 hours, respectively, upon treatment with ritonavir and ketoconazole. The apparent intrinsic clearance (CL int, app ) of erlotinib was lowered 16-fold by ritonavir and 1.9-fold by ketoconazole. Efavirenz and rifampin decreased t 1/2 of erlotinib from 10.3 6 1.1 to 5.0 6 1.5 and 3.4 6 0.2 hours, respectively. Efavirenz and rifampin increased the CL int, app of erlotinib by 2.2-and 2-fold, respectively. Our results suggest that to achieve desired drug exposure, the clinically used dose (150 mg daily) of erlotinib may have to be significantly reduced (25 mg every other day) or increased (300 mg daily), respectively, when ritonavir or efavirenz is coadministered.

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Section: Methodsmentioning

confidence: 99%

Ritonavir and Efavirenz Significantly Alter the Metabolism of Erlotinib—an Observation in Primary Cultures of Human Hepatocytes That Is Relevant to HIV Patients with Cancer

et al. 2013

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“…Oral absolute bioavailability of erlotinib was shown to be (mean) 59% (95% CI 55-63) in healthy subjects [7] and (median) 76% (90% CI 53-111) in cancer patients [8]. Both Cmax and AUC24 values tended to be proportional to the erlotinib dose in the dose range of 25-200 mg/ day.…”

Section: Introductionmentioning

confidence: 95%

“…Wide interindividual variability in erlotinib exposure (up to 7-fold) was seen in all pharmacokinetic studies, which remains mostly unexplained [8].…”

Section: Introductionmentioning

confidence: 98%

Bioequivalence of a New Generic Formulation of Erlotinib Hydrochloride 150 mg Tablets versus Tarceva in Healthy Volunteers under Fasting Conditions

Jawhari¹

2014

J Bioequiv Availab

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“…Erlotinib which is used in treatment of various solid tumors such as non-small cell lung cancer is available in oral form (Clay et al, 2005;Smith, 2005;Qi et al, 2012). Oral bioavailability of erlotinib was obtained 59% and 76% respectively in healthy volunteers and cancer patients (Ranson et al, 2010). No data are available regarding the marketing of other formulation type of this drug.…”

Section: Introductionmentioning

confidence: 99%

Synthesis, Characterization and in vitro Anti-Tumoral Evaluation of Erlotinib-PCEC Nanoparticles

Barghi¹,

Asgari²,

Barar³

et al. 2015

Asian Pacific Journal of Cancer Prevention

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Background: Development of a nanosized polymeric delivery system for erlotinib was the main objective of this research. Materials and Methods: Poly caprolactone-polyethylene glycol-polycaprolactone (PCEC) copolymers with different compositions were synthesized via ring opening polymerization. Formation of triblock copolymers was confirmed by HNMR as well as FT-IR. Erlotinib loaded nanoparticles were prepared by means of synthesized copolymers with solvent displacement method. Results: Physicochemical properties of obtained polymeric nanoparticles were dependent on composition of used copolymers. Size of particles was decreased with decreasing the PCL/PEG molar ratio in used copolymers. Encapsulation efficiency of prepared formulations was declined by decreasing their particle size. Drug release behavior from the prepared nanoparticles exhibited a sustained pattern without a burst release. From the release profiles, it can be found that erlotinib release rate from polymeric nanoparticles is decreased by increase of CL/PEG molar ratio of prepared block copolymers. Based on MTT assay results, cell growth inhibition of erlotinib has a dose and time dependent pattern. After 72 hours of exposure, the 50% inhibitory concentration (IC50) of erlotinib hydrochloride was appeared to be 14.8 μM. Conclusions: From the obtained results, it can be concluded that the prepared PCEC nanoparticles in this study might have the potential to be considered as delivery system for erlotinib.

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A phase I dose-escalation and bioavailability study of oral and intravenous formulations of erlotinib (Tarceva®, OSI-774) in patients with advanced solid tumors of epithelial origin

Abstract: A 100 mg single IV dose of erlotinib, given as a 30-min infusion, was well tolerated with only minor adverse events and the high level of bioavailability of oral erlotinib was confirmed.

Cited by 31 publications

References 4 publications

Ritonavir and Efavirenz Significantly Alter the Metabolism of Erlotinib—an Observation in Primary Cultures of Human Hepatocytes That Is Relevant to HIV Patients with Cancer

Ritonavir and Efavirenz Significantly Alter the Metabolism of Erlotinib—an Observation in Primary Cultures of Human Hepatocytes That Is Relevant to HIV Patients with Cancer

Bioequivalence of a New Generic Formulation of Erlotinib Hydrochloride 150 mg Tablets versus Tarceva in Healthy Volunteers under Fasting Conditions

Synthesis, Characterization and in vitro Anti-Tumoral Evaluation of Erlotinib-PCEC Nanoparticles

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