Afatinib pharmacokinetics and metabolism after oral administration to healthy male volunteers

Stopfer, Peter; Marzin, Kristell; Narjes, H.; Ganßer, Dietmar; Shahidi, Mehdi; Uttereuther-Fischer, Martina; Ebner, Thomas

doi:10.1007/s00280-011-1803-9

Cited by 121 publications

(99 citation statements)

References 17 publications

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“…A clinical ADME study has also been reported for afatinib (Stopfer et al, 2012), another covalent binding EGFR-TKI. Similar to the data reported here, [ 14 C]-afatinib was excreted predominantly in feces (85.4% of dose), with urinary elimination a minor route.…”

Section: Discussionmentioning

confidence: 99%

Metabolic Disposition of Osimertinib in Rats, Dogs, and Humans: Insights into a Drug Designed to Bind Covalently to a Cysteine Residue of Epidermal Growth Factor Receptor

Dickinson

Cantarini

Collier

et al. 2016

Drug Metabolism and Disposition

106

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Preclinical and clinical studies were conducted to determine the metabolism and pharmacokinetics of osimertinib and key metabolites AZ5104 and AZ7550. Osimertinib was designed to covalently bind to epidermal growth factor receptors, allowing it to achieve nanomolar cellular potency . Covalent binding was observed in incubations of radiolabeled osimertinib with human and rat hepatocytes, human and rat plasma, and human serum albumin. Osimertinib, AZ5104, and AZ7550 were predominantly metabolized by CYP3A. Seven metabolites were detected in human hepatocytes, also observed in rat or dog hepatocytes at similar or higher levels. After oral administration of radiolabeled osimertinib to rats, drug-related material was widely distributed, with the highest radioactivity concentrations measured at 6 hours postdose in most tissues; radioactivity was detectable in 42% of tissues 60 days postdose. Concentrations of [ 14 C]-radioactivity in blood were lower than in most tissues. After the administration of a single oral dose of 20 mg of radiolabeled osimertinib to healthy male volunteers, ∼19% of the dose was recovered by 3 days postdose. At 84 days postdose, mean total radioactivity recovery was 14.2% and 67.8% of the dose in urine and feces. The most abundant metabolite identified in feces was AZ5104 (∼6% of dose). Osimertinib accounted for ∼1% of total radioactivity in the plasma of non-small cell lung cancer patients after 22 days of 80-mg osimertinib once-daily treatment; the most abundant circulatory metabolites were AZ7550 and AZ5104 (<10% of total osimertinibrelated material). Osimertinib is extensively distributed and metabolized in humans and is eliminated primarily via the fecal route.

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Section: Discussionmentioning

confidence: 99%

Metabolic Disposition of Osimertinib in Rats, Dogs, and Humans: Insights into a Drug Designed to Bind Covalently to a Cysteine Residue of Epidermal Growth Factor Receptor

Dickinson

Cantarini

Collier

et al. 2016

Drug Metabolism and Disposition

106

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“…Drug-related AEs occurring in !10% patients in combined 20 mg (n ¼ 16) and 30 mg (n ¼ 2) afatinib once-daily dose groups, overall, and by maximum CTCAE grade Afatinib once daily þ trastuzumab MedDRA preferred term All, n (%) Grade 1, n (%) Grade 2, n (%) Grade 3, n (%) Patients with drug-related AEs 17 (94) 2 (11) 4 (22) 11 ( metabolism, and is excreted via the enterohepatic system. The in vitro metabolic profile of afatinib and pharmacokinetic data suggest no interaction between afatinib and cytochrome P450 substrates (20). Trastuzumab has a half-life of up to 28.5 days (21) and has shown additive effects with other agents, including taxanes and vinorelbine (22,23).…”

Section: Discussionmentioning

confidence: 99%

Phase I Study to Assess the Combination of Afatinib with Trastuzumab in Patients with Advanced or Metastatic HER2-Positive Breast Cancer

Ring

Wheatley

Hatcher

et al. 2015

Clinical Cancer Research

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Purpose: The HER2 mAb, trastuzumab, is a standard therapy for patients with HER2-positive breast cancer before acquired resistance. Afatinib, an irreversible, oral, small-molecule ErbB family blocker, shows clinical activity in trastuzumab-refractory HER2-positive breast cancer.Experimental Design: This phase I study used a 3þ3 dose escalation to determine the MTD of oral once-daily afatinib in combination with the recommended dose of intravenous trastuzumab (4 mg/kg week 1; 2 mg/kg/wk thereafter). Adult women with confirmed advanced/metastatic HER2-positive breast cancer were eligible.Results: Of 18 patients treated, 16 received daily afatinib 20 mg and two 30 mg. Overall, 4 of 13 and 2 of 2 patients receiving afatinib 20 mg and 30 mg, respectively, experienced dose-limiting toxicity (DLT; all CTCAE grade 3 diarrhea). Most frequent treatment-related adverse events were diarrhea (94%), rash (56%), and fatigue (56%). Overall, pharmacokinetic profiles of afatinib and trastuzumab in combination were consistent with the known characteristics of each alone. Overall, objective response and disease control rates were 11% and 39%, respectively, with median progression-free survival 111.0 days (95% confidence interval, 56.0-274.0).Conclusions: The MTD of afatinib was 20 mg daily combined with the recommended weekly dose of trastuzumab, with 1 of 6 patients showing DLTs in the dose escalation. However, additional DLTs occurred in the dose-expansion phase meaning that this MTD cannot be recommended for phase II development without strict diarrhea management. There was no evidence suggesting relevant pharmacokinetic drug-drug interactions. Signs of clinical activity were seen in trastuzumab-resistant HER2-positive breast cancer, suggesting further investigation with optimal diarrhea management is warranted.

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“…Determination of AFB alone was reported in two recent studies in human plasma using UPLC-DAD [10], LC-MS [11], with two other liquid chromatographic procedures published for its quantitation in tablets [12,13]. Moreover, one recent study reported AFB simultaneous determination with other TKIs namely, vandetanib, pazopanib, and dasatinib in human plasma using HPLC-DAD [14] with the AFB linearity range 0.7 -7.0 µgmL -1 , which is higher than its reported C max (maximum plasma concentration) value of 6.19 -7.58 ngmL -1 [11] and 11.6 -40.8 ngmL -1 after administration of single and multiple doses of different AFB concentrations [15]. On the other hand, individual CBZ quantification was reported using HPLC-UV [16], LC-MS/MS [17,18] in rat plasma with one study using micellar enhanced spectrofluorimetry in human plamsa [19].…”

Section: Introductionmentioning

confidence: 99%

Liquid chromatographic-tandem mass spectrometric assay for simultaneous quantitation of tofacitinib, cabozantinib and afatinib in human plasma and urine

Kadi¹,

Darwish²,

Attwa³

et al. 2017

Trop. J. Pharm Res

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Afatinib pharmacokinetics and metabolism after oral administration to healthy male volunteers

Abstract: Afatinib displayed a complete mass balance with the main route of excretion via feces. Afatinib undergoes minimal metabolism.

Cited by 121 publications

References 17 publications

Metabolic Disposition of Osimertinib in Rats, Dogs, and Humans: Insights into a Drug Designed to Bind Covalently to a Cysteine Residue of Epidermal Growth Factor Receptor

Metabolic Disposition of Osimertinib in Rats, Dogs, and Humans: Insights into a Drug Designed to Bind Covalently to a Cysteine Residue of Epidermal Growth Factor Receptor

Phase I Study to Assess the Combination of Afatinib with Trastuzumab in Patients with Advanced or Metastatic HER2-Positive Breast Cancer

Liquid chromatographic-tandem mass spectrometric assay for simultaneous quantitation of tofacitinib, cabozantinib and afatinib in human plasma and urine

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