We are analyzing https://link.springer.com/article/10.1007/s40262-016-0440-1.

Title:
Clinical Pharmacokinetics and Pharmacodynamics of Afatinib | Clinical Pharmacokinetics
Description:
Afatinib is an oral, irreversible ErbB family blocker that covalently binds to the kinase domains of epidermal growth factor receptor (EGFR), human EGFRs (HER) 2, and HER4, resulting in irreversible inhibition of tyrosine kinase autophosphorylation. Studies in healthy volunteers and patients with advanced solid tumours have shown that once-daily afatinib has time-independent pharmacokinetic characteristics. Maximum plasma concentrations of afatinib are reached approximately 2–5 h after oral administration and thereafter decline, at least bi-exponentially. Food reduces total exposure to afatinib. Over the clinical dose range of 20–50 mg, afatinib exposure increases slightly more than dose proportional. Afatinib metabolism is minimal, with unchanged drug predominantly excreted in the faeces and approximately 5 % in urine. Apart from the parent drug afatinib, the major circulation species in human plasma are the covalently bound adducts to plasma protein. The effective elimination half-life is approximately 37 h, consistent with an accumulation of drug exposure by 2.5- to 3.4-fold based on area under the plasma concentration–time curve (AUC) after multiple dosing. The pharmacokinetic profile of afatinib is consistent across a range of patient populations. Age, ethnicity, smoking status and hepatic function had no influence on afatinib pharmacokinetics, while females and patients with low body weight had increased exposure to afatinib. Renal function is correlated with afatinib exposure, but, as for sex and body weight, the effect size for patients with severe renal impairment (approximately 50 % increase in AUC) is only mildly relative to the extent of unexplained interpatient variability in afatinib exposure. Afatinib has a low potential as a victim or perpetrator of drug–drug interactions, especially with cytochrome P450-modulating agents. However, concomitant treatment with potent inhibitors or inducers of the P-glycoprotein transporter can affect the pharmacokinetics of afatinib. At a dose of 50 mg, afatinib does not have proarrhythmic potential.
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eu/docs/en_gb/document_library/epar_-_product_information/human/002280/wc500152392 eu/docs/en_gb/document_library/epar_-_procedural_steps_taken_and_scientific_information_after_authorisation/human/002280/wc500177054 eu/docs/en_gb/document_library/epar_-_public_assessment_report/human/002280/wc500152394 /content/dam/internet/opu/clinicaltrial/com_en/results/1200/1200 gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm292362 gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm204959 gov/downloads/regulatoryinformation/guidances/ucm126833 european medicines agency gov/drugsatfda_docs/nda/2013/201292orig1s000clinpharmr gov/drugsatfda_docs/nda/2013/201292orig1s000pharmr tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4 advanced egfr mutation-positive small-cell lung cancer major drug-related component key pharmacokinetic parameters plasma concentration–time curve drug–drug interaction profile human α1-acid glycoprotein plasma concentration–time profile drug–drug interaction potential potential drug–drug interaction real terminal half-life l858r/t790m double mutation cyp-related interaction potential drug–drug interaction studies prolonged terminal half-life full size image atp-competitive 4-anilinoquinazoline derivative article download pdf time-independent pharmacokinetic profile gmean terminal half-life inhibit wild-type egfr egfr-mutant lung cancers afatinib terminal half-lives time-matched qt interval time-independent pharmacokinetic characteristics potent p-gp inhibitors cytochrome p450-modulating agents egfr mutation-positive egfr mutation positive refractory solid tumors p-gp-mediated transport creatinine clearance 79 ml/min effective elimination half-life afatinib inhibits p-gp metastatic lung adenocarcinoma efflux transporter p-gp yang jc h2-receptor antagonists small cell transformation

Questions {❓}

Epidermal growth factor receptor dependence in human tumors: more than just expression?

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         headline:Clinical Pharmacokinetics and Pharmacodynamics of Afatinib
         description:Afatinib is an oral, irreversible ErbB family blocker that covalently binds to the kinase domains of epidermal growth factor receptor (EGFR), human EGFRs (HER) 2, and HER4, resulting in irreversible inhibition of tyrosine kinase autophosphorylation. Studies in healthy volunteers and patients with advanced solid tumours have shown that once-daily afatinib has time-independent pharmacokinetic characteristics. Maximum plasma concentrations of afatinib are reached approximately 2–5 h after oral administration and thereafter decline, at least bi-exponentially. Food reduces total exposure to afatinib. Over the clinical dose range of 20–50 mg, afatinib exposure increases slightly more than dose proportional. Afatinib metabolism is minimal, with unchanged drug predominantly excreted in the faeces and approximately 5 % in urine. Apart from the parent drug afatinib, the major circulation species in human plasma are the covalently bound adducts to plasma protein. The effective elimination half-life is approximately 37 h, consistent with an accumulation of drug exposure by 2.5- to 3.4-fold based on area under the plasma concentration–time curve (AUC) after multiple dosing. The pharmacokinetic profile of afatinib is consistent across a range of patient populations. Age, ethnicity, smoking status and hepatic function had no influence on afatinib pharmacokinetics, while females and patients with low body weight had increased exposure to afatinib. Renal function is correlated with afatinib exposure, but, as for sex and body weight, the effect size for patients with severe renal impairment (approximately 50 % increase in AUC) is only mildly relative to the extent of unexplained interpatient variability in afatinib exposure. Afatinib has a low potential as a victim or perpetrator of drug–drug interactions, especially with cytochrome P450-modulating agents. However, concomitant treatment with potent inhibitors or inducers of the P-glycoprotein transporter can affect the pharmacokinetics of afatinib. At a dose of 50 mg, afatinib does not have proarrhythmic potential.
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            Drug Interaction Study
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      headline:Clinical Pharmacokinetics and Pharmacodynamics of Afatinib
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         Drug Interaction Study
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