Population pharmacokinetics of afatinib, an irreversible ErbB family blocker, in patients with various solid tumors

Freiwald, Matthias; Schmid, Ulrike; Fleury, Angèle; Wind, Sven; Stopfer, Peter; Staab, Alexander

doi:10.1007/s00280-014-2403-2

Cited by 47 publications

(60 citation statements)

References 19 publications

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“…The current analysis showing that mild and moderate hepatic impairment had no obvious effect on the pharmacokinetics of a single afatinib dose is consistent with data from a population pharmacokinetic analysis of patients with advanced solid tumours receiving continuous doses of afatinib [18]. In this analysis, hepatic impairment, either based on individual clinical laboratory tests (alanine transaminase, aspartate transaminase and bilirubin) or a composite liver dysfunction measure, had no significant influence on afatinib exposure.…”

Section: Discussionsupporting

confidence: 87%

Pharmacokinetics of afatinib in subjects with mild or moderate hepatic impairment

Schnell

Buschke

Fuchs

et al. 2014

Cancer Chemother Pharmacol

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PurposeAfatinib, an oral irreversible ErbB family blocker, undergoes minimal metabolism by non-enzyme-catalysed adduct formation with proteins or nucleophilic small molecules and is predominantly non-renally excreted via the entero-hepatic system. This trial assessed whether mild or moderate hepatic impairment influences the pharmacokinetics of afatinib.MethodsThis was an open-label single-dose study. Pharmacokinetic parameters after afatinib 50 mg were investigated in subjects with mild (n = 8) or moderate (n = 8) hepatic impairment (Child-Pugh A and B) and healthy controls (n = 16) matched for age, weight and gender. Plasma and urine samples for pharmacokinetic assessment were collected before and up to 10 days after dosing. Additional blood samples were drawn to determine ex vivo plasma protein binding of afatinib. Primary endpoints were comparisons of afatinib Cmax and AUC0–∞ between subjects with hepatic impairment and healthy matched controls. Study progression was based on drug-related toxicity (CTCAE v. 3.0) and Cmax of afatinib.ResultsAfatinib pharmacokinetic profiles and plasma protein binding were similar in subjects with impaired liver function and healthy controls. Compared with matched controls, the afatinib-adjusted geometric mean ratio for AUC0–∞ was 92.6 % (90 % CI 68.0–126.3 %) and Cmax was 109.5 % (90 % CI 82.7–144.9 %) for subjects with mild hepatic impairment, and 94.9 % (90 % CI 72.3–124.5 %) and 126.9 % (90 % CI 86.0–187.2 %), respectively, for subjects with moderate hepatic impairment. For all parameters, the 90 % CI included 100 %. Afatinib was generally well tolerated with no serious adverse events reported.ConclusionMild to moderate hepatic impairment had no clinically relevant effect on the pharmacokinetics of a single 50 mg dose of afatinib, implying that adjustments to the starting dose of afatinib are not considered necessary in this patient population.

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Section: Discussionsupporting

confidence: 87%

Pharmacokinetics of afatinib in subjects with mild or moderate hepatic impairment

Schnell

Buschke

Fuchs

et al. 2014

Cancer Chemother Pharmacol

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“…This might be partially explained by increased afatinib plasma exposure in these patients, as gender and body weight were previously identified as covariates for exposure [18]. In line with this, pharmacokinetic analyses suggested that dose reductions tended to occur in patients who had higher initial afatinib plasma concentrations, with tolerability-guided dose modification reducing excessive afatinib exposure.…”

Section: Efficacysupporting

confidence: 57%

Effect of dose adjustment on the safety and efficacy of afatinib for EGFR mutation-positive lung adenocarcinoma: post hoc analyses of the randomized LUX-Lung 3 and 6 trials

et al. 2016

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“…The afatinib concentrations required for those effects are lower than the maximal plasma concentrations reported in patients of one study [42]. However, lower maximal concentrations have been reported in other studies [43][44][45][46][47][48][49][50] and the vast majority of patients are probably not going to reach afatinib plasma levels of 1000 ng/ml and above and are therefore not prone to develop the effects analyzed in this paper. Nevertheless, those high concentrations could be reached following accidental overexposure to afatinib.…”

Section: Discussioncontrasting

confidence: 43%

Inhibitory Effect of Afatinib on Platelet Activation and Apoptosis

Cao

Bhuyan

Umbach

et al. 2017

Cell Physiol Biochem

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Background/Aims: The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor afatinib is used for the treatment of several malignancies. Afatinib is at least partially effective by triggering apoptosis of tumor cells. Platelets may similarly undergo apoptosis, which is characterized by caspase 3 activation, cell shrinkage and phosphatidylserine translocation. However, an effect of afatinib on platelets has never been reported. The present study explored whether treatment of platelets with afatinib modifies platelet activation and apoptosis in the absence and presence of platelet activators thrombin or collagen related peptide (CRP). Methods: Platelets isolated from wild-type mice were exposed for 30 minutes to afatinib (18 µg/ml) without or with subsequent treatment with thrombin (0.005 U/ml or 0.01 U/ml) or CRP (2 µg/ml or 5 µg/ml). Flow cytometry was employed to estimate Orai1 abundance at the platelet surface with specific antibodies, cytosolic Ca 2+ -activity ([Ca 2+ ] i ) from Fluo-3 fluorescence, platelet degranulation from P-selectin abundance, integrin activation from α IIb β 3 integrin abundance, caspase activity utilizing an Active Caspase-3 Staining kit, phosphatidylserine abundance from annexin-V-binding, platelet volume from forward scatter and aggregation utilizing staining with CD9-APC and CD9-PE. Results: In the absence of thrombin and CRP, the administration of afatinib (18 µg/ml) slightly, but significantly, increased [Ca 2+ ] i and annexin-V-binding, but did not significantly modify Orai1 abundance, P-selectin abundance, activated α IIb β 3 integrin, cell volume, caspase activity and aggregation. Exposure of platelets to 0.005 U/ml or 0.01 U/ml thrombin or 2 µg/ml or 5 µg/ ml CRP was followed by a significant increase of Orai1 abundance, increase of [Ca 2+ ] i , P-selectin abundance, α IIb β 3 integrin activity, annexin-V-binding, caspase activity, and aggregation, as well as a significant decrease of forward scatter, all effects significantly blunted (thrombin) or virtually abolished (CRP) by afatinib. Conclusions: Afatinib is a powerful inhibitor of platelet activation, platelet apoptosis and platelet aggregation.H. Cao and A. Al Mamun Bhuyan contributed equally and thus share first authorship.

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Population pharmacokinetics of afatinib, an irreversible ErbB family blocker, in patients with various solid tumors

Cited by 47 publications

References 19 publications

Pharmacokinetics of afatinib in subjects with mild or moderate hepatic impairment

Pharmacokinetics of afatinib in subjects with mild or moderate hepatic impairment

Effect of dose adjustment on the safety and efficacy of afatinib for EGFR mutation-positive lung adenocarcinoma: post hoc analyses of the randomized LUX-Lung 3 and 6 trials

Inhibitory Effect of Afatinib on Platelet Activation and Apoptosis

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