A phase I, dose-escalation trial of continuous- and pulsed-dose afatinib combined with pemetrexed in patients with advanced solid tumors

Chu, Quincy S.; Sangha, Randeep; Hotte, Sébastien J.; Sergenson, Gwen; Schnell, David; Chand, Vikram K.; Hirte, Hal W.

doi:10.1007/s10637-014-0139-9

Cited by 8 publications

(5 citation statements)

References 35 publications

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“…Afatinib further significantly blunted thrombin and CRP induced platelet aggregation. 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.…”

Section: Discussioncontrasting

confidence: 46%

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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Section: Discussioncontrasting

confidence: 46%

Inhibitory Effect of Afatinib on Platelet Activation and Apoptosis

Cao

Bhuyan

Umbach

et al. 2017

Cell Physiol Biochem

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“…The pharmacokinetics of afatinib have been studied in combination with standard chemotherapy agents, including letrozole [ 47 ], paclitaxel [ 48 ], pemetrexed [ 49 ], docetaxel [ 50 ], vinorelbine [ 51 ], temozolomide [ 52 ], trastuzumab [ 53 , 54 ], nintedanib [ 55 ], carboplatin [ 56 ], paclitaxel/bevacizumab [ 56 ], cisplatin/paclitaxel [ 56 , 57 ] and cisplatin/5-fluorouracil [ 57 ]. In most of these studies, the primary objective was to determine the maximum tolerated dose of the combination treatment in patients with advanced solid tumours.…”

Section: Drug–drug Interactionsmentioning

confidence: 99%

Clinical Pharmacokinetics and Pharmacodynamics of Afatinib

et al. 2016

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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.Electronic supplementary materialThe online version of this article (doi:10.1007/s40262-016-0440-1) contains supplementary material, which is available to authorized users.

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“…Cell membrane scrambling and cell shrinkage are hallmarks of eryptosis, the suicidal erythrocyte death. The afatinib concentrations required for the stimulation of eryptosis are within the range of concentrations encountered in the plasma of patients [43]. The stimulation of eryptosis may thus well explain the anemia following afatinib treatment [31].…”

Section: Discussionmentioning

confidence: 90%

“…Side effects of afatinib include skin rash [6], xerosis [6], paronchia [6], stomatitis [6,41], diarrhea [6,41], heart failure [42], neutropenia [41], leukopenia [41], and anemia [41,43]. Afatinib is in part effective by inducing apoptosis [44][45][46][47][48][49][50][51][52][53][54][55][56][57], an effect involving oxidative stress [46].…”

Section: Introductionmentioning

confidence: 99%

Stimulation of Eryptosis by Afatinib

Bhuyan

Läng

2018

Cell Physiol Biochem

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Background/Aims: The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor afatinib is primarily utilized for the treatment of non-small cell lung carcinoma. The drug is at least partially effective by triggering suicidal tumor cell death. Side effects of afatinib treatment include anemia. At least in theory, afatinib induced anemia could be secondary to stimulation of suicidal erythrocyte death or eryptosis, characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine translocation to the erythrocyte surface. Signaling potentially stimulating eryptosis include increase of cytosolic Ca 2+ activity ([Ca 2+ ] i ), induction of oxidative stress, and increase of ceramide abundance. The present study explored, whether afatinib induces eryptosis and, if so, whether its effect involves Ca 2+ entry, oxidative stress, and/or ceramide. Methods: Flow cytometry was employed to quantify phosphatidylserine exposure at the cell surface from annexin-V-binding, cell volume from forward scatter, [Ca 2+ ] i from Fluo3-fluorescence, reactive oxygen species (ROS) abundance from DCFDA dependent fluorescence, and ceramide abundance utilizing specific antibodies. Results: A 48 hours exposure of human erythrocytes to afatinib (≥ 4 µg/ml) significantly increased the percentage of annexin-V-binding cells and significantly decreased forward scatter. Afatinib significantly increased Fluo3-fluorescence, DCFDA fluorescence and ceramide abundance. The effect of afatinib on annexin-V-binding and forward scatter was significantly blunted by removal of extracellular Ca 2+ . Conclusions: Afatinib triggers phospholipid scrambling of the erythrocyte cell membrane, an effect at least in part due to Ca 2+ entry, oxidative stress, and ceramide.

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A phase I, dose-escalation trial of continuous- and pulsed-dose afatinib combined with pemetrexed in patients with advanced solid tumors

Abstract: Continuous- or pulsed-dose afatinib combined with pemetrexed exhibited a manageable safety profile. Pulsed dosing conferred no apparent safety or dose advantage. Continuous-dose afatinib 30 mg/day with pemetrexed is recommended for phase II studies.

Cited by 8 publications

References 35 publications

Inhibitory Effect of Afatinib on Platelet Activation and Apoptosis

Inhibitory Effect of Afatinib on Platelet Activation and Apoptosis

Clinical Pharmacokinetics and Pharmacodynamics of Afatinib

Stimulation of Eryptosis by Afatinib

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