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Clinical Pharmacokinetics and Pharmacodynamics of Afatinib
Open accessAbstract
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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![Fig. 1 Structural formula of afatinib (BIBW 2992): N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[[(3S)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4-(dimethylamino)-2-butenamide](/paper-figures/0b60558294a3441abe0b834e6cae0cdd/clinical-pharmacokinetics-and-pharmacodynamics-of-afatinib-figure-1.jpg)
![Fig. 2 Geometric mean afatinib plasma concentration–time profiles after single doses and at steady-state following oral administration of afatinib (20–50 mg) once daily to cancer patients (linear scale). n = maximum number of patients contributing to the geometric mean of each time point for afatinib single doses and at steady-state. Reproduced from Wind et al. [34], with permission of Springer](/paper-figures/068cd3a2c72841e9b1b49814b60c5239/clinical-pharmacokinetics-and-pharmacodynamics-of-afatinib-figure-2.jpg)
![Fig. 3 Ratios (point estimates and 95 % confidence interval based on bootstrap analysis) of afatinib population mean exposure at steady state (AUCτ) predicted by the population pharmacokinetic model for different scenarios compared with a typical patient. *Typical patient was female with NSCLC, body weight 62 kg, creatinine clearance 79 mL/min, ECOG score of 1, alkaline phosphatase 106 U/L, lactate dehydrogenase 241 U/L, total protein 72 g/L, receiving afatinib 40 mg once daily. The solid vertical line indicates the population mean for the typical patient, and the shaded area is the 90 % prediction interval for interpatient variability. The vertical dotted lines indicate the bioequivalence limits (80–125 %). The 2.5th, 25th, 75th and 97.5th percentiles of the baseline values observed in the analysed population are shown for body weight, alkaline phosphatase, lactate dehydrogenase and total protein. Data for the creatinine clearance subgroups are based on the US FDA classification of renal function [41]. AUC τ area under the drug plasma concentration–time curve over a uniform dosing interval τ, ECOG Eastern Cooperative Oncology Group, NSCLC non-small cell lung cancer. Reproduced from Freiwald et al. [35], with permission of Springer](/paper-figures/b5a2bbcc47834eb2b25c4dfb2b172758/clinical-pharmacokinetics-and-pharmacodynamics-of-afatinib-figure-3.jpg)
![Fig. 4 Effect of ritonavir and rifampicin on afatinib exposure. Broken vertical lines illustrate the no-effect boundaries (0.8–1.25) used in the assessment. AUC area under the plasma concentration–time curve, CI confidence interval, C max maximum plasma concentration. Reproduced from Wind et al. [45], with permission of Springer](/paper-figures/b806ae505f9040169e5b624515355c0a/clinical-pharmacokinetics-and-pharmacodynamics-of-afatinib-figure-4.jpg)
![Fig. 5 Comparison of afatinib trough plasma concentrations on days 22 and 43 in patients who remained on afatinib 40 mg, reduced their dose to 30 mg, or escalated to 50 mg in the LUX-Lung 3 trial [19, 63]. Striped boxes indicate patients who remained on 40 mg until day 43 (cycle 3, visit 1, n = 126). Grey boxes indicate patients who reduced their dose to 30 mg before day 43 (n = 38; only 10 of these patients had valid trough concentrations on afatinib 40 mg at day 22 [cycle 2, visit 1; the rest had either no pharmacokinetic sampling due to dose interruption, were already receiving afatinib 30 mg, or were excluded due to invalid sampling]). White boxes indicate patients who dose escalated to 50 mg before cycle 3, visit 1 (n = 14)](/paper-figures/a9cbaae66c0c47fdb3b8188f0c788ef1/clinical-pharmacokinetics-and-pharmacodynamics-of-afatinib-figure-5.jpg)
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“concomitant administration of ritonavir, a well-known, potent inhibitor of P-glycoprotein and BCRP (another ATP binding cassette drug transporter inhibitor) has shown no relevant impact on afatinib pharmacokinetics in healthy male adults.”
From Afatinib for the treatment of EGFR mutation-positive NSCLC: A review of clinical findings (2020) · cites this paper as [62]
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“Afatinib is highly soluble across the physiological pH range of 1–7.5 and is not expected to interact with acid-reducing agents.”
From Afatinib for the treatment of EGFR mutation-positive NSCLC: A review of clinical findings (2020) · cites this paper as [62]
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“Smoking status does not impact the pharmacokinetics of afatinib”
From Afatinib for the treatment of EGFR mutation-positive NSCLC: A review of clinical findings (2020) · cites this paper as [62]
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“P-glycoprotein inducers such as rifampicin can reduce afatinib exposure.”
From Afatinib for the treatment of EGFR mutation-positive NSCLC: A review of clinical findings (2020) · cites this paper as [62]
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“afatinib does not relevantly inhibit or induce CYP enzymes, including those involved in drug metabolism.62 Therefore, the risk of interactions between afatinib and co-administered drugs that undergo CYP enzyme metabolism is thought to be minimal.”
From Afatinib for the treatment of EGFR mutation-positive NSCLC: A review of clinical findings (2020) · cites this paper as [62]
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“Afatinib is a substrate and inhibitor of P-glycoprotein in vitro, and concomitant use of strong P-glycoprotein inhibitors can increase exposure to afatinib.”
From Afatinib for the treatment of EGFR mutation-positive NSCLC: A review of clinical findings (2020) · cites this paper as [62]
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Citations
Cites
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“AUCs area under the drug plasma concentration–time curve over a uniform dosing interval s, ECOG Eastern Cooperative Oncology Group, NSCLC non-small cell lung cancer.”
BackgroundInfluentialThe T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP
Yun, C.-H., Mengwasser, K. E., Toms, A. V., Woo, M. S., Greulich, H., Wong, K.-K., Meyerson, M., & Eck, M. J. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0709662105 · Cited by 2,118
EGFR Antagonists in Cancer Treatment
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“The first-generation EGFR– TKIs, erlotinib and gefitinib, compete reversibly with adenosine triphosphate (ATP) for binding to the intracellular catalytic domain of EGFR tyrosine kinase and thus inhibit EGFR autophosphorylation and downstream signalling [2].”
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“AUCs area under the drug plasma concentration–time curve over a uniform dosing interval s, ECOG Eastern Cooperative Oncology Group, NSCLC non-small cell lung cancer.”
ResultInfluentialYang, J. C.-H., Wu, Y.-L., Schuler, M., Sebastian, M., Popat, S., Yamamoto, N., Zhou, C., Hu, C.-P., O'Byrne, K., Feng, J., et al. (2015) · The Lancet Oncology · doi:10.1016/s1470-2045(14)71173-8 · Cited by 1,574
BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models
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Miller, V. A., Hirsh, V., Cadranel, J., Chen, Y.-M., Park, K., Kim, S.-W., Zhou, C., Su, W.-C., Wang, M., Sun, Y., et al. (2012) · The Lancet Oncology · doi:10.1016/s1470-2045(12)70087-6 · Cited by 961 · cited 1×
“0, NSCLC non-small cell lung cancer, TKI tyrosine kinase inhibitor a TKI-naı̈ve patients in LUX-Lung 2 [59] and LUX-Lung 3 [19] who received an afatinib starting dose of 40 mg b TKI-resistant NSCLC patients in LUX-Lung 1 [60] and LUX-Lung 4 [61, 62] who received an afatinib starting dose of 50 mg c Both NSCLC patient…”
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“In cell-free in vitro kinase assays, afatinib showed nanomolar potency to inhibit wild-type EGFR, HER2 and ErbB4 (ErbB3 misses critical amino acid residues responsible for enzymatic activity, and thus has a much weaker tyrosine kinase activity) [15, 16, 24].”
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Epidermal Growth Factor Receptor Dependence in Human Tumors: More Than Just Expression?
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Soria, J.-C., Felip, E., Cobo, M., Lu, S., Syrigos, K., Lee, K. H., Göker, E., Georgoulias, V., Li, W., Isla, D., et al. (2015) · The Lancet Oncology · doi:10.1016/s1470-2045(15)00006-6 · Cited by 433 · cited 1×
“In patients with lung squamous cell cancer, afatinib has also demonstrated a significant increase in PFS and OS compared with erlotinib [22].”
BackgroundYang, J. C., Shih, J., Su, W., Hsia, T., Tsai, C., Ou, S. I., Yu, C., Chang, G., Ho, C., Sequist, L. V. D., et al. (2012) · The Lancet Oncology · doi:10.1016/s1470-2045(12)70086-4 · Cited by 413 · cited 1×
“0, NSCLC non-small cell lung cancer, TKI tyrosine kinase inhibitor a TKI-naı̈ve patients in LUX-Lung 2 [59] and LUX-Lung 3 [19] who received an afatinib starting dose of 40 mg b TKI-resistant NSCLC patients in LUX-Lung 1 [60] and LUX-Lung 4 [61, 62] who received an afatinib starting dose of 50 mg c Both NSCLC patient…”
BackgroundYap, T. A., Vidal, L., Adam, J., Stephens, P., Spicer, J., Shaw, H., Ang, J., Temple, G., Bell, S., Shahidi, M., et al. (2010) · Journal of Clinical Oncology · doi:10.1200/jco.2009.26.7278 · Cited by 349 · cited 1×
“5–24 h) (Tables 2, 3) [34], delayed slightly by food intake (Cmax occurs at 3–8 h) [30].”
BackgroundSelf-citationKatakami, N., Atagi, S., Goto, K., Hida, T., Horai, T., Inoue, A., Ichinose, Y., Koboyashi, K., Takeda, K., Kiura, K., et al. (2013) · Journal of Clinical Oncology · doi:10.1200/jco.2012.45.0981 · Cited by 326 · cited 1×
“0, NSCLC non-small cell lung cancer, TKI tyrosine kinase inhibitor a TKI-naı̈ve patients in LUX-Lung 2 [59] and LUX-Lung 3 [19] who received an afatinib starting dose of 40 mg b TKI-resistant NSCLC patients in LUX-Lung 1 [60] and LUX-Lung 4 [61, 62] who received an afatinib starting dose of 50 mg c Both NSCLC patient…”
BackgroundEmerging Evidence of the Impact of Kidney Disease on Drug Metabolism and Transport
Nolin, T. D., Naud, J., Leblond, F. A., & Pichette, V. (2008) · Clinical Pharmacology & Therapeutics · doi:10.1038/clpt.2008.59 · Cited by 277 · cited 1×
“Based on the low urinary excretion of afatinib-related radioactivity (\5 %) found in the ADME study [40], the renal impairment study [39] and the PopPK analysis [35], it may be hypothesized that non-renal elimination pathways of afatinib are impacted by renal function, such as a decrease in expression and/or activity…”
BackgroundEskens, F. A. L. M., Mom, C. H., Planting, A. S. T., Gietema, J. A., Amelsberg, A., Huisman, H., van Doorn, L., Burger, H., Stopfer, P., Verweij, J., et al. (2008) · British Journal of Cancer · doi:10.1038/sj.bjc.6604108 · Cited by 234
Self-citationWu, S.-G., Liu, Y.-N., Tsai, M.-F., Chang, Y.-L., Yu, C.-J., Yang, P.-C., Yang, J. C.-H., Wen, Y.-F., & Shih, J.-Y. (2016) · Oncotarget · doi:10.18632/oncotarget.7189 · Cited by 234
Reardon, D. A., Nabors, B., Mason, W. P., Perry, J., Shapiro, W., Kavan, P., Mathieu, D., Phuphanich, S., Cseh, A., Fu, Y., et al. (2014) · Neuro-Oncology · doi:10.1093/neuonc/nou160 · Cited by 195 · cited 1×
“[50], vinorelbine [51], temozolomide [52], trastuzumab [53, 54], nintedanib [55], carboplatin [56], paclitaxel/bevacizumab [56], cisplatin/paclitaxel [56, 57] and cisplatin/”
Self-citationLin, N., Winer, E. P., Wheatley, D. A., Carey, L., Houston, S. J., Mendelson, D. S., Münster, P. N., Frakes, L., Kelly, S., García, A. A., et al. (2012) · Breast Cancer Research and Treatment · doi:10.1007/s10549-012-2003-y · Cited by 192 · cited 1×
“[50], vinorelbine [51], temozolomide [52], trastuzumab [53, 54], nintedanib [55], carboplatin [56], paclitaxel/bevacizumab [56], cisplatin/paclitaxel [56, 57] and cisplatin/”
Self-citationZhang, Y., Zhang, L., Abraham, S., Apparaju, S., Wu, T. ‐., Strong, J., Xiao, S., Aj, A., Thummel, K., Leeder, J. S., et al. (2008) · Clinical Pharmacology & Therapeutics · doi:10.1038/clpt.2008.208 · Cited by 165
Dual inhibition of ErbB1 (EGFR/HER1) and ErbB2 (HER2/neu)
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“Newer, so called ‘second-generation’ EGFR–TKIs, including afatinib and dacomitinib, differ from erlotinib or gefitinib in that they form irreversible covalent bonds to the ATP-binding site of the EGFR receptor, and also target multiple ErbB family members, including HER2, which plays a key role in ErbB activation [14].”
BackgroundAfatinib pharmacokinetics and metabolism after oral administration to healthy male volunteers
Stopfer, P., Marzin, K., Narjes, H., Gansser, D., Shahidi, M., Uttereuther-Fischer, M., & Ebner, T. (2012) · Cancer Chemotherapy and Pharmacology · doi:10.1007/s00280-011-1803-9 · Cited by 137 · cited 4×
“Since metabolism of afatinib is negligible [40], there is no effect on biliary excretion of predominantly unchanged afatinib, consistent with findings from the PopPK model, which showed that the presence of liver dysfunction associated with liver metastases had no significant impact on the exposure (AUC) of afatinib […”
BackgroundMethodResultInfluentialSelf-citationModjtahedi, H., Cho, B. C., Michel, M. C., & Solca, F. (2014) · Naunyn-Schmiedeberg s Archives of Pharmacology · doi:10.1007/s00210-014-0967-3 · Cited by 109 · cited 2×
“Structural modelling studies demonstrate that it harbours a reactive acrylamide group that covalently binds to specific cysteine (Cys) residues in the kinase domains of EGFR (Cys(773)), HER2 (Cys(805)), and HER4 (Cys(803)) receptors [15, 16, 24].”
BackgroundWind, S., Schmid, M., Erhardt, J., Goeldner, R.-G., & Stopfer, P. (2013) · Clinical Pharmacokinetics · doi:10.1007/s40262-013-0091-4 · Cited by 94 · cited 9×
“To characterise the pharmacokinetics of afatinib in a large number of patients with advanced solid tumours, a meta-analysis of five phase I trials [29–32] and one phase II trial [33] in patients with advanced solid tumours (n = 221) who received afatinib (10–100 mg doses) was performed using non-compartmental analysis…”
BackgroundMethodInfluentialSelf-citationMurakami, H., Tamura, T., Takahashi, T., Nokihara, H., Naito, T., Nakamura, Y., Nishio, K., Seki, Y., Sarashina, A., Shahidi, M., et al. (2011) · Cancer Chemotherapy and Pharmacology · doi:10.1007/s00280-011-1738-1 · Cited by 88
Effects of Tobacco Smoking and Nicotine on Cancer Treatment
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“This was expected based on the minor metabolism of afatinib, in which CYP enzymes such as CYP1A1/1A2, which are induced by smoking [58], play a negligible role.”
BackgroundTachibana, T., Kato, M., Watanabe, T., Mitsui, T., & Sugiyama, Y. (2009) · Xenobiotica · doi:10.1080/00498250902846252 · Cited by 67 · cited 1×
“As exposure to ritonavir was sufficient to inhibit BCRP in the two studies [46], it is assumed that a possible interaction with BCRP inhibitors is also covered by the drug–drug interaction studies with ritonavir.”
BackgroundPharmacokinetic Drug Interactions of Afatinib with Rifampicin and Ritonavir
Wind, S., Giessmann, T., Jungnik, A., Brand, T., Marzin, K., Bertulis, J., Hocke, J., Gansser, D., & Stopfer, P. (2014) · Clinical Drug Investigation · doi:10.1007/s40261-013-0161-2 · Cited by 63 · cited 4×
“Two drug–drug interaction studies in healthy subjects evaluated the effect on afatinib exposure of the potent P-gp and BCRP inhibitor ritonavir (200 mg twice daily) administered 1 h before, concomitantly, or 6 h after afatinib [45].”
BackgroundMethodInfluentialSelf-citationFreiwald, M., Schmid, U., Fleury, A., Wind, S., Stopfer, P., & Staab, A. (2014) · Cancer Chemotherapy and Pharmacology · doi:10.1007/s00280-014-2403-2 · Cited by 54 · cited 9×
“pharmacokinetic (PopPK) model using data from 927 patients with advanced solid tumours included in seven phase II/III studies [35].”
BackgroundMethodResultInfluentialSelf-citationMarshall, J. L., Hwang, J., Eskens, F. A. L. M., Burger, H., Malik, S. M., Uttenreuther‐Fischer, M., Stopfer, P., Ould-Kaci, M., Cohen, R. B., & Lewis, N. L. (2012) · Investigational New Drugs · doi:10.1007/s10637-012-9890-y · Cited by 46
Self-citationPharmacokinetics of afatinib in subjects with mild or moderate hepatic impairment
Schnell, D., Buschke, S., Fuchs, H., Gansser, D., Goeldner, R.-G., Uttenreuther-Fischer, M., Stopfer, P., Wind, S., Petersen-Sylla, M., Halabi, A., et al. (2014) · Cancer Chemotherapy and Pharmacology · doi:10.1007/s00280-014-2484-y · Cited by 44 · cited 3×
“A terminal half-life of 70–80 h was determined after single-dose administration and subsequent pharmacokinetic sampling up to 312 h [38, 39], and up to approximately 340 h after multiple dosing in patients who stopped afatinib therapy after at least 6 months of treatment and had pharmacokinetic sampling up to 6 weeks…”
BackgroundMethodSelf-citationGordon, M. S., Mendelson, D. S., Gross, M. E., Uttenreuther‐Fischer, M., Ould-Kaci, M., Zhao, Y., Stopfer, P., & Agus, D. B. (2012) · Investigational New Drugs · doi:10.1007/s10637-012-9904-9 · Cited by 37
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Self-citationSuder, A., Ang, J. E., Kyle, F. J., Harris, D., Rudman, S. M., Kristeleit, R. S., Solca, F., Uttenreuther‐Fischer, M., Pemberton, K., Pelling, K., et al. (2015) · European Journal of Cancer · doi:10.1016/j.ejca.2015.07.041 · Cited by 29 · cited 1×
“The pharmacokinetics of afatinib have been studied in combination with standard chemotherapy agents, including letrozole [47], paclitaxel [48], pemetrexed [49], docetaxel”
BackgroundSelf-citationAwada, A. H., Dumez, H., Hendlisz, A., Wolter, P., Besse‐Hammer, T., Uttenreuther‐Fischer, M., Stopfer, P., Fleischer, F., Piccart, M. J., & Schöffski, P. (2012) · Investigational New Drugs · doi:10.1007/s10637-012-9880-0 · Cited by 28 · cited 1×
“[50], vinorelbine [51], temozolomide [52], trastuzumab [53, 54], nintedanib [55], carboplatin [56], paclitaxel/bevacizumab [56], cisplatin/paclitaxel [56, 57] and cisplatin/”
Self-citationRing, A. E., Wheatley, D. A., Hatcher, H. M., Laing, R. W., Plummer, R., Uttenreuther‐Fischer, M., Temple, G., Pelling, K., & Schnell, D. (2014) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-14-1812 · Cited by 26 · cited 1×
“[50], vinorelbine [51], temozolomide [52], trastuzumab [53, 54], nintedanib [55], carboplatin [56], paclitaxel/bevacizumab [56], cisplatin/paclitaxel [56, 57] and cisplatin/”
Self-citationInfluence of Renal Impairment on the Pharmacokinetics of Afatinib: An Open-Label, Single-Dose Study
Wiebe, S., Schnell, D., Külzer, R., Gansser, D., Weber, A., Wallenstein, G., Halabi, A., Conrad, A., & Wind, S. (2017) · European Journal of Drug Metabolism and Pharmacokinetics · doi:10.1007/s13318-016-0359-9 · Cited by 24 · cited 4×
“In a single-dose study of afatinib 40 mg in subjects with moderate (n = 8) or severe (n = 8) renal impairment (estimated glomerular filtration rate [eGFR] 30–59 and 15–29 mL/min, respectively) and healthy matched controls (n = 14) [39], the plasma concentration–time profile of afatinib was similar in both groups.”
BackgroundMethodInfluentialSelf-citationMolife, L. R., Rudman, S. M., Alam, S. M., Tan, D. S. W., Kristeleit, H., Middleton, G., PROPPER, D. J., Bent, L., Stopfer, P., Uttenreuther‐Fischer, M., et al. (2013) · Cancer Chemotherapy and Pharmacology · doi:10.1007/s00280-013-2286-7 · Cited by 18 · cited 6×
“To characterise the pharmacokinetics of afatinib in a large number of patients with advanced solid tumours, a meta-analysis of five phase I trials [29–32] and one phase II trial [33] in patients with advanced solid tumours (n = 221) who received afatinib (10–100 mg doses) was performed using non-compartmental analysis…”
BackgroundMethodInfluentialSelf-citationGunzer, K., Joly, F., Ferrero, J.-., Gligorov, J., de Mont-Serrat, H., Uttenreuther‐Fischer, M., Pelling, K., Wind, S., Bousquet, G., & Misset, J. L. (2016) · SpringerPlus · doi:10.1186/s40064-015-1601-7 · Cited by 17 · cited 1×
“The pharmacokinetics of afatinib have been studied in combination with standard chemotherapy agents, including letrozole [47], paclitaxel [48], pemetrexed [49], docetaxel”
BackgroundSelf-citationMukai, H., Masuda, N., Ishiguro, H., Mitsuma, A., Shibata, T., Yamamura, J., Toi, M., Watabe, A., Sarashina, A., Uttenreuther‐Fischer, M., et al. (2015) · Cancer Chemotherapy and Pharmacology · doi:10.1007/s00280-015-2826-4 · Cited by 16 · cited 1×
“[50], vinorelbine [51], temozolomide [52], trastuzumab [53, 54], nintedanib [55], carboplatin [56], paclitaxel/bevacizumab [56], cisplatin/paclitaxel [56, 57] and cisplatin/”
Song, X., Varker, H., Eichelbaum, M. F., Stopfer, P., Shahidi, M., Wilson, K. L., Kaiser, R., & Finnern, H. W. (2011) · Lung Cancer · doi:10.1016/j.lungcan.2011.01.016 · Cited by 15 · cited 1×
“In routine clinical practice, afatinib may offer a number of theoretical advantages compared with first-generation TKIs, notably the lack of CYP-related interaction potential, thereby decreasing the risk of drug–drug interactions [64].”
BackgroundSelf-citationChu, Q. S.-C., Sangha, R. S., Hotte, S. J., Sergenson, G., Schnell, D., Chand, V. K., & Hirte, H. W. (2014) · Investigational New Drugs · doi:10.1007/s10637-014-0139-9 · Cited by 11 · cited 1×
“The pharmacokinetics of afatinib have been studied in combination with standard chemotherapy agents, including letrozole [47], paclitaxel [48], pemetrexed [49], docetaxel”
BackgroundSelf-citationYang, J. C., Ahn, M., Dickgreber, N. J., Halmos, B., Hirsh, V., Hochmair, M. J., Levy, B. P., de Marinis, F., Mok, T. S. K., O'Byrne, K. J., et al. (2015) · Journal of Clinical Oncology · doi:10.1200/jco.2015.33.15_suppl.8073 · Cited by 11
Self-citationGordon, M. S., Springett, G. M., Su, Y. B., Ould-Kaci, M., Wind, S., Zhao, Y., & LoRusso, P. M. (2015) · Future Oncology · doi:10.2217/fon.15.50 · Cited by 10 · cited 1×
“[50], vinorelbine [51], temozolomide [52], trastuzumab [53, 54], nintedanib [55], carboplatin [56], paclitaxel/bevacizumab [56], cisplatin/paclitaxel [56, 57] and cisplatin/”
Self-citationMorán, T., Palmero, R., Provencio, M., Insa, A., Majem, M., Reguart, N., Bosch‐Barrera, J., Isla, D., Lee, C. P., Kraemer, S., et al. (2014) · Annals of Oncology · doi:10.1093/annonc/mdu349.27 · Cited by 3
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“6 ng/mL in those with only Grade 1–2 rash.(29) A consistent relationship between exposure and response has not been found yet for afatinib.”
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“The anti-tumor agent afatinib (an ATP-competitive 4-anilinoquinazoline derivative), an irreversible epidermal growth factor receptor tyrosine kinase inhibitor, has proven efficacious in phase III trials in patients with non-small cell lung cancer, which is known as the third most common cause of bone metastases [84].”
Background
Metadata
- Authors
- Wind, S., Schnell, D., Ebner, T., Freiwald, M., & Stopfer, P.
- Affiliations
- Boehringer Ingelheim (Germany) (DE)
- Corresponding author
- Wind, Sven
- Venue
- Clinical Pharmacokinetics
- Published
- 2016-07-28
- Volume
- 56
- Issue
- 3
- Pages
- 235-250
- ISSN
- 0312-5963 (ISSN-L)
- 1179-1926
- PMC
- PMC5315738
- OpenAlex
- W2484071785
- Cited by
- 206
- References
- 53
- Citations by year
- 2026: 14 · 2025: 23 · 2024: 21 · 2023: 28 · 2022: 35 · 2021: 18 · 2020: 24 · 2019: 15 · 2018: 17 · 2017: 9 · 2016: 1
- FWCI
- 1.41
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Clinical Pharmacokinetics (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Funders
- Boehringer Ingelheim
- Topics
- Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Keywords
- afatinib, EGFR, HER2, ErbB4, pharmacokinetics, pharmacodynamics, food effect, dose proportionality, renal dysfunction, P-glycoprotein, drug-drug interactions, covalent protein adducts, drug-induced arrhythmia, interindividual variability, advanced solid tumors
- MeSH terms
- Afatinib, Animals, Drug Interactions, Humans, Kidney, Liver, Neoplasms, Protein Binding, Quinazolines, Radiation-Sensitizing Agents, ATP Binding Cassette Transporter, Subfamily B, Member 1, Protein Kinase Inhibitors, ErbB Receptors
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