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Cited by 206HER2/EGFR in Cancer ResearchPharmacogenetics and Drug MetabolismLung Cancer Treatments and Mutations

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Clinical Pharmacokinetics and Pharmacodynamics of Afatinib

Open access
Wind, Sven, Schnell, David, Ebner, Thomas, Freiwald, Matthias, Stopfer, Peter·2017·Clinical Pharmacokinetics
DOI 10.1007/s40262-016-0440-1PMC PMC5315738
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Abstract

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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Figures

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
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-butenamideCC BY-NC · PubMed Central
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
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 SpringerCC BY-NC · PubMed Central
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
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 SpringerCC BY-NC · PubMed Central
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
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 SpringerCC BY-NC · PubMed Central
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)
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)CC BY-NC · PubMed Central

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Metadata

Authors
Wind, S., Schnell, D., Ebner, T., Freiwald, M., & Stopfer, P.
Affiliations
Boehringer Ingelheim (Germany) (DE)
Corresponding author
Wind, Sven
ORCID
Venue
Clinical Pharmacokinetics
Publisher
Springer Science and Business Media LLC
Published
2016-07-28
Volume
56
Issue
3
Pages
235-250
ISSN
  • 0312-5963 (ISSN-L)
  • 1179-1926
DOI
10.1007/s40262-016-0440-1
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
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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