Pharmacokinetics of Afatinib, a Selective Irreversible ErbB Family Blocker, in Patients with Advanced Solid Tumours

Wind, Sven; Schmid, Marion; Erhardt, Julia; Goeldner, Rainer-Georg; Stopfer, Peter

doi:10.1007/s40262-013-0091-4

Cited by 94HER2/EGFR in Cancer ResearchPharmacogenetics and Drug MetabolismLung Cancer Treatments and Mutations

Pharmacokinetics of Afatinib, a Selective Irreversible ErbB Family Blocker, in Patients with Advanced Solid Tumours

Wind, Sven, Schmid, Marion, Erhardt, Julia, Goeldner, Rainer-Georg, Stopfer, Peter·2013·Clinical Pharmacokinetics

DOI 10.1007/s40262-013-0091-4

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Abstract

Background and objective Afatinib is a potent, irreversible, ErbB family blocker in clinical development for the treatment of a variety of solid tumours. This study evaluated the pharmacokinetics of afatinib (10-100 mg once daily) in cancer patients.Methods Data from 221 patients with advanced solid tumours in four phase I and one phase II trial were analysed using non-compartmental methods.Results Within each dose group, the shape of the geometric mean plasma concentration-time profiles after single and multiple doses were comparable. Maximum plasma concentration (C(max)) values were achieved 2-5 h after dosing and thereafter declined at least bi-exponentially. Steady-state plasma concentrations were attained within 8 days after the start of dosing. The geometric mean terminal elimination half-life at steady state was about 37 h. Repeated dosing resulted in a 2.77-fold accumulation based on the area under the plasma concentration-time curve (AUC), and 2.11-fold accumulation based on C(max) values. A slightly more than dose-proportional increase in afatinib exposure was observed. There was moderate intra-individual variability in afatinib trough concentration values (the geometric coefficient of variation (gCV) ranged from 22.2 to 67.5 %). The inter-patient variability in plasma concentrations was moderate to high (e.g. at the 40 mg dose, the gCVs ranged from 35.6 to 221 %). The exposure to afatinib (as measured by AUC and C(max)) correlated with the severity of the most common adverse events of afatinib--diarrhoea and rash.Conclusion The pharmacokinetic profile of afatinib supports a once-daily dosage regimen. As expected for this patient population, the pharmacokinetic parameters of afatinib showed moderate to high inter-patient variability. Afatinib exhibits non-linear pharmacokinetics.

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The elimination half-life of afatinib is 37 h following repeat dosing, and steady-state plasma concentrations are achieved within 8 days of multiple dosing.
“The elimination half-life of afatinib is 37 h following repeat dosing,50,56 and steady-state plasma concentrations are achieved within 8 days of multiple dosing.”
From Afatinib for the treatment of EGFR mutation-positive NSCLC: A review of clinical findings (2020) · cites this paper as [56]
Other first-, second-, and third-generation TKIs had IC50 values above clinically achievable plasma concentrations previously observed in patients.
“By contrast, other first-, second-, and third-generation TKIs had IC50 values that were above the clinically achievable plasma concentrations previously observed in patients31,41,42,43,44,45.”
From Mechanisms and clinical activity of an EGFR and HER2 exon 20–selective kinase inhibitor in non–small cell lung cancer (2018) · cites this paper as [31]

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Clinical Pharmacokinetics and Pharmacodynamics of Afatinib
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Influence of Renal Impairment on the Pharmacokinetics of Afatinib: An Open-Label, Single-Dose Study
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Afatinib pharmacokinetics and metabolism after oral administration to healthy male volunteers
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Self-citation

Authors: Wind, S., Schmid, M., Erhardt, J., Goeldner, R.-G., & Stopfer, P.
Affiliations: Boehringer Ingelheim (Germany) (DE)
Corresponding author: Wind, Sven
ORCID: Wind, Sven
Goeldner, Rainer-Georg
Stopfer, Peter
Venue: Clinical Pharmacokinetics
Publisher: Springer Science and Business Media LLC
Published: 2013-06-28
Volume: 52
Issue: 12
Pages: 1101-1109
ISSN: 0312-5963 (ISSN-L)
1179-1926
DOI: 10.1007/s40262-013-0091-4
OpenAlex: W2062869295
Cited by: 94
References: 27
Citations by year: 2026: 2 · 2025: 3 · 2024: 3 · 2023: 8 · 2022: 6 · 2021: 6 · 2020: 6 · 2019: 5 · 2018: 9 · 2017: 5 · 2016: 14 · 2015: 7 · 2014: 17 · 2013: 3
FWCI: 7.31
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
Locations: Clinical Pharmacokinetics (publishedVersion)
PubMed (publishedVersion)
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, pharmacokinetics, advanced solid tumors, dose proportionality, interpatient variability, within-person variability, nonlinear pharmacokinetics, drug accumulation, elimination half-life, adverse events, diarrhea, rash, once-daily dosing, cancer patients
MeSH terms: Afatinib, Adolescent, Adult, Aged, Aged, 80 and over, Antineoplastic Agents, Female, Humans, Male, Middle Aged, Neoplasms, Quinazolines, Erb-b2 Receptor Tyrosine Kinases, Protein Kinase Inhibitors, Young Adult

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Pharmacokinetics of Afatinib, a Selective Irreversible ErbB Family Blocker, in Patients with Advanced Solid Tumours

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