Modulation of Fexofenadine Pharmacokinetics by Osimertinib in Patients With Advanced EGFR-Mutated Non–Small Cell Lung Cancer

Emiliano Calvo, Jong-Seok Lee, Sang We Kim, Victor Moreno, Javier deCastro Carpeno, Doris Weilert, Gianluca Laus, Helen Mann, Karthick Vishwanathan

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Osimertinib is a potent, third-generation, irreversible, central nervous system active epidermal growth factor receptor (EGFR)–tyrosine kinase inhibitor (TKI) that selectively inhibits EGFR-TKI sensitizing and EGFR T790M resistance mutations. It is approved for first-line treatment of patients with advanced non–small cell lung cancer (NSCLC) whose tumors have EGFR exon 19 deletions or exon 21 L858R mutations, and for patients with T790M-positive advanced NSCLC whose disease has progressed on or after EGFR-TKI therapy. This study investigated the pharmacokinetics (PK) of fexofenadine (P-glycoprotein substrate) following single- and multiple-dose osimertinib in patients with advanced NSCLC who have progressed on prior EGFR-TKI therapy. This open-label, phase 1 study (NCT02908750) comprised the PK phase and continued access phase. The former comprised 2 distinct periods with a 3- to 7-day washout: treatment period 1 (n = 24, fexofenadine 120 mg, day 1) and treatment period 2 (fexofenadine 120 mg + osimertinib 80 mg single dose on days 1 and 39 and osimertinib 80 mg once daily from days 4 to 41). Patients could continue osimertinib 80 mg once daily based on investigator's discretion in the continued access phase. Fexofenadine area under the plasma concentration–time curve and maximum concentration increased by 56% (90% confidence interval [CI], 35.4–78.6) and 76% (90%CI, 49.3–108.3) following coadministration with osimertinib single dose, and by 27% (90%CI, 11.2–45.8) and 25% (90%CI, 5.6–48.1) when given with osimertinib at steady state, respectively. Following osimertinib coadministration, median fexofenadine time to maximum concentration increased by approximately 30 minutes compared with time to maximum concentration following fexofenadine alone. No new osimertinib safety findings were observed. The increase in fexofenadine exposure following osimertinib coadministration shows osimertinib as a weak P-glycoprotein inhibitor.

Original languageEnglish
Pages (from-to)1099-1109
Number of pages11
JournalJournal of Clinical Pharmacology
Volume59
Issue number8
DOIs
StatePublished - 1 Aug 2019

Fingerprint

fexofenadine
Epidermal Growth Factor Receptor
Non-Small Cell Lung Carcinoma
Pharmacokinetics
Protein-Tyrosine Kinases
Confidence Intervals
P-Glycoprotein
Exons
osimertinib

Keywords

  • P-glycoprotein
  • drug interaction
  • fexofenadine
  • non–small cell lung cancer
  • osimertinib

Cite this

Calvo, Emiliano ; Lee, Jong-Seok ; Kim, Sang We ; Moreno, Victor ; deCastro Carpeno, Javier ; Weilert, Doris ; Laus, Gianluca ; Mann, Helen ; Vishwanathan, Karthick. / Modulation of Fexofenadine Pharmacokinetics by Osimertinib in Patients With Advanced EGFR-Mutated Non–Small Cell Lung Cancer. In: Journal of Clinical Pharmacology. 2019 ; Vol. 59, No. 8. pp. 1099-1109.
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title = "Modulation of Fexofenadine Pharmacokinetics by Osimertinib in Patients With Advanced EGFR-Mutated Non–Small Cell Lung Cancer",
abstract = "Osimertinib is a potent, third-generation, irreversible, central nervous system active epidermal growth factor receptor (EGFR)–tyrosine kinase inhibitor (TKI) that selectively inhibits EGFR-TKI sensitizing and EGFR T790M resistance mutations. It is approved for first-line treatment of patients with advanced non–small cell lung cancer (NSCLC) whose tumors have EGFR exon 19 deletions or exon 21 L858R mutations, and for patients with T790M-positive advanced NSCLC whose disease has progressed on or after EGFR-TKI therapy. This study investigated the pharmacokinetics (PK) of fexofenadine (P-glycoprotein substrate) following single- and multiple-dose osimertinib in patients with advanced NSCLC who have progressed on prior EGFR-TKI therapy. This open-label, phase 1 study (NCT02908750) comprised the PK phase and continued access phase. The former comprised 2 distinct periods with a 3- to 7-day washout: treatment period 1 (n = 24, fexofenadine 120 mg, day 1) and treatment period 2 (fexofenadine 120 mg + osimertinib 80 mg single dose on days 1 and 39 and osimertinib 80 mg once daily from days 4 to 41). Patients could continue osimertinib 80 mg once daily based on investigator's discretion in the continued access phase. Fexofenadine area under the plasma concentration–time curve and maximum concentration increased by 56{\%} (90{\%} confidence interval [CI], 35.4–78.6) and 76{\%} (90{\%}CI, 49.3–108.3) following coadministration with osimertinib single dose, and by 27{\%} (90{\%}CI, 11.2–45.8) and 25{\%} (90{\%}CI, 5.6–48.1) when given with osimertinib at steady state, respectively. Following osimertinib coadministration, median fexofenadine time to maximum concentration increased by approximately 30 minutes compared with time to maximum concentration following fexofenadine alone. No new osimertinib safety findings were observed. The increase in fexofenadine exposure following osimertinib coadministration shows osimertinib as a weak P-glycoprotein inhibitor.",
keywords = "P-glycoprotein, drug interaction, fexofenadine, non–small cell lung cancer, osimertinib",
author = "Emiliano Calvo and Jong-Seok Lee and Kim, {Sang We} and Victor Moreno and {deCastro Carpeno}, Javier and Doris Weilert and Gianluca Laus and Helen Mann and Karthick Vishwanathan",
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Calvo, E, Lee, J-S, Kim, SW, Moreno, V, deCastro Carpeno, J, Weilert, D, Laus, G, Mann, H & Vishwanathan, K 2019, 'Modulation of Fexofenadine Pharmacokinetics by Osimertinib in Patients With Advanced EGFR-Mutated Non–Small Cell Lung Cancer', Journal of Clinical Pharmacology, vol. 59, no. 8, pp. 1099-1109. https://doi.org/10.1002/jcph.1403

Modulation of Fexofenadine Pharmacokinetics by Osimertinib in Patients With Advanced EGFR-Mutated Non–Small Cell Lung Cancer. / Calvo, Emiliano; Lee, Jong-Seok; Kim, Sang We; Moreno, Victor; deCastro Carpeno, Javier; Weilert, Doris; Laus, Gianluca; Mann, Helen; Vishwanathan, Karthick.

In: Journal of Clinical Pharmacology, Vol. 59, No. 8, 01.08.2019, p. 1099-1109.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Modulation of Fexofenadine Pharmacokinetics by Osimertinib in Patients With Advanced EGFR-Mutated Non–Small Cell Lung Cancer

AU - Calvo, Emiliano

AU - Lee, Jong-Seok

AU - Kim, Sang We

AU - Moreno, Victor

AU - deCastro Carpeno, Javier

AU - Weilert, Doris

AU - Laus, Gianluca

AU - Mann, Helen

AU - Vishwanathan, Karthick

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N2 - Osimertinib is a potent, third-generation, irreversible, central nervous system active epidermal growth factor receptor (EGFR)–tyrosine kinase inhibitor (TKI) that selectively inhibits EGFR-TKI sensitizing and EGFR T790M resistance mutations. It is approved for first-line treatment of patients with advanced non–small cell lung cancer (NSCLC) whose tumors have EGFR exon 19 deletions or exon 21 L858R mutations, and for patients with T790M-positive advanced NSCLC whose disease has progressed on or after EGFR-TKI therapy. This study investigated the pharmacokinetics (PK) of fexofenadine (P-glycoprotein substrate) following single- and multiple-dose osimertinib in patients with advanced NSCLC who have progressed on prior EGFR-TKI therapy. This open-label, phase 1 study (NCT02908750) comprised the PK phase and continued access phase. The former comprised 2 distinct periods with a 3- to 7-day washout: treatment period 1 (n = 24, fexofenadine 120 mg, day 1) and treatment period 2 (fexofenadine 120 mg + osimertinib 80 mg single dose on days 1 and 39 and osimertinib 80 mg once daily from days 4 to 41). Patients could continue osimertinib 80 mg once daily based on investigator's discretion in the continued access phase. Fexofenadine area under the plasma concentration–time curve and maximum concentration increased by 56% (90% confidence interval [CI], 35.4–78.6) and 76% (90%CI, 49.3–108.3) following coadministration with osimertinib single dose, and by 27% (90%CI, 11.2–45.8) and 25% (90%CI, 5.6–48.1) when given with osimertinib at steady state, respectively. Following osimertinib coadministration, median fexofenadine time to maximum concentration increased by approximately 30 minutes compared with time to maximum concentration following fexofenadine alone. No new osimertinib safety findings were observed. The increase in fexofenadine exposure following osimertinib coadministration shows osimertinib as a weak P-glycoprotein inhibitor.

AB - Osimertinib is a potent, third-generation, irreversible, central nervous system active epidermal growth factor receptor (EGFR)–tyrosine kinase inhibitor (TKI) that selectively inhibits EGFR-TKI sensitizing and EGFR T790M resistance mutations. It is approved for first-line treatment of patients with advanced non–small cell lung cancer (NSCLC) whose tumors have EGFR exon 19 deletions or exon 21 L858R mutations, and for patients with T790M-positive advanced NSCLC whose disease has progressed on or after EGFR-TKI therapy. This study investigated the pharmacokinetics (PK) of fexofenadine (P-glycoprotein substrate) following single- and multiple-dose osimertinib in patients with advanced NSCLC who have progressed on prior EGFR-TKI therapy. This open-label, phase 1 study (NCT02908750) comprised the PK phase and continued access phase. The former comprised 2 distinct periods with a 3- to 7-day washout: treatment period 1 (n = 24, fexofenadine 120 mg, day 1) and treatment period 2 (fexofenadine 120 mg + osimertinib 80 mg single dose on days 1 and 39 and osimertinib 80 mg once daily from days 4 to 41). Patients could continue osimertinib 80 mg once daily based on investigator's discretion in the continued access phase. Fexofenadine area under the plasma concentration–time curve and maximum concentration increased by 56% (90% confidence interval [CI], 35.4–78.6) and 76% (90%CI, 49.3–108.3) following coadministration with osimertinib single dose, and by 27% (90%CI, 11.2–45.8) and 25% (90%CI, 5.6–48.1) when given with osimertinib at steady state, respectively. Following osimertinib coadministration, median fexofenadine time to maximum concentration increased by approximately 30 minutes compared with time to maximum concentration following fexofenadine alone. No new osimertinib safety findings were observed. The increase in fexofenadine exposure following osimertinib coadministration shows osimertinib as a weak P-glycoprotein inhibitor.

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