Pharmacokinetic and dose‐finding study of osimertinib in patients with impaired renal function and low body weight

• Published in: Cancer science Vol. 114; no. 5; pp. 2087 - 2097
• Main Authors: Fujiwara, Yutaka, Makihara, Reiko, Hase, Tetsunari, Hashimoto, Naozumi, Naito, Tomoyuki, Tsubata, Yukari, Okuno, Takae, Takahashi, Toshiaki, Kobayashi, Haruki, Shinno, Yuki, Zenke, Yoshitaka, Ikeda, Takaya, Hosomi, Yukio, Watanabe, Kageaki, Kitazono, Satoru, Sakiyama, Naomi, Makino, Yoshinori, Yamamoto, Noboru
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.05.2023; John Wiley and Sons Inc
• Subjects: Aniline Compounds - adverse effects; Body Weight; Carcinoma, Non-Small-Cell Lung - drug therapy; Chemotherapy; Chronic obstructive pulmonary disease; Creatinine; Dialysis; Diarrhea; Epidermal growth factor; Epidermal growth factor receptors; epidermal growth factor receptor–mutated non–small cell lung carcinoma; Females; Glomerular filtration rate; Humans; Kidney - physiology; Leukocytes; low body weight; Lung cancer; Lung diseases; Lung Neoplasms - drug therapy; Metabolites; Mutation; Neutrophils; Non-small cell lung carcinoma; Oral administration; Original; ORIGINAL ARTICLES; osimertinib; Patients; Pharmacokinetics; Protein Kinase Inhibitors - adverse effects; Renal function; renal impairment; Renal Insufficiency; Safety; Small cell lung carcinoma; Toxicity; pharmacokinetics; epidermal growth factor receptor-mutated non-small cell lung carcinoma; low body weight; osimertinib; renal impairment
• ISSN: 1347-9032; 1349-7006
• DOI: 10.1111/cas.15736

The safety of osimertinib is limited in patients with severe or moderate renal impairment, or low body weight. This study aimed to investigate the safety, pharmacokinetics (PK) and recommended dose (RD) of osimertinib in patients with epidermal growth factor receptor (EGFR)‐mutated non–small cell lung cancer (NSCLC) with impaired renal function and low body weight. Thirty‐one eligible patients were enrolled and allocated into four cohorts: A, normal renal function (estimated glomerular filtration rate [eGFR] ≥ 50 mL/min/1.73 m2) and normal body weight (≥45 kg); B, moderate renal impairment (eGFR = 30‐50 mL/min/1.73 m2); C, low body weight (<45 kg); and D, severe renal impairment (eGFR <30 mL/min/1.73 m2 or undergoing dialysis). PK parameters and safety were evaluated with a starting dose of 80 mg osimertinib administered orally once daily in cohorts A, B, and C and 40 mg once daily in cohort D. The PK parameters in cohorts A, B, and C were found to be similar. No dose‐limiting toxicity was observed, and the RD was determined to be 80 mg once daily in patients with moderate renal function and low body weight. Four serious adverse events, acneiform rash, diarrhea, QTc prolongation, and interstitial lung disease, were noted. Although the PK parameters of osimertinib were similar across all cohorts, toxicity occurred more frequently in patients with impaired renal function and low body weight. Clinicians should prescribe osimertinib with caution in NSCLC patients with impaired renal function and low body weight. This study aimed to investigate the safety, pharmacokinetics, and recommended dose of osimertinib in patients with EGFR‐mutated NSCLC with impaired renal function and low body weight. This study demonstrated that the PK parameters of osimertinib were similar across all cohorts but toxicity occurred more frequently in patients with impaired renal function and low body weight.