Randomized study of individualized pharmacokinetically‐guided dosing of paclitaxel compared with body‐surface area dosing in Chinese patients with advanced non‐small cell lung cancer

• Published in: British journal of clinical pharmacology 2019-10, Vol.85 (10), p.2292-2301
• Main Authors: Zhang, Jie, Zhou, Fei, Qi, Huiwei, Ni, Huijuan, Hu, Qiong, Zhou, Caicun, Li, Yunying, Baburina, Irina, Courtney, Jodi, Salamone, Salvatore J.
• Format: Article
• Language: English
• Subjects: Aged; Antineoplastic Combined Chemotherapy Protocols - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - pharmacokinetics; Asian Continental Ancestry Group; Body Surface Area; Carboplatin - administration & dosage; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - pathology; Dose-Response Relationship, Drug; Female; Hematologic Diseases - chemically induced; Hematologic Diseases - epidemiology; Humans; Lung Neoplasms - drug therapy; Lung Neoplasms - pathology; Male; Middle Aged; Neoplasm Staging; neutropenia; non‐small cell lung cancer; Original; paclitaxel; Paclitaxel - administration & dosage; Paclitaxel - pharmacokinetics; pharmacokinetics; Precision Medicine; Progression-Free Survival; Prospective Studies; Survival Rate; therapeutic drug monitoring
• ISSN: 0306-5251; 1365-2125
• DOI: 10.1111/bcp.13982

Aims This prospective, randomized study was initiated to assess the impact of pharmacokinetically (PK)‐guided paclitaxel (PTX) dosing on toxicity and efficacy compared with body‐surface area (BSA)‐based dosing in Chinese non‐small cell lung cancer patients. Methods A total of 319 stage IIIB/IV non‐small cell lung cancer patients receiving first‐line chemotherapy were enrolled. Patients were randomized to receive 3‐weekly carboplatin plus PTX at a starting dose of 175 mg/m2 with subsequent PTX dosing based on either BSA or PK‐guided dosing targeting time above a PTX plasma concentration of 0.05 μmol/L (PTXTc > 0.05) between 26 and 31 hours. The primary safety endpoint was grade 4 haematological toxicity. The secondary endpoints were neuropathy, objective response rate, progression‐free survival and overall survival. Results In total, 275 (86%) patients completed ≥2 cycles of chemotherapy (140 in BSA arm and 135 in PK arm). In cycle 1, with the same PTX dose, average PTXTc > 0.05 was 37 hours (range = 18–57 hours). Over cycles 2–4, patients in the PK arm had significantly lower average PTX doses and exposure compared with the BSA arm (128 vs 161 mg/m2, P < .0001 and 29 vs 35 hours, P < .0001). PK‐guided dosing significantly reduced the cumulative incidence of grade 4 haematological toxicity (15% vs 24%, P = .004), grade 4 neutropenia (15% vs 23%, P = .009) and grade ≥ 2 neuropathy (8% vs 21%, P = .005). Objective response rate (32% vs 26%, P = .28) and overall survival (21.0 vs 24.0 months, P = .815) were similar in PK and BSA arms. Progression‐free survival was slightly improved in PK arm (4.67 vs 4.17 months, P = .026). Conclusion PK‐guided PTX dosing significantly reduced grade 4 haematological toxicities and grade ≥ 2 neuropathy without an adverse impact on clinical outcomes.