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A pharmacokinetic and safety study of single dose intravenous combretastatin A4 phosphate in Chinese patients with refractory solid tumours
Author(s) -
He Xuexin,
Li Su,
Huang He,
Li Zhiming,
Chen Likun,
Ye Sheng,
Huang Jiajia,
Zhan Jing,
Lin Tongyu
Publication year - 2011
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/j.1365-2125.2011.03928.x
Subject(s) - medicine , pharmacokinetics , adverse effect , refractory (planetary science) , pharmacology , toxicity , gastroenterology , physics , astrobiology
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Three pharmacokinetic and safety studies for combretastatin A4 phosphate (CA4P), the first vascular disrupting agent, have been conducted in Western countries. • The maximum tolerated dose (MTD) was approximately 60–68 mg m −2 . • CA4P‐related grade 3 or 4 adverse events were tumour pain, dyspnoea, hypoxia and syncope in patients who received doses ≥50 mg m −2 . WHAT THIS STUDY ADDS • This is the first pharmacokinetic and safety study conducted in East Asian patients. • There appeared to be a trend that Chinese patients metabolized CA4 more rapidly and had greater neurotoxicity than patients in Western countries. • We observed favourable clinical responses in patients with refractory nasopharyngeal carcinoma. • CA4P‐induced acute renal failure was seen in one dehydrated Chinese patient. AIMS This trial was conducted to evaluate the safety and pharmacokinetics of combretastatin A4 phosphate (CA4P) given intravenously as a single dose to Chinese patients with refractory solid tumours. METHODS Twenty‐five patients were treated with single doses of CA4P according to a dose escalation scheme: 5, 10, 20, 33, 50, 65 and 85 mg m −2 infused intravenously over 30 min. RESULTS CA4P was generally well tolerated at ≤65 mg m −2 . Transient, moderate increases in the heart rate‐corrected QT interval occurred at all doses. CA4P produced a transient dose‐dependent increase in neural and gastrointestinal toxicities. Acute renal failure occurred in one dehydrated patient who had also taken paracetamol. There were seven episodes of dose‐limiting toxicity at doses ≥65 mg m −2 , including two episodes of reversible ataxia at 85 mg m −2 . For CA4P, at 50 mg m −2 , mean (SD) peak plasma concentration ( C max ) was 0.99 (0.33) µ m , area under the curve from time zero to time of last quantifiable concentration (AUC(0, t )) was 1.42 (0.30) µ m h and terminal elimination half‐life ( t 1/2 ) was 1.81 (0.61) h. At 65 mg m −2 , C max was 1.73 (0.62) µ m , AUC(0, t ) was 3.19 (1.47) µ m h and t 1/2 was 1.90 (0.61) h. One patient with nasopharyngeal carcinoma had an obvious clinical response with central necrosis in the metastatic lung mass. CONCLUSION Doses ≤65 mg m −2 given as 30 min infusions define the maximum tolerated dose in East Asian patients, and doses in the range of 50–65 mg m −2 have been selected for further studies.