{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T04:44:19Z","timestamp":1768538659226,"version":"3.49.0"},"reference-count":31,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2011,5,12]],"date-time":"2011-05-12T00:00:00Z","timestamp":1305158400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brit J Clinical Pharma"],"published-print":{"date-parts":[[2011,6]]},"abstract":"<jats:p> <jats:bold>WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT<\/jats:bold> <\/jats:p><jats:p>\u2022\u2003Three pharmacokinetic and safety studies for combretastatin A4 phosphate (CA4P), the first vascular disrupting agent, have been conducted in Western countries.<\/jats:p><jats:p>\u2022\u2003The maximum tolerated dose (MTD) was approximately 60\u201368\u2003mg\u2003m<jats:sup>\u22122<\/jats:sup>.<\/jats:p><jats:p>\u2022\u2003CA4P\u2010related grade 3 or 4 adverse events were tumour pain, dyspnoea, hypoxia and syncope in patients who received doses \u226550\u2003mg\u2003m<jats:sup>\u22122<\/jats:sup>.<\/jats:p><jats:p> <jats:bold>WHAT THIS STUDY ADDS<\/jats:bold> <\/jats:p><jats:p>\u2022\u2003This is the first pharmacokinetic and safety study conducted in East Asian patients.<\/jats:p><jats:p>\u2022\u2003There appeared to be a trend that Chinese patients metabolized CA4 more rapidly and had greater neurotoxicity than patients in Western countries.<\/jats:p><jats:p>\u2022\u2003We observed favourable clinical responses in patients with refractory nasopharyngeal carcinoma.<\/jats:p><jats:p>\u2022\u2003CA4P\u2010induced acute renal failure was seen in one dehydrated Chinese patient.<\/jats:p><jats:p><jats:bold>AIMS<\/jats:bold> 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.<\/jats:p><jats:p><jats:bold>METHODS<\/jats:bold> Twenty\u2010five patients were treated with single doses of CA4P according to a dose escalation scheme: 5, 10, 20, 33, 50, 65 and 85\u2003mg\u2003m<jats:sup>\u22122<\/jats:sup> infused intravenously over 30\u2003min.<\/jats:p><jats:p><jats:bold>RESULTS<\/jats:bold> CA4P was generally well tolerated at \u226465\u2003mg\u2003m<jats:sup>\u22122<\/jats:sup>. Transient, moderate increases in the heart rate\u2010corrected QT interval occurred at all doses. CA4P produced a transient dose\u2010dependent 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\u2010limiting toxicity at doses \u226565\u2003mg\u2003m<jats:sup>\u22122<\/jats:sup>, including two episodes of reversible ataxia at 85\u2003mg\u2003m<jats:sup>\u22122<\/jats:sup>. For CA4P, at 50\u2003mg\u2003m<jats:sup>\u22122<\/jats:sup>, mean (SD) peak plasma concentration (<jats:italic>C<\/jats:italic><jats:sub>max<\/jats:sub>) was 0.99 (0.33) \u00b5<jats:sc>m<\/jats:sc>, area under the curve from time zero to time of last quantifiable concentration (AUC(0,<jats:italic>t<\/jats:italic>)) was 1.42 (0.30) \u00b5<jats:sc>m<\/jats:sc>\u2003h and terminal elimination half\u2010life (<jats:italic>t<\/jats:italic><jats:sub>1\/2<\/jats:sub>) was 1.81 (0.61) h. At 65\u2003mg\u2003m<jats:sup>\u22122<\/jats:sup>, <jats:italic>C<\/jats:italic><jats:sub>max<\/jats:sub> was 1.73 (0.62) \u00b5<jats:sc>m<\/jats:sc>, AUC(0,<jats:italic>t<\/jats:italic>) was 3.19 (1.47) \u00b5<jats:sc>m<\/jats:sc>\u2003h and <jats:italic>t<\/jats:italic><jats:sub>1\/2<\/jats:sub> was 1.90 (0.61) h. One patient with nasopharyngeal carcinoma had an obvious clinical response with central necrosis in the metastatic lung mass.<\/jats:p><jats:p><jats:bold>CONCLUSION<\/jats:bold> Doses \u226465\u2003mg\u2003m<jats:sup>\u22122<\/jats:sup> given as 30\u2003min infusions define the maximum tolerated dose in East Asian patients, and doses in the range of 50\u201365\u2003mg\u2003m<jats:sup>\u22122<\/jats:sup> have been selected for further studies.<\/jats:p>","DOI":"10.1111\/j.1365-2125.2011.03928.x","type":"journal-article","created":{"date-parts":[[2011,1,29]],"date-time":"2011-01-29T08:42:26Z","timestamp":1296290546000},"page":"860-870","source":"Crossref","is-referenced-by-count":31,"title":["A pharmacokinetic and safety study of single dose intravenous combretastatin A4 phosphate in Chinese patients with refractory solid 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