Metabolism of patupilone in patients with advanced solid tumor malignancies.
A phase 1, open-label, non-randomized, single center study was conducted to determine the pharmacokinetics, distribution, metabolism, elimination, and mass balance of patupilone in patients with advanced solid tumors. Five patients with advanced solid tumors received 10 mg/m(2) (1.1 MBq) of (14) C-radiolabeled patupilone at cycle 1 as a 20-minute intravenous infusion every 3 weeks until disease progression. Sequential samples of blood/plasma were taken for 3 weeks and urine and fecal samples were collected for seven days after the first dose of patupilone. Patupilone blood levels decreased rapidly after the infusion. The compound showed a large volume of distribution (Vss: 2242 L). The main radiolabeled component in blood was patupilone itself, accompanied by the lactone hydrolysis products that are unlikely to contribute to the pharmacological effect of patupilone. The blood clearance of patupilone was relatively low at 14 L/h. The administered radioactivity dose was excreted slowly (46 % of dose up to 168 h) but ultimately accounted for 91 % of the dose by extrapolation. The fecal excretion of radioactivity was 2-3 times higher than the urinary excretion consistent with hepato-biliary elimination. Three patients had progressive disease and two patients had stable disease as their best response. Patupilone was generally well tolerated in patients with advanced solid tumors with no newly occurring safety events compared to previous clinical studies. In adult solid tumor patients, intravenous radiolabeled patupilone undergoes extensive metabolism with fecal excretion of radioactive metabolites predominating over renal excretion.
Institute For Drug Development, Cancer Therapy and Research Center at the University of Texas Health Science Center, San Antonio, TX, USA.
Kevin R
KR
Kelly
Markus
M
Zollinger
Frédéric
F
Lozac'h
Eugene
E
Tan
Alain
A
Mita
Felix
F
Waldmeier
Patrick
P
Urban
Suraj
S
Anand
Yanfeng
Y
Wang
Piet
P
Swart
Chris
C
Takimoto
Monica
M
Mita
D000970:Antineoplastic Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use / Q000652:urine; D034261:Epothilones / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use / Q000652:urine; D005243:Feces / Q000737:chemistry; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D050257:Tubulin Modulators / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use / Q000652:urine
D000970:Antineoplastic Agents; D034261:Epothilones; D050257:Tubulin Modulators; C093788:epothilone B