Pharmacokinetics of paclitaxel and carboplatin after orthotopic liver transplantation

Abstract

2095 Background: Paclitaxel is one of the most widely used chemotherapy agents and its metabolism and excretion takes place mainly through hepatic extraction and billiary secretion. Liver transplantation has become a frequent therapy for some hepatic diseases, and some patients become long term survivors after transplant. Those patients require immunosupresive therapy, and are at increased risk to develop tumors. Despite these facts, nothing is known about metabolism and pharmacokinetics of Paclitaxel in recipients of transplanted livers, since no studies have ever been reported. Methods: A 65 year old, male patient that received a transplanted liver in 1995 for ethylic cirrhosis developed metastatic non-small cell lung cancer in 2003. Chemotherapy with Paclitaxel 175 mg/ m2 and Carboplatin AUC =6 was offered, but due to lack of knowledge of Paclitaxel metabolism by transplanted livers, pharmacokinetic studies were done in order to make appropriate dose modifications if required. Blood levels of Paclitaxel and Carboplatin were assessed at different time intervals following drug infusion. Drug concentrations were determined by a validated reverse-phase HPLC method with ultraviolet detection. Pharmacokinetic parameters were estimated by noncompartimental analysis with WinNonlin v.1.5. Results: During the first cycle, pharmacokinetic parameters of Paclitaxel were: AUC 8,63 μ mol x h/ L; Cmax = 2,46 μ mol/ L; CL = 37,1 L/ h.. Similar results were obtained in subsequent cycles. These values are within the expected range in non-transplanted patients with normal liver function (Huizing MT, et al. J Clin Oncol 1993) and therefore can be considered normal. Carboplatin AUC during the first cycle was 7,67mg h/L, reflecting the well-known margin of error for AUC calculated by clinical equations. Conclusions: Recipients of normally functioning transplanted livers can adequately metabolize Paclitaxel and achieve normal plasmatic levels of the drug. Pharmacokinetic monitoring allows treatment with full dose Paclitaxel and Carboplatin to liver transplanted patients if they develop tumors in which these drugs are active. No significant financial relationships to disclose.