ORIGINAL ARTICLE Population pharmacokinetics of PM00104 (Zalypsis Ò ) in cancer patients Carlos Pe´rez-Ruixo • Bele´n Valenzuela • Carlos Ferna´ndez Teruel • Mario Gonza´lez-Sales • Bernardo Miguel-Lillo • Arturo Soto-Matos • Juan Jose´ Pe´rez-Ruixo Received: 11 January 2011 / Accepted: 28 March 2011 / Published online: 18 May 2011 Ó Springer-Verlag 2011 Abstract Objective The aim of this study was to characterize the population pharmacokinetics of PM00104 (Zalypsis Ò ) in cancer patients. Methods A total of 135 patients included in four phase I clinical trials who receive intravenous PM00104 at doses ranging from 53 to 5,000 lg/m 2 and administered as 1-, 3-, or 24-h infusion every 3 weeks or as 1-h infusion on days 1, 8, and 15 of a 28-day cycle, or 1-h infusion daily during 5 consecutive days every 3 weeks were included in the anal- ysis. Pharmacokinetic data were analyzed with non-linear mixed effect model using NONMEM VI software. The effect of selected patient covariates on PM00104 pharmacokinetics was investigated. Model evaluation was performed using predictive checks and non-parametric bootstrap. Results An open four-compartment catenary linear model with first-order elimination was developed to best describe the data. Plasma clearance and its between-subject vari- ability was 43.7 L/h (34%). Volume of distribution at steady state was 822 L (117%). Within the range of covariates studied, age, sex, body size variables, aspartate aminotransferase, alanine aminotransferase, alkaline phos- phatase, total bilirubin, lactate dehydrogenase, creatinine clearance, albumin, total protein, hemoglobin, performance status, liver metastases, dose-limiting toxicity, and stable disease for 3 months were not statistically related to PM00104 pharmacokinetic parameters. Bootstrap and pos- terior predictive check evidenced the model was deemed appropriate to describe the time course of PM00104 plasma concentrations in cancer patients. Conclusions The integration of phase I pharmacokinetic data demonstrated PM00104 linear elimination from plasma, dose proportionality up to 5,000 lg/m 2 , and time- independent pharmacokinetics. No clinically relevant covariates were identified as predictors of PM00104 pharmacokinetics. Keywords Cancer  PM00104  Phase I  Clinical trial  Population pharmacokinetics  NONMEM Introduction PM00104 (Zalypsis Ò ) is a new synthetic cytotoxic agent related to jorumycins [1]. Although the exact mechanism of action of PM00104 has not been completely elucidated, preliminary insights suggest PM00104 exhibits effects on C. Pe´rez-Ruixo (&)  M. Gonza´lez-Sales Consulting Projects for Research, Picayo, 3 Puzol, 46530 Valencia, Spain e-mail: carlos@cpr-projects.com B. Valenzuela Pharmaceutical Sciences Department, University Miguel Hernandez, Alicante, Spain Present Address: B. Valenzuela Platform of Oncology, USP Hospital San Jaime, Torrevieja, Alicante, Spain C. Ferna´ndez Teruel  B. Miguel-Lillo  A. Soto-Matos Clinical Pharmacology Department, Pharma Mar SA, Colmenar Viejo, Madrid, Spain J. J. Pe´rez-Ruixo Pharmaceutical Sciences Department, University Miguel Hernandez, Alicante, Spain Present Address: J. J. Pe´rez-Ruixo Pharmacokinetics and Drug Metabolism, AMGEN, Valencia, Spain 123 Cancer Chemother Pharmacol (2012) 69:15–24 DOI 10.1007/s00280-011-1644-6