TITLE:
Population Pharmacokinetics of UCN-01
AUTHORS:
Charlene A. Baksh, Martin J. Edelman, Edward A. Sausville, William D. Figg, Hao Zhu, Kenneth S. Bauer
KEYWORDS:
Pharmacokinetics; UCN-01; 7-Hydroxystaurosporine; Pharmacometrics; Population Modeling; Phase I; Clinical Pharmacology
JOURNAL NAME:
Journal of Cancer Therapy,
Vol.4 No.10,
December
25,
2013
ABSTRACT: UCN-01 (7-Hydroxystaurosporine) is an
investigational anticancer agent that is currently being evaluated as targeted
therapy in phase II clinical studies. The aims of this work were to describe
the population pharmacokinetics of UCN-01 in patients with advanced solid
tumors, and to identify covariates in patients with advanced solid tumors that
affected the pharmacokinetic parameters of UCN-01. The utility of performing
this research is to provide optimization of treatment and individualized dose
therapy for minimization of toxicity. So, in addition to elucidating the
population pharmacokinetic parameter estimates from a Phase I trial where
UCN-01 was given in combination with carboplatin in patients with advanced
solid tumors, and a trial where the drug was given alone as a 72-hour infusion
in the same type of population, a covariate analysis was performed in order to
identify pharmacokinetic determinants of UCN-01. Using NONMEM to perform
nonlinear mixed-effects modeling, a linear two-compartment model was found to
provide the best fit for UCN-01 data. A meta-analysis was performed, which
included pooled 3-hour and 72-hour infusion data, and provided population
pharmacokinetic estimates for CL (0.0157 L/hr [6.1%RSE]), V1 (2.51 L [10.0% RSE]), Q (4.05 L/hr [14.3% RSE]), and V2 (8.39 L [6.6% RSE]). Inter-individual variability
was found for each of the main pharmacokinetic parameters to be ETACL (44.9% [20.8% RSE]), ETAV1 (43.9% [39.8% RSE]), ETAQ (6.09% [62.5% RSE]), and ETAV2 (4.17% [30.0% RSE]). Body surface area was found to
be a statistically-significant variable from one of the individual study
analyses (3-hour infusion). Population PK modeling has contributed to a better
understanding of the clinical pharmacology of UCN-01. Dose individualization
may improve treatment with UCN-01. Further clinical development may be
supported by optimization of combination chemotherapy.