| 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 thesis 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. These aims were based on the hypothesis that the pharmacokinetic parameters of UCN-01 in patients with advanced solid tumors are influenced by measurable covariates. 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]), Vc (2.51 L [10.0 %RSE]), Q (4.05 L/hr [14.3 %RSE]), and Vp (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]), ETAVc (43.9% [39.8 %RSE]), ETA Q (6.09% [62.5 %RSE]), and ETAVp (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. By building on the new knowledge gained of UCN-01 pharmacokinetics, further clinical development may be supported by optimization of usage of UCN-01 in combination chemotherapy. |
