Population Pharmacokinetics of UCN-01

Charlene A. Baksh, Martin J. Edelman, Edward A. Sausville, William D. Figg, Hao Zhu, Kenneth S. Bauer

Clinical Pharmacology Research Core, National Cancer Institute, National Institutes of Health, Bethesda, USA.
Department of Pharmacy Practice and Science, University of Maryland Baltimore, School of Pharmacy, Baltimore, USA.
Office of Clinical Pharmacology, Food and Drug Administration, Silver Spring, USA.
University of Maryland Greenbaum Cancer Center, Baltimore, USA.

DOI: 10.4236/jct.2013.410183                

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.

Keywords

Pharmacokinetics; UCN-01; 7-Hydroxystaurosporine; Pharmacometrics; Population Modeling; Phase I; Clinical Pharmacology

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1]	E. Fuse, T. Kuwabara, A. Sparreboom, E. A. Sausville and W. D. Figg, “Review of UCN-01 Development: A Lesson in the Importance of Clinical Pharmacology,” The Journal of Clinical Pharmacology, Vol. 45, No. 4, 2005, pp. 394-403. http://dx.doi.org/10.1177/0091270005274549
[2]	Z. H. Israili and P. G. DaytonHuman, “Alpha-1-Glycoprotein and Its Interactions with Drugs,” Drug Metabolism Reviews, Vol. 33, No. 2, 2001, pp. 161-235. http://dx.doi.org/10.1081/DMR-100104402
[3]	S. L. Beal and L. B. Sheiner, “NONMEM Users Guide Part VII: Conditional Estimation Methods,” 2nd Edition, NONMEM Project Group, San Francisco, 1998.
[4]	M. J. Edelman, K. S. Bauer Jr., S. Wu, R. Smith, S. Bisacia and J. Dancey, “Phase I and Pharmacokinetic Study of 7-Hydroxystaurosporine and Carboplatin in Advanced Solid Tumors,” Clinical Cancer Research, Vol. 13, No., 2007, pp. 2667-2674. http://dx.doi.org/10.1158/1078-0432.CCR-06-1832
[5]	K. S. Bauer, R. M. Lush, M. A. Rudek, C. Shih, E. Sausville, W. D. Figg, “A High-Performance Liquid Chromatography Method Using Ultraviolet and Fluorescence Detection for the Quantitation of UCN-01, 7-Hydroxystaurosporine, from Human Plasma and Saliva,” Biomedical Chromatography, Vol. 14, No. 5, 2000, pp. 338-343. http://dx.doi.org/10.1002/1099-0801(200008)14:5<338::AID-BMC993> 3.0.CO;2-6
[6]	E. A. Sausville, S. G. Arbuck, R. Messmann, et al., “Phase I Trial of 72-Hour Continuous Infusion UCN-01 in Patients with Refractory Neoplasms,” Journal of Clinical Oncology, Vol. 19, 2001, pp. 2319-2333.
[7]	S. Akinaga, K. Gomi, M. Morimoto, T. Tamaoki and M. Okabe, “Antitumor Activity of UCN-01, a Selective Inhibitor of Protein Kinase C, in Murine and Human Tumor Models,” Cancer Research, Vol. 51, No. 18, 1991, pp. 4888-4892.
[8]	R. H. Mathijssen, F. A. de Jong, W. J. Loos, J. M. van der Bol, J. Verweij and A. Sparreboom, “Flat-Fixed Dosing versus Body Surface Area Based Dosing of Anticancer Drugs in Adults: Does it Make a Difference?[See Comment],” Oncologist, Vol. 12, No. 8, 2007, pp. 913-923. http://dx.doi.org/10. 1634/theoncologist.12-8-913