OBJECTIVE: UCN-01 (7-hydroxystaurosporine) is a small molecule cyclin-dependent kinase modulator currently under clinical development as an anticancer agent. In vitro studies have demonstrated that UCN-01 is strongly bound to the acute-phase reactant alpha (1)-acid glycoprotein (AAG). Here, we examined the role of protein binding as a determinant of the pharmacokinetic behavior of UCN-01 in patients. EXPERIMENTAL DESIGN: Pharmacokinetic data were obtained from a group of 41 patients with cancer receiving UCN-01 as a 72-hour i.v. infusion (dose, 3.6 to 53 mg/m(2)/day). RESULTS: Over the tested dose range, total drug clearance was distinctly nonlinear (P = 0.0076) and increased exponentially from 4.33 mL/hour (at 3.6 mg/m(2)/day) to 24.1 mL/hour (at 54 mg/m(2)/day). As individual values for AAG increased, values for clearance decreased in a linear fashion (R(2) = 0.264; P = 0.0008), although the relationship was shallow, and the data showed considerable scatter. Interestingly, no nonlinearity in the unbound concentration (P = 0.083) or fraction at the peak plasma concentration of UCN-01 was apparent (P = 0.744). CONCLUSION: The results suggest the following: (1) that extensive binding to AAG may explain, in part, the unique pharmacokinetic profile of UCN-01 described previously with a small volume of distribution and slow systemic clearance, and (2) that measurement of total UCN-01 concentrations in plasma is a poor surrogate for that of the pharmacologically active fraction unbound drug.
OBJECTIVE:UCN-01 (7-hydroxystaurosporine) is a small molecule cyclin-dependent kinase modulator currently under clinical development as an anticancer agent. In vitro studies have demonstrated that UCN-01 is strongly bound to the acute-phase reactant alpha (1)-acid glycoprotein (AAG). Here, we examined the role of protein binding as a determinant of the pharmacokinetic behavior of UCN-01 in patients. EXPERIMENTAL DESIGN: Pharmacokinetic data were obtained from a group of 41 patients with cancer receiving UCN-01 as a 72-hour i.v. infusion (dose, 3.6 to 53 mg/m(2)/day). RESULTS: Over the tested dose range, total drug clearance was distinctly nonlinear (P = 0.0076) and increased exponentially from 4.33 mL/hour (at 3.6 mg/m(2)/day) to 24.1 mL/hour (at 54 mg/m(2)/day). As individual values for AAG increased, values for clearance decreased in a linear fashion (R(2) = 0.264; P = 0.0008), although the relationship was shallow, and the data showed considerable scatter. Interestingly, no nonlinearity in the unbound concentration (P = 0.083) or fraction at the peak plasma concentration of UCN-01 was apparent (P = 0.744). CONCLUSION: The results suggest the following: (1) that extensive binding to AAG may explain, in part, the unique pharmacokinetic profile of UCN-01 described previously with a small volume of distribution and slow systemic clearance, and (2) that measurement of total UCN-01 concentrations in plasma is a poor surrogate for that of the pharmacologically active fraction unbound drug.
Authors: William Wargin; Helmut Thomas; Lilian Clohs; Carl St-Louis; Niels Ejskjaer; Maria Gutierrez; Laura Shaughnessy; Gordana Kosutic Journal: Clin Drug Investig Date: 2009 Impact factor: 2.859
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Authors: Ellen K Kick; Brett B Busch; Richard Martin; William C Stevens; Venkataiah Bollu; Yinong Xie; Brant C Boren; Michael C Nyman; Max H Nanao; Lam Nguyen; Artur Plonowski; Ira G Schulman; Grace Yan; Huiping Zhang; Xiaoping Hou; Meriah N Valente; Rangaraj Narayanan; Kamelia Behnia; A David Rodrigues; Barry Brock; James Smalley; Glenn H Cantor; John Lupisella; Paul Sleph; Denise Grimm; Jacek Ostrowski; Ruth R Wexler; Todd Kirchgessner; Raju Mohan Journal: ACS Med Chem Lett Date: 2016-10-23 Impact factor: 4.345