TY - JOUR
T1 - Effects of α1-acid glycoprotein on the clinical pharmacokinetics of 7-hydroxystaurosporine
AU - Sparreboom, Alex
AU - Chen, Huachen
AU - Acharya, Milin R.
AU - Senderowicz, Adrian M.
AU - Messmann, Richard A.
AU - Kuwabara, Takashi
AU - Venzon, David J.
AU - Murgo, Anthony J.
AU - Headlee, Donna
AU - Sausville, Edward A.
AU - Figg, William D.
PY - 2004/10/15
Y1 - 2004/10/15
N2 - 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 α1-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/m2/day) to 24.1 mL/hour (at 54 mg/m2/day). As individual values for AAG increased, values for clearance decreased in a linear fashion (R2 = 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.
AB - 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 α1-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/m2/day) to 24.1 mL/hour (at 54 mg/m2/day). As individual values for AAG increased, values for clearance decreased in a linear fashion (R2 = 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.
UR - http://www.scopus.com/inward/record.url?scp=6044220124&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-04-0805
DO - 10.1158/1078-0432.CCR-04-0805
M3 - Article
C2 - 15501960
AN - SCOPUS:6044220124
SN - 1078-0432
VL - 10
SP - 6840
EP - 6846
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 20
ER -