Cabazitaxel in Patients with Renal Impairment

Madrid—Renal impairment had no clinically meaningful effect on the pharmacokinetic activity of cabazitaxel (Cbz). That was one of the findings of an open-label, multicenter study conducted recently. Study results were presented during a poster session at the EMSO 2014 Congress in Madrid. The poster was titled Pharmacokinetic Activity of Cabazitaxel in Patients with Renal Impairment.

The study was designed to assess the pharmacokinetic activity in patients with advanced solid tumors and normal or impaired renal function.

Patients in cohort A had normal control with creatinine clearance (CrCL] of >80 mL/min/1.73 m2, patients in cohort B had moderate renal impairment with CrCL 30-<50 mL/min/1.73 m2, and patients in cohort C had severe renal impairment with CrCl <30 mL/min/1.73 m2. Patients in cohorts A and B received Cbz at a dose of 25 mg/m2 every 3 weeks. For patients in cohort C, the dose was 20 mg/m2, which could be increased to 25 mg/m2.

Cbz pharmacokinetic activity was the primary end point (clearance normalized to body surface area [CL/BSA]; area under the curve normalized to dose [AUC/dose]). Non-compartmental analysis and individual modeling using a 3-compartment open model with first-order elimination were utilized to calculate pharmacokinetic parameters.

Log PK parameters and Cbz unbound fraction (FU) were analyzed using linear regression and linear mixed models, respectively. Log CrCl corresponding to the mean of each cohort’s CrCl interval was used to determine geometric mean (GM) estimates (moderate and severs renal impairment: 40 and 15 mL/min/1.73 m2, respectively). GM ratios (GMRs) were expressed versus control (90 mL/min/1.73 m2).

Twenty-five patients received a median of 3 Cbz cycles (range 1-20: cohort A, 5 [2-13]; cohort B, 3 [1-15]; cohort C, 5 [1-20], and 24 were eligible for PK analysis (8/cohort). For patients with moderate and severe renal impairment compared with controls, geometric mean ratio estimates were: CL/BSA 0.95 (90% confidence interval [CI], 0.80-1.13) and 0.89 (90% CI, 0.61-1.32), respectively; AUC/dose 1.06 (90% CI, 0.88-1.27) and 1.14 (90% CI, 0.76-1.71), respectively; and FU 0.99 (90% CI, 0.94-1.04) and 0.97 (90% CI, 0.87-1.09), respectively.

Estimated slope of linear regression of log parameters versus log CrCl was: CL/BSA 0.06 (90% CI, -0.15-0.28); AUC/dose -0.07 (90% CI, -0.30-0.16; Cbz FU 0.02 (90% CI, -0.05-0.08). Cbz safety was consistent with previous reports.

“Renal impairment had no clinically meaningful effect on Cbz pharmacokinetics. Non-significant trends of increasing AUC and decreasing Cbz CL with greater renal impairment were seen,” the researchers summarized.

Source: Azaro A, Rodon J, Machiels J, et al. Pharmacokinetic (PK) activity of cabazitaxel (Cbz) in patients with renal impairment. Poster presented at ESMO 2014 Congress, Madrid, Spain. September 27, 2014.

Madrid—Renal impairment had no clinically meaningful effect on the pharmacokinetic activity of cabazitaxel (Cbz). That was one of the findings of an open-label, multicenter study conducted recently. Study results were presented during a poster session at the EMSO 2014 Congress in Madrid. The poster was titled Pharmacokinetic Activity of Cabazitaxel in Patients with Renal Impairment.

The study was designed to assess the pharmacokinetic activity in patients with advanced solid tumors and normal or impaired renal function.

Patients in cohort A had normal control with creatinine clearance (CrCL] of >80 mL/min/1.73 m2, patients in cohort B had moderate renal impairment with CrCL 30-<50 mL/min/1.73 m2, and patients in cohort C had severe renal impairment with CrCl <30 mL/min/1.73 m2. Patients in cohorts A and B received Cbz at a dose of 25 mg/m2 every 3 weeks. For patients in cohort C, the dose was 20 mg/m2, which could be increased to 25 mg/m2.

Cbz pharmacokinetic activity was the primary end point (clearance normalized to body surface area [CL/BSA]; area under the curve normalized to dose [AUC/dose]). Non-compartmental analysis and individual modeling using a 3-compartment open model with first-order elimination were utilized to calculate pharmacokinetic parameters.

Log PK parameters and Cbz unbound fraction (FU) were analyzed using linear regression and linear mixed models, respectively. Log CrCl corresponding to the mean of each cohort’s CrCl interval was used to determine geometric mean (GM) estimates (moderate and severs renal impairment: 40 and 15 mL/min/1.73 m2, respectively). GM ratios (GMRs) were expressed versus control (90 mL/min/1.73 m2).

Twenty-five patients received a median of 3 Cbz cycles (range 1-20: cohort A, 5 [2-13]; cohort B, 3 [1-15]; cohort C, 5 [1-20], and 24 were eligible for PK analysis (8/cohort). For patients with moderate and severe renal impairment compared with controls, geometric mean ratio estimates were: CL/BSA 0.95 (90% confidence interval [CI], 0.80-1.13) and 0.89 (90% CI, 0.61-1.32), respectively; AUC/dose 1.06 (90% CI, 0.88-1.27) and 1.14 (90% CI, 0.76-1.71), respectively; and FU 0.99 (90% CI, 0.94-1.04) and 0.97 (90% CI, 0.87-1.09), respectively.

Estimated slope of linear regression of log parameters versus log CrCl was: CL/BSA 0.06 (90% CI, -0.15-0.28); AUC/dose -0.07 (90% CI, -0.30-0.16; Cbz FU 0.02 (90% CI, -0.05-0.08). Cbz safety was consistent with previous reports.

“Renal impairment had no clinically meaningful effect on Cbz pharmacokinetics. Non-significant trends of increasing AUC and decreasing Cbz CL with greater renal impairment were seen,” the researchers summarized.

Source: Azaro A, Rodon J, Machiels J, et al. Pharmacokinetic (PK) activity of cabazitaxel (Cbz) in patients with renal impairment. Poster presented at ESMO 2014 Congress, Madrid, Spain. September 27, 2014.