PAC Fixed Dose: Pharmacokinetics of a 1-Hour Paclitaxel Infusion and Comparison to BSA-Normalized Drug Dosing

Abstract

The aim of this study was to determine thepharmacokinetics (PKs) of a 175-mg fixed dose of paclitaxel(PAC) after a 1-h infusion in cancer patients and to comparethem with the PK parameters from a study with a dose normalizedto the body surface area (BSA) (100 mg/m²). Patientsand Methods: PAC PKs were studied during the firstcourse of therapy in 13 patients. A fixed dose of 175 mg PACwas administered weekly by a 1-h infusion to patients withadvanced cancer. Total PAC in serum was quantified byhigh-performance liquid chromatography (HPLC). PK parameterswere calculated by non-compartmental and modeldependentmethods. Results: The mean BSA of 12 patients(1 patient excluded from all analyses because of prolongedinfusion duration) was 1.79 m² (coefficient of variation (CV)7.8%), the mean dose referred to the individual BSAs was98.3 mg/m² (CV 8.3%). The mean area under the curve(AUC) was 6,193 ng/ml × h (CV 46%), the mean plasmaclearance (Clp) was 19.7 l/h/m² (CV 45%), and the volume ofdistribution at steady state (Vss) was 121.6 l/m2 (CV 52%).The mean residence time (MRT) was 7.6 h (CV 46%), themean distribution half-life (t½ α) of PACtot was 0.4 h (CV62%), and the elimination half-life (t½ β) 10.0 h (CV 42%).Maximum plasma concentration Cmax was 3,161 ng/ml(CV 36%). The mean time above 0.05 μM (42.7 ng/ml) was19.7 h, and the mean time above 0.1 μM (85.4 ng/ml) was10.6 h. Conclusions: In this study, a fixed dose of PAC of175 mg corresponds to a mean BSA-normalized dose of98.3 mg/m² (range 88.8-117.4 mg/m²). A higher variability ofPK parameters was observed compared to previously publishedresults of a PK study with BSA-normalized dosing of100 mg/m2. However, the AUC and the time above thresholdconcentrations did not depend on the dose. Therefore, afixed dose of 175 mg weekly could be an option for palliativetreatment with PAC and may offer a simple but effectiveschedule for PAC treatment.