A phase II/pharmacokinetic trial of high-dose progesterone in combination with paclitaxel

Purpose: The purpose of this study was to investigate the effect of high-do se progesterone, an inhibitor of P glycoprotein, on the pharmacokinetics an d toxicity of paclitaxel. Patients and methods: A total of 29 patients with various tumors were treated with single-agent paclitaxel (125 mg/m(2) admi nistered over 3 h once every 3 weeks) until progression of disease, at whic h point high-dose progesterone (3 g administered i.v. over 24 h) was added to the paclitaxel treatment program in 20 patients (13 women, 7 men). Pharm acokinetic studies of paclitaxel administered alone and with progesterone w ere performed in eight patients. Results: The pharmacokinetic parameters of paclitaxel were highly variable. High-dose progesterone increased the peak plasma levels (3.00 +/- 0.94 vs. 4.15 +/- 1.63 mu M; P = 0.029; mean +/- S D) and the area under the curve (AUC; 14.3 +/- 4.75 vs. 17.3 +/- 5.59 mu M x h; P = 0.006) of paclitaxel. The absolute neutrophil and platelet nadir c ounts did not differ significantly between the paclitaxel and the combined treatment cycles. Three of the 20 patients documented to have progressive d isease on paclitaxel alone had partial responses when high-dose progesteron e was added to the paclitaxel regimen. Conclusion: Progesterone had a stati stically significant impact on the pharmacokinetics of paclitaxel, The addi tion of high-dose progesterone to paclitaxel is feasible, but the small num ber of patients prevents conclusions being drawn about the clinical efficac y of combined progesterone and paclitaxel.