A phase I and pharmacokinetic study of bi-daily dosing of oral paclitaxel in combination with cyclosporin A.

Purpose: To investigate dose escalation of bi-daily (b.i.d.) oral paclitaxel in combination with cyclosporin A in order to improve and prolong the systemic exposure to paclitaxel and to explore the maximum tolerated dose and dose limiting toxicity (DLT) of this combination.

Patients And Methods: A total of 15 patients received during course 1 two doses of oral paclitaxel (2 x 60, 2 x 90, 2 x 120, or 2 x 160 mg/m2) 7 h apart in combination with 15 mg/kg of cyclosporin A, co-administered to enhance the absorption of paclitaxel. During subsequent courses, patients received 3-weekly intravenous paclitaxel at a dose of 175 mg/m2 as a 3-h infusion.

Results: Toxicities observed following b.i.d. dosing of oral paclitaxel were generally mild and included toxicities common to paclitaxel administration and mild gastrointestinal toxicities such as nausea, vomiting, and diarrhea, which occurred more often at the higher dose levels. Dose escalation of b.i.d. oral paclitaxel from 2 x 60 to 2 x 160 mg/m2 did not result in a significant increase in the area under the plasma concentration-time curve (AUC) of paclitaxel. The AUC after doses of 2 x 60, 90, 120, and 160 mg/m2 were 3.77 +/- 2.70, 4.57 +/- 2.43, 3.62 +/- 1.58, and 8.58 +/- 7.87 microM.h, respectively. The AUC achieved after intravenous administration of paclitaxel 175 mg/m2 was 17.95 +/- 3.94 microM.h.

Conclusion: Dose increment of paclitaxel did not result in a significant additional increase in the AUC values of the drug. Dose escalation of the b.i.d. dosing regimen was therefore not continued up to DLT. As b.i.d. dosing appeared to result in higher AUC values compared with single-dose administration (data which we have published previously), we recommend b.i.d. dosing of oral paclitaxel for future studies. Although pharmacokinetic data are difficult to interpret, due to the limited number of patients at each dose level and the large interpatient variability, we recommend the dose level of 2 x 90 mg/m2 for further investigation, as this dose level showed the highest systemic exposure to paclitaxel combined with good safety.