Pharmacokinetics And Toxicities Of Oral Docetaxel Formulations Co-Administered With Ritonavir In Phase I Trials

Introduction: Docetaxel is widely used as intravenous (IV) chemotherapy. Oral docetaxel is co-administered with the cytochrome P450 3A4 and P-glycoprotein inhibitor ritonavir to increase oral bioavailability. This research explores the relationship between the pharmacokinetics (PK) and toxicity of this novel oral chemotherapy.Methods: The patients in two phase I trials were treated with different oral docetaxel formulations in combination with ritonavir in different dose levels, ranging from 20 to 80 mg docetaxel with 100 to 200 mg ritonavir a day. The patients were categorized based on the absence or occurrence of severe treatment-related toxicity (grade >= 3 or any grade leading to treatment alterations). The docetaxel area under the plasma concentration-time curve (AUC) and maximum plasma concentration (C-max) were associated with toxicity.Results: Thirty-four out of 138 patients experienced severe toxicity, most frequently observed as mucositis, fatigue, diarrhea, nausea and vomiting. The severe toxicity group had a significantly higher docetaxel AUC (2231 +/- 1405 vs 1011 +/- 830 ng/mL*h, p<0.0001) and C-max (218 +/- 178 vs 119 +/- 77 ng/mL, p<0.0001) as compared to the patients without severe toxicity. When extrapolated from IV PK data, the patients without severe toxicity had a similar cumulative docetaxel AUC as with standard 3-weekly IV docetaxel, while the C-max was up to 10-fold lower with oral docetaxel and ritonavir.Conclusion: Severe toxicity was observed in 25% of the patients treated with oral docetaxel and ritonavir. This toxicity seems related to the PK, as the docetaxel AUC(0-inf) and C-max were up to twofold higher in the severe toxicity group as compared to the non-severe toxicity group. Future randomized trials will provide a further evaluation of the toxicity and efficacy of the new weekly oral docetaxel and ritonavir regimen in comparison to standard IV docetaxel.