Pharmacokinetics and Toxicities of Oral Docetaxel Formulations Co-Administered with Ritonavir in Phase I Trials

Abstract

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.

Keywords:

• oral docetaxel
• ritonavir
• pharmacokinetics
• toxicity

Disclosure

Jos Beijnen has received a grant for translational research (ZonMw code 40-41200-98-004) for clinical development of oral taxanes. The two trials that were reviewed in this article were conducted as investigator-initiated phase I trials in the Netherlands Cancer Institute. After their completion, Modra Pharmaceuticals BV was founded as a spin-off company of the Netherlands Cancer Institute, focusing on the further clinical development of oral taxanes co-administrated with ritonavir. Jos H. Beijnen is a part-time employee and shareholder of Modra Pharmaceuticals Holding BV and is a patent holder on oral taxane formulations. The other authors report no conflicts of interest in this work.