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.

Enhancement of the Oral Availability of Cabazitaxel Using the Cytochrome P450 3A (CYP3A) Inhibitor Ritonavir in Mice

“…The plasma AUC of docetaxel could be enhanced 7.3-fold with coadministration of ritonavir, whereas the plasma AUC of paclitaxel showed a 2.5-fold enhancement . These preclinical results have been used as a basis to develop oral administration regimens for paclitaxel and especially docetaxel, which are currently tested and optimized in humans. ,, Currently, an oral docetaxel formulation (ModraDoc006) in combination with ritonavir is tested in clinical trials. , Taking all results of the present study together, they form a good starting point to test an oral cabazitaxel formulation in combination with ritonavir in a small patient population. An oral drug formulation is more patient-friendly, and besides it allows metronomic chemotherapy .…”

“…10 These preclinical results have been used as a basis to develop oral administration regimens for paclitaxel and especially docetaxel, which are currently tested and optimized in humans. 9,36,37 Currently, an oral docetaxel formulation (ModraDoc006) in combination with ritonavir is tested in clinical trials. 19,36 Taking all results of the present study together, they form a good starting point to test an oral cabazitaxel formulation in combination with ritonavir in a small patient population.…”

Pharmacological Potential of Lathyrane-Type Diterpenoids from Phytochemical Sources

“…However, new approaches are being considered to avoid the invasive nature of the intravenous route, for example, currently in clinical trial is a novel oral formulation of the anticancer drug, Docetaxel. It is co-administered with cytochrome P450 3A4 and the P-gp inhibitor ritonavir; this strategy has demonstrated increased oral bioavailability [ 92 ].…”

The inhibitory and inducing effects of ritonavir on hepatic and intestinal CYP3A and other drug-handling proteins

“…This is one example of a drug that can be boosted by ritonavir, but in the future, this may also be possible for other drugs. Additionally, for some currently running research programs, lower doses of ritonavir compared to the typically used boosting doses could also be of value, especially when combining ritonavir with (cyto-)toxic drugs [20] , [21] , [23] . These classes of drugs have a higher risk of (severe) side effects and this initial risk will increase when such drugs are boosted by ritonavir due to higher plasma exposure.…”