CYP3A4 Activity in Patients With Prostate Cancer Versus Male Patients With Other Solid Tumours

Description

The metabolizing enzyme cytochrome P450 (CYP) 3A4 is an important factor in the pharmacokinetics (PK) of many (anticancer) drugs, including taxanes [1]. Recently, it has been reported that the PK of intravenous docetaxel are different in patients with castration resistant prostate cancer, as compared to patients with other types of solid tumours [2]. Different phase I studies with the oral docetaxel formulation ModraDoc006 in combination with ritonavir (denoted as ModraDoc006/r), were conducted in our institute in patients with hormone-sensitive prostate cancer (HSPC), metastatic castration-resistant prostate cancer (mCRPC) and other types of solid tumours [3-5]. The exposure to docetaxel and ritonavir after administration of the same dose and schedule of ModraDoc006/r was substantial lower in prostate cancer patients as compared to the patients with other types of solid tumours. In contrast to the 1.8-fold difference reported with IV docetaxel, the difference in the area under the plasma concentration versus time curve (AUC) was 2.8-fold with oral ModraDoc006/r treatment [2-5]. The PK-curves of docetaxel and ritonavir are shown in figure 1A and 1B.

The underlying mechanism for these observations remains to be elucidated. The lower docetaxel exposure with IV and oral docetaxel treatment and the lower ritonavir exposure with ModraDoc006/r treatment might be related to a higher CYP3A4 activity in prostate cancer patients. Therefore, it is important to directly compare the CYP3A4 activity with a phenotyping test in prostate cancer patients and patients with other types of solid tumours.

As a potential cause for this, CYP3A4 activity might be altered by medical castration. Franke et al. showed that the clearance of docetaxel was higher in castrated versus non-castrated prostate cancer patients. However, comparison of the CYP3A4 activity in the castrated versus the prostate cancer patients with normal levels of testosterone showed no significant differences [6]. However, this was done in 6 CRPC patients, of which one patient had an extremely low CYP3A4 activity. The intravenous erythomycin breath test that was used in this study only reflects the hepatic CYP3A4 activity and not the gastro-intestinal CYP3A4 activity. The latter is important in treatment with oral docetaxel (ModraDoc006) in combination with ritonavir. Furthermore, erythomycin is also a substrate for P-glycoprotein (P-gp), indicating that the erythomycin breath test might reflect P-gp activity as well as CYP3A4 activity [7,8]. Therefore, it is necessary to evaluate prostate cancer patients with a phenotyping test that includes both the hepatic and gastro-intestinal CYP3A4-activity.

Midazolam is one of the most frequently used test compounds used for evaluation of CYP3A4 activity [9-11]. Midazolam has several advantages over other CYP3A4 probes such as erythromycin, dapsone, quinine, and nifedipine [11]. First, midazolam is selectively metabolized by CYP3A4 [9,10]. Furthermore, midazolam clearance after both oral and intravenous administration is a widely accepted and validated metric of CYP3A4 activity [9-11]. Continuing, midazolam AUC and metabolite clearance to its major metabolite 1-hydroxy midazolam correlate well with hepatic CYP3A content [11-13]. Also, midazolam PK are highly sensitive to changes in CYP3A4 activity [9-11]. Therefore, oral midazolam will be used in this study to further evaluate the CYP3A4 activity in prostate cancer patients in comparison to patients with other types of solid tumours. To further differentiate between gastro-intestinal and hepatic CYP3A4 activity, evaluation with both oral and intravenous midazolam is included in this study.

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