New study below.
"enzalutamide induces the CYP3A4 enzyme and taxanes are metabolized by this enzyme"
Many aging men are on non-PCa meds. Worth asking if dosages will be diluted by Xtandi.
The Pharma attitude to liver enzymes, rather than inhibiting them, is to use ten times as much drug, say, on the basis that the liver will destroy 90%. But in the case of Xtandi, there seems to be a case for inhibiting excess production of CYP3A4.
Anyway, in the new study: "A potential clinically relevant 22% ... reduction in cabazitaxel exposure was found with concomitant enzalutamide use."
"Since recent study results support the use of a lower standard cabazitaxel dose of 20 mg/m2, the clinical relevance of this interaction may be substantial, since the addition of enzalutamide may result in sub-therapeutic cabazitaxel exposure."
Presumably, there is some patient variation in the CYP3A4 response which might complicate things.
-Patrick
ncbi.nlm.nih.gov/pubmed/291...
Clin Cancer Res. 2017 Nov 17. pii: clincanres.2336.2017. doi: 10.1158/1078-0432.CCR-17-2336. [Epub ahead of print]
Influence of Enzalutamide on Cabazitaxel Pharmacokinetics; a Drug-Drug Interaction Study in Metastatic Castration Resistant Prostate Cancer (mCRPC) Patients.
Belderbos BPS1, Bins S2, van Leeuwen RWF3, Oomen-de Hoop E1, van der Meer N4, de Bruijn P5, Hamberg P6, Overkleeft ENM7, van der Deure WM8, Lolkema M9, de Wit R10, Mathijssen RHJ11.
Author information
Abstract
PURPOSE:
In ongoing clinical research on metastatic castration-resistant prostate cancer (mCRPC) treatment, the potential enhanced efficacy of the combination of taxanes with AR-targeted agents, i.e. enzalutamide and abiraterone, is currently being explored. Since enzalutamide induces the CYP3A4 enzyme and taxanes are metabolized by this enzyme, a potential drug-drug interaction needs to be investigated.
DESIGN:
Therefore, we performed a pharmacokinetic cross-over study in mCRPC patients who were scheduled for treatment with cabazitaxel Q3W (25 mg/m2). Patients were studied for three consecutive cabazitaxel cycles. Enzalutamide (160 mg QD) was administered concomitantly after the first cabazitaxel cycle, during 6 weeks. Primary endpoint was the difference in mean area under the curve (AUC) between the first (cabazitaxel monotherapy) and third cabazitaxel cycle, when enzalutamide was added.
RESULTS:
A potential clinically relevant 22% (95%CI: 9-34%, p=0.005) reduction in cabazitaxel exposure was found with concomitant enzalutamide use. The geometric mean AUC0-24h of cabazitaxel was 181 ng*h/mL (95%CI 150-219 ng*h/mL) in cycle 3 and 234 ng*h/mL (95%CI 209-261 ng*h/mL) in cycle 1 This combination did not result in excessive toxicity, while PSA response was promising.
CONCLUSIONS:
We found a significant decrease in cabazitaxel exposure when combined with enzalutamide. In an era of clinical trials on combination strategies for mCRPC, it is important to be aware of clinically relevant drug-drug interactions. Since recent study results support the use of a lower standard cabazitaxel dose of 20 mg/m2, the clinical relevance of this interaction may be substantial, since the addition of enzalutamide may result in sub-therapeutic cabazitaxel exposure.
Copyright ©2017, American Association for Cancer Research.
PMID: 29150561 DOI: 10.1158/1078-0432.CCR-17-2336
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