Journal
PHARMACEUTICS
Volume 14, Issue 10, Pages -Publisher
MDPI
DOI: 10.3390/pharmaceutics14102101
Keywords
pharmacokinetics; drug-drug interaction; CYP metabolism; Akt inhibitor; androgen receptor inhibitor; ipatasertib; darolutamide
Categories
Funding
- Genentech Inc.
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This study evaluated the pharmacokinetics, safety, and tolerability of Ipatasertib and Daholutamide in patients with metastatic castration-resistant prostate cancer. The results showed a mild reduction in the exposure of Ipatasertib when administered in combination with Daholutamide, which was not clinically significant. Additionally, the combination therapy was well-tolerated with minimal side effects in patients.
Ipatasertib is a selective, small molecule Akt inhibitor that is currently being developed for the treatment of metastatic castration-resistant prostate cancer. Darolutamide is an androgen receptor (AR) inhibitor that is approved for the treatment of non-metastatic castration-resistant prostate cancer. Ipatasertib is metabolized by CYP3A4 to form a less active metabolite M1 (G-037720). Ipatasertib is also a weak time-dependent CYP3A4 inhibitor. Darolutamide is a mild CYP3A4 inducer and is metabolized into an active keto-darolutamide metabolite via CYP3A4. In this Phase 1b open-label, single sequence crossover study, ipatasertib pharmacokinetics safety and tolerability were evaluated in combination with darolutamide in metastatic castration-resistant prostate cancer (n = 15 patients). Specifically, the effect of 600 mg BID of darolutamide on 400 mg QD ipatasertib was evaluated in this study. Based on pharmacokinetic analysis, a mild reduction in ipatasertib AUC(0-24 h,ss )and C-max,C-ss exposures was observed (similar to 8% and similar to 21%, respectively) when administered in combination with darolutamide, which is considered not clinically meaningful. M1 exposures were similar with and without darolutamide administration. Darolutamide and keto-darolutamide exposures in combination with ipatasertib were similar to previously reported exposures for single agent darolutamide. Overall, the combination appears to be well-tolerated in the metastatic castration-resistant prostate cancer indication with very few AEs.
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