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Drug-Drug Interaction Study to Evaluate the Pharmacokinetics, Safety, and Tolerability of Ipatasertib in Combination with Darolutamide in Patients with Advanced Prostate Cancer.
Sutaria, Dhruvitkumar S; Rasuo, Grozdana; Harris, Adam; Johnson, Ryan; Miles, Dale; Gallo, Jorge Daniel; Sane, Rucha.
Afiliação
  • Sutaria DS; Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
  • Rasuo G; F. Hoffmann-La Roche AG, 4070 Basel, Switzerland.
  • Harris A; Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
  • Johnson R; Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
  • Miles D; Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
  • Gallo JD; F. Hoffmann-La Roche AG, 4070 Basel, Switzerland.
  • Sane R; Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
Pharmaceutics ; 14(10)2022 Oct 01.
Article em En | MEDLINE | ID: mdl-36297536
ABSTRACT
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 AUC0-24 h,ss and Cmax,ss exposures was observed (~8% and ~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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Texto completo: 1 Base de dados: MEDLINE Idioma: En Ano de publicação: 2022 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Idioma: En Ano de publicação: 2022 Tipo de documento: Article