Evaluation of Clinically Relevant Drug–Drug Interactions and Population Pharmacokinetics of Darolutamide in Patients with Nonmetastatic Castration-Resistant Prostate Cancer: Results of Pre-Specified and Post Hoc Analyses of the Phase III ARAMIS Trial
Background: Darolutamide, an androgen receptor antagonist with a distinct molecular structure, significantly prolonged metastasis-free survival versus placebo in the phase III ARAMIS study in men with nonmetastatic castration-resistant prostate cancer (nmCRPC). In this population, polypharmacy for a...
| Publicado en: | Targeted Oncology Vol. 14; no. 5; pp. 527 - 540 |
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| Autores principales: | , , , , , , , , , , , , , , , |
| Formato: | research tables/charts randomized controlled trial Journal Article |
| Publicado: |
Springer Nature
Oct2019
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| Acceso en línea: | Ver este registro en EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=139186169&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 139186169 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 17762596 47DQ jtl: Targeted Oncology issn: 17762596 maglogo: N pubinfo: dt: Oct2019 vid: 14 iid: 5 pid: 237 pub: Springer Nature place: New York, New York artinfo: ui: 139186169 139186169 NLM31571095 139186169 10.1007/s11523-019-00674-0 NLM31571095 139186169 ppf: 527 ppct: 13 formats: fmt: – @attributes: type: T – @attributes: type: P tig: atl: Evaluation of Clinically Relevant Drug–Drug Interactions and Population Pharmacokinetics of Darolutamide in Patients with Nonmetastatic Castration-Resistant Prostate Cancer: Results of Pre-Specified and Post Hoc Analyses of the Phase III ARAMIS Trial aug: au: Shore, Neal Zurth, Christian Fricke, Robert Gieschen, Hille Graudenz, Kristina Koskinen, Mikko Ploeger, Bart Moss, Jonathan Prien, Olaf Borghesi, Gustavo Petrenciuc, Oana Tammela, Teuvo L. Kuss, Iris Verholen, Frank Smith, Matthew R. Fizazi, Karim affil: Carolina Urologic Research Center, 823 82nd Parkway, Suite B, 29572, Myrtle Beach, SC, USA sug: subj: Drug Interactions Adverse Drug Event Epidemiology Antineoplastic Agents Therapeutic Use Androgen Antagonists Therapeutic Use Prostatic Neoplasms Drug Therapy Heterocyclic Compounds Therapeutic Use Placebos Male Prostatic Neoplasms Epidemiology Double-Blind Studies Aged Heterocyclic Compounds Pharmacokinetics Antilipemic Agents Therapeutic Use Neoplasm Recurrence, Local Androgen Antagonists Pharmacokinetics Surgery, Urogenital Comorbidity Neoplasm Metastasis Middle Age Incidence Polypharmacy Aged, 80 and Over Human Randomized Controlled Trials Random Assignment Aged: 65+ years Middle Aged: 45-64 years Aged, 80 & over Male ab: Background: Darolutamide, an androgen receptor antagonist with a distinct molecular structure, significantly prolonged metastasis-free survival versus placebo in the phase III ARAMIS study in men with nonmetastatic castration-resistant prostate cancer (nmCRPC). In this population, polypharmacy for age-related comorbidities is common and may increase drug-drug interaction (DDI) risks. Preclinical/phase I study data suggest darolutamide has a low DDI potential-other than breast cancer resistance protein/organic anion transporter protein substrates (e.g., statins), no clinically relevant effect on comedications is expected.Objective: Our objective was to evaluate the effect of commonly administered drugs on the pharmacokinetics of darolutamide and the effect of comedications potentially affected by darolutamide on safety in patients with nmCRPC.Patients and Methods: Comorbidities and comedication use in the 1509 ARAMIS participants treated with darolutamide 600 mg twice daily or placebo were assessed. A population pharmacokinetic analysis evaluated whether comedications affected the pharmacokinetics of darolutamide in a subset of 388 patients. A subgroup analysis of adverse events (AEs) in statin users versus nonusers was conducted.Results: Most participants (median age 74 years) had at least one comorbidity (98.4% in both arms) and used at least one comedication (98.7% with darolutamide vs. 98.0% with placebo); these were similar across study arms. Despite frequent use of comedications with DDI potential, no significant effects on darolutamide pharmacokinetics were identified. Comedications included lipid-modifying agents (34.5%), β-blockers (29.7%), antithrombotics (42.8%), and systemic antibiotics (26.9%). AE incidence was similar across study arms in statin users and nonusers. Study limitations include the small sample size for sub-analyses.Conclusions: These analyses suggest the pharmacokinetic profile of darolutamide is not affected by a number of commonly administered drugs in patients with nmCRPC. Although pharmacokinetic data have indicated that darolutamide has the potential to interact with rosuvastatin, used to assess DDI in these studies, this finding did not seem to translate into increased AEs due to statin use in the ARAMIS trial. Clinicaltrials.gov identifier: NCT02200614. pubtype: Academic Journal doctype: research tables/charts randomized controlled trial Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
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