Darolutamide & Rosuvastatin

[pjoshea13]

Two new papers below [1] [2].

[1] "Rosuvastatin exposure increased 5.2-fold with darolutamide"

However:

[2] "Although pharmacokinetic data have indicated that darolutamide has the potential to interact with rosuvastatin, used to assess DDI {drug-drug interaction} in these studies, this finding did not seem to translate into increased AEs {adverse events} due to statin use in the ARAMIS trial."

-Patrick

[1] ncbi.nlm.nih.gov/pubmed/315...

Eur J Drug Metab Pharmacokinet. 2019 Sep 30. doi: 10.1007/s13318-019-00577-5. [Epub ahead of print]

Drug-Drug Interaction Potential of Darolutamide: In Vitro and Clinical Studies.

Zurth C1, Koskinen M2, Fricke R3, Prien O4, Korjamo T2, Graudenz K4, Denner K4, Bairlein M3, von Bühler CJ3, Wilkinson G4, Gieschen H4.

Author information

1

Bayer AG, Berlin, Germany. [e-mail].

2

Orion Corporation, Orion Pharma, Espoo, Finland.

3

Bayer AG, Wuppertal, Germany.

4

Bayer AG, Berlin, Germany.

Abstract

BACKGROUND AND OBJECTIVES:

Darolutamide is a novel androgen receptor (AR) antagonist approved for the treatment of nonmetastatic castration-resistant prostate cancer (nmCRPC). Accordingly, the drug-drug interaction (DDI) potential of darolutamide was investigated in both nonclinical and clinical studies.

METHODS:

In vitro studies were performed to determine the potential for darolutamide to be a substrate, inducer or inhibitor for cytochrome P450 (CYP) isoforms, other metabolizing enzymes and drug transporters. A phase I drug-interaction study in healthy volunteers evaluated the impact of co-administering rifampicin [CYP3A4 and P-glycoprotein (P-gp) inducer] and itraconazole [CYP3A4, P-gp and breast cancer resistance protein (BCRP) inhibitor] on the pharmacokinetics of darolutamide. Two further phase I studies assessed the impact of co-administering oral darolutamide on the pharmacokinetics of midazolam (sensitive CYP3A4 substrate) and dabigatran etexilate (P-gp substrate) and the impact on the pharmacokinetics of co-administered rosuvastatin [a substrate for BCRP, organic anion-transporting polypeptide (OATP)1B1, OATP1B3 and organic anion transporter (OAT)3].

RESULTS:

In vitro, darolutamide was predominantly metabolized via oxidative biotransformation catalyzed by CYP3A4 and was identified as a substrate for P-gp and BCRP. The enzymatic activity of nine CYP isoforms was not inhibited or slightly inhibited in vitro with darolutamide, and a rank order and mechanistic static assessment indicated that risk of clinically relevant DDIs via CYP inhibition is very low. In vitro, darolutamide exhibited no relevant induction of CYP1A2 or CYP2B6 activity. Inhibition of BCRP-, P-gp-, OAT3-, MATE1-, MATE2-K-, OATP1B1- and OATP1B3-mediated transport was observed in vitro. Phase I data showed that darolutamide exposure increased 1.75-fold with co-administered itraconazole and decreased by 72% with rifampicin. Co-administration of darolutamide with CYP3A4/P-gp substrates showed no effect or only minor effects. Rosuvastatin exposure increased 5.2-fold with darolutamide because of BCRP and probably also OATPB1/OATPB3 inhibition.

CONCLUSIONS:

Darolutamide has a low potential for clinically relevant DDIs with drugs that are substrates for CYP or P-gp; increased exposure of BCRP and probably OATP substrates was the main interaction of note.

PMID: 31571146 DOI: 10.1007/s13318-019-00577-5

***

[2] ncbi.nlm.nih.gov/pubmed/315...

Target Oncol. 2019 Sep 30. doi: 10.1007/s11523-019-00674-0. [Epub ahead of print]

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.

Shore N1, Zurth C2, Fricke R2, Gieschen H2, Graudenz K2, Koskinen M3, Ploeger B2, Moss J4, Prien O2, Borghesi G2, Petrenciuc O2, Tammela TL5, Kuss I2, Verholen F2, Smith MR6, Fizazi K7.

Author information

1

Carolina Urologic Research Center, 823 82nd Parkway, Suite B, Myrtle Beach, SC, 29572, USA. [e-mail].

2

Bayer AG, Berlin, Germany.

3

Orion Corporation Orion Pharma, Espoo, Finland.

4

BAST Inc. Ltd., Loughborough, UK.

5

Tampere University Hospital and Tampere University, Tampere, Finland.

6

Massachusetts General Hospital Cancer Center, Boston, USA.

7

Institut Gustave Roussy, Université Paris-Sud, Villejuif, France.

Abstract

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.

PLAIN-LANGUAGE-SUMMARY:

Darolutamide is a medicine used to treat men with prostate cancer that has not spread to other parts of the body (nonmetastatic). Often, these patients are taking other medicines for common age-related illnesses. Taking more than one medicine at the same time increases the chances of what is known as drug–drug interactions. Drug–drug interactions can decrease how well the medicines work or may sometimes increase side effects.To test for possible drug–drug interactions in men with prostate cancer who take darolutamide alongside other medicines.Men with nonmetastatic prostate cancer who were being treated with a medicine that lowers testosterone, a chemical in the body that causes prostate cancer tumors to grow. Participants took two darolutamide 300 mg tablets, or an inactive placebo, twice a day. WHAT DID THE RESEARCHERS MEASURE?: The researchers documented the number of medicines taken by each participant and the number of other medical conditions that they had. Tests were done to find out whether other medicines affected the way that darolutamide works in the body and whether patients taking darolutamide alongside other medicines experienced more side effects.As would be expected, based on the typical age of patients with prostate cancer, more than 90% of participants in this study used medicines other than darolutamide to manage common age-related illnesses or medical conditions. Taking medicines alongside darolutamide did not impact how darolutamide worked in the body and did not increase the number of side effects experienced by patients. Darolutamide is known to interact with rosuvastatin, a cholesterol-lowering drug. However, in this study, there was no overall increase in side effects among darolutamide-treated patients who took this type of drug compared with in those who did not.In this study of patients with nonmetastatic prostate cancer, limited drug–drug interactions were seen when taking darolutamide alongside other medicines given to these patients to manage age-related medical conditions.

PMID: 31571095 DOI: 10.1007/s11523-019-00674-0