Clinical Pharmacokinetics of the Androgen Receptor Inhibitor Darolutamide in Healthy Subjects and Patients with Hepatic or Renal Impairment

Zurth, Christian; Nykänen, Pirjo; Wilkinson, Gary; Taavitsainen, Päivi; Vuorela, Annamari; Huang, Fenix W. D.; Reschke, Susanne; Koskinen, Mikko

doi:10.1007/s40262-021-01078-y

Cited by 11 publications

(10 citation statements)

References 19 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Lack of inhibition may be the result of extensive protein binding by darolutamide and keto-darolutamide in vivo, which is 92% and 99% in human plasma, respectively, possibly hampering their inhibitory potential. 33 Another explanation for the lack of inhibition could be that additional hepatic uptake transporters in vivo that are not inhibited by darolutamide, compensate for the transport of substrates. Regardless, our in vivo findings are consistent with our in vitro findings suggesting that there is no DDI between darolutamide and docetaxel.…”

Section: Discussionmentioning

confidence: 99%

“…Yet, no inhibition of Oatp1b was observed in vivo. Lack of inhibition may be the result of extensive protein binding by darolutamide and keto‐darolutamide in vivo, which is 92% and 99% in human plasma, respectively, possibly hampering their inhibitory potential 33 . Another explanation for the lack of inhibition could be that additional hepatic uptake transporters in vivo that are not inhibited by darolutamide, compensate for the transport of substrates.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Darolutamide does not interfere with OATP‐mediated uptake of docetaxel

Buck,

Talebi,

Drabison

et al. 2024

Intl Journal of Cancer

View full text Add to dashboard Cite

The addition of darolutamide, an androgen receptor signalling inhibitor, to therapy with docetaxel has recently been approved as a strategy to treat metastatic prostate cancer. OATP1B3 is an SLC transporter that is highly expressed in prostate cancer and is responsible for the accumulation of substrates, including docetaxel, into tumours. Given that darolutamide inhibits OATP1B3 in vitro, we sought to characterise the impact of darolutamide on docetaxel pharmacokinetics. We investigated the influence of darolutamide on OATP1B3 transport using in vitro and in vivo models. We assessed the impact of darolutamide on the tumour accumulation of docetaxel in a patient‐derived xenograft (PDX) model and on an OATP1B biomarker in patients. Darolutamide inhibited OATP1B3 in vitro at concentrations higher than the reported Cmax. Consistent with these findings, in vivo studies revealed that darolutamide does not influence the pharmacokinetics of Oatp1b substrates, including docetaxel. Docetaxel accumulation in PDX tumours was not decreased in the presence of darolutamide. Metastatic prostate cancer patients had similar levels of OATP1B biomarkers, regardless of treatment with darolutamide. Consistent with a low potential to inhibit OATP1B3‐mediated transport in vitro, darolutamide does not significantly impede the transport of Oatp1b substrates in vivo or in patients. Our findings support combined treatment with docetaxel and darolutamide, as no OATP1B3 transporter based drug–drug interaction was identified.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Darolutamide does not interfere with OATP‐mediated uptake of docetaxel

Buck,

Talebi,

Drabison

et al. 2024

Intl Journal of Cancer

View full text Add to dashboard Cite

show abstract

“…The major metabolite, keto-darolutamide, is formed rapidly with a similar time to C max ( t max ) [ 10 ]. The plasma exposure of keto-darolutamide is higher than that of darolutamide [ 7 , 31 , 32 ]. Following the administration of [ 14 C]darolutamide 300 mg as an oral solution to healthy volunteers in a fasting state, the absolute bioavailability was 98.9% [ 31 ].…”

Section: Pharmacokinetic Properties Of Darolutamidementioning

confidence: 99%

“…The plasma exposure of keto-darolutamide is higher than that of darolutamide [ 7 , 31 , 32 ]. Following the administration of [ 14 C]darolutamide 300 mg as an oral solution to healthy volunteers in a fasting state, the absolute bioavailability was 98.9% [ 31 ]. When the same dose was administered as a tablet, absolute bioavailability decreased to 29.9%, indicating low solubility and incomplete absorption [ 31 ].…”

Section: Pharmacokinetic Properties Of Darolutamidementioning

confidence: 99%

“…Following the administration of [ 14 C]darolutamide 300 mg as an oral solution to healthy volunteers in a fasting state, the absolute bioavailability was 98.9% [ 31 ]. When the same dose was administered as a tablet, absolute bioavailability decreased to 29.9%, indicating low solubility and incomplete absorption [ 31 ]. Due to its low solubility (logP darolutamide = 1.9) and high permeability, darolutamide is classified as a Biopharmaceuticals Classification System Class II drug [ 10 , 33 ].…”

Section: Pharmacokinetic Properties Of Darolutamidementioning

confidence: 99%

See 1 more Smart Citation

Clinical Pharmacokinetics and Pharmacodynamics of the Next Generation Androgen Receptor Inhibitor—Darolutamide

Podgoršek,

Mehra,

van Oort

et al. 2023

Clin Pharmacokinet

View full text Add to dashboard Cite

Darolutamide is a next-generation androgen receptor signaling inhibitor (ARSI) currently approved for the treatment of nonmetastatic castration-resistant prostate cancer (nmCRPC) and metastatic hormone sensitive prostate cancer (mHSPC). Studies suggest that darolutamide also has the potential to be used to treat other stages of prostate cancer (PC), suggesting that its indications will broaden in the near future. Since ARSIs show similar efficacy for the treatment of PC, pharmacokinetic properties of these drugs and patient characteristics could help physicians decide which drug to select. This review provides an overview of the pharmacokinetic and pharmacodynamic properties of darolutamide. One of the most important pharmacological advantages of darolutamide is its low brain distribution and therefore limited seizure potential and central nervous system adverse effects. In addition, darolutamide has little drug–drug interaction potential and is unlikely to alter the exposure of other cytochrome P450 or P-glycoprotein substrates. Nevertheless, it may significantly increase the exposure of breast cancer resistant protein (BCRP) substrates. The limited solubility and bioavailability of darolutamide increases when taken together with food, regardless of the fat content. Darolutamide is excessively metabolized by oxidation and glucuronidation and excreted in the urine and feces. For this reason, dose reduction is required in patients with moderate and severe renal or severe hepatic impairment. Although no exposure–response relationship was observed with darolutamide, less advanced stages of PC showed better PSA response on treatment. Overall, darolutamide has some advantageous pharmacological properties that may lead to its preferred use, when broader registered, in selected patients across different disease stages.

show abstract

Darolutamide in Japanese patients with metastatic hormone‐sensitive prostate cancer: Phase 3 ARASENS subgroup analysis

Uemura,

Kikukawa,

Hashimoto

et al. 2024

Cancer Medicine

View full text Add to dashboard Cite

BackgroundIn the global ARASENS study (NCT02799602), darolutamide plus androgen‐deprivation therapy (ADT) and docetaxel significantly reduced risk of death by 32.5% versus placebo plus ADT and docetaxel (hazard ratio [HR] 0.68; 95% confidence interval [CI] 0.57–0.80; p < 0.0001), with a favorable safety profile in patients with metastatic hormone‐sensitive prostate cancer (mHSPC). We investigated outcomes in Japanese participants.MethodsPatients were randomized 1:1 to oral darolutamide 600 mg twice daily or placebo, plus ADT and docetaxel. The primary endpoint was overall survival.ResultsThe Japanese subgroup comprised 148 patients (darolutamide 63, placebo 85). In the Japanese versus overall population, more patients were aged ≥75 years (darolutamide/placebo 35%/22% vs. 16%/17%) and had body mass index <25 kg/m2 (78%/79% vs. 46%/43%), The ECOG performance status 0 (92%/88% vs. 72%/71%), de novo mHSPC (95%/97% vs. 86%/87%), and Gleason score ≥8 (94%/92% vs. 78%/79%). Median treatment duration was 43.3/15.4 months for darolutamide/placebo. The overall survival HR for darolutamide versus placebo was 0.91 (95% CI 0.50–1.64), despite 85% of patients in the placebo group receiving subsequent life‐prolonging therapy. Darolutamide prolonged time to castration‐resistant prostate cancer (HR 0.31; 95% CI 0.17–0.55). Treatment‐emergent adverse event incidences were generally similar between groups. Adverse events known to be associated with docetaxel (e.g., neutropenia) were more frequent in the Japanese versus overall population.ConclusionIn conclusion, efficacy outcomes showed positive trends for darolutamide plus ADT and docetaxel in Japanese patients with mHSPC, consistent with the overall population, despite higher risk factors. The combination was well tolerated, with no new safety signals in Japanese patients.

show abstract

Clinical Pharmacokinetics of the Androgen Receptor Inhibitor Darolutamide in Healthy Subjects and Patients with Hepatic or Renal Impairment

Cited by 11 publications

References 19 publications

Darolutamide does not interfere with OATP‐mediated uptake of docetaxel

Darolutamide does not interfere with OATP‐mediated uptake of docetaxel

Clinical Pharmacokinetics and Pharmacodynamics of the Next Generation Androgen Receptor Inhibitor—Darolutamide

Darolutamide in Japanese patients with metastatic hormone‐sensitive prostate cancer: Phase 3 ARASENS subgroup analysis

Contact Info

Product

Resources

About