Pharmacokinetic Drug–Drug Interaction of Apalutamide, Part 1: Clinical Studies in Healthy Men and Patients with Castration-Resistant Prostate Cancer

Durán, Ignacio; Carles, Joan; Bulat, Iurie; Hellemans, Peter; Mitselos, Anna; Ward, Peter; Jiao, James; Armas, Danielle; Chien, Caly

doi:10.1007/s40262-020-00882-2

Cited by 37 publications

(34 citation statements)

References 26 publications

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“… Liver (phenotyping) Breckenridge and Orme ( 1971 ), O’Reilly et al ( 1980 ), Udall ( 1975 ) Endothelin receptor antagonists Bosentan PXR Liver (phenotyping) van Giersbergen et al ( 2002 ), Weber et al ( 1999a ) Kinase inhibitor Dabrafenib PXR Liver (phenotyping) Suttle et al ( 2015 ) CYP2C19 Antiandrogens Apalutamide PXR? Liver (phenotyping) Duran et al ( 2020 ) Enzalutamide PXR Liver (phenotyping) Gibbons et al ( 2015 ) Antibiotics Dicloxacillin PXR Liver (phenotyping) Stage et al ( 2018 ) Rifampicin PXR Liver (phenotyping), duodenum Feng et al ( 1998 ), Oscarson et al ( 2007 ), Zhou et al ( 1990 ), Zilly et al ( 1975 ) Antiepileptics Carbamazepine CAR/PXR Liver (expression) Oscarson et al ( 2006 ) Phenytoin CAR/PXR Liver (phenotyping) Richter et al ( 1980 ) Antimalarials …”

Section: The In Vivo Induction Of Human Cyp Enzymes With Drugs Herbamentioning

confidence: 99%

“… Skin Smith et al ( 2003 ) CYP3A4 Antiandrogens Apalutamide PXR? Liver (phenotyping) Duran et al ( 2020 ) Enzalutamide PXR Liver (phenotyping) Belderbos et al ( 2018 ), Gibbons et al ( 2015 ), Schwartzberg et al ( 2017 ) Antibiotics Dicloxacillin PXR Liver (phenotyping) Stage et al ( 2018 ) Flucloxacillin PXR Liver (phenotyping) Fan et al ( 2019 ) Nafcillin PXR Liver (phenotyping) Lang et al ( 2003 ) Rifabutin PXR Liver (phenotyping) Barditch-Crovo et al ( 1999 ), Perucca et al ( 1988 ) Rifampicin PXR Liver (phenotyping and expression), duodenum Greiner et al ( 1999 ), Kolars et al ( 1992 ), Marschall et al ( 2005 ), McAllister et al ( 1983 ), Ohnhaus and Park ( 1979 ), Perucca et al ( 1988 ) Rifapentine PXR Liver (phenotyping) Birmingham et al ( 1978 ), Vital Durand et al ( 1986 ) Antidiarrheals ...…”

Section: The In Vivo Induction Of Human Cyp Enzymes With Drugs Herbamentioning

confidence: 99%

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Inhibition and induction of CYP enzymes in humans: an update

et al. 2020

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The cytochrome P450 (CYP) enzyme family is the most important enzyme system catalyzing the phase 1 metabolism of pharmaceuticals and other xenobiotics such as herbal remedies and toxic compounds in the environment. The inhibition and induction of CYPs are major mechanisms causing pharmacokinetic drug–drug interactions. This review presents a comprehensive update on the inhibitors and inducers of the specific CYP enzymes in humans. The focus is on the more recent human in vitro and in vivo findings since the publication of our previous review on this topic in 2008. In addition to the general presentation of inhibitory drugs and inducers of human CYP enzymes by drugs, herbal remedies, and toxic compounds, an in-depth view on tyrosine-kinase inhibitors and antiretroviral HIV medications as victims and perpetrators of drug–drug interactions is provided as examples of the current trends in the field. Also, a concise overview of the mechanisms of CYP induction is presented to aid the understanding of the induction phenomena.

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Section: The In Vivo Induction Of Human Cyp Enzymes With Drugs Herbamentioning

confidence: 99%

Section: The In Vivo Induction Of Human Cyp Enzymes With Drugs Herbamentioning

confidence: 99%

Inhibition and induction of CYP enzymes in humans: an update

et al. 2020

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“…In vivo, multiple daily doses of apalutamide decreased the AUC of midazolam (a CYP3A substrate), omeprazole (a CYP2C19 substrate), warfarin (a CYP2C9 substrate), pioglitazone (a CYP2C8 substrate), fexofenadine (a P-gp substrate), rosuvastatin (a BCRP and OATP1B1 substrate) by 92%, 85%, 46%, 18%, 30%, and 41%, respectively. 13,14 Although multiple DDI studies were conducted, the applicant conducted PBPK analyses to simulate untested DDI scenarios, such as the effects of a CYP2C8 inhibitor (gemfibrozil), a CYP3A inhibitor (such as ketoconazole), and an inducer (such as rifampin) on the PK of apalutamide and M3 at steady state. In addition, it was important to estimate the total potency ad-justed exposure change in DDI scenarios since the exposure changes of apalutamide and the active major metabolite (M3) were in the opposite directions when apalutamide was coadministered with gemfibrozil.…”

Section: S170mentioning

confidence: 99%

“…In addition, it was important to estimate the total potency ad-justed exposure change in DDI scenarios since the exposure changes of apalutamide and the active major metabolite (M3) were in the opposite directions when apalutamide was coadministered with gemfibrozil. [13][14][15] The success of this PBPK analysis was based on detailed in vitro and in vivo absorption, distribution, metabolism, and excretion profiles of the apalutamide and M3, as well as the appropriate validation of all the PBPK models. The PBPK models of apalutamide and M3 were developed using data from several studies: in vitro, human mass balance, PK, and multiple clinical DDIs.…”

Section: S170mentioning

confidence: 99%

Application of PBPK Modeling and Simulation for Regulatory Decision Making and Its Impact on US Prescribing Information: An Update on the 2018‐2019 Submissions to the US FDA's Office of Clinical Pharmacology

Zhang

Yang

Grimstein

et al. 2020

The Journal of Clinical Pharma

120

132

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Since 2016, results from physiologically based pharmacokinetic (PBPK) analyses have been routinely found in the clinical pharmacology section of regulatory applications submitted to the US Food and Drug Administration (FDA). In 2018, the Food and Drug Administration's Office of Clinical Pharmacology published a commentary summarizing the application of PBPK modeling in the submissions it received between 2008 and 2017 and its impact on prescribing information. In this commentary, we provide an update on the application of PBPK modeling in submissions received between 2018 and 2019 and highlight a few notable examples.

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“…Apalutamide pharmacokinetics is mostly mediated by CYP2C8 and CYP3A4 and several interactions with other drugs, which are inducers of these cytochromes, have been described. The co-administration of strong CYP2C8 inhibitors, such as gemfibrozil, has been reported to determine an apalutamide area under the curve (AUC) increasing of about 68% [22]. In contrast, a single dose of CYP3A4 inhibitor, such as itraconazolo, has no effect on apalutamide clearence.…”

Section: Mechanism Of Action Metabolism and Clinical Usementioning

confidence: 99%

Renal and Cardiovascular Toxicities by New Systemic Treatments for Prostate Cancer

Saltalamacchia

Frascaroli

Bernardo

et al. 2020

Cancers

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Prostate cancer (PC) is the most common male cancer in Western Countries. In recent years, the treatment of relapsed or metastatic disease had benefited by the introduction of a variety of new different drugs. In consideration of the relative long survival of PC patients, side effects of these drugs must be considered and monitored. In this review, we analyzed the newly developed therapies for PC treatment, describing the mechanism of action, the metabolism and latest clinical trials that led to the approval of these drugs in clinical practice. We then evaluated the cardiovascular and renal side effects from pivotal phase III and II studies and meta-analyses. Cardiovascular side effects are the most frequent, in particular hypertension, while renal toxicity is rarer and not well described in literature. Therefore, there is a need to better define the effects of these therapies, in order to personalize patient treatment on the basis of their comorbidities and preferences, in addition to their symptoms and disease load.

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Pharmacokinetic Drug–Drug Interaction of Apalutamide, Part 1: Clinical Studies in Healthy Men and Patients with Castration-Resistant Prostate Cancer

Cited by 37 publications

References 26 publications

Inhibition and induction of CYP enzymes in humans: an update

Inhibition and induction of CYP enzymes in humans: an update

Application of PBPK Modeling and Simulation for Regulatory Decision Making and Its Impact on US Prescribing Information: An Update on the 2018‐2019 Submissions to the US FDA's Office of Clinical Pharmacology

Renal and Cardiovascular Toxicities by New Systemic Treatments for Prostate Cancer

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