A Microdose Cocktail to Evaluate Drug Interactions in Patients with Renal Impairment.

Szczegóły
Abstrakt

Tytuł:: A Microdose Cocktail to Evaluate Drug Interactions in Patients with Renal Impairment.
Autorzy:: Tatosian DA; Merck & Co., Inc., Kenilworth, New Jersey, USA.
Yee KL; Merck & Co., Inc., Kenilworth, New Jersey, USA.
Zhang Z; Merck & Co., Inc., Kenilworth, New Jersey, USA.
Mostoller K; Merck & Co., Inc., Kenilworth, New Jersey, USA.
Paul E; Merck & Co., Inc., Kenilworth, New Jersey, USA.
Sutradhar S; Merck & Co., Inc., Kenilworth, New Jersey, USA.
Larson P; Merck & Co., Inc., Kenilworth, New Jersey, USA.
Chhibber A; Merck & Co., Inc., Kenilworth, New Jersey, USA.
Wen J; Merck & Co., Inc., Kenilworth, New Jersey, USA.
Wang YJ; Merck & Co., Inc., Kenilworth, New Jersey, USA.
Lassman M; Merck & Co., Inc., Kenilworth, New Jersey, USA.
Latham AH; Merck & Co., Inc., Kenilworth, New Jersey, USA.
Pang J; Merck & Co., Inc., Kenilworth, New Jersey, USA.
Crumley T; Merck & Co., Inc., Kenilworth, New Jersey, USA.
Gillespie A; Data Management and Biometrics, Celerion, Lincoln, Nebraska, USA.
Marricco NC; Data Management and Biometrics, Celerion, Lincoln, Nebraska, USA.
Marenco T; Data Management and Biometrics, Celerion, Lincoln, Nebraska, USA.
Murphy M; Data Management and Biometrics, Celerion, Lincoln, Nebraska, USA.
Lasseter KC; Clinical Pharmacology of Miami, Inc, Miami, Florida, USA.
Marbury TC; Orlando Clinical Research Center, Orlando, Florida, USA.
Tweedie D; Merck & Co., Inc., Kenilworth, New Jersey, USA.; Currently Independent Consultant, Harleysville, Pennsylvania, USA.
Chu X; Merck & Co., Inc., Kenilworth, New Jersey, USA.
Evers R; Merck & Co., Inc., Kenilworth, New Jersey, USA.
Stoch SA; Merck & Co., Inc., Kenilworth, New Jersey, USA.
Źródło:: Clinical pharmacology and therapeutics [Clin Pharmacol Ther] 2021 Feb; Vol. 109 (2), pp. 403-415. Date of Electronic Publication: 2020 Oct 26.
Typ publikacji:: Clinical Trial, Phase II; Journal Article; Randomized Controlled Trial; Research Support, Non-U.S. Gov't
Język:: English
Imprint Name(s):: Publication: 2015- : Hoboken, NJ : Wiley
Original Publication: St. Louis : C.V. Mosby
MeSH Terms:: Drug Interactions/*physiology
Kidney Diseases/*metabolism
ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism ; ATP Binding Cassette Transporter, Subfamily G, Member 2/metabolism ; Area Under Curve ; Biomarkers/metabolism ; Healthy Volunteers ; Humans ; Liver-Specific Organic Anion Transporter 1/metabolism ; Midazolam/pharmacokinetics ; Rifampin/pharmacokinetics
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Substance Nomenclature:: 0 (ATP Binding Cassette Transporter, Subfamily B, Member 1)
0 (ATP Binding Cassette Transporter, Subfamily G, Member 2)
0 (Biomarkers)
0 (Liver-Specific Organic Anion Transporter 1)
R60L0SM5BC (Midazolam)
VJT6J7R4TR (Rifampin)
Entry Date(s):: Date Created: 20200725 Date Completed: 20210521 Latest Revision: 20210521
Update Code:: 20240104
DOI:: 10.1002/cpt.1998
PMID:: 32705692
: Czasopismo naukowe

Renal impairment (RI) is known to influence the pharmacokinetics of nonrenally eliminated drugs, although the mechanism and clinical impact is poorly understood. We assessed the impact of RI and single dose oral rifampin (RIF) on the pharmacokinetics of CYP3A, OATP1B, P-gp, and BCRP substrates using a microdose cocktail and OATP1B endogenous biomarkers. RI alone had no impact on midazolam (MDZ), maximum plasma concentration (C max ), and area under the curve (AUC), but a progressive increase in AUC with RI severity for dabigatran (DABI), and up to ~2-fold higher AUC for pitavastatin (PTV), rosuvastatin (RSV), and atorvastatin (ATV) for all degrees of RI was observed. RIF did not impact MDZ, had a progressively smaller DABI drug-drug interaction (DDI) with increasing RI severity, a similar 3.1-fold to 4.4-fold increase in PTV and RSV AUC in healthy volunteers and patients with RI, and a diminishing DDI with RI severity from 6.1-fold to 4.7-fold for ATV. Endogenous biomarkers of OATP1B (bilirubin, coproporphyrin I/III, and sulfated bile salts) were generally not impacted by RI, and RIF effects on these biomarkers in RI were comparable or larger than those in healthy volunteers. The lack of a trend with RI severity of PTV and several OATP1B biomarkers, suggests that mechanisms beyond RI directly impacting OATP1B activity could also be considered. The DABI, RSV, and ATV data suggest an impact of RI on intestinal P-gp, and potentially BCRP activity. Therefore, DDI data from healthy volunteers may represent a worst-case scenario for clinically derisking P-gp and BCRP substrates in the setting of RI.
(© 2020 Merck Sharp & Dohme Corp. Clinical Pharmacology & Therapeutics © 2020 American Society for Clinical Pharmacology and Therapeutics.)

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