title: Clinical pharmacology basis of deriving dosing recommendations for dabigatran in patients with severe renal impairment.
abstract: The objective of this work was to derive a dosing regimen for dabigatran in patients with severe renal impairment by modeling and simulation. Data from a dedicated renal impairment study were used to model the pharmacokinetics of dabigatran in normal and renal-impaired subjects. Model parameters were used to simulate the average concentration time-course of dabigatran following various dosing regimens. Pharmacokinetics of dabigatran in normal and renal-impaired subjects were best described by a 2-compartment open model with first-order absorption and elimination. Simulations were performed to select an appropriate regimen that reasonably matched the exposures on an average with those observed in subjects with moderate renal impairment who did not require a dose adjustment because of a favorable benefit-risk. Dabigatran 150 mg given once daily resulted in 35% higher average C(max, ss), whereas a 75 mg once daily regimen resulted in 42% lower average Cτ, relative to that observed with 150 mg administered twice daily in subjects with moderate renal impairment. A twice daily regimen of dabigatran 75 mg resulted in a reasonable matching of exposures and was selected as an appropriate dosing regimen in patients with severe renal impairment. This recommendation was incorporated in the dosing and recommendation section of dabigatran product insert.
authors.affiliation: Office of Clinical Pharmacology, Center for Drug Evaluation and Research, US Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD 20993, USA. Rajnikanth.Madabushi@fda.hhs.gov
authors.forename: Sudharshan
authors.initials: S
authors.lastname: Hariharan
authors.forename: Rajanikanth
authors.initials: R
authors.lastname: Madabushi
mesh_terms: D000328:Adult; D000368:Aged; D000991:Antithrombins / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D001562:Benzimidazoles / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D003198:Computer Simulation; D000069604:Dabigatran; D005260:Female; D006801:Humans; D007674:Kidney Diseases / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D055815:Young Adult; D015091:beta-Alanine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics
chemical_list: D000991:Antithrombins; D001562:Benzimidazoles; D015091:beta-Alanine; D000069604:Dabigatran