title: Optimal individualized dosing strategies: A pharmacologic approach to developing dynamic treatment regimens for continuous-valued treatments.
abstract: There have been considerable advances in the methodology for estimating dynamic treatment regimens, and for the design of sequential trials that can be used to collect unconfounded data to inform such regimens. However, relatively little attention has been paid to how such methodology could be used to advance understanding of optimal treatment strategies in a continuous dose setting, even though it is often the case that considerable patient heterogeneity in drug response along with a narrow therapeutic window may necessitate the tailoring of dosing over time. Such is the case with warfarin, a common oral anticoagulant. We propose novel, realistic simulation models based on pharmacokinetic-pharmacodynamic properties of the drug that can be used to evaluate potentially optimal dosing strategies. Our results suggest that this methodology can lead to a dosing strategy that performs well both within and across populations with different pharmacokinetic characteristics, and may assist in the design of randomized trials by narrowing the list of potential dosing strategies to those which are most promising.
authors.affiliation: Department of Epidemiology, Biostatistics and Occupational Health, McGill University, 1020 Pine Avenue West, Montreal, QC H3A 1A2, Canada.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Rich
authors.affiliation: Department of Epidemiology, Biostatistics and Occupational Health, McGill University, 1020 Pine Avenue West, Montreal, QC H3A 1A2, Canada.
authors.forename: Erica E M
authors.initials: EE
authors.lastname: Moodie
authors.affiliation: Department of Mathematics and Statistics, McGill University, 805 Sherbrooke Street West, Montreal, QC H3A 2K6, Canada.
authors.forename: David A
authors.initials: DA
authors.lastname: Stephens
mesh_terms: D000925:Anticoagulants / Q000008:administration & dosage / Q000493:pharmacokinetics; D002985:Clinical Protocols; D003198:Computer Simulation; D054796:Drug Dosage Calculations; D006801:Humans; D057285:Precision Medicine / Q000379:methods*; D014859:Warfarin / Q000008:administration & dosage / Q000493:pharmacokinetics
chemical_list: D000925:Anticoagulants; D014859:Warfarin
keywords: Adaptive individualized dosing; Anticoagulation therapy; Continuous doses; Dynamic treatment regimens; G-estimation