title: Estimation of the comparative therapeutic superiority of QD and BID dosing regimens, based on integrated analysis of dosing history data and pharmacokinetics.
abstract: Once-daily dosing almost invariably shows a slightly higher percentage of prescribed doses taken than does twice-daily dosing. Many pharmaceutical scientists, regulators, and prescribers have considered this finding to signify the therapeutic superiority of once-daily dosing. The therapeutically more relevant question, however, is not the percentage of prescribed doses taken but the comparative impact of missed doses on the pharmacologic effects of a drug under the two dosing regimens. A key point in this regard is that the pharmacokinetic equivalent of a single missed once-daily dose is 2-3 sequentially omitted twice-daily doses. Thus, an important parameter in comparing the two regimens is the probability of two or three twice-daily doses being sequentially omitted, versus the probability of missing a single once-daily dose. Our data indicate that the probability of sequential omission of 2-3 twice daily doses is half the probability of omission of a single once-daily dose. For that reason, a twice-daily regimen could prove to be superior to a once-daily regimen in maintaining drug concentrations within a therapeutically desirable range. A more important consideration, however, is to maintain not just the concentration of drug in plasma, but the drug's therapeutic action. The duration of therapeutic drug action following a last-taken dose is not only drug-specific, but also, for some drug, dependent on the pharmacodynamic properties. Judging the comparative superiority of one dosing regimen over another requires knowledge of the drug's duration action after a last-taken dose, plus knowledge of the comparative probabilities of the various patterns of dose omission. When applied to HIV protease inhibitors, a twice-daily regimen appears to be better than an once-daily regimen in maintaining therapeutically effective drug actions.
authors.affiliation: Department of Mathematics, University of Liège, B37, 12, Grande Traverse, Liege 4000, Belgium. l.comte@ulg.ac.be
authors.forename: Laetitia
authors.initials: L
authors.lastname: Comté
authors.forename: Bernard
authors.initials: B
authors.lastname: Vrijens
authors.forename: Eric
authors.initials: E
authors.lastname: Tousset
authors.forename: Paul
authors.initials: P
authors.lastname: Gérard
authors.forename: John
authors.initials: J
authors.lastname: Urquhart
mesh_terms: D000465:Algorithms; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D015658:HIV Infections / Q000188:drug therapy; D017320:HIV Protease Inhibitors / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D006801:Humans; D008954:Models, Biological; D016017:Odds Ratio; D010349:Patient Compliance; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D017320:HIV Protease Inhibitors