title: Bayesian population approaches to the analysis of dose escalation studies.
abstract: In dose escalation studies cohorts of subjects are given increasing doses of a candidate drug to assess safety and tolerability, pharmacokinetics and pharmacological response. The escalation is carried on until a predefined stopping limit is achieved, often identified by a pharmacokinetic endpoint such as peak plasma concentration or area under the plasma concentration-time profile. In the present work, the application of Bayesian methodologies to Phase I dose escalation studies is explored. A Bayesian population model is devised, which provides predictions of dose-response and dose-risk curves, both for individuals already enrolled in the trial and for a new, previously untested subject. Empirical and fully Bayesian estimation algorithms are worked out. Such methods provide equivalent performances on both experimental and simulated datasets. With respect to previous work, it is quantitatively proven not only that a more general and flexible model is identifiable, but also that such flexibility is needed in real scenarios.
authors.affiliation: Department of Computer Engineering and Systems Science, University of Pavia, Pavia, Italy. alberto.russu@unipv.it
authors.forename: Alberto
authors.initials: A
authors.lastname: Russu
authors.forename: Giuseppe
authors.initials: G
authors.lastname: De Nicolao
authors.forename: Italo
authors.initials: I
authors.lastname: Poggesi
authors.forename: Marta
authors.initials: M
authors.lastname: Neve
authors.forename: Roberto
authors.initials: R
authors.lastname: Gomeni
mesh_terms: D001499:Bayes Theorem; D017321:Clinical Trials, Phase I as Topic / Q000379:methods* / Q000706:statistics & numerical data*; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D023381:Endpoint Determination / Q000379:methods*; D006801:Humans; D016013:Likelihood Functions; D008954:Models, Biological; D015233:Models, Statistical; D004364:Pharmaceutical Preparations / Q000097:blood; D010599:Pharmacokinetics
chemical_list: D004364:Pharmaceutical Preparations