title: Dynamic calibration of pharmacokinetic parameters in dose-finding studies.
abstract: We introduce a dose-finding algorithm to be used to identify a level of dose that corresponds to some given targeted response. Our motivation arises from problems where the response is a continuously measured quantity, typically some pharmacokinetic parameter. We consider the case where an agreed level of response has been determined from earlier studies on some population and the purpose of the current trial is to obtain the same, or a comparable, level of response in a new population. This relates to bridging studies. The example driving our interest comes from studies on drugs for HIV that have already been evaluated in adults and where the new studies are to be carried out in children. These drugs have the ability to produce some given mean pharmacokinetic response in the adult population, and the goal is to calibrate the dose in order to obtain a comparable response in the childhood population. In practice, it may turn out that the dose producing some desired mean response is also associated with an unacceptable rate of toxicity. In this case, we may need to reevaluate the target response and this is readily achieved. In simulations, the algorithm can be seen to work very well. In the most challenging situations for the method, those where the targeted response corresponds to a region of the dose-response curve that is relatively flat, the algorithm can still perform satisfactorily.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, LSTA, Université Pierre et Marie Curie-Paris 6, Paris, France. jmoquigley@gmail.com
authors.forename: John
authors.initials: J
authors.lastname: O'Quigley
authors.forename: Michael D
authors.initials: MD
authors.lastname: Hughes
authors.forename: Terry
authors.initials: T
authors.lastname: Fenton
authors.forename: Lixia
authors.initials: L
authors.lastname: Pei
mesh_terms: D000328:Adult; D000465:Algorithms; D002648:Child; D017321:Clinical Trials, Phase I as Topic / Q000379:methods*; D003198:Computer Simulation; D015658:HIV Infections / Q000188:drug therapy; D006801:Humans; D019469:Indinavir / Q000493:pharmacokinetics; D010599:Pharmacokinetics
chemical_list: D019469:Indinavir