title: Constructing a prediction interval for time to reach a threshold concentration based on a population pharmacokinetic analysis: an application to basiliximab in renal transplantation.
abstract: Basiliximab is an immunosuppressant chimeric monoclonal antibody directed to the human interleukin-2 receptor alpha-chain used for prevention of acute rejection episodes in organ transplantation. The minimally effective serum concentration necessary to saturate receptor epitopes in kidney transplant patients is 0.2 microgram/ml. To guide dose selection for Phase 3 efficacy trials, a population pharmacostatistical model was fitted to intensively sampled Phase 2 pharmacokinetic data. This served as a basis from which to examine candidate dose regimens with respect to the duration over which receptor-saturating concentrations would be achieved posttransplant. Three prediction methods were assessed: one based on simulations, and two others based on first-order approximation using either inverse regression or inversion of confidence intervals. An 80% prediction interval was generated by each method to evaluate its predictive performance against prospectively collected Phase 3 data in 39 renal transplant patients who received two injections of 20 mg basiliximab, one prior to surgery and one on Day 4 posttransplant. All methods provided correct prediction of the duration of receptor-saturating concentration. As anticipated, the best performance was obtained from the simulation method which predicted 30 values in the 80% prediction interval, 19.7-52.7 days. The actually observed 80% interval from the Phase 3 data was 23.7-58.3 days.
authors.affiliation: INSERM U436, Paris, France.
authors.forename: F
authors.initials: F
authors.lastname: Mentré
authors.forename: J
authors.initials: J
authors.lastname: Kovarik
authors.forename: C
authors.initials: C
authors.lastname: Gerbeau
mesh_terms: D000465:Algorithms; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics*; D000077552:Basiliximab; D002138:Calibration; D003198:Computer Simulation; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics*; D016030:Kidney Transplantation / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D015233:Models, Statistical; D017711:Nonlinear Dynamics; D011153:Population; D011237:Predictive Value of Tests; D011993:Recombinant Fusion Proteins
chemical_list: D000911:Antibodies, Monoclonal; D007166:Immunosuppressive Agents; D011993:Recombinant Fusion Proteins; D000077552:Basiliximab