Constructing a prediction interval for time to reach a threshold concentration based on a population pharmacokinetic analysis: an application to basiliximab in renal transplantation

J Pharmacokinet Biopharm. 1999 Apr;27(2):213-30. doi: 10.1023/a:1020658023774.

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.

Publication types

  • Clinical Trial
  • Clinical Trial, Phase II
  • Clinical Trial, Phase III
  • Randomized Controlled Trial

MeSH terms

  • Algorithms
  • Antibodies, Monoclonal / pharmacokinetics*
  • Basiliximab
  • Calibration
  • Computer Simulation
  • Double-Blind Method
  • Female
  • Humans
  • Immunosuppressive Agents / pharmacokinetics*
  • Kidney Transplantation / physiology*
  • Male
  • Middle Aged
  • Models, Statistical
  • Nonlinear Dynamics
  • Population
  • Predictive Value of Tests
  • Recombinant Fusion Proteins*

Substances

  • Antibodies, Monoclonal
  • Immunosuppressive Agents
  • Recombinant Fusion Proteins
  • Basiliximab