Lutz Harnisch, Willi Weber,Hoechst Marion Roussel
Clinical Development, Frankfurt/Main, Germany
The purpose of searching for drug-drug interactions (DDIs) is to characterize subgroups of populations which require different dosing regimens compared to the normal population. The population pharmacokinetic screen technology (1) can be used to search for DDIs, and it’s capability has already been shown (2). Nevertheless, the number of potential drug permutations in a typical clinical trial is prohibitively large. Thus, one is compelled to use a drug grouping technique, using knowledge of the chemistry and pharmacology of the drugs involved. If a DDI is not found, little can be said about the real absence of the DDI in question, because the null hypothesis (no DDI is present) can only be accepted if there is enough certainty that a DDI would have been found if one had existed. Therefore, the sensitivity of the dataset has to be tested by means of simulations. These simulations can declare confidence limits for each DDI in question for the rejection of the null hypothesis in a specific dataset.
1. Peck-CC; Barr-WH; Benet-LZ; Collins-J; Desjardins-RE; Furst-DE; Harter-JG; Levy-G; Ludden-T; Rodman-JH; et-al, Opportunities for integration of pharmacokinetics, pharmacodynamics, and toxicokinetics in rational drug development, J-Clin-Pharmacol. 1994 Feb; 34(2): 111 – 9.
2. Antal-EJ; Grasela-TH Jr; Ereshefsky-L; Wells-BG; Evans-RL; Smith-RB, A multi-center study to evaluate the pharmacokinetic and clinical interactions between alprazolam and imipramine, J-Pharmacokinet-Biopharm. 19/3 suppl. (93S-100S) 1991.
Reference: PAGE 6 () Abstr 602 [www.page-meeting.org/?abstract=602]
Poster: oral presentation