Utility of NONMEM

From HARRISONF@cder.fda.gov Tue Jul 9 07:29:46 1996 Subject: Utility of NONMEM I don't have the references at hand, but NONMEM has also been tested in bioequivalence: RD Heparin, analyzed and published by the sponsor's people, around 1993 Interesting conjectures, for all low-molecular weight heparins: The macro-molecule appears to continue changing its length during storage, changing its time-PD profile when used. Subtle changes in manufacturing process might change the distribution of lengths of the macro-molecules and thereby change the time-PD profiles, changing safety and efficacy. Outcome affected whether the drug product was considered to have a sufficiently stable manufacturing process for approval, and was considered for routine GMP and showing generic bioequivalence. ? I heard a bioequivalence was done by Nancy Sambol Although FDA generally uses AUC and Cmax to evaluate bioequivalence, for some drugs, a more rigorous model-based approach may be needed to show equivalence in safety and therapeutic effect. For example, I vaguely remember DDI having a 1-1.5 hour half life with daily dosing. DDI appears to follow a typical antibiotic "paradigm", in which the goal is to get the concentration above some threshold at which it starts to kill or prevent reproduction of the parasite, keep it there for a while, and drop back so the patient won't get unacceptable side effects. I beleive flexible, model-based tools like NONMEM may be sufficiently useful in such cases to justify the additional human labor needed for analysis and to persuade the concerned parties that the analysis is valid. In summary, I'm sure NONMEM and similar softwares have a niche in the drug development (and treatment) process. The questions I wonder about are the current and future sizes and locations of the niche.