Why Highly Variable Drugs are Safer. Leslie Z. Benet, Ph.D. Professor of Biopharmaceutical Sciences University of California San Francisco FDA Advisory Committee for Pharmaceutical Science Rockville, MD October 6, 2006. I have made two previous presentations on this topic to ACPS.
Leslie Z. Benet, Ph.D.
Professor of Biopharmaceutical Sciences
University of California San Francisco
FDA Advisory Committee for Pharmaceutical Science
October 6, 2006
relatively minor concern for drugs with
narrow therapeutic indices?
NTIDrugs Frequently Proposed
to Limit Generic Substitution
Conjugated Estrogens 42 14-15
Cyclosporine (Neoral Package Insert) 20-50 9-21
Furosemide 59 15
Levothyroxine sodium 20 <20
Phenytoin sodium 51 10-15
Theophyllin sustained release 31 11-14 Warfarin sodium 53 6-11
Black numbers(Benet, Transplant. Proc. 31: 1642-44. 1999)
(µT - µR)2 + D2 + (WT2 - WR2) <
For wide-therapeutic index highly variable drugs we should not have to study an excessive number of patients to prove that two equivalent products meet preset (one size fits all ) statistical criteria.
This is because ,by definition, highly variable approved drugs must have a wide therapeutic index, otherwise there would have been significant safety issues and lack of efficacy during Phase 3
Highly variable narrow therapeutic index drugs are dropped in Phase 2 since it is not possible to prove either efficacy or safety.
Should pharmacogenetics be considered in setting the criteria?
For some drugs, high variability may be the result of genetic polymorphisms
Can we make some general conclusions as to when metabolic and transporter genetic polymorphisms will be important clinically in terms of drug disposition?
CYP 2D6 For sure MDR1 No
CYP 2C19 Yes OATPs Yes
CYP 2C9 Yes OCTs Yes
CYP 3A4 No OATs Probably
CYP 1A2 Maybe MRP2 Maybe
UGT 1A1 Maybe Other ABC
NAT2 No transporters ??
It is important to note that when I presented the recommendations of the Expert Panel (2001) as well as my own recommendations (2004) to the ACPS, the following were also stated:
There is no scientific basis or rationale for the point estimate recommendations
2. There is no belief that addition of the point estimate criteria will improve the safety of approved generic drugs
3. The point estimate recommendations are only “political” to give greater assurance to clinicians and patients who are not familiar (don’t understand) the statistics of highly variable drugs