Bioequivalence and Bioavailability Forum

Hi Anand,

❝ Why drug having highly variable […] any specific reason?

A manifold of reasons:

• Drugs in BCS Class IV (low permeability & solubility) generally show high variability (both within and between subjects). See also the BDDCS (introduced by Wu and Benet)^1,2.
  
• The high variability may as well be not a property of he drug itself, but of the formulation*. Delayed release pro­ducts are infamous for that. Here it is mainly the physiologic variability in gastric transit which hurts (where mono­lithic formulations ≥ multi­particular ones).
  
• High first-pass effect or presystemic metabolization in the gut wall. Enzymes might also get sat­u­rated at higher doses. In such a case variability increases with dose.
  
• Excipients may influence trans­porters in the gut wall, gastric motility, in vivo solubilty / stability.
  
• And, and, and…

In the context of BE: If high variability is to a larger extent related to the formulation and you are thinking about reference-scaling I would suggest a pilot study in a fully replicated design (RTRT|TRTR or RTR|TRT). If CV_wT < CV_wR you will get a reward in the required sample size of the pivotal study. Try this in :

library(PowerTOST)
CV <- 0.4
# FDA
sampleN.RSABE(CV=CV, theta0=0.9, design="2x2x4", details=F)
sampleN.RSABE(CV=CVp2CV(CV=CV, ratio=0.67), theta0=0.9, design="2x2x4", details=F)
# EMA
sampleN.scABEL(CV=CV, theta0=0.9, design="2x2x4", details=F)
sampleN.scABEL(CV=CVp2CV(CV=CV, ratio=0.67), theta0=0.9, design="2x2x4", details=F)


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1. Wu C-Y, Benet LZ. Predicting drug disposition via application of BCS: transport/absorption/elimination interplay and develop­ment of a biopharmaceutics drug disposition classification system. Pharm Res. 2005;22(1):11–23. doi:10.1007/s11095-004-9004-4.
   
2. Benet LZ, Broccatelli F, Oprea TI. BDDCS Applied to Over 900 Drugs. AAPS J. 2011;13(4):519–47. doi:10.1208/s12248-011-9290-9.  free resource
   

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• Hence, the distinction between HVDs (Highly Variable Drugs) and HVDPs (Highly Variable Drug Pro­ducts). The former show high variability already if administered as a solution.