Bioequivalence and Bioavailability Forum

Physiologically based pharmacokinetic models coupled with pharmacodynamic (PBPK/PD) models can be useful to identify whether current bioequivalence criteria is overly conservative or venture­some for different drugs. A PBPK model constructed with Simcyp Simulator^® using reported bio­phar­ma­ceutics parameters for ibuprofen was coupled with two published PD models: one for anti­pyresis and one for dental pain relief. Using products with doses of 400 mg and 10 mg/kg as “reference (R)” drug products, virtual products with doses of 280 mg and 7 mg/kg, respectively, could be inter­preted as representing bioinequivalent test (T) drug products, as the point estimate for the ratios T/R are well below the bioequivalence limits. Despite being bioinequivalent in terms of PK, these lower doses were shown to be therapeutically equivalent to the higher doses because of the flat dose–re­sponse relationship of ibuprofen. Sensitivity analysis of the PBPK/PD models de­mon­strated that gas­tric emptying time, dissolution rate and small intestine pH are variables that influence ibuprofen PK, but do not seem to significantly affect its PD. It was concluded that cur­rent bioequivalent guid­ance might be unnecessarily restrictive for ibuprofen products.

• Cristofoletti R, Dressman JB. Use of Physiologically Based Pharmacokinetic Models Coupled with Pharmacodynamic Models to Assess the Clinical Relevance of Current Bioequivalence Criteria for Generic Drug Products Containing Ibuprofen. J Pharm Sci. 2014;103(10):3263–75. doi:10.1002/jps.24076.