Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
2484679 | Journal of Pharmaceutical Sciences | 2014 | 13 Pages |
Abstract
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 400Â mg and 10 mg/kg as “reference (R)” drug products, virtual products with doses of 280Â 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.
Keywords
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Authors
Rodrigo Cristofoletti, Jennifer B. Dressman,