An approach to characterize pharmacokinetic‐pharmacodynamic bioequivalence of propofol

Bioequivalence assumes, that two different formulations of drugs with comparable pharmacokinetics (PK) cause comparable pharmacodynamics (PD) or therapeutic effects. To compare the PK/PD relationship of different drug formulations, such approach is not established. The electroencephalogram (EEG) is widely used to investigate the effects of anesthetic drugs on the central nervous system. Therefore, we compared the PD of two different formulations of propofol on the bispectral index (BIS) of EEG. In a randomized double‐blind two way cross‐over study, twenty healthy volunteers received 2 mg/kg BW of 2% propofol (test) and disoprivan 2% (reference), respectively, on different days by a programmed infusion pump during one minute. The individual concentration‐effect relationship of propofol where described using a sigmoidal E max model. Test and reference where bioequivalent by standard pharmacokinetic measures. After start of infusion the BIS decreased rapidly within two minutes and returned to baseline after 15 minutes. No significant differences in pharmacodynamic parameters where observed: E 0 95±2 vs. 96±3, E max 40±13 vs. 46±15, and EC 50 1191±311 vs. 1214±367 mcg/L (test vs. reference, mean±SD; n=17). In conclusion, two PK bioequivalent formulations of propofol where also not different in PK/PD comparison. In specific therapeutic areas, the use of PK/PD data may improve the generic drug development process but pharmacodynamic bioequivalence needs further characterization. Clinical Pharmacology & Therapeutics (2004) 75 , P3–P3; doi: 10.1016/j.clpt.2003.11.010