Pharmacon Research, Berlin, Germany
The FDA Guidance for Industry „Pharmacokinetics in Patients with Impaired Hepatic Function" suggests characterization of impairment of liver function by using different clearance tests like indocyanine green, antipyrine and oxazepam. The diagnostic value of these function tests has been evaluated in a pharmacokinetic trial in hepatically impaired patients and healthy controls.
Methods
A total number of 18 subjects were enrolled in a pharmacokinetic trial with a new chemical entity. 12 subjects had varying degrees of hepatic impairment (Child-Pugh A and B) and 6 subjects did not have hepatic impairment. In an approach to characterize deficiencies in hepatic function, hepatic drug metabolism was examined in all subjects by using a cocktail design with three different model compounds: antipyrine to express phase-I oxidation (unspecific), oxazepam to express phase-II conjugation and indocyanine green (ICG) to express hepatic blood flow. Clearance tests were correlated to the new chemical entity, the clinical Child-Pugh score as well as among each other.
Results
The apparent plasma clearance of the new chemical entity was correlated with those of antipyrine, oxazepam and indocyanine green (ICG) as model compounds for hepatic function. Oxazepam exhibited a poor correlation (r=0.421), but the correlations with antipyrine clearance (r=0.617) and ICG clearance (r=0.639) also were not overly expressed. All clearances showed a decreasing trend with increasing impairment of hepatic function. Oxazepam and antipyrine correlated well with the ICG clearance so that hepatic blood flow seems to be the major discriminating factor.