Application of Hill's equation for estimating area under the concentration-time curve (AUC) and use of time to AUC 90% for expressing kinetics of drug disposition.
BACKGROUND
Half life and its derived pharmacokinetic parameters are calculated on an assumption that the terminal phase of drug disposition follows a constant rate of disposition. In reality, this assumption may not necessarily be the case. A new method is needed for analyzing PK parameters if the disposition does not follow a first order PK kinetic.


METHODS
Cumulative area under the concentration-time curve (AUC) is plotted against time to yield a hyperbolic (or sigmoidal) AUC-time relationship curve which is then analyzed by Hill's equation to yield AUC(inf), time to achieving AUC50% (T(AUC50%)) or AUC90% (T(AUC90%)), and the Hill's slope.


RESULTS
From these parameters, an AUC-time relationship curve can be reconstructed. Projected plasma concentration can be calculated for any time point. Time at which cumulative AUC reaches 90% (T(AUC90%)) can be used as an indicator for expressing how fast a drug is cleared. Clearance is calculated in a traditional manner (i.v. dose/AUC(inf)), and the volume of distribution is proposed to be calculated at T(AUC50%) (0.5 i.v. dose/plasma concentration at T(AUC50%)).


CONCLUSIONS
This method of estimating AUC is applicable for both i.v. and oral data. It is concluded that the Hill's equation can be used as an alternative method for estimating AUC and analysis of PK parameters if the disposition does not follow a first order kinetic. T(AUC90%) is proposed to be used as an indicator for expressing how fast a drug is cleared from the system.
Cheng
Hsien C
HC
Safety Pharmacology, Drug Safety Evaluation, 1041 Route 202/206, sanofi-aventis, Bridgewater, NJ 08807, USA. hsien.cheng@sanofi-aventis.com
D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D006207:Half-Life; D004364:Pharmaceutical Preparations / Q000097:blood* / Q000378:metabolism; D051381:Rats; D014018:Tissue Distribution / Q000502:physiology
D004364:Pharmaceutical Preparations