Physiology-based simulations of a pathological condition: prediction of pharmacokinetics in patients with liver cirrhosis.
BACKGROUND
Liver cirrhosis is a progressive disease characterized by loss of functional hepatocytes with concomitant connective tissue and nodule formation in the liver. The morphological and physiological changes associated with the disease substantially affect drug pharmacokinetics. Whole-body physiologically based pharmacokinetic (WB-PBPK) modelling is a predictive technique that quantitatively relates the pharmacokinetic parameters of a drug to such (patho-)physiological conditions.


OBJECTIVE
To extend an existing WB-PBPK model, based on the physiological changes associated with liver cirrhosis, which allows for prediction of drug pharmacokinetics in patients with liver cirrhosis.


METHODS
The literature was searched for quantitative measures of the physiological changes associated with the presence of Child-Pugh class A through C liver cirrhosis. The parameters that were included were the organ blood flows, cardiac index, plasma binding protein concentrations, haematocrit, functional liver volume, hepatic enzymatic activity and glomerular filtration rate. Predictions of pharmacokinetic profiles and parameters were compared with literature data for the model compounds alfentanil, lidocaine (lignocaine), theophylline and levetiracetam.


RESULTS
The predicted versus observed plasma concentration-time profiles for alfentanil and lidocaine were similar, such that the pharmacokinetic changes associated with Child-Pugh class A, B and C liver cirrhosis were adequately described. The theophylline elimination half-life was greatly increased in Child-Pugh class B and C patients compared with controls, as predicted by the model. Levetiracetam urinary excretion was consistently reduced with disease progression and very closely resembled observed values.


CONCLUSIONS
Consideration of the physiological differences between healthy individuals and patients with liver cirrhosis was important for the simulation of drug pharmacokinetics in this compromised group. The WB-PBPK model was altered to incorporate these physiological differences with the result of adequate simulation of drug pharmacokinetics. The information provided in this study will allow other researchers to further validate this liver cirrhosis model within a WB-PBPK model.
Competence Center Systems Biology, Bayer Technology Services GmbH, Leverkusen, Germany. aedginto@uwaterloo.ca
Andrea N
AN
Edginton
Stefan
S
Willmann
D015760:Alfentanil / Q000493:pharmacokinetics*; D006801:Humans; D000077287:Levetiracetam; D008012:Lidocaine / Q000493:pharmacokinetics*; D008103:Liver Cirrhosis / Q000378:metabolism*; D008954:Models, Biological; D010889:Piracetam / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D013806:Theophylline / Q000493:pharmacokinetics*
D015760:Alfentanil; D000077287:Levetiracetam; D008012:Lidocaine; D013806:Theophylline; D010889:Piracetam