Doctor of Philosophy
Wesley J. Poynor
An important principle of pharmacokinetic modeling is to use the least complicated model possible that adequately describes the process studied. Pharmacokinetic studies in peritoneal dialysis often attempt to describe the time course of drug concentration in the dialysate. Peritoneal dialysis patients are subjected to the inconvenience and risk of infection associated with sampling peritoneal fluid. Alternative pharmacokinetic models were used to study drug distribution during continuous ambulatory peritoneal dialysis (CAPD). Efficient pharmacokinetic models of distribution in the peritoneal cavity were described for three drugs and the classes they represent.
Procainamide pnarmacokinetics were determined in six CAPD patients. The time course of procainamide or N-acetylprocainamide (NAPA) in the peritoneal fluid is of less interest than the amount cleared through the peritoneum. Therefore the peritoneal cavity is treated as a terminal compartment. Procainamide and NAPA exhibited mean elimination half-lives of 26 and 42.9 hours respectively. CAPD accounted for 1.1% and 13% of total body clearance of procainamide and NAPA respectively.
Phenytoin pharmacokinetics were studied to determine the time course of dialysate phenytoin concentrations with respect to drug unbound to plasma proteins (free phenytoin). The peritoneal cavity was modeled as part of the peripheral compartment. CAPD did not prove to be an effective elimination pathway for phenytoin, accounting for only 2.1% of total body clearance of phenytoin.
Closed compartment pharmacokinetic theory was investigated as an alternative modeling method when the drug has no other elimination pathway than the peritoneal cavity. In this case, vancomycin closed compartment pharmacokinetics were compared to open model analysis. Both models were used to predict an end of dwell concentration by fitting the data from a previous dwell. It was found that the closed model approach required less data and provided prediction close to the open model predictions.
The model used depends on the underlying pharmacokinetic characteristics of the drug and the aims of the study. A terminal compartment method is sufficient when only clearance due to CAPO is required. When the drug is not administered intraperitoneally, the peritoneal space can be described as part of the peripheral compartment. Closed compartment pharmacokinetics are useful when the drug in question is eliminated only through the peritoneum. Whatever model is used, the investigator must consider the integrity of the peritoneal membranes, ultrafiltration, and volume shifts within the peritoneal cavity.
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