Key result
A novel four-compartment PBPK heart model successfully predicted amitriptyline concentrations across cardiac tissue layers, estimating a total cardiac clearance of 0.316 L/h.
A novel four-compartment PBPK heart model demonstrates feasibility in predicting active drug concentrations within specific locations of cardiac tissue.
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PBPK models may estimate cardiac drug levels where sampling is infeasible; leaves open clinical utility pending validation.
In the field of cardiac drug efficacy and safety assessment, information on drug concentration in heart tissue is desirable. Because measuring drug concentrations in human cardiac tissue is challenging in healthy volunteers, mathematical models are used to cope with such limitations. With a goal of predicting drug concentration in cardiac tissue, we have developed a whole-body PBPK model consisting of seventeen perfusion-limited compartments. The proposed PBPK heart model consisted of four compartments: the epicardium, midmyocardium, endocardium, and pericardial fluid, and accounted for cardiac metabolism using CYP450. The model was written in R. The plasma:tissues partition coefficients (Kp) were calculated in Simcyp Simulator. The model was fitted to the concentrations of amitriptyline in plasma and the heart. The estimated parameters were as follows: 0.80 for the absorption rate [h −1 ], 52.6 for Kp rest , 0.01 for the blood flow through the pericardial fluid [L/h], and 0.78 for the P-parameter describing the diffusion between the pericardial fluid and epicardium [L/h]. The total cardiac clearance of amitriptyline was calculated as 0.316 L/h. Although the model needs further improvement, the results support its feasibility, and it is a first attempt to provide an active drug concentration in various locations within heart tissue using a PBPK approach.
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Tylutki et al. (2017) studied Cardiac drug concentration prediction. Amitriptyline was evaluated on Total cardiac clearance of amitriptyline. A novel four-compartment PBPK heart model successfully predicted amitriptyline concentrations across cardiac tissue layers, estimating a total cardiac clearance of 0.316 L/h.
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