Tk-GV Renal Clearance Algorithm Using Tikhonov Regularization
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Solution Overview
Problem
Current methods for estimating renal plasma clearance, such as gold standard tests and curve fitting models, are impractical, inaccurate, and fail to adequately model renal elimination mechanisms, particularly in patients with low renal function, due to issues like anaphylactic reactions, lengthy data collection periods, and overestimation of clearance rates.
Innovation Solution
The Tk-GV method uses a computer program with a gamma variate function and Tikhonov regularization to model drug plasma concentration, minimizing error in renal plasma clearance calculations, allowing for precise and accurate renal function estimation with fewer samples over a shorter period.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If gold standard tests (inulin constant infusion or 24-hour AUC integration) are used to measure renal plasma clearance, then measurement accuracy is improved, but the testing time and complexity increase significantly making it impractical for clinical settings
Solution Approach 1:
The patent segments the 24-hour continuous monitoring requirement into a simplified 2-hour sampling protocol using a bolus injection followed by plasma sampling at specific time points (0.5, 1, 1.5, and 2 hours). This segmentation reduces the testing duration from 24 hours to 2 hours while maintaining measurement accuracy through strategically selected sampling times that capture the elimination phase kinetics.
Solution Approach 2:
The patent applies preliminary action by performing a bolus injection of inulin followed by immediate plasma sampling at predetermined time points, rather than requiring continuous 24-hour urine collection. The mathematical model (gamma variate function) is pre-programmed to calculate clearance from these limited samples, eliminating the need for extended monitoring and complex urine collection procedures.
2Measurement precision
If inulin constant infusion is used to measure glomerular filtration rate, then measurement accuracy is improved, but the risk of anaphylactic shock increases
Solution Approach 1:
The patent inverts the traditional constant infusion approach by using a bolus injection followed by elimination phase sampling instead of continuous infusion. This reversal eliminates the prolonged exposure to inulin that causes anaphylactic reactions while still allowing accurate measurement of renal clearance through the elimination kinetics captured in the first 2 hours post-injection.
Solution Approach 2:
The patent extracts only the essential measurement component (plasma concentration during elimination phase) from the problematic constant infusion protocol. By removing the continuous infusion element and relying solely on the elimination phase kinetics after a single bolus dose, the method retains measurement accuracy while eliminating the harmful prolonged exposure that triggers anaphylaxis.
3Loss of time
If curve fitting models (SET or GV) are used to estimate renal plasma clearance, then testing time is reduced, but measurement accuracy deteriorates due to overestimation of clearance rates
Solution Approach 1:
The patent changes the mathematical model parameters by selecting specific sampling time points (0.5, 1, 1.5, and 2 hours) that optimize the gamma variate function fit to capture the elimination phase kinetics. This parameter optimization ensures accurate clearance estimation without overestimation, while maintaining the shortened 2-hour testing duration. The model parameters are tuned to minimize bias in the clearance calculation.
Data Source
AI summary
Plasma concentration of a compound of interest is measured in two or ideally 4 or more blood samples taken from a patient over a period of time following bolus injection. The measured values are input into a computer processor programmed to execute a computer program comprising an algorithm that uses the gamma variate (GV) function to model drug plasma concentration, then uses Tikhonov regularization to perform the fit, selecting a regularization constant so that the relative error in the plasma clearance is minimized. One or more output values representative of renal function are generated.