In Vivo Bioavailability and Bioequivalence Using Threshold Responses and KD
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Solution Overview
Problem
Existing methods for determining bioavailability and bioequivalence of drugs in vivo in humans are inadequate as they rely on peak plasma concentrations, which do not accurately reflect drug efficacy due to differences in metabolic patterns and transfer times to tissue sites.
Innovation Solution
Measure drug concentrations at receptor sites and responses to obtain intrinsic activities and dissociation constants (KD values) in vivo in humans, using a method that directly assesses drug effectiveness by measuring onset time, threshold doses, and intrinsic activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If plasma concentration measurements are used to estimate bioavailability, then the measurement process is simple and non-invasive, but the accuracy of bioavailability determination deteriorates because plasma concentrations do not accurately reflect drug efficacy at receptor sites
Solution Approach 1:
The patent uses plasma concentration measurements as an intermediary to indirectly assess drug efficacy at receptor sites. By establishing mathematical relationships between plasma concentrations and receptor site concentrations, the method translates easily obtainable plasma data into meaningful efficacy parameters without directly measuring receptor interactions in vivo.
Solution Approach 2:
The patent transforms the measurement approach by changing from direct receptor site concentration measurement to plasma concentration measurement with mathematical correction. This parameter change allows use of simpler, non-invasive plasma sampling while maintaining accuracy through correction factors derived from pharmacokinetic-pharmacodynamic modeling.
2Measurement precision
If radio labelled drugs are used to determine in vivo binding parameters, then direct measurement of drug-receptor interaction is achieved, but the method becomes unsuitable for human studies due to radiation safety concerns and altered binding characteristics
Solution Approach 1:
The patent creates a mathematical model that copies the essential features of radio labelled drug binding behavior using non-radioactive drugs. By measuring plasma concentrations and applying pharmacokinetic-pharmacodynamic relationships, the method replicates the information obtained from radio labelled studies without the harmful effects of radiation or altered binding characteristics.
Solution Approach 2:
The patent replaces expensive, hazardous radio labelled compounds with inexpensive, safe non-radioactive drugs. The method uses readily available clinical drug substances and eliminates the need for complex radiochemistry while providing equivalent or superior information for human studies.
3Ease of manufacture
If in vitro KD values from cell cultures are used to predict in vivo drug behavior, then laboratory measurements are straightforward and controllable, but the values fail to predict actual in vivo efficacy due to metabolic and transfer time differences
Solution Approach 1:
The patent establishes a feedback loop between in vitro measurements and in vivo observations. By comparing predicted in vivo behavior from in vitro data with actual clinical outcomes, the method refines pharmacokinetic-pharmacodynamic models to improve predictive accuracy while maintaining the simplicity of in vitro screening.
Solution Approach 2:
The patent uses plasma concentration-time profiles as an intermediary to bridge in vitro and in vivo measurements. This intermediary allows translation of controlled laboratory data into clinically relevant predictions by accounting for metabolic processes and tissue transfer dynamics that occur in the living system.
Data Source
AI summary
Bioequivalence and/or bioavailability data are mandatory for filing of NDA and ANDA. Presently in absence of proper procedures estimates of these data through peak plasma level concentrations and time to reach peak plasma levels are used. The method suffers from the serious drawback that peak plasma levels do not correlate with efficacy due to delay in transfer to tissue sites as well as differences in metabolic patterns in drugs. Here we have devised a novel method for determination of bioavailability and bioequivalence from measurement of threshold times and concentrations, intrinsic activity, and dissociation constants in vivo in humans. The method essentially determines Intrinsic activities and threshold doses through measurement of drug responses in humans and then uses a mathematical expression to determine KD values of drugs, in vivo, in humans. The process may be applied to animals as well. The method would go a long way in evaluation of true bioavailability and bioequivalence and would also be useful in design.