Improving the Accuracy of Total Body Clearance Measurement
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Issue Date
2017
Authors
LaPorte, Brandon '17
Degree
MS in Pharmaceutical Sciences
Advisor
Musteata, Marcel F
Committee Members
Zheng, HaiAn
Voigt, Jeffrey M.
Voigt, Jeffrey M.
Journal Title
Journal ISSN
Volume Title
Abstract
Purpose Studies have showed that by assuming arteriovenous drug concentrations are homogenous after intravenous (IV) bolus injection, the determination of total body clearance based on venous drug concentrations is often inaccurate. Therefore, this investigation seeks to identify current inaccuracies in clearance calculations and to find an approach for accurately determining the correct value of total body clearance (Cl). By knowing the actual value of Cl pharmacologists can better understand drug disposition and ultimately design better drug dosing regimens.
Methods An in vitro fluidic pharmacokinetic (PK) profile generator was assembled based on relevant PK parameters of a rat in order to generate profiles corresponding to a physiological model consisting of a circulatory system, rapidly equilibrating tissue (RET), slowly equilibrating tissue (SET), and drug eliminating organ (DEO). Pumps and tubing were used to create the device and a spectrophotometric assay was used to determine the drug concentration, data was collected automatically online. Drug elimination was achieved with a fluid exchange pump or via a dialysis filter. The setup was used to generate bi-exponential concentration versus time curves. From these PK profiles, the value of Cl was calculated using established equations as well as recently proposed models (such as Berezhkovskiy\342\200\231s approach).
Results The device successfully generated 29 different types of PK profiles corresponding to various sampling sites, administration locations, and fluid flow rates. The results show large differences in Cl values calculated with published equations relative to the actual value of Cl (measured based on fluid volume and amount of drug eliminated), ranging from -25% up to 200%. Moreover, alterations in sampling site, administration location, or fluid flow rates each influence the extent of error in clearance determinations.
Conclusions This is first time these experiments were performed accurately in an in vitro system. The data shows that a significant drug concentration gradient exists within the circulatory system and tissues. This gradient depends on blood flow rates, administration location, and drug properties. Because of this gradient, the location of the sampling and administration sites influences the calculated area under the curve (AUC). This can lead to significant errors and variability in experimental determination of total body Cl. The best way to address this issue is to inject a drug at a peripheral location to allow for sufficient mixing and then sample from a large vein. Extrapolating for missing data can also lead to large errors in clearance calculation; this can be addressed by collecting more samples early after IV bolus administration or by collecting data during steady state conditions for an IV infusion.
Methods An in vitro fluidic pharmacokinetic (PK) profile generator was assembled based on relevant PK parameters of a rat in order to generate profiles corresponding to a physiological model consisting of a circulatory system, rapidly equilibrating tissue (RET), slowly equilibrating tissue (SET), and drug eliminating organ (DEO). Pumps and tubing were used to create the device and a spectrophotometric assay was used to determine the drug concentration, data was collected automatically online. Drug elimination was achieved with a fluid exchange pump or via a dialysis filter. The setup was used to generate bi-exponential concentration versus time curves. From these PK profiles, the value of Cl was calculated using established equations as well as recently proposed models (such as Berezhkovskiy\342\200\231s approach).
Results The device successfully generated 29 different types of PK profiles corresponding to various sampling sites, administration locations, and fluid flow rates. The results show large differences in Cl values calculated with published equations relative to the actual value of Cl (measured based on fluid volume and amount of drug eliminated), ranging from -25% up to 200%. Moreover, alterations in sampling site, administration location, or fluid flow rates each influence the extent of error in clearance determinations.
Conclusions This is first time these experiments were performed accurately in an in vitro system. The data shows that a significant drug concentration gradient exists within the circulatory system and tissues. This gradient depends on blood flow rates, administration location, and drug properties. Because of this gradient, the location of the sampling and administration sites influences the calculated area under the curve (AUC). This can lead to significant errors and variability in experimental determination of total body Cl. The best way to address this issue is to inject a drug at a peripheral location to allow for sufficient mixing and then sample from a large vein. Extrapolating for missing data can also lead to large errors in clearance calculation; this can be addressed by collecting more samples early after IV bolus administration or by collecting data during steady state conditions for an IV infusion.
Citation
LaPorte, B. Improving the accuracy of total body clearance measurement [thesis]. Ann Arbor (MI): Proquest LLC; 2017. 68 p.
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