Intravenous (IV) dosing refers to the administration of a drug directly into the bloodstream by injection (bolus) or continuous infusion. This is a favored route to dose test articles given its straightforward nature as compounds bypass first-pass metabolism and enter systemic circulation instantaneously and completely. This can be a great method to gauge efficacy or target engagement before tuning oral bioavailability or to better understand toxicity at very high exposures of the compound.
This particular curve fit aims to model the decay (elimination) phase of an IV bolus drug dose in a biological system. Please note, this curve fit and many of the calculated readouts are also highly applicable to microsomal and hepatocyte stability assays. If you are interested in modeling exponential decay data sets in a different context than ADME, please see this article.
To implement the Intravenous Dosing: Exponential Decay curve fit, users can follow these steps:
- Creating readouts for input data such as timepoint and plasma concentration
- Creating a plot type readout to generate the curve fit
- Data calculations for different intercepts (optional)
- Editing and saving the curve
Let’s work through an example where we will implement this curve fit within our “Pharmacokinetics IV Dosing” protocol.
Create a numerical readout for the X-axis values:
Create a numerical readout for the Y-axis values:
Create a readout to plot the curve and calculate any optional intercept values:
Pro tip: Consider adding readout definitions marked as protocol conditions for parameters such as species and dose. This will allow users to automatically calculate outputs such as the AUC for each dose in each species as shown below. Additionally, consider implementing different concentration readouts, such as plasma and brain, to automate calculations like brain to plasma ratio (AUCBrain/ AUCPlasma). In order to ensure data integrity, CDD recommends implementing species as a pick list data type and dose as a pick list if users commonly use the same doses or as a number if the dose will be highly variable across different runs.
Fit Parameters:
The PK Intravenous Dosing: Exponential Decay curve fit is performed using the following equation:
This equation models first order exponential decay where if Cmin equals zero, the drug has been completely cleared from the system simplifying the equation to the pure first order kinetics exponential decay:
y= C0e^-kt
Where
Y= The drug concentration at time, t
C0= The initial concentration of drug at t=0
Cmin= The minimum concentration the drug reaches as it is eliminated over time t- the non zero asymptote
Ke= The elimination rate constant
t= time after initial administration
The elimination rate constant Ke is the fraction of drug eliminated per unit time expressed with units of time^-1 (hour^-1).
The following parameters will automatically be calculated by CDD Vault for this plot type:
- C0 - concentration at zero time
- Cmin - concentration at infinite time
- Ke - elimination rate constant
- T1/2 - half-life (ln(2)/Ke)
- Tau - mean life time (1/Ke)
- AUC - area under curve in observed interval (0, t)
- AUCt-inf - extrapolated AUC after last measurement (Cmin / Ke)
- AUC0-inf - extrapolated total area under the curve (AUC + AUCt-inf)
- Plateau = Cmin
- Span - C0 - Cmin
- N - total number of data points used to perform the curve fit
- R-squared
Half life is calculated using Ke, the elimination rate constant.
T ½ = ln(2)/ Ke
Tau represents the time constant, a measure that quantifies how quickly the drug concentration approaches Cmin. Tau is expressed in the same units as the X axis and is computed as the reciprocal of Ke.
Tau= 1/Ke
Area under the curve:
- The CDD Vault AUC is calculated as the (positive area - negative area) under the curve where:
- The curve is defined as straight line connections between responses, not the fitted curve (Linear Trapezoidal Non-uniform grid method)
- Units are (response units *dose_units)
- The baseline is set at the negative control mean or 0 if control data is not available
Suggested additional calculations:
Please note that all auto-calculated parameters listed above can be used in custom calculations as separate readouts. These parameters can be accessed within our robust formula editor.
- Different tissues: i.e., brain to plasma ratio: AUC brain/ AUC plasma
- Clearance= Ke * Volume of distribution
- Volume of distribution = Dose/ C0
- Absolute bioavailability= 100*((AUCPO*DoseIV)/(AUCIV*DosePO))