Skip to 0 minutes and 14 seconds This is the pharmacokinetics of therapeutic proteins. A typical sketch. So here is the distribution phase and the elimination phase. So biologics are transported following lymphatic absorption into the vascular space as I mentioned earlier. And this is followed by a relatively quick distribution into the interstitial space. And therefore the distribution phase. Biologics then become equilibrated between the vascular space and the interstitial space, while the intracellular distribution also takes place. Now the distribution is primarily limited in the extracellular space and is characterized by a relatively small volume distribution of about 14 to 20 liters. By contrast, small molecules commonly exhibit volume of distribution of greater than 1 liter per kilo that is greater than total body weight.
Skip to 1 minute and 34 seconds So let’s look at the volume of distribution. We have 5 liters of blood of which 3 liter is the plasma. The interstitial fluid has about 12 liters. So the plasma and the interstitial water make up the extracellular water which is about 15 L which is where the therapeutic proteins distributed primarily. And the total body water is 42 liters because of the intracellular water has another 27 liters.
Skip to 2 minutes and 22 seconds Now how do we interpret the volume of distribution for therapeutic proteins? Remember that the derivation of volume diffusion typically assumes that elimination happens through the central compartment only. And we know this assumption is not quite true for therapeutic proteins because of the non-specific proteolysis and the receptor-mediated elimination. And volume is underestimated because of underestimation of clearance. Here V is underestimated because clearance is underestimated.
Skip to 3 minutes and 11 seconds So volume distribution is less meaningful in biologics than in small molecule drugs. And for biologics, imaging study to actually quantify the drug distribution in specific tissues or organs is more meaningful.
Pharamcokinetic Characteristics of Biologics
Compared to small molecule drugs, biologics have unique characteristics in absorption, distribution, metabolism, and elimination. Pharmacokinetics of a biologics is typically characterized by a two-compartment model, with three key parameters, half-life, volume of distribution and clearance. The volume of distribution reflects the relationship between the amount of drug in the body at steady-state and plasma drug concentration. It is a mathematical concept, which does not necessarily reflect a physiological or “real” distribution space, although for biologics, they are more closely related. The model dependent estimation of the volume of distribution will be discussed.
PK of biologics is generally known to be characterized by a two-compartment model, with three key parameters, half-life, volume of distribution and clearance. The volume of distribution is reflective of the extracellular space, which is about 15-20 liters. It’s considered to be small (<1 l/kg) compared to small molecules. It is to be noted that model dependent volume of distribution is likely underestimated, due to the invalid assumption that clearance occurs only from the central compartment. Therefore, imaging study to actually measure biologics distribution in specific tissues or organs is more meaningful.