PK of biologics

Question 1

Absorption

Answer 1

Due to their size (>3 KDa) they are not well absorbed orally.

SC or IM injection most common. they absorb through the lymphatic system very slowly.

Question 2

Distribution

Answer 2

Their target is most commonly surface proteins.

therapeutic proteins need to partition from inside tissue into the interstitial space

biologics tend to have small Vd, being confined to the plasma and ECF.

Transcytosis is mediated by FcRn on vascular endothelial cells. movement across plasma membrane - can be bidirectional

Question 3

elimination

Answer 3

mainly by proteolytic catabolism with the reticuloendothelial system - this is lysosomal degradation.

The elimination rate depends on the lymph flow rate and protein catabolism.

the recycling of mAbs via the FcRn pathway can alter the elimination rate. only antibody biologics can undergo FcRn recycling. need the Fab for FcRN recycling. this tends to make non mAbs have shorter half-lives compared to them.

As such they have long half lives of weeks/months.

Renal elimination is almost absent due to their sizes. the overall negative charge of the glomerular capillary membrane means that cations and neutral proteins filter better than anions of the same size.

Question 4

Nonlinear PK of mAbs

Answer 4

the target mediated elimination and FcRn recycling are saturable processes.

the level of abundance of the target antigen can impact the nonlinearity of elimination. e.g., as the disease resolves the target becomes more limited. at lower doses, the PK is altered due to the interaction between the drug and target receptor - target mediated drug disposition (TMDD) this occurs mainly for membrane bound antigens. TMDD is when a large proportion of the drug in the body is bound to the target as opposed to being found systemically. as doses increase, the proportion bound to the target decreases.

Question 5

Factors leading to variability in biologics PK

Answer 5

body size: due to low Vd. as such dosing is normally done b based on body weight or body surface area. more applied to therapeutic proteins.

Burdens of the disease: heightened expression of the target in high disease burdens. leads to varied target mediated elimination - varied PK. particularly for mAbs

Serum albumin is also recycled by FcRn, so fluctuations in the [albumin] can alter mAb clearance. low levels of albumin could lead to increased target mediated clearance - sub therapeutic levels.

allelic variation in genes that are involved in mAb recycling, target expression or catabolism can alter mAb PK.