The Antibody Drug Absorption Following Subcutaneous or Intramuscular Administration and Its Mathematical Description by Coupling Physiologically Based Absorption Process with the Conventional Compartment Pharmacokinetic Model

Abstract

The main objective of this paper is to propose a quantitative model to describe the absorption process for monoclonal antibody (mAb) following subcutaneous (SC) or intramuscular (IM) administration. A hybrid model was established by coupling the physiologically based absorption process with a conventional pharmacokinetic-pharmacodynamic (PK-PD) or PK model associated with intravenous infusion. Key physiological parameters evaluated include the volume distribution before systemic absorption, mAb drug clearance during lymphatic transport, the neonatal Fc receptor (FcRn) capacity, the intrinsic drug clearance via lysosomal proteolytic process, and the lymphatic flow rate. Sensitivity analyses were performed to identify those physiological parameters significantly impacting time to peak concentration (T max ) or drug bioavailability. Simulation results showed that lymphatic flow rate is the only influential factor to T max . Lymphatic transit time and drug clearance during lymphatic transport are most influential to bioavailability but not identifiable in their effects. Bioavailability is positively related to the lymphatic flow only at its low range (i.e., at <0.5-fold of the selected value of 0.043 mL/min). The rest of physiological parameters only have marginal effects on either drug bioavailability or T max . Finally, simulation results confirmed lymphatic transport as the major route of mAb delivery.

Pharmacokinetics of Monoclonal Antibodies

“…Similar to the distribution processes for mAbs, uptake of IgG molecules after injection into the interstitial space of s.c. tissues is largely driven by convective transport with only minor contribution from distribution processes. Transcytosis of IgG via FcRn contributes also, although only minimally to s.c. absorption . In line with other therapeutic proteins for which the percentage of recovery in lymphatic vs. blood vessels is increasing with increasing molecular weight, mAb absorption after s.c. administration is nearly exclusively facilitated by the lymphatic system rather than the vascular system.…”

Drug Development of Therapeutic Monoclonal Antibodies

“…As therapeutic proteins are to an increasing degree taken up into the lymphatic system with increasing molecular weight via convective transport, degradation during the passage through the lymphatic system can substantially limit the systemic bioavailability of a subcutaneously administered MAb [76]. Physiologically based pharmacokinetic modeling suggests that the elimination rate during lymphatic transport and the transit time for the drug movement from the administration site through the lymphatic system into the systemic circulation are the major determinants for bioavailability, leading in many cases to the typical bioavailability range of 50-70 % for subcutaneously administered MAbs [77,78].…”

Development of therapeutic proteins: advances and challenges

“…Moreover, the route of administration of therapeutic proteins cannot be neglected because different routes may have different advantages and disadvantages. For instance, parenteral routes, including intravenous (IV), subcutaneous (SC), and intramuscular (IM), are known to bypass the gastrointestinal enzymatic degradation; however, the bioavailability of these therapeutic proteins is known to be reduced after SC and IM administration as compared with the IV route because the SC and IM routes may face minor presystemic degradation (Meibohm and Braeckman, 2008;Zhao et al, 2013).…”