Pharmacokinetics and Pharmacodynamics Modeling and Simulation Systems to Support the Development and Regulation of Liposomal Drugs

Abstract

Liposomal formulations have been developed to improve the therapeutic index of encapsulated drugs by altering the balance of on- and off-targeted distribution. The improved therapeutic efficacy of liposomal drugs is primarily attributed to enhanced distribution at the sites of action. The targeted distribution of liposomal drugs depends not only on the physicochemical properties of the liposomes, but also on multiple components of the biological system. Pharmacokinetic⁻pharmacodynamic (PK⁻PD) modeling has recently emerged as a useful tool with which to assess the impact of formulation- and system-specific factors on the targeted disposition and therapeutic efficacy of liposomal drugs. The use of PK⁻PD modeling to facilitate the development and regulatory reviews of generic versions of liposomal drugs recently drew the attention of the U.S. Food and Drug Administration. The present review summarizes the physiological factors that affect the targeted delivery of liposomal drugs, challenges that influence the development and regulation of liposomal drugs, and the application of PK⁻PD modeling and simulation systems to address these challenges.

Keywords: EPR effect; PBPK model; liposomal drugs; modeling and simulation; pharmacokinetic–pharmacodynamics; regulatory review.

Figure 1

Multiscale physiological barriers to the targeted distribution of liposomal drugs. The dose fraction change was obtained from references [70,71]. MPS—mononuclear phagocyte system; IFP—interstitial fluid pressure; ECM—extracellular matrix.

Figure 2

A general PBPK model diagram for liposomal drugs. (A) A generic dual-layer PBPK model. The black solid line represents the blood flow and the blue dashed line depicts the lymph flow. (B) A tumor tissue compartment model for liposomes. The distribution from blood to drug target involves liposome extravasation, diffusion of the released payload between blood and interstitial fluid, direct or tissue-associated macrophage-mediated release of the payload, tumor cell endocytosis of liposomes, intracellular release of the payload in tumor cells, target binding, and recycling of intact liposomes through lymph back to the blood. Q—blood flow; CL_r—renal clearance; CL_h—hepatic clearance.