Author: Tilda Barliya PhD
Title: Factors affecting the PK of the nanocarrier.
Category: Nanotechnology in drug delivery
A plethora of new products are emerging as potential therapeutic agents. This calls for detailed studies of their unique pharmacologic characteristics and mechanisms of action in humans. This review written by Caron WP et al (Zamboni’s group) provides a major overview of the factors that affect the pharmacokinetics (PK) and pharmacodynamics (PD) of nanoparticle carries in preclinical models and patients (1). I will use this article as the main source as it was so nicely written yet many other references are added within.
The disposition of carrier-mediated agents (CMAs) is dependent on the carrier and not on the parent drug, until the drug is released from the carrier into the system and includes encapsulated (the drug within or bound to the carrier), released (the active drug that gets released from the carrier), and sum total (encapsulated drug plus released drug).
After the drug has been released from its carrier, it is pharmacologically active and subjected to the same routes of metabolism and clearance (CL) as the non-carrier form of the drug (1,2).
In theory, the PK disposition of the drug after it is released from the carrier should be the same as after administration of the small-molecule or standard formulations. Therefore, the pharmacology and PK of CMAs are complex and call for comprehensive analytical studies to assess the disposition of encapsulated and released forms of the drug in plasma and tumor.
Interindividual variability in drug exposure, represented by area under the plasma concentration– time curve (AUC) of the encapsulated drug and several factor can potentially affect it:
- Physical characteristics of the CMA (size, charge, surface modification). Figure 1
- Host-associated characteristics such as gender and age as well as the host mononuclear phagocyte system (MPS), which is a collective term for the immune cells.
Figure 1 here (=figure 3 in the original paper. ref 1) : Nanoparticle clearance and biocompatibility are dependent on various factors including physical characteristics of the carrier as well as physiologic parameters such as the mononuclear phagocyte system (MPS) (reticuloendothelial system (RES)) recognition and enhanced permeability and retention (EPR) effect. There are qualitative relationships between the independent variables, namely, particle size, particle zeta-potential (surface charge), and solubility, and the dependent variable, namely, biocompatibility. Biocompatibility, or extent of exposure (area under the plasma concentration–time curve), includes the route of uptake and clearance (shown in green as the EPR effect and renal and biliary clearance), cytotoxicity (shown in red, can represent either efficacy or toxicities/ adverse events in anticancer treatment), and MPS/RES recognition (shown in blue).
The effect on the immune cells is divided into two categories: (i) responses to nanoparticles that are specifically modified to stimulate the immune system (e.g., vaccine carriers) and (ii) undesirable interactions and/or side-effects.
Immune cells that participate in nanoparticle uptake are circulating monocytes, platelets, leukocytes, and dendritic cells in the bloodstream (3,4). In addition, nanoparticles can be taken up in tissues by phagocytes, e.g., by Kupffer cells in the liver, by dendritic cells in the lymph nodes, by B cells in the spleen, and by macrophages
Uptake mechanisms may occur through different pathways and can often be facilitated by the adsorption of opsonins to the nanoparticle surface
- Particle size: In one study of liposomes, particles that had a hydrodynamic diameter between 100 and 200 nm had a fourfold higher rate of uptake in tumors than particles <50 nm or >300 nm.
- Surface modification: Conjugated PEG polymer onto the surface- is known to minimize opsonization and thus subsequent decreased rate of MPS uptake overall plasma exposures of drugs contained within PEGylated liposomes were six fold higher than those contained within non-PEGylated liposomes
- Surface charge: Uncharged liposomes have lower CLs than either positively or negatively charged liposomes (probably due to reduced opsonization by MPS. rate of CL from blood was significantly higher for negatively charged particles than for uncharged particles
It can be summarized as for their rate of clearance from highest (left) to lowest (right) as:
Note: PEGylation can alter the alter this rate significantly for example,
Levchenko et al. showed that the negative charge on liposomes can be shielded with this physical alteration, leading to a significantly reduced rate of liver uptake and consequent prolongation of their presence in circulating blood (5).
- Age: In some cases, age-related effects on the PK of some PEGylated liposomal agents have been reported, where in younger male patients (<60) there was a higher rate of clearance of two different agents (Doxil and CDK602) compared to older patients (>60). In other words, in older age, the CL rate was lower and therefore higher AUC/dose. No relation to age was observed for female patients, in the same study.
Alterations in the PK and PD of CMAs may involve accerelated decline in immune system functioning, specifically the association between aging and the functioning of monocytes (6). In theory, there is a loss of MPS activity or function in elderly patients, and this decreases the CL of CMAs by the MPS, leading to increased drug exposures and toxicity in elderly patients. In terms of efficacy, greater age was inversely proportional to progression-free survival; however, no correlation was found between age and overall survival.
- Gender: In similar study to the one presented above, female patients had overall lower CL of DOXIL, IHL-305 and CDK602 compared to male patients of the same age.
The basis for the gender-related differences in the PK and PD of CMAs is unclear. It has been hypothesized that some of the differences may be attributed to the effects of sex hormones such as testosterone and estrogen on immune cell function.
Delivery of CMAs Into Tumor
Major advances in the understanding of tumor biology have led to the discovery of targeted agents that can deliver drugs to the desired site while minimizing exposure in normal tissues, thereby minimizing the associated adverse effects. Whereas conventional drugs encounter numerous obstacles en route to their target, CMAs can take advantage of a tumor’s leaky vasculature to extravasate into tissue, via the enhanced permeability and retention effect (EPR).
Note: The extend of the EPR effect is highly debated since although passive targeting through the EPR effect has been a key concept in delivering CMAs to tumors, it does not ensure uniform delivery to all regions of tumor. Furthermore, not all tumors exhibit an EPR effect, and the permeability of vessels may not be the same across any single tumor.
Active targeting may overcome these limitations. The CMAs can be enabled to bind to specific cells in a tumor by using surface attached ligands that are capable of recognizing and binding to cells of interest.
Antibody-mediated targeting has been the method of choice, other targeting strategies using nucleic acids, carbohydrates, peptides, aptamers, vitamins, and other agents are also being evaluated.
Other major points that can affect the PK disposition
- The linearity and nonlinearity of the CLs of a drug (might be associated with the dose like with S-CKD602)(7).
- Drug-drug interaction (single agent vs combination)
- Body composition (Body surface area, body weight)
There are a multitude of properties of CMAs that differ from those of the active small-molecule drugs they contain. These differences lead to significant variability in the PK and PD of carrier- mediated drugs. It has been shown that physical properties, the MPS, the presence of tumors in the liver, EPRs, drug–drug interactions, age, and gender all contribute in varying degrees to the PK disposition and PD end points of CMAs in patients.
Areas of research that can aid in an understanding of how these agents should be used and how we may predict their actions in patients include pharmacogenomics, cellular function (probing the MPS), more sensitive and accurate analytical PK methods, and identification of the optimal preclinical (animal and in vitro) models.
1. W P Caron, G Song, P Kumar, S Rawal and W C Zamboni.Interpatient PK and PD variability of carrier-mediated anticancer agent. Clinical Pharmacology and Therapeutics 2012 91, 802-812 http://www.nature.com/clpt/journal/vaop/ncurrent/full/clpt201212a.html
2. Zamboni, W.C. Liposomal, nanoparticle, and conjugated formulations of anticancer agents. Clin. Cancer Res. 11, 8230–8234 (2005).
3. Dobrovolskaia, M.A., Aggarwal, P., Hall, J.B. & McNeil, S.E. Preclinical studies to understand nanoparticle interaction with the immune system and its potential effects on nanoparticle biodistribution. Mol. Pharm. 5, 487–495 (2008). http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2613572/
4. Dobrovolskaia, M.A. & McNeil, S.E. Immunological properties of engineered nanomaterials. Nat. Nanotechnol. 2, 469–478 (2007). http://www.ncbi.nlm.nih.gov/pubmed/18654343
5. Levchenko, T.S., Rammohan, R., Lukyanov, A.N., Whiteman, K.R. & Torchilin, V.P. Liposome clearance in mice: the effect of a separate and combined presence of surface charge and polymer coating. Int. J. Pharm. 240, 95–102 (2002). http://www.ncbi.nlm.nih.gov/pubmed/12062505
6. Lloberas, J. & Celada, A. Effect of aging on macrophage function. Exp. Gerontol. 37, 1325–1331 (2002). http://www.ncbi.nlm.nih.gov/pubmed/12559402
7. Zamboni, W.C. et al. Pharmacokinetic study of pegylated liposomal CKD-602 (S-CKD602) in patients with advanced malignancies. Clin. Pharmacol. Ther. 86, 519–526 (2009). http://www.nature.com/clpt/journal/v86/n5/abs/clpt2009141a.html