Whole-body Pharmacokinetic Model Research Articles

Multiphysics modeling and simulation of local transport and absorption kinetics of intramuscularly injected lipid nanoparticles.

Recent clinical applications of mRNA vaccines highlight the critical role of drug delivery, especially when using lipid nanoparticles (LNPs) as the carrier for genetic payloads. However, kinetic and transport mechanisms for locally injected LNPs, such as lymphatic or cellular uptake and drug release, remain poorly understood. Herein, we developed a bottom-up multiphysics computational model to simulate the injection and absorption processes of LNPs in muscular tissues. Our purpose was to seek underlying connections between formulation attributes and local exposure kinetics of LNPs and the delivered drug. We were also interested in modeling the absorption kinetics from the local injection site to the systemic circulation. In our model, the tissue was treated as the homogeneous, poroelastic medium in which vascular and lymphatic vessel densities are considered. Tissue deformation and interstitial fluid flow (modeled using Darcy's Law) were also implemented. Transport of LNPs was described based on diffusion and advection; local disintegration and cellular uptake were also integrated. Sensitivity analyses of LNP and drug properties and tissue attributes were conducted using the simulation model. It was found that intrinsic tissue porosity and lymphatic vessel density affect the local transport kinetics; diffusivity, lymphatic permeability, and intracellular update kinetics also play critical roles. Simulated results were commensurate with experimental observations. This study could shed light on the development of LNP formulations and enable further development of whole-body pharmacokinetic models.

Pharmacokinetic Approach for Dynamic Breast MRI to Indicate Signal Intensity Time Curves of Benign and Malignant Lesions by Using the Tumor Flow Residence Time

The objective of this study was to evaluate a novel pharmacokinetic approach integrating a tumor model in a whole-body pharmacokinetic model to simulate contrast media-induced signal intensity time curves of breast tumors on dynamic contrast-enhanced magnetic resonance mammography. A recently developed, whole-body pharmacokinetic model, which describes the distribution and excretion of renally discharged contrast media, has been expanded by integrating a tumor model. The parameters of the general approach including exchange between plasma and interstitium were set as fixed values; only 2 tumor-specific parameters, blood volume fraction Vblood and blood flow kt, were varied. These parameters were adjusted with regard to signal intensity time course data of histologically verified benign and malignant mass-like breast lesions on clinical magnetic resonance imaging examinations (1.5 T) using 2 different contrast media (gadopentetate dimeglumine and gadoterate meglumine) and 2 application doses (0.1 and 0.2 mmol kg body weight). Thus, measured signal intensity time curves were compared with simulated gadolinium (Gd) concentration time curves calculated by the pharmacokinetic model. Benign lesions showed continuous signal increase; malignant tumors presented fast initial signal increase followed by washout effect. According to the pharmacokinetic approach, the variation of the Vblood/kt ratio, which defined the tumor flow residence time τr, led to Gd concentration time curves congruent with the shapes of the measured signal intensity time curves. Low values of τr were characteristic for malignant tumors, and high values were typical for benign lesions; τr of 200 seconds best separated malignant from benign tumors. Thus, the dynamic magnetic resonance imaging data can be well approximated by the pharmacokinetic model considering 2 contrast media and application doses. The calculated Gd concentration time curves of 0.1 mmol kg body weight gadopentetate dimeglumine and gadoterate meglumine overlapped for benign lesions; the curve of gadoterate meglumine was by a factor of 0.8 below the curve of gadopentetate dimeglumine for malignant tumors. Doubling the application dose of gadopentetate dimeglumine from 0.1 to 0.2 mmol kg led to an increase in the Gd concentration time curves for benign lesions but not for malignant tumors. High Gd concentrations with values greater than 1 mmol L were calculated in the vessels of the malignant tumors, outside the determined range of the linear relationship between Gd concentration and signal intensity due to saturation effects. On the basis of this pharmacokinetic model, the contrast media-induced time curves on dynamic contrast-enhanced magnetic resonance mammography can be classified by a single kinetic parameter, the tumor flow residence time τr, into benign (τr >200 seconds) and malignant (τr <200 seconds) curve shapes. Possible clinical application of this model is to create pharmacokinetic maps, displaying tumor flow residence times, for computer-assisted diagnosis, which may be integrated into clinical routine for the diagnosis of breast lesions.

Application of a whole-body pharmacokinetic model for targeted radionuclide therapy to NM404 and FLT

We have previously developed a model that provides relative dosimetry estimates for targeted radionuclide therapy (TRT) agents. The whole-body and tumor pharmacokinetic (PK) parameters of this model can be noninvasively measured with molecular imaging, providing a means of comparing potential TRT agents. Parameter sensitivities and noise will affect the accuracy and precision of the estimated PK values and hence dosimetry estimates. The aim of this work is to apply a PK model for TRT to two agents with different magnitudes of clearance rates, NM404 and FLT, explore parameter sensitivity with respect to time and investigate the effect of noise on parameter precision and accuracy. Twenty-three tumor bearing mice were injected with a ‘slow-clearing’ agent, 124I-NM404 (n = 10), or a ‘fast-clearing’ agent, 18F-FLT (3′-deoxy-3′-fluorothymidine) (n = 13) and imaged via micro-PET/CT pseudo-dynamically or dynamically, respectively. Regions of interest were drawn within the heart and tumor to create time-concentration curves for blood pool and tumor. PK analysis was performed to estimate the mean and standard error of the central compartment efflux-to-influx ratio (k12/k21), central elimination rate constant (kel), and tumor influx-to-efflux ratio (k34/k43), as well as the mean and standard deviation of the dosimetry estimates. NM404 and FLT parameter estimation results were used to analyze model accuracy and parameter sensitivity. The accuracy of the experimental sampling schedule was compared to that of an optimal sampling schedule found using Cramer–Rao lower bounds theory. Accuracy was assessed using correlation coefficient, bias and standard error of the estimate normalized to the mean (SEE/mean). The PK parameter estimation of NM404 yielded a central clearance, kel (0.009 ± 0.003 h−1), normal body retention, k12/k21 (0.69 ± 0.16), tumor retention, k34/k43 (1.44 ± 0.46) and predicted dosimetry, Dtumor (3.47 ± 1.24 Gy). The PK parameter estimation of FLT yielded a central elimination rate constant, kel (0.050 ± 0.025 min−1), normal body retention, k12/k21 (2.21 ± 0.62) and tumor retention, k34/k43 (0.65 ± 0.17), and predicted dosimetry, Dtumor (0.61 ± 0.20 Gy). Compared to experimental sampling, optimal sampling decreases the dosimetry bias and SEE/mean for NM404; however, it increases bias and decreases SEE/mean for FLT. For both NM404 and FLT, central compartment efflux rate constant, k12, and central compartment influx rate constant, k21, possess mirroring sensitivities at relatively early time points. The instantaneous concentration in the blood, C0, was most sensitive at early time points; central elimination, kel, and tumor efflux, k43, are most sensitive at later time points. A PK model for TRT was applied to both a slow-clearing, NM404, and a fast-clearing, FLT, agents in a xenograft murine model. NM404 possesses more favorable PK values according to the PK TRT model. The precise and accurate measurement of k12, k21, kel, k34 and k43 will translate into improved and precise dosimetry estimations. This work will guide the future use of this PK model for assessing the relative effectiveness of potential TRT agents.

Increase of Plasma VEGF after Intravenous Administration of Bevacizumab Is Predicted by a Pharmacokinetic Model

Vascular endothelial growth factor (VEGF) is one of the most potent cytokines targeted in antiangiogenic therapies. Bevacizumab, a recombinant humanized monoclonal antibody to VEGF, is being used clinically in combination with chemotherapy for colorectal, non-small cell lung and breast cancers, and as a single agent for glioblastoma and is being tested for other types of cancer in numerous clinical trials. It has been reported that the intravenous injection of bevacizumab leads to an increase of plasma VEGF concentration in cancer patients. The mechanism responsible for this counterintuitive increase has not been elucidated, although several hypotheses have been proposed. We use a multiscale systems biology approach to address this problem. We have constructed a whole-body pharmacokinetic model comprising three compartments: blood, normal tissue, and tumor tissue. Molecular interactions among VEGF-A family members, their major receptors, the extracellular matrix, and an anti-VEGF ligand are considered for each compartment. Diffusible molecules extravasate, intravasate, are removed from the healthy tissue through the lymphatics, and are cleared from the blood.

The biological effectiveness of targeted radionuclide therapy based on a whole-body pharmacokinetic model

Biologically effective dose (BED) may be more of a relevant quantity than absorbed dose for establishing tumour response relationships. By taking into account the dose rate and tissue-specific parameters such as repair and radiosensitivity, it is possible to compare the relative biological effects of different targeted radionuclide therapy (TRT) agents. The aim of this work was to develop an analytical tumour BED calculation for TRT that could predict a relative biological effect based on normal body and tumour pharmacokinetics. This work represents a step in the direction of establishing relative pharmacokinetic criteria of when the BED formalism is more applicable than absorbed dose for TRT. A previously established pharmacokinetic (PK) model for TRT was used and adapted into the BED formalism. An analytical equation for the protraction factor, which incorporates dose rate and repair rate, was derived. Dose rates within the normal body and tumour were related to the slopes of their time–activity curves which were determined by the ratios of their respective PK parameters. The relationships between the tumour influx-to-efflux ratio (k34:k43), central compartment efflux-to-influx ratio (k12:k21), central elimination (kel), and tumour repair rate (μ), and tumour BED were investigated. As the k34:k43 ratio increases and the k12:k21 ratio decreases, the difference between tumour BED and D increases. In contrast, as the k34:k43 ratios decrease and the k12:k21 ratios increase, the tumour BED approaches D. At large k34:k43 ratios, the difference between tumour BED and D increases to a maximum as kel increases. At small k34:k43 ratios, the tumour BED approaches D at very small kel. At small μ and small k34:k43 ratios, the tumour BED approaches D. For large k34:k43 ratios, large μ values cause tumour BED to approach D. This work represents a step in the direction of establishing relative PK criteria of when the BED formalism is more applicable than absorbed dose for TRT. It also provides a framework by which the biological effects of different TRT agents can be compared in order to predict efficacy.

Modeling of Human Dermal Absorption of Octamethylcyclotetrasiloxane (D4) and Decamethylcyclopentasiloxane (D5)

In this study, data for human dermal absorption of octamethylcyclotetrasiloxane, D(4), and decamethylcyclopentasiloxane, D(5), through axilla skin in vivo are interpreted using pharmacokinetic models of dermal absorption by adding the dermal exposure route to inhalation physiologically based pharmacokinetics models developed previously. The compartmental model describing dermal absorption of these compounds included volatilization of the applied chemical from the skin surface, diffusion of absorbed chemical back to the skin surface and evaporation of this chemical from the skin surface after the applied dose had cleared from the application site, uptake from the skin compartment into blood, and a storage compartment within the skin. Data from exposures in volunteers (i.e., D(4) and D(5) concentrations in exhaled air and plasma) were used to estimate model parameters. In volunteers exposed to either D(4) or D(5), the maximum concentration of chemical in exhaled air reached a maximum at or prior to 1 h following administration of the test chemical. Based on model calculations, the percent of applied dose of D(4) that was absorbed into systemic circulation for men and women was 0.12 and 0.30%, respectively; for D(5) about 0.05% of the applied dose was absorbed for both men and women. For both D(4) and D(5), model calculations indicate that more than 83% of the chemical that reached systemic circulation was eliminated by exhalation within 24 h. These whole-body pharmacokinetic models for dermal absorption of two semi-volatile compounds provide a valuable tool for understanding factors controlling their dermal absorption through axilla skin and for applying results from these studies in consumer product risk assessments.

Antibody-Directed Effector Cell Therapy of Tumors: Analysis and Optimization Using a Physiologically Based Pharmacokinetic Model

The failure of the cellular immune response to stop solid tumor growth has been the subject of much research. Although the mechanisms for tumor evasion of immune response are poorly understood, one viable explanation is that tumor-killing lymphocytes cannot reach the tumor cells in sufficient quantity to keep the tumor in check. Recently, the use of bifunctional antibodies. (BFAs) has been proposed as a way to direct immune cells to the tumor: one arm of the antibody is specific for a known tumor-associated antigen and the other for a lymphocyte marker such as CD3. Injecting this BFA should presumably result in cross-linking of lymphocytes. (either endogenous or adoptively transferred) with tumor cells, thereby enhancing therapy. Results from such an approach, however, are often disappointing- frequently there is no benefit gained by using the BFA. We have analyzed the retargeting of endogenous effector cells by BFA using a physiologically based whole-body pharmacokinetic model that accounts for interactions between all relevant species in the various organs and tumor. Our results suggest that the design of the BFA is critical and the binding constants of the antigen and lymphocyte binding epitopes need to be optimized for successful therapy.

Modelling and simulation of the nonlinear dose-plasma concentration response of phenylbutazone on periodic multiple oral dosing: A mechanistic approach

The dose-ranging pharmacokinetics of phenylbutazone on periodic multiple oral dosing have previously been shown to be nonlinear, inasmuch as there is a plateauing of steady-state plasma concentrations with increasing dose. The mechanistic hypothesis of saturable protein binding, postulated to explain this behaviour was tested, in the context of whole-body pharmacokinetic modelling of the observed dose dependancy, using the circuit simulation program SPICE2. The alternate hypothesis, operating singly or in tandem, of loss of unabsorbed drug due to gastrointestinal emptying, saturable absorption, change in the volume of distribution of the drug, were also examined. Within the constraints of the proposed whole-body pharmacokinetic model, the absorption kinetics of increasing oral daily doses of phenylbutazone were shown to be saturable in their mechanism.