Eric Lueshen

Interspecies scaling in pharmacokinetics: A novel whole-body physiologically based modeling framework to discover drug biodistribution mechanisms in vivo

Drug approval processes require extensive testing and have recently put more emphasis on understanding mechanistic drug action in the body including toxicity and safety.1 Consequently, there is an urgent need in the pharmaceutical industry to develop mechanistic pharmacokinetic (PK) models able to both expedite knowledge gain from experimental trials and, simultaneously, address safety concerns. We previously developed a first principles based whole-body PK model, which incorporated physiological dimensions and drug mass transport. In this follow-up article, we demonstrate how the first principles model in combination with novel physiological scaling laws yields more reliable interspecies and intraspecies extrapolation of drug biodistribution. We show how experimental dose-response data in rats for immunosuppressant cyclosporin are sufficient for predicting the biodistribution of this drug in pigs, monkeys, and humans. The predicted drug concentrations extrapolated by interspecies scaling laws match well with the experimental measurements. These promising results demonstrate that the whole-body PK modeling approach not only elucidates drug mechanisms from a biochemical standpoint, but offers better scaling precision. Better models can substantially accelerate the introduction of drug leads to clinical trials and eventually to the market by offering more understanding of the drug mechanisms, aiding in therapy design, and serving as an accurate dosing tool.

Pharmacokinetics, Pharmacodynamics and Drug Metabolism Interspecies Scaling in Pharmacokinetics: A Novel Whole-Body Physiologically Based Modeling Framework to Discover Drug Biodistribution Mechanisms In Vivo

Drug approval processes require extensive testing and have recently put more emphasis on understanding mechanistic drug action in the body including toxicity and safety.1 Consequently, there is an urgent need in the pharmaceutical industry to develop mechanistic pharmacokinetic (PK) models able to both expedite knowledge gain from experimental trials and, simultaneously, address safety concerns. We previously developed a first principles based whole-body PK model, which incorporated physiological dimensions and drug mass transport. In this follow-up article, we demonstrate how the first principles model in combination with novel physiological scaling laws yields more reliable interspecies and intraspecies extrapolation of drug biodistribution. We show how experimental dose-response data in rats for immunosuppressant cyclosporin are sufficient for predicting the biodistribution of this drug in pigs, monkeys, and humans. The predicted drug concentrations extrapolated by interspecies scaling laws match well with the experimental measurements. These promising results demonstrate that the whole-body PK modeling approach not only elucidates drug mechanisms from a biochemical standpoint, but offers better scaling precision. Better models can substantially accelerate the introduction of drug leads to clinical trials and eventually to the market by offering more understanding of the drug mechanisms, aiding in therapy design, and serving as an accurate dosing tool.

Methods for Determining Agent Concentration Profiles in Agarose Gel During Convection-Enhanced Delivery

Convection-enhanced delivery (CED) is a promising technique to deliver large molecular weight drugs to the human brain for treatment of Parkinsons, Alzheimers, or brain tumors. Researchers have used agarose gels to study mechanisms of agent transport in soft tissues like brain due to its similar mechanical and transport properties. However, inexpensive quantitative techniques to precisely measure achieved agent distribution in agarose gel phantoms during CED are missing. Such precise measurements of concentration distribution are needed to optimize drug delivery. An optical experimental method to accurately quantify agent concentration in agarose is presented. A novel geometry correction algorithm is used to determine real concentrations from observable light intensities captured by a digital camera. We demonstrate the technique in dye infusion experiments that provide cylindrical and spherical distributions when infusing with porous membrane and conventional single-port catheters, respectively. This optical method incorporates important parameters, such as optimum camera exposure, captured camera intensity calibration, and use of collimated light source for maximum precision. We compare experimental results with numerical solutions to the convection diffusion equation. The solutions of convection-diffusion equations in the cylindrical and spherical domains were found to match the experimental data obtained by geometry correction algorithm.

Intrathecal magnetic drug targeting using gold-coated magnetite nanoparticles in a human spine model.

AIM We aimed to magnetically guide and locally confine nanoparticles in desired locations within the spinal canal to achieve effective drug administration for improved treatment of chronic pain, cancers, anesthesia and spasticity. MATERIALS & METHODS We developed a physiologically and anatomically consistent in vitro human spine model to test the feasibility of intrathecal magnetic drug targeting. Gold-coated magnetite nanoparticles were infused into the model and targeted to specific regions using external magnetic fields. Experiments and simulations aiming to determine the effect of key parameters, such as magnet strength, duration of magnetic field exposure, magnet location and ferrous implants, on the collection efficiency of superparamagnetic nanoparticles in targeted regions were performed. RESULTS An 891% increase in nanoparticle collection efficiency within the target region was achieved using intrathecal magnetic drug targeting when compared with the control. Nanoparticle collection efficiency at the target region increased with time and reached a steady value within 15 min. Ferrous epidural implants generated sufficiently high-gradient magnetic fields, even when magnets were placed at a distance equal to the space between a patients epidermis and spinal canal. CONCLUSION Our experiments indicate that intrathecal magnetic drug targeting is a promising technique for concentrating and localizing drugs at targeted sites within the spinal canal for treating diseases affecting the CNS.

Optimal Catheter Placement for Chemotherapy

Abstract This paper addresses the problem of optimal administration of chemotherapeutic agents for the treatment of brain tumors by convection-enhanced drug delivery. The optimal catheter position is located by a novel optimization technique, which simultaneously maximizes drug concentration in the desired brain region, while ensuring that the final drug concentration does not fall below a therapeutically effective level or rise above the toxic threshold in non-treatment areas. A modified finite volume discretization method is used inside a nonlinear hybrid optimization algorithm. The distributed optimization problem with an embedded transport problem is solved on a coarse computational mesh, while searching for the optimal catheter position in a separate continuous coordinate system. In order to obtain continuous positional dependency of the objective function, two reference systems are used for solving the transport equations. The first analytical method projects the outflow from a specific catheter position inside the coarse finite volume cell onto its vertices. Once the cell face flux resulting from a specific continuous catheter positions are thus determined, the remaining two-dimensional transport problem is solved rigorously with a classical finite element method. A score function φ evaluates the match between the drug distributions achieved by a particular catheter placement with the therapy goals. Genetic inheritance adjusts the catheter locations to identify the globally optimal solution. Using the novel multi-scale algorithm, it is possible to optimize catheter placement and design, as well as to control drug distribution volume without the need for mesh refinement for different catheter positions.

Backflow-free catheters for efficient and safe convection-enhanced delivery of therapeutics

Convection-enhanced delivery (CED) is an invasive drug delivery technique used to target specific regions of the brain for the treatment of cancer and neurodegenerative diseases while bypassing the blood-brain barrier. In order to prevent the possibility of backflow, low volumetric flow rates are applied which limit the achievable drug distribution volumes from CED. This can render CED treatment ineffective since a small convective flow produces narrow drug distribution inside the treatment region. Novel catheter designs and CED protocols are needed to improve the drug distribution inside the treatment region. This is especially important when administering toxic chemotherapeutics which could adversely affect other organs if backflow occurred and these drugs entered the circulating blood stream. In order to help elucidate the causes of backflow and to design backflow-free catheters, we have studied the impact that microfluid flow has on deformable brain phantom gels experimentally as well as numerically. We found that fluid injections into porous media have considerable effects on local transport properties such as porosity and hydraulic conductivity. These phenomena not only alter the bulk flow velocity distribution of the microfluid flow due to the changing porosity, but significantly modify flow direction and even volumetric flow distribution due to induced local hydraulic conductivity anisotropy. These studies led us to the development of novel backflow-free catheters with safe volumetric flow rates up to 10 µL/min. The catheter designs, numerical simulations and experimental results are described throughout this article.

Intrathecal Magnetic Drug Targeting: A New Approach to Treating Diseases of the Central Nervous System

Intrathecal (IT) drug delivery is a standard technique which involves direct injection of drugs into the cerebrospinal fluid (CSF)-filled space within the spinal canal to treat many diseases of the central nervous system. Currently, in order to reach the therapeutic drug concentration at certain locations within the spinal canal, high drug doses are used. With no method to deliver the large drug doses locally, current IT drug delivery treatments are hindered with wide drug distributions throughout the central nervous system (CNS) which cause harmful side effects. In order to overcome the current limitations of IT drug delivery, we have developed the novel method of intrathecal magnetic drug targeting (IT-MDT). Gold-coated magnetite nanoparticles are infused into a physiologically and anatomically relevant in vitro human spine model and then targeted to a specific site using external magnetic fields, resulting in a substantial increase in therapeutic nanoparticle localization at the site of interest. Experiments aiming to determine the effect of key parameters such as magnet strength, duration of magnetic field exposure, location of magnetic field, and ferrous implants on the collection efficiency of our superparamagnetic nanoparticles in the targeting region were performed. Our experiments indicate that intrathecal magnetic drug targeting and implant-assisted IT-MDT are promising techniques for concentrating and localizing drug-functionalized nanoparticles at required target sites within the spinal canal for potential treatment of diseases affecting the central nervous system.© 2013 ASME