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Monoclonal antibodies (MAbs), produced for specific tumor antigens, can be linked with radioisotopes or metabolic toxins and administered intraperitoneally (i.p.) to treat metastatic cancer located on the peritoneum. Despite their specific binding properties, these proteins distribute to the serosal surface of all tissues surrounding the cavity in the same manner as other serum proteins. Recent data have raised a problem of access of the solution containing the MAb to significant portions of the peritoneal surface. If the MAb does arrive at the surface of the tumor, it penetrates via diffusion and convection. The rapidity and depth of penetration of the MAb are very dependent on the binding characteristics of the MAb to the tumor cells. Current data indicate that tumors often have a large interstitial space relative to normal muscle, and this can accelerate both diffusion and convection. However, a highly permeable tumor vasculature in the absence of lymphatic drainage has also been shown to produce interstitial pressure gradients from the center toward the periphery of the tumor, setting up a potential outward flow which may be a significant barrier to the movement of MAbs into the nodule. While theoretical mechanisms of diffusion, convection, and binding are well established, there is still a great need for in vivo data.

The origin and magnitude of potential errors in whole-blood sampling are prredicted on the basis of a mathematical model. The model describes the kinetics of solute metabolism, breakdown, and interphase distribution (i.e., partitioning and exchange between formed elements and plasma) within a blood sample during sample withdrawal and storage. The model is applied to the determination of the integral over time of solute concentration in the plasma (area-under-the-curve, or AUC) from a sample withdrawn through an arterial or venous catheter. Errors in AUC determination can be substantial and are strongly dependent on the duration of sampling (T), the rate constants for solute degradation processes, the rate constant for solute exchange between the formed elements and the plasma (ke). ,nd the equilibrium ratio for distribution of the solute between formed elements and plasma (R). When the value of the dimensionless group keT/R is small, little solute exchanges between plasma water and formed elements before the two phases of the blood are separated. When keT/R is large, the solute distribution is close to equilibrium at all times. In these two keT/R limits, the contribution of solute redistribution to sampling error is small. Sizable errors resulting from redistribution are associated with intermediate values of keT/R, even in the absence of metabolism and despite rapid separation of the phases at the end of the withdrawal period. Chemical conversion within either of the blood phases introduces additional sampling error under most circumstances.

For many compounds (neurotrophic factors, antibodies, growth factors, genetic vectors, enzymes) slow diffusion in the brain severely limits drug distribution and effect after direct drug administration into brain parenchyma. We investigated convection as a means to enhance the distribution of the large and small molecules 111In-labeled transferrin (111In-Tf; M(r), 80,000) and [14C]sucrose (M(r), 359) over centimeter distances by maintaining a pressure gradient during interstitial infusion into white matter to generate bulk flow through the brain interstitium. The volume of distribution (Vd) containing > or = 1% concentration of infusion solution increased linearly with the infusion volume (Vi) for 111In-Tf(Vd/Vi, 6:1) and [14C]sucrose (Vd/Vi, 13:1). Twenty-four hours after infusion, the distribution of 111In-Tf was increased and more homogeneous, and penetration into gray matter had occurred. By using convection to supplement simple diffusion, enhanced distribution of large and small molecules can be obtained in the brain while achieving drug concentrations orders of magnitude greater than systemic levels.

Purpose Sustained-release intravitreal drug implants for posterior segment diseases are associated with significant complications. As an alternative, subconjunctival infusions of drug to the episclera of the back of the eye have been performed, but results in clinical trials for macular diseases showed mixed Results To improve understanding of transscleral drug delivery to the posterior segment, the distribution and clearance of gadolinium-diethylene-triamino-penta-acetic acid (Gd-DTPA) infused in the subconjunctival or intrascleral space was investigated by means of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Methods In anesthetized rabbits, catheters were placed anteriorly in the subconjunctival or intrascleral space and infused with Gd-DTPA at 1 and 10 muL/min. Distribution and clearance of Gd-DTPA were measured using DCE-MRI. Histologic examination was performed to assess ocular toxicity of the delivery system. results. Subconjunctival infusions failed to produce detectable levels of Gd-DTPA in the back of the eye. In contrast, intrascleral infusions expanded the suprachoroidal layer and delivered Gd-DTPA to the posterior segment. Suprachoroidal clearance of Gd-DTPA followed first-order kinetics with an average half-life of 5.4 and 11.8 minutes after intrascleral infusions at 1 and 10 muL/min, respectively. Histologic examination demonstrated expansion of the tissues in the suprachoroidal space that normalized after infusion termination. Conclusions An intrascleral infusion was successful in transporting Gd-DTPA to the posterior segment from an anterior infusion site with limited anterior segment exposure. The suprachoroidal space appears to be an expandible conduit for drug transport to the posterior segment. Further studies are indicated to explore the feasibility of clinical applications.

Object. The activity of γ-aminobutyric acid (GABA), the principal inhibitory neurotransmitter, is reduced in the hippocampus in patients with complex partial seizures from mesial temporal sclerosis. To provide preliminary safety and distribution data on using convection-enhanced delivery of agents to treat complex partial seizures and to test the efficacy and safety of regional selective neuronal suppression, the authors infused muscimol, a GABA-A receptor agonist, directly into the hippocampus of nonhuman primates using an integrated catheter electrode. Methods. Ten rhesus monkeys were divided into three groups: 1) use of catheter electrode alone (four monkeys); 2) infusion of escalating concentrations of muscimol followed by vehicle (three monkeys); and 3) infusion of vehicle and subsequent muscimol mixed with muscimol tracer (three monkeys). Infusions were begun 5 days after catheter electrode placement and continued for 5.6 days before switching to the other agent. Head magnetic resonance (MR) images and electroencephalography recordings were obtained before and during the infusions. Brain histological studies and quantitative autoradiography were performed. Neurological function was normal in controls and when muscimol concentrations were 0.125 mM or less, whereas higher concentrations (0.5 and 1 mM) produced reversible apathy and somnolence. Fluid distribution was demonstrated on MR images and muscimol distribution was demonstrated on autoradiographs throughout the hippocampus and adjacent white matter. Conclusions. Targeted modulation of neuronal activity is a reasonable research strategy for the investigation and treatment of medically intractable epilepsy.

Both theory and clinical studies demonstrate that drug concentrations in the peritoneal cavity can greatly exceed concentrations in the plasma following intraperitoneal administration. This regional advantage has been associated with clinical activity, including surgically documented complete responses in ovarian cancer patients with persistent or recurrent disease following systemic therapy, and has produced a survival advantage in a recent phase III trial. Two pharmacokinetic problems appear to limit the effectiveness of intraperitoneal therapy: poor tumor penetration by the drug and incomplete irrigation of serosal surfaces by the drug-containing solution. We have examined these problems in the context of a very simple, spatially distributed model. If D is the diffusivity of the drug in a tissue adjacent to the peritoneal cavity and k is the rate constant for removal of the drug from the tissue by capillary blood, the model predicts that (for slowly reacting drugs) the characteristic penetration distance is (D/k) 1/2 and the apparent permeability of the surface of a peritoneal structure is (Dk) 1/2. The permeabilityarea product used in classical pharmacokinetic calculations for the peritoneal cavity as a whole is the sum of the products of the tissue-specific permeabilities and the relevant superficial surface areas. Since the model is mechanistic, it provides insight into the expected effect of procedures such as pharmacologic manipulation or physical mixing. We observe that large changes in tissue penetration may be difficult to achieve but that we have very little information on the transport characteristics within tumors in this setting or their response to vasoactive drugs. Enhanced mixing is likely to offer significant potential for improved therapy; however, procedures easily applicable to the clinical setting have not been adequately investigated and should be given high priority. Clinical studies indicate that an increase in irrigated area may be achieved in many patients by individualizing the dialysate volume and consideration of patient position. [J Natl Cancer Inst 1997;89:480-7]

A technique is described for plasma sampling by continuous membrane plasmapheresis performed on blood flowing through an extracorporeal arteriovenous shunt. The plasmapheresis sampler in the shunt employs replaceable commercial planar membranes 2.5 cm in diameter. Validation tests were conducted for 0.6-μm pore diameter microporous membranes with several low-molecular-weight, nonmetabolized solutes that either rapidly equilibrate between plasma and formed elements or remain extracellular. Ex vivo tests were performed for bolus intravenous administration to rabbits. The technique yielded values for time-averaged plasma concentrations comparable to those obtained with serial blood and continuous blood withdrawal methods. The new technique should be particularly advantageous when the distribution of the solute of interest between plasma and formed elements of the blood undergoes significant changes during the sampling interval as a result of binding, exchange, or metabolism in the formed element phase.

Background: Pegylated liposomal formulations contain lipid conjugated to polyethylene glycol. These formulations of anticancer agents have been designed to prolong the drug circulation time, increase tumor delivery, and improve the therapeutic index. The disposition of encapsulated drug is dictated by the liposomal carriers, thus altering the pharmacokinetic (PK) profile of the drug. Allometric scaling is based on a power-log relationship between body weight (W) and drug clearance (CL) among mammals and has been used to compare the PK of small molecule drugs across species. However, it has not been used to compare PK of liposomes or nanoparticle agents. The objectives of this study were to use allometric scaling to: 1) compare the disposition of pegylated liposomal drugs across species and determine the best scaling model, and 2) predict PK parameters of pegylated liposomal drugs in patients. Methods: PK studies of pegylated liposomal CKD-602 (S-CKD602), pegylated liposomal doxorubicin (PLD), and pegylated liposomal cisplatin (SPI-077) were performed at the maximum tolerated dose (MTD) in male and female rats and dogs and in patients with advanced solid tumors as part of phase I studies. Plasma samples were analyzed for sum total (encapsulated + released) drug. The standard allometric equation, CL = a(W)m (a = empirical coefficient; m = allometric exponent) was used to evaluate the relationship between W and CL in each species. The relationship between measures of the mononuclear phagocyte system (MPS) and CL were also evaluated, by substituting the MPS-associated factors for W (liver weight, spleen weight, spleen blood flow, liver blood flow, and monocyte count). Dedrick Plots were used to determine scaling feasibility. Results: Standard allometric scaling using W showed that CL scaled across all agents: [S-CKD602 (R2 = 0.92), PLD (R2 = 0.90), and SPI-077 (R2 = 0.98).] However, the percent (%) difference from scaled predicted and observed PK parameters in humans were still > 30%. All MPS associated factors showed correlation with the CL of all three agents (R2 > 0.90). Based on R2 values, total monocyte count displayed the strongest correlation (R2 = 0.99) with drug clearance across the three species for all three agents. Conclusions: The model that scaled CL the best across all species was the standard allometric method when using potential measures of the MPS, including liver weight, spleen weight, and total monocyte count compared to W. The selection of PK parameters, physiological variables, and pegylated liposomal agent used in this study all contribute to the determination of the optimal scaling method. However, a consistent and predictive allometric model with new methods of allometric scaling and measures of MPS function need to be developed for pegylated liposomal agents. This potential new method could then be used to facilitate the development of future liposomal and nanoparticle agents. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 373. doi:10.1158/1538-7445.AM2011-373

Physiologic pharmacokinetic models are a useful interface between exposure models and risk assessment models by providing a means to estimate tissue concentrations of reactive chemical species at the site of action. The models utilize numerous parameters that can be characterized as anatomical, such as body size or tissue volume; physiological, such as tissue blood perfusion rates, clearances, and metabolism; thermodynamic, such as partition coefficients; and transport, such as membrane permeabilities. The models provide a format to investigate how these parameters can influence the disposition of chemicals throughout the body, which is an important consideration in interpreting toxicity studies. Physiologic models can take into account nonlinear effects related to clearance, metabolism, or transport. They allow for extrapolation of tissue concentration from high dose to low dose experiments and from species to species and can account for temporal variations in dose.

Artificial capillaries perfused with culture medium provide a matrix in which cells can attain tissue-like densities in vitro. Products secreted into the medium can be measured as indicators of cell function or may be recovered for other purposes without disturbing the culture.