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Rituximab is a monoclonal antibody directed against the CD20 B-cell antigen and is approved for the treatment of B-cell lymphoma. We investigated the pharmacokinetics of rituximab following intravitreal administration to assess the feasibility of treating primary intraocular lymphoma. Intravitreal injections of rituximab 0.1 ml (1 mg) were performed in rabbits. Drug concentrations in the aqueous and vitreous humor were measured at intervals from 2 to 17 days after administration. The half-life of the total amount of rituximab in the two compartments was calculated to be 4.7 days. The aqueous and vitreous humor drug levels decayed in parallel maintaining an average ratio of approximately seven. Fitting the data to a two-compartment model yielded a clearance from the aqueous humor of 1.2 microl/min. The clearance was less than the reported rate of aqueous humor outflow indicating that elimination by this route could have been sufficient to account for the disappearance of the drug from the eye. The duration of time over which sustained levels of rituximab were achieved suggest that intravitreal administration warrants further investigation as an approach to treating vitreous and anterior chamber infiltrates in patients with primary intraocular lymphoma.

We have developed a pharmacokinetic model for monoclonal antibodies (mAb) to aid in investigating protocols for targeting small primary tumors or sites of metastatic disease. The model describes the uptake of systemically-administered antibody by a prevascular spherical tumor nodule embedded in normal tissue. The model incorporates plasma kinetics, transcapillary transport, interstitial diffusion, binding reactions, and lymphatic clearance. Antigen internalization can easily be incorporated. Simulations obtained from a three-dimensional finite element analysis are used to assess errors in predictions from earlier models in which the influence of the normal tissue was collapsed into a boundary condition at the tumor surface. The model employing a Dirichlet boundary condition substantially overpredicted the mean total tumor mAb concentration at all times. Although the model with a concentration-dependent flux (composite) boundary condition underpredicted mAb concentration, the discrepancy with finite element results is only notable at early times. Sensitivity analyses were performed on mAb dose and on the coefficients for mAb diffusion in the tissue regions, since reported antibody diffusivity values have varied over 30-fold. The results of the study suggest that mAb diffusivity and mAb binding site density in tumors should have major influences on optimizing doses and scheduling of mAb administration in tumor targeting protocols.

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.

The rate of disappearance of fluorouracil from peritoneal fluid has been experimentally measured and mathematically modeled. The experimental data were obtained following the instillation of 50 ml of dialysis fluid which contained an initial fluorouracil concentration ranging from 24 microM to 12 mM. The rate of disappearance was strongly dependent upon concentration. A distributed model has been formulated which incorporates concepts of diffusion with saturable metabolism and nonsaturable capillary uptake in the tissue surrounding the peritoneal fluid. This model successfully describes the experimental observations and also suggests that the effective penetration depth into tissue is highly dependent upon concentration.

Methotrexate uptake by murine Lewis lung tumor was measured in vivo over a wide dose range. The data were analyzed according to a model previously developed for tissues in which methotrexate uptake is rate limited by transport across the cell membrane. Methotrexate transport in this tumor followed Michaelis-Menten kinetics with a rate constant for permeability (k/K) of 0.012 min-1. The methotrexate binding capacity of dihydrofolate reductase in the tumor was not exceeded at any dose studied. A low membrane permeability in conjunction with a high dihydrofolate reductase level explains the resistance of this tumor to methotrexate.

The application of flameless atomic absorption spectrophotometry to the quantitation of platinum in body fluids and tissues is described. The method was used on samples obtained from humans and beagles treated with the anticancer drug cis-dichlorodiammine platinum. It can be used to detect platinum concentrations in biological tissues and fluids down to ∼30 ppb. The results obtained by this method were compared with those obtained by neutron activation analysis and were found to be lower in all cases.

The contribution of the lungs to the total body clearance of drugs is examined in a framework that emphasizes their anatomical position. For intravenous administration, the lung is the only organ other than blood that can account for a total body clearance in excess of the cardiac output. Systemic arterial drug concentration and tissue drug exposure are inversely proportional to total body clearance. Although the role of the lung has been overshadowed by that of the liver, several examples are presented to demonstrate that a relatively small amount of pulmonary activity can produce a large reduction in systemic arterial drug concentration. For oral administration, first-pass elimination by the liver and lungs in series results in a synergistic increase in total body clearance. Nonlinear effects caused by saturation of elimination pathways are also examined. Increased emphasis on experimental investigation of the pulmonary contribution is warranted, especially for drugs with high apparent clearance.

Mice were chronically exposed to between 1 × 10 −8 and 5 × 10 −9 M plasma methotrexate (MTX) for 2 months. No signs of toxicity were manifested except minor facial hair loss. At the end of this time they were sacrificed, and the activity of dihydrofolate reductase in crude Tris extracts of small intestine, femur, liver and kidney was determined at pH 7.0 and 8.6. At pH 7.0 the enzyme activity was maintained at control levels in small intestine and femur but was decreased to half of controls in liver and kidney. The enzyme activity at pH 8.6 was increased significantly above controls in small intestine and femur but remained at control levels in liver and kidney. These results suggest that some organs adapt to the chronic presence of MTX by increasing their enzyme synthesis rate while other organs are able to function normally for prolonged periods of time with less than normal amounts of active enzyme.

The pharmacokinetics of 1-β- d -arabinofuranosylcytosine (Ara-C) and 1-β- d -arabinofuranosyluracil (Ara-U) are related to enzyme kinetics in vitro in mice, monkeys, dogs and humans by means of a mathematical model. The model is physiologic and permits the incorporation of chemical reactions in appropriate anatomic sites with kinetic characteristics of their local environment. A lean tissue compartment plays an important role as a reservoir. The kidney clearance of Ara-C exhibits essentially the same variation with body weight as inulin.