Comparison of Two Pharmacodynamic Transduction Models for the Analysis of Tumor Therapeutic Responses in Model Systems

Semi-mechanistic pharmacodynamic (PD) models that capture tumor responses to anticancer agents with fidelity can provide valuable insights that could aid in the optimization of dosing regimens and the development of drug delivery strategies. This study evaluated the utility and potential interchangeability of two transduction-type PD models: a cell distribution model (CDM) and a signal distribution model (SDM). The evaluation was performed by simulating dense and sparse tumor response data with one model and analyzing it using the other. Performance was scored by visual inspection and precision of parameter estimation. Capture of tumor response data was also evaluated for a liposomal formulation of paclitaxel in the paclitaxel-resistant murine Colon-26 model. A suitable PK model was developed by simultaneous fitting of literature data for paclitaxel formulations in mice. Analysis of the simulated tumor response data revealed that the SDM was more flexible in describing delayed drug effects upon tumor volume progression. Dense and sparse data simulated using the CDM were fit very well by the SDM, but under some conditions, data simulated using the SDM were fitted poorly by the CDM. Although both models described the dose-dependent therapeutic responses of Colon-26 tumors, the fit by the SDM contained less bias. The CDM and SDM are both useful transduction models that recapitulate, with fidelity, delayed drug effects upon tumor growth. However, they are mechanistically distinct and not interchangeable. Both fit some types of tumor growth data well, but the SDM appeared more robust, particularly where experimental data are sparse

Clinical Pharmacokinetics and Pharmacodynamics of Biologic Therapeutics for Treatment of Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is a multifactorial autoimmune disease with potentially severe clinical manifestation that mainly affects women of childbearing age. Patients who do not respond to standard-of-care therapies, such as corticosteroids and immunosuppressants, require biologic therapeutics that specifically target a single or multiple SLE pathogenesis pathways. This review summarizes the clinical pharmacokinetic and pharmacodynamic characteristics of biologic agents that are approved, used off-label, or in the active pipeline of drug development for SLE patients. Depending on the type of target, the interacting biologics may exhibit linear (non-specific) or nonlinear (target-mediated) disposition profiles, with terminal half-lives varying from approximately 1 week to 1 month. Biologics given by subcutaneous administration, which offers dosing flexibility over intravenous administration, demonstrated a relatively slow absorption with a time to maximum concentration of approximately 1 day to 2 weeks and a variable bioavailability of 30–82 %. The population pharmacokinetics of monoclonal antibodies were best described by a two-compartment model with central clearance and steady-state volume of distribution ranging from 0.176 to 0.215 L/day and 3.60–5.29 L, respectively. The between-subject variability in pharmacokinetic parameters were moderate (20–79 %) and could be partially explained by body size. The development of linked pharmacokinetic-pharmacodynamic models incorporating SLE disease biomarkers are an attractive strategy for use in dosing regimen simulation and optimization. The relationship between efficacy/adverse events and biologic concentration should be evaluated to improve clinical trial outcomes, especially for biologics in the advanced phase of drug development. New strategies, such as model-based precision dosing dashboards, could be utilized to incorporate information collected from therapeutic drug monitoring into pharmacokinetic/pharmacodynamic models to enable individualized dosing in real time