Development of PBPK model for intra-articular injection in human: methotrexate solution and rheumatoid arthritis case study

A physiologically based model describing the dissolution, diffusion, and transfer of drug from the intra-articular (IA) space to the plasma, was developed for GastroPlus® v9.8. The model is subdivided into compartments representing the synovial fluid, synovium, and cartilage. The synovium is broken up into two sublayers. The intimal layer acts as a diffusion barrier between the synovial fluid and the subintimal layer. The subintimal layer of the synovium has fenestrated capillaries that allow the free drug to be transported into systemic circulation. The articular cartilage is broken up into 10 diffusion sublayers as it is much thicker than the synovium. The cartilage acts as a depot tissue for the drug to diffuse into from synovial fluid. At later times, the drug will diffuse from the cartilage back into synovial fluid once a portion of the dose enters systemic circulation. In this study, a listing of all relevant details and equations for the model is presented. Methotrexate was chosen as a case study to show the application and utility of the model, based on the availability of intravenous (IV), oral (PO) and IA administration data in patients presenting rheumatoid arthritis (RA) symptoms. Systemic disposition of methotrexate in RA patients was described by compartmental pharmacokinetic (PK) model with PK parameters extracted using the PKPlus™ module in GastroPlus®. The systemic PK parameters were validated by simulating PO administration of methotrexate before being used for simulation of IA administration. For methotrexate, the concentrations of drug in the synovial fluid and plasma were well described after adjustments of physiological parameters to account for RA disease state, and with certain assumptions about binding and diffusion. The results indicate that the model can correctly describe PK profiles resulting from administration in the IA space, however, additional cases studies will be required to evaluate ability of the model to scale between species and/or doses.

Computational model-based assessment of baroreflex function from response to Valsalva maneuver

Functional metrics of autonomic control of heart rate, including baroreflex sensitivity, have been shown to be strongly associated with cardiovascular risk. A decrease in baroreflex sensitivity with aging is hypothesized to represent a contributing causal factor in the etiology of primary hypertension. To assess baroreflex function in human subjects, two complementary methods to simulate the response in heart rate elicited by the Valsalva maneuver were developed and applied to data obtained from a cohort of healthy normal volunteers. The first method is based on representing the baroreflex arc as a simple linear filter, transforming changes in arterial pressure to changes in R-R interval. The second method invokes a physiologically based model for arterial mechanics, afferent baroreceptor strain-dependent firing, and control of heart rate via central autonomic response to changes in afferent inputs from aortic and carotid sensors. Analysis based on the linear filter model reveals that the effective response time of the baroreflex arc tends to increase with age in healthy subjects and that the response time/response rate is a predictor of resting systolic pressure. Similar trends were obtained based on the physiologically based model. Analysis of the Valsalva response using the physiologically based model further reveals that different afferent inputs from the carotid sinus and the aortic arch baroreceptors govern different parts of the heart rate response. The observed relationship between baroreflex sensitivity and systolic pressure is surprising because hypertensive subjects were excluded from the study, and there was no observed relationship between arterial pressure and age. NEW & NOTEWORTHY We introduce two methods to assess baroreflex function from data recorded from human subjects performing the Valsalva maneuver. Results demonstrate that the baroreflex response time tends to increase with age in healthy subjects, that response time represents a predictor of resting systolic pressure, and that the Valsalva response reveals different effects mediated by baroreceptors in the carotid sinus compared with those in the aortic arch.