METHODS: Medical records of renal transplant patients at Penang General Hospital were retrospectively analyzed. A time-dissociated PKPD model with covariate effects was developed using NONMEM to evaluate renal graft function response, quantified as estimated glomerular filtration rate (eGFR), toward the cyclosporine cumulative exposure (area under the concentration-time curve). The final model was integrated into a tool to predict the potential outcome. Individual eGFR predictions were evaluated based on the clinical response recorded as acute rejection/nephrotoxicity events.
RESULTS: A total of 1256 eGFR readings with 2473 drug concentrations were obtained from 107 renal transplant patients receiving cyclosporine. An Emax drug effect with a linear drug toxicity model best described the data. The baseline renal graft level (E0), maximum effect (Emax), area under the concentration-time curve achieving 50% of the maximum effect, and nephrotoxicity slope were estimated as 12.9 mL·min-1·1.73 m-2, 50.7 mL·min-1·1.73 m-2, 1740 ng·h·mL-1, and 0.00033, respectively. The hemoglobin level was identified as a significant covariate affecting the E0. The model discerned acute rejection from nephrotoxicity in 19/24 cases.
CONCLUSIONS: A time-dissociated PKPD model successfully described a large number of observations and was used to develop an online tool to predict renal graft response. This may help discern early rejection from nephrotoxicity, especially for patients unwilling to undergo a biopsy or those waiting for biopsy results.
METHODS: A three-dimensional finite element model of two-piece threaded dental implant with internal hexagonal connection and mandibular bone block was constructed. Response surface method through face-centred central composite design was applied to examine the influence of two independent factors variables using three levels. The analysis model was fitted to a second-order polynomial equation to determine the response values.
RESULTS: The results showed that the implant stiffness was more effective than the horizontal load value in increasing the stress and strain energy density transfers. The interaction between both factors was significant in decreasing the likelihood of bone resorption. Decreasing the implant stiffness and horizontal load value led to the increased stress transfer and unexpected decrease in the strain energy density, except at the minimum level of the horizontal load. The increase in the implant stiffness and horizontal load value (up to medium level) have increased the strain energy transfer to the bone.
CONCLUSIONS: The stress and strain energy density were transferred distinctively at the bone-implant interface. The role of both implant stiffness and parafunctional loading is important and should be highlighted in the preoperative treatment planning and design of dental implant.