Influence of Genotype on Warfarin Maintenance Dose Predictions Produced Using a Bayesian Dose Individualization Tool.

BACKGROUND: A previously established Bayesian dosing tool for warfarin was found to produce biased maintenance dose predictions. In this study, we aimed (1) to determine whether the biased warfarin dose predictions previously observed could be replicated in a new cohort of patients from 2 different clinical settings, (2) to explore the influence of CYP2C9 and VKORC1 genotype on predictive performance of the Bayesian dosing tool, and (3) to determine whether the previous population used to develop the kinetic-pharmacodynamic model underpinning the Bayesian dosing tool was sufficiently different from the test (posterior) population to account for the biased dose predictions. METHODS: The warfarin maintenance doses for 140 patients were predicted using the dosing tool and compared with the observed maintenance dose. The impact of genotype was assessed by predicting maintenance doses with prior parameter values known to be altered by genetic variability (eg, EC50 for VKORC1 genotype). The prior population was evaluated by fitting the published kinetic-pharmacodynamic model, which underpins the Bayesian tool, to the observed data using NONMEM and comparing the model parameter estimates with published values. RESULTS: The Bayesian tool produced positively biased dose predictions in the new cohort of patients (mean prediction error [95% confidence interval]; 0.32 mg/d [0.14-0.5]). The bias was only observed in patients requiring ≥7 mg/d. The direction and magnitude of the observed bias was not influenced by genotype. The prior model provided a good fit to our data, which suggests that the bias was not caused by different prior and posterior populations. CONCLUSIONS: Maintenance doses for patients requiring ≥7 mg/d were overpredicted. The bias was not due to the influence of genotype nor was it related to differences between the prior and posterior populations. There is a need for a more mechanistic model that captures warfarin dose-response relationship at higher warfarin doses.

Development of bilayer and trilayer nanofibrous/microfibrous scaffolds for regenerative medicine.

Many biomaterial scaffolds have been developed for use in tissue engineering usually for populating with a single cell-type. In this study we demonstrate the production of bilayer and trilayer nanofibrous/microfibrous biodegradable scaffolds suitable for the support, proliferation and yet segregation of different tissues - here used to separate soft tissue from bone forming tissue and keratinocytes from fibroblasts. Essentially we describe a nanofibre barrier membrane which is permeable to nutrients coupled with attached microfibers (either on one side or both sides) to support the proliferation of different cell types either side but prevents migration of cells across the barrier. Such membranes would be suitable for guided tissue regeneration in areas where one wishes to support both soft and hard tissues but keep them separated. We describe a sterile bilayer membrane electrospun from polyhydroxybutyrate-co-hydroxyvalerate (PHBV) (nanofibres) and polylactic acid (PLA) or poly ε-caprolactone (PCL) (microfibres) and a trilayer membrane electrospun in layers of PLA, PHBV, then PLA. These membranes are biocompatible, biodegradable and capable of supporting two different cell populations.