Gray's time-varying coefficients model for posttransplant survival of pediatric liver transplant recipients with a diagnosis of cancer

Transplantation is often the only viable treatment for pediatric patients with end-stage liver disease. Making well-informed decisions on when to proceed with transplantation requires accurate predictors of transplant survival. The standard Cox proportional hazards (PH) model assumes that covariate effects are time-invariant on right-censored failure time; however, this assumption may not always hold. Gray's piecewise constant time-varying coefficients (PC-TVC) model offers greater flexibility to capture the temporal changes of covariate effects without losing the mathematical simplicity of Cox PH model. In the present work, we examined the Cox PH and Gray PC-TVC models on the posttransplant survival analysis of 288 pediatric liver transplant patients diagnosed with cancer. We obtained potential predictors through univariable (P < 0.15) and multivariable models with forward selection (P < 0.05) for the Cox PH and Gray PC-TVC models, which coincide. While the Cox PH model provided reasonable average results in estimating covariate effects on posttransplant survival, the Gray model using piecewise constant penalized splines showed more details of how those effects change over time. © 2013 Yi Ren et al

Intestinal drug absorption, cytochrome P450-mediated metabolism, and transport after small bowel transplantation

Small bowel allograft recipients require multiple medications after transplant, many of which are orally administered cytochrome P450 3A (CYP3A) and/or p-glycoprotein (p-gp) substrates. A previous study in dogs has shown that surgical manipulation of the intestine, ischemia-reperfusion injury, and activation of the immune system lead to suppression of CYP3A and p-gp function in the early post-transplant period, presumably due to release of pro-inflammatory cytokines, a suppression that diminishes over time. The work presented in this dissertation compares intestinal CYP3A (using midazolam) and p-gp (using fexofenadine) expression and function in small bowel transplant recipients in the early post-transplant period (the first 40 days after surgery, n=16) and later (four to 12 months) post transplant (n=10) as well as with 16 age- and gender-matched healthy control subjects. Oral bioavailability and oral AUC of midazolam were significantly higher in transplant subjects early post-transplant, but no different from controls at four to 12 months post-transplant. The oral AUC ratio of 1’hydroxymidazolam to midazolam, a measure of the extent of CYP3A-mediated metabolism, was significantly lower in the early post-transplant period compared with controls, but at the later period no difference was observed. No difference in fexofenadine AUC was observed between subject groups, and although Tmax of fexofenadine was significantly higher in transplant subjects at both time periods as compared with healthy controls, AUC and Cmax were more influenced by route of administration (jejunostomy tube vs. oral) and transplant subtype (modified multivisceral vs. isolated intestine) than by ileal ABCB1 expression. AUC0-7 and Cmax of oral tacrolimus (a CYP3A/p-gp substrate) were significantly higher early post transplant. Overall this work presents strong evidence for an early immune-mediated suppression of intestinal CYP3A that eventually returns to normal in stable intestinal transplant patients, indicating that bioavailability of highly soluble, highly permeable CYP3A substrates such as midazolam will be significantly increased early post-transplant, requiring the use of caution in their dosing during this time and by extrapolation, during other times of high immune activation, such as acute rejection. These findings have clinical relevance for appropriate medication use in small bowel transplant recipients