Opioids in Chronic Kidney Disease Patients Undergoing Hemodialysis

Clinical Trial Simulation Design and Investigational Plan: Our study sample will consist of a group of 10 randomly selected virtual Caucasian hemodialysis patients with Stage 5 chronic kidney disease (CKD) and a group of 10 randomly selected Caucasian age and weight matched healthy controls. Patients, 5 women and 5 men in each group, will be synthesized using clinical trial simulation techniques from the case report data reported by Lee, Leng, and Cooper and the experiments by Kirvela and coworkers. Our goal is to learn about the populations from which the study samples are drawn. To meet this goal, the investigators will perform Monte Carlo simulation. Both virtual control subjects and experimental hemodialysis patients meeting all inclusion/exclusion criteria will be studied in two phases. In phase 1, subjects will receive a ceiling dose of controlled-release oxycodone hydrochloride (hereafter CR-OC) totaling 40 mg twice daily for 2 weeks prior to the experimental hemodialysis procedure on day 15. Because patients in the hemodialysis group will be anuric, they will undergo hemodialysis three times weekly.10 During that time, they will receive supplemental oral immediate-release oxycodone every 4 h as needed to control their pain up to a visual analog scale level of \< 3. These pain levels would correspond with plasma oxycodone concentrations of 20-50 ng/mL. Patients will be instructed to take their last dose of CR-OC 2 to 3 hours before starting the experimental hemodialysis procedure. This dosing schedule will ensure that the time to CR-OC's maximum concentration (Tmax) and its maximum concentration (Cmax) will be reached at the time of blood sampling at t = 0, enabling accurate assessment of CR-OC's elimination with negligible influence from absorption or redistribution. At 8:00 am on the 15th day, and this is phase 2 of the study, each individual will undergo hemodialysis for 4 hours. Two independent simultaneous blood samples for measurement of plasma oxycodone concentrations from both arterial inflow (Cin) and venous outflow (Cout) sites will be obtained immediately upon starting hemodialysis (t = 0) and immediately after hemodialysis before shutting off the machine (t = 4). For all calculations and ODE/PDE modeling (see Model Diagram), the oxycodone concentrations from those samples will be combined and averaged. Oxycodone's intradialytic extraction ratio will be calculated from the simultaneously sampled arterial (inflow) and venous (outflow) plasma oxycodone concentrations by dividing their difference by the arterial plasma oxycodone concentrations. Controls will eat three light meals and a bedtime snack daily. Hemodialysis patients will eat a standard renal diet. Foods will be free of known inhibitors of CYP2D6. Individuals will be digitally abstained from nicotine, caffeine, grapefruit juice and alcohol during the course of the study.