Opioids in Chronic Kidney Disease Patients Undergoing Hemodialysis
Opioids in Chronic Kidney Disease Patients Undergoing Hemodialysis
To measure oxycodone's intradialytic mass transfer rate coefficient and oxycodone's removal
 rate using an ODE/PDE hemodialysis model. To implement a rational clinical strategy for
 estimating a patient's post-hemodialysis oxycodone restoration dose using results from an
 ODE/PDE model of 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.
Inclusion Criteria:

 -  Healthy, non-smoking, opioid intolerant Caucasian men and women controls.

 -  Hemodialysis patients age 44 ± 10 (mean ± SD) years and normal controls 36 ± 9 years.

 -  No statistically significant difference in weight between hemodialysis and control
 patients.

 -  Mean serum creatinine concentrations of 7.29 ± 1.48 mg/dL in hemodialysis patients and
 0.81 ± 0.12 mg/dL in controls (normal 0.7 to 1.3 mg/dL for men and 0.6 to 1.1 mg/dL
 for women)

 -  Mean urine output of 1.83 ± 0.47 mL/hr (44 ± 11 mL/24 hr) in hemodialysis patients and
 62.32 ± 16.01 mL/hr (1496 ± 384 mL/24 hr) in controls.

 -  Patients in both groups with normal liver function. Serum prothrombin time (PT/INR),
 aPTT, albumin, bilirubin (direct and indirect), liver transaminases, gamma-glutamyl
 transferase and alkaline phosphatase normal.

 Exclusion Criteria:

 -  In both groups, a clinically significant electrocardiogram (ECG) abnormality.

 -  An uncontrolled clinically significant cardiovascular condition other than end-stage
 kidney disease.

 -  Elevated transaminases, alkaline phosphatase, bilirubin, low phosphodiesterase,
 elevated ammonia levels, low glucose, elevated lactate, elevated creatinine, and
 hypoxia (hepatorenal syndrome)

 -  Serum positive for HIV, hepatitis BsAg, or Hepatitis C

 -  A history of drug or alcohol abuse within the past 24 months

 -  Currently participating (or participated within the previous 30 days in an
 investigational therapeutic or device study

 -  Female who is pregnant, nursing, or of child-bearing potential not practicing
 effective contraceptive methods.