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.

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.