Racial comparisons of everolimus pharmacokinetics and pharmacodynamics in adult kidney transplant recipients.
BACKGROUND
There is limited data analyzing the pharmacokinetic (PK) and pharmacodynamic (PD) properties of everolimus (EVR) between African Americans and Caucasians. The purpose of this study was to determine and compare the EVR PKs and concentration-associated efficacy and toxicity in African American and Caucasian adult kidney transplant recipients.


METHODS
This was a retrospective PK and PD analysis of all patients who received EVR at the Medical University of South Carolina Transplant Center between 2006 and 2012.


RESULTS
Forty-three patients received EVR (22 African Americans, 21 Caucasians). Baseline demographics, immunosuppression, and immunologic risk were similar between races, except for preexisting hypertension, deceased donor type, and cold ischemic time, which were higher in African American patients. PK analysis revealed that African American patients received higher initial EVR doses (2.1 ± 0.8 versus 1.6 ± 0.6 mg/d, P = 0.036), leading to higher early EVR concentrations (EVR >6 ng/mL during the first 60 days: 36% versus 10%, P = 0.037). Efficacy analysis demonstrated similar EVR effects on acute rejection rates (9% versus 10%, P = 0.961), chronic allograft changes (18% versus 14%, P = 0.729), and renal function, with both groups having improved creatinine clearance with EVR therapy (ΔeGFR: 27 versus 12 mL·min·1.73 m). Toxicity analysis demonstrated that African American patients had a trend toward higher rates of EVR discontinuation (46% versus 19%, P = 0.065) and significantly more diarrhea/gastrointestinal intolerance (73% versus 38%, P = 0.022).


CONCLUSIONS
These results demonstrate EVR therapy is effective at preventing rejection and improving graft function in both African American and Caucasian adult renal transplant patients. Conflicting with previous mammalian target of rapamycin PK/PD analyses in African American patients, this study cohort demonstrated higher early EVR levels in the African American patients.
*Division of Transplant Surgery; †College of Medicine; ‡Department of Pharmacy Services; and §Division of Transplant Nephrology, Medical University of South Carolina, Charleston, South Carolina.
David J
DJ
Taber
Lindsey
L
Belk
Holly
H
Meadows
Nicole
N
Pilch
James
J
Fleming
Titte
T
Srinivas
John
J
McGillicuddy
Charles
C
Bratton
Kenneth
K
Chavin
Prabhakar
P
Baliga
D000328:Adult; D001741:Black or African American; D000368:Aged; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D000068338:Everolimus; D005260:Female; D005500:Follow-Up Studies; D006084:Graft Rejection / Q000517:prevention & control; D006085:Graft Survival / Q000187:drug effects; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D007677:Kidney Function Tests; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D054063:Superior Sagittal Sinus; D044465:White People
D007166:Immunosuppressive Agents; D000068338:Everolimus; D020123:Sirolimus