Exposure-response relationships for everolimus in de novo kidney transplantation: defining a therapeutic range.
BACKGROUND
Exposure, safety, and efficacy data from the two everolimus randomized, double-blind phase 3 trials were evaluated to identify a therapeutic concentration range applicable in de novo kidney transplantation.


METHODS
A total of 695 evaluable everolimus-treated patients received either 0.75 or 1.5 mg bid in addition to corticosteroids and cyclosporine (troughs 150-400 ng/ml in month 1 and 100-300 ng/ml thereafter). A total of 3355 everolimus trough levels (Cmin) were obtained in weeks 1 and 2 and months 1, 2, 3, and 6 after transplantation. Each patient's average Cmin was calculated and the values were divided into quintiles: 1.0-3.4, 3.5-4.5, 4.6-5.7, 5.8-7.7, 7.8-15.0 ng/ml (139 patients per quintile). Efficacy was freedom from biopsy-confirmed acute rejection. Safety measures were maximum total cholesterol and triglyceride levels and minimum leukocyte and platelet counts. A sigmoid exposure-response model was used to test the significance of these Cmin-efficacy and Cmin-safety relationships.


RESULTS
Freedom from acute rejection was significantly related to Cmin with an incidence of 68% at 1.0-3.4 ng/ml, 81-86% at 3.5-7.7 ng/ml, and 91% at 7.8-15.0 ng/ml (P=0.03). The incidence of hypercholesterolemia, defined as >6.5 mmol/liter, ranged from 76 to 87% over the exposure range without a significant relation to Cmin (P=0.37). The incidence of hypertriglyceridemia, defined as >2.9 mmol/liter, rose from 59 to 77% across the exposure groups (P=0.02). Leukocytopenia, defined as <4x10(9)/liter, occurred in 11-19% of patients across the exposure quintiles showing no relationship to Cmin (P=0.76). The incidence of thrombocytopenia, defined as <100x10(9)/liter, occurred in </=10% of patients in the first 3 Cmin quintiles and was 14 and 17% in Cmin quintiles 4 and 5 (P=0.21).


CONCLUSIONS
A significantly increased risk of acute rejection was observed at everolimus trough levels <3 ng/ml. This is a lower therapeutic concentration limit when everolimus is used with conventionally dosed cyclosporine. Because hyperlipidemias responded to counter-measure therapies and thrombocytopenia had an overall low incidence of 12%, everolimus-related adverse events were manageable up to the highest troughs observed in this population of 15 ng/ml. An upper therapeutic concentration limit is likely more than 15 ng/ml but a precise value could not be derived from these data.
Kovarik
John M
JM
Novartis Pharmaceuticals, Basel, Switzerland.
Kaplan
Bruce
B
Tedesco Silva
Hélio
H
Kahan
Barry D
BD
Dantal
Jacque
J
Vitko
Stefan
S
Boger
Robert
R
Rordorf
Christiane
C
D000305:Adrenal Cortex Hormones / Q000627:therapeutic use; D002784:Cholesterol / Q000097:blood; D016572:Cyclosporine / Q000097:blood / Q000627:therapeutic use; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D000068338:Everolimus; D005500:Follow-Up Studies; D006084:Graft Rejection / Q000453:epidemiology / Q000517:prevention & control*; D006801:Humans; D006937:Hypercholesterolemia / Q000139:chemically induced / Q000453:epidemiology; D015228:Hypertriglyceridemia / Q000139:chemically induced / Q000453:epidemiology; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D015994:Incidence; D016030:Kidney Transplantation / Q000276:immunology* / Q000502:physiology; D007958:Leukocyte Count; D007970:Leukopenia / Q000453:epidemiology; D010976:Platelet Count; D012449:Safety; D020123:Sirolimus / Q000009:adverse effects / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000627:therapeutic use*; D013921:Thrombocytopenia / Q000453:epidemiology; D013997:Time Factors; D014280:Triglycerides / Q000097:blood
D000305:Adrenal Cortex Hormones; D007166:Immunosuppressive Agents; D014280:Triglycerides; D016572:Cyclosporine; D002784:Cholesterol; D000068338:Everolimus; D020123:Sirolimus