Everolimus in de novo cardiac transplantation: pharmacokinetics, therapeutic range, and influence on cyclosporine exposure.
We evaluated exposure, safety, and efficacy data from an international Phase 3 trial of everolimus in de novo heart transplantation to characterize the longitudinal pharmacokinetics of everolimus and cyclosporine and to identify a therapeutic concentration range for everolimus. We randomized 634 patients to receive either 0.75 mg everolimus twice daily, 1.5 mg everolimus twice daily, or azathioprine in addition to corticosteroids and cyclosporine. At 8 visits during the first 6 months after transplantation, we obtained 2,328 everolimus trough levels (Cmin) and 129 area-under-the-curve (AUC) profiles over the dosing interval in patients treated with everolimus; we collected 3,258 cyclosporine trough concentrations and 174 profiles in all 3 treatment arms. We used median-effect analysis to characterize exposure-response associations between everolimus average Cmin vs freedom from biopsy-confirmed acute rejection; maximum cholesterol, low density lipoprotein, triglyceride, and creatinine levels; and minimum leukocyte and platelet counts. Everolimus Cmins averaged 5.2 +/- 3.8 ng/ml and 9.4 +/- 6.3 ng/ml at the lower and upper dose levels. A 17% underproportionality was noted in Cmins; however, peak exposure and AUC were consistent with dose proportionality. Everolimus exposure was stable during the 6-month period. Interindividual variability was 37% for AUC and 40% for Cmin. The latter parameter was not influenced to a clinically relevant extent by sex, age, or weight. The Cmin was well correlated with AUC (r2 = 0.81). Everolimus Cmin was significantly related to freedom from rejection (p = 0.02) with 3 ng/ml being an informative lower threshold for efficacy. Thrombocytopenia, defined as <75 x 10(9)/liter, was related significantly to Cmin (p = 0.03); however, the incidence in this study was too low to establish an upper end for the therapeutic range. Lower doses of cyclosporine (by 15% to 19%) were used in patients treated with everolimus to achieve cyclosporine Cmins and AUCs similar to those in patients treated with azathioprine. Everolimus exposure was dose proportional and stable during the first 6 months after transplantation. Interindividual pharmacokinetic variability was high but not influenced by common demographic covariates. We observed a significantly increased risk of acute rejection at everolimus trough levels <3 ng/ml, which constitutes the lower therapeutic concentration limit when everolimus is used with conventionally dosed cyclosporine. Everolimus-related adverse events were manageable up to the highest troughs (22 ng/ml) observed in this population. We could not derive a precise upper therapeutic concentration limit from these data.
Kovarik
John M
JM
Novartis Pharmaceuticals, Novartis Pharma AG, Building WSJ 27.4093, 4002 Basel, Switzerland. john.kovarik@pharma.novartis.com
Eisen
Howard
H
Dorent
Richard
R
Mancini
Donna
D
Vigano
Mario
M
Rouilly
Marisel
M
Hsu
Chyi-Hung
CH
Rordorf
Christiane
C
D000305:Adrenal Cortex Hormones / Q000627:therapeutic use; D019540:Area Under Curve; D001379:Azathioprine / Q000627:therapeutic use; D016572:Cyclosporine / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D000068338:Everolimus; D005260:Female; D006084:Graft Rejection / Q000517:prevention & control; D016027:Heart Transplantation; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D012449:Safety; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use*
D000305:Adrenal Cortex Hormones; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D000068338:Everolimus; D001379:Azathioprine; D020123:Sirolimus