Exposure-response relationships for everolimus in de novo kidney transplantation: Defining a therapeutic range

John M. Kovarik, Bruce Kaplan, Hélio Tedesco Silva, Barry D. Kahan, Jacque Dantal, Stefan Vitko, Robert Boger, Christiane Rordorf

Research output: Contribution to journalArticle

121 Citations (Scopus)

Abstract

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 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 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

Original languageEnglish (US)
Pages (from-to)920-925
Number of pages6
JournalTransplantation
Volume73
Issue number6
StatePublished - Mar 27 2002
Externally publishedYes

Fingerprint

Kidney Transplantation
Incidence
Safety
Therapeutics
Hypertriglyceridemia
Leukopenia
Sigmoid Colon
Hypercholesterolemia
Platelet Count
Leukocyte Count
Thrombocytopenia
Cyclosporine
Adrenal Cortex Hormones
Triglycerides
Transplantation
Cholesterol
Everolimus
Biopsy

ASJC Scopus subject areas

  • Transplantation
  • Immunology

Cite this

Kovarik, J. M., Kaplan, B., Silva, H. T., Kahan, B. D., Dantal, J., Vitko, S., ... Rordorf, C. (2002). Exposure-response relationships for everolimus in de novo kidney transplantation: Defining a therapeutic range. Transplantation, 73(6), 920-925.

Exposure-response relationships for everolimus in de novo kidney transplantation : Defining a therapeutic range. / Kovarik, John M.; Kaplan, Bruce; Silva, Hélio Tedesco; Kahan, Barry D.; Dantal, Jacque; Vitko, Stefan; Boger, Robert; Rordorf, Christiane.

In: Transplantation, Vol. 73, No. 6, 27.03.2002, p. 920-925.

Research output: Contribution to journalArticle

Kovarik, JM, Kaplan, B, Silva, HT, Kahan, BD, Dantal, J, Vitko, S, Boger, R & Rordorf, C 2002, 'Exposure-response relationships for everolimus in de novo kidney transplantation: Defining a therapeutic range', Transplantation, vol. 73, no. 6, pp. 920-925.
Kovarik JM, Kaplan B, Silva HT, Kahan BD, Dantal J, Vitko S et al. Exposure-response relationships for everolimus in de novo kidney transplantation: Defining a therapeutic range. Transplantation. 2002 Mar 27;73(6):920-925.
Kovarik, John M. ; Kaplan, Bruce ; Silva, Hélio Tedesco ; Kahan, Barry D. ; Dantal, Jacque ; Vitko, Stefan ; Boger, Robert ; Rordorf, Christiane. / Exposure-response relationships for everolimus in de novo kidney transplantation : Defining a therapeutic range. In: Transplantation. 2002 ; Vol. 73, No. 6. pp. 920-925.
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abstract = "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 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 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",
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T2 - Defining a therapeutic range

AU - Kovarik, John M.

AU - Kaplan, Bruce

AU - Silva, Hélio Tedesco

AU - Kahan, Barry D.

AU - Dantal, Jacque

AU - Vitko, Stefan

AU - Boger, Robert

AU - Rordorf, Christiane

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N2 - 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 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 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

AB - 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 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 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

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