Pharmacokinetics of an Everolimus-Cyclosporine Immunosuppressive Regimen Over the First 6 Months After Kidney Transplantation

Abstract

The pharmacokinetics of everolimus were characterized over the first 6 months post transplant in 731 patients receiving either 0.75 or 1.5 mg bid everolimus in addition to cyclosporine and corticosteroids. Pharmacokinetic data consisted of 4014 everolimus trough concentrations (Cmin) obtained in all patients and 659 area under the concentration-time curve (AUC) -profiles obtained at months 2, 3, and 6 in a subset of 261 patients. Cmins averaged 4.3 -2.4 and 7.2 -4.2 ng/mL at 0.75 and 1.5 mg bid, indicating a 20% under-proportionality at the upper dose level. Cmins were 19-34% lower in the first month compared with months 2 through 6-values. AUC was dose-proportional and stable over time, averaging 77 -32 and 136 -57 ng h mL À1 at the two dose levels. Within-and between-patient variability in AUC were 27% and 31%, respectively. There was no influence of sex, age (16-66 years), or weight (42-132 kg) on AUC. Everolimus exposure was significantly lower by an average 20% in blacks. Everolimus exposure was relatively stable over the first 6 months post transplant, with no major departure from dose-proportionality over the therapeutic dose range. Weight-adjusted dosing (mg/ kg) does not appear warranted. Black patients may have lower bioavailability and/or higher clearance of everolimus compared with white patients.

High-performance liquid chromatography with ultraviolet detection for therapeutic drug monitoring of everolimus

“…The observed profiles were in agreement with recently published pharmacokinetic studies [9,23], thus confirming that the assay was unaffected by any interferences due to concomitant medications or drug metabolites and was also able to discriminate between close blood concentrations.…”

“…At the upper limit of quantification, set at 200 ng/mL, we observed a slight decrease in the within-day performance of the method. It should be mentioned, however, that this value greatly exceeds everolimus concentrations found in different pharmacokinetic studies [9,23].…”

Everolimus Versus Azathioprine in Maintenance Lung Transplant Recipients: An International, Randomized, Double-Blind Clinical Trial

“…The average dose and exposure of everolimus remained stable between 12 and 24 months. The steadystate pharmacokinetics of everolimus in lung transplant patients were similar to those in renal and cardiac transplant patients treated with a similar dose (23,24). None of the differences are significant.…”

Long-term outcome of everolimus treatment in transplant patients

“…13 The bioavailability of everolimus is affected by food, as shown by delays in time to reach peak concentration (t max ) of up to a median 1.75 hours and reductions in C max by up to a mean of 60%, associated with high-fat meals with respect to the fasting state, in studies including 24 healthy volunteers and six renal transplant recipients. 17 Although systemic exposure to everolimus was reduced to a more modest extent (by 16% in volunteers and 21% in patients), consistent administration of the drug either with or without food is recommended to minimize variability in patient exposure.…”

“…13 Mean minimum trough blood everolimus concentrations (C min ) should be maintained above the therapeutic threshold of 3 ng/mL. Moreover, mean C min values were also maintained above the therapeutic threshold in cardiac transplant recipients receiving everolimus 1.5 mg/day or 3 mg/day over 6 months.…”