John M Kovarik

..Sotrastaurin is a protein kinase C inhibitor in the development for prevention of organ rejection after renal transplantation...

..In this study we evaluated exposure, safety and efficacy data from an international trial of everolimus. We sought to identify a tolerated and efficacious range for blood levels of this agent in maintenance lung transplant recipients...

..Conversion to once-daily dosing was associated with a decrease in nighttime mean arterial blood pressure...

..The authors determined the effect of combining a single dose of fingolimod with steady-state atenolol or diltiazem on heart rate and mean arterial pressure...

..The authors compared the pharmacokinetics and pharmacological effects of the immunomodulator fingolimod in healthy white and Asian subjects for potential ethnic differences...

..The pharmacokinetics and lymphocyte responses to the immunomodulator fingolimod (FTY720) were characterized after oral and intravenous administration...

..We explored relationships between blood levels of fingolimod (FTY720) and everolimus versus treated biopsy-proven acute rejection (BPAR) in an open-label trial in de novo kidney transplant recipients...

..We characterized the pharmacokinetics of tacrolimus and everolimus in a combined immunosuppressive regimen...

..This rational and systematic approach to drug interactions on everolimus yielded clinically useful, structured guidelines for dose adjustment...

..Isoproterenol did not alter the pharmacokinetics of fingolimod. The pure beta-agonist isoproterenol can reverse the heart rate reduction that occurs transiently after initiating fingolimod treatment...

..3-fold due to a pharmacokinetic interaction. We assessed this drug interaction for potential differences when the innovator formulation is replaced by a generic cyclosporine...

..Whether a higher dose of sotrastaurin is needed to compensate for this in the short-term after surgery will be addressed in future clinical trials...

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..The authors determined the effect of combining sotrastaurin with the calcineurin inhibitor cyclosporine on the pharmacokinetics and biomarker responses to both drugs...

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..The authors determined whether a pharmacokinetic interaction occurs between sotrastaurin and everolimus, both of which are substrates and inhibitors of CYP3A4...

..Sotrastaurin is an immunosuppressant that reduces T-lymphocyte activation via protein kinase C inhibition. The effect of CYP3A4 inhibition by ketoconazole on the pharmacokinetics of sotrastaurin, a CYP3A4 substrate, was investigated...

..The authors determined whether intravenous atropine can prevent or counteract the negative chronotropic effect of the immunomodulator fingolimod...

..The clinician, however, should be aware of this interaction and bear in mind the possibility of a fingolimod dose reduction based on clinical monitoring...

..FTY720 is a sphingosine-1-phosphate receptor agonist intended for use in immunoprophylaxis regimens to prevent acute rejection after organ transplantation...

..25 and 5 mg/day, respectively. Exposure-response modeling provided evidence that 5 mg/day FTY720 resulted in a near-maximal dynamic effect of this drug on lymphocytes...

..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...

..This study was performed to provide guidance on administration with respect to meals and to measure pharmacologic responses in healthy subjects...

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..The dispersible tablet formulation should be taken consistently either with or without food to minimize fluctuations in exposure over time...

..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...

..To assess the influence of the CYP3A4 enzyme inducer rifampin on the pharmacokinetics of the immunosuppressant everolimus to provide guidance for their coadministration...

..Maintaining everolimus troughs in the range 3 to 8 ng/mL in the first posttransplant year with reduced-exposure cyclosporine is associated with good efficacy and safety profiles...

..For patients with severe hepatic impairment (Child-Pugh class C), a standard first dose of fingolimod could be given followed by a maintenance dose that is reduced by half from the normal maintenance dose...

..FTY720 did not increase the QRS or QT interval. These results confirm that the first dose of FTY720 has a mild to moderate negative chronotropic effect...

..In clinical development trials, everolimus has demonstrated the ability to reduce the incidence of acute rejection episodes, cytomegalovirus infection and cardiac vasculopathy, thus addressing the primary causes of allograft dysfunction...

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..An upper therapeutic concentration limit is likely more than 15 ng/ml but a precise value could not be derived from these data...

..The first dose is given before surgery and the second on day 4 after transplantation...

..Dosing of everolimus needs to be adjusted to take into account an average threefold increase in everolimus exposure when cyclosporine is added to the regimen...

..Therapeutic monitoring of everolimus concentrations would be helpful after the removal of cyclosporine to individually titrate everolimus exposure...

..Concomitant administration of potent inhibitors of the cytochrome P450 isozyme CYP3A may reduce everolimus clearance and increase its blood concentrations...

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..CONCLUSIONS: Everolimus exhibited dose-proportional, stable exposure during the first post-transplant year. For a 4-fold range of everolimus doses there were no differential effects on cyclosporine dosing or pharmacokinetics...

..Fingolimod is thus a promising new therapy for eligible patients with MS, with a predictable pharmacokinetic profile that allows effective once-daily oral dosing...

..Cyclosporine bioavailability is unaltered when Neoral is administered diluted in apple juice or orange juice compared with tap water which conforms to the cyclosporine product label...

..An association among FTY720 blood concentration, decrease in lymphocyte counts, and freedom from acute rejection episodes has been observed in early clinical development trials in de novo kidney transplantation...

..We sought to quantify the influence of the CYP3A inhibitor erythromycin on the pharmacokinetics of everolimus, a CYP3A substrate...

..Everolimus did not appear to alter ketoconazole predose concentrations. Given the magnitude of this drug interaction, use of ketoconazole should be avoided if possible in everolimus-treated patients...

..We sought to define the influence of verapamil, an inhibitor of CYP3A and P-glycoprotein, on the pharmacokinetics of everolimus, a substrate of this enzyme and transporter...

..Further exploration for exposure-effect relationships in a larger population is warranted...

..Hence, no dosing adjustment is deemed necessary when basiliximab is used in triple immunosuppressive therapy including either azathioprine or mycophenolate mofetil...

..liver), and across age groups (pediatric vs. adult patients). Average C2 values achieved with current pediatric cyclosporine dosing practices cluster around the target C2 ranges recommended for adults...

..Based on the available cyclosporin pharmacokinetic data in adults, no age-related administration adaptations appear necessary for its use in the elderly...

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..The first dose should be given within 6 h after organ perfusion and the second on day 4 after transplantation. A supplemental dose may be considered for patients with a large volume of drained ascites fluid relative to body size...

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..Therapeutic monitoring would be a helpful adjunct to subsequent titration of everolimus exposure in this subpopulation. Everolimus has not been assessed in patients with severe hepatic impairment...

..Although hepatic impairment elicited changes in the disposition of FTY720, the magnitude of these changes suggests that the FTY720 dose does not need to be adjusted in mild or moderate hepatic-impaired patients...

..5 mg/day, showed that the simulated BPAR rate (with TDM) was 21% versus 26% in the group with fixed dosing. Therefore, TDM in heart transplantation could optimize immunosuppressive efficacy and reduce treatment-related toxicity...

..C2 is the best single-point predictor of the AUC0-4 in lung transplant recipients with and without CF...

..The steady-state pharmacokinetics of everolimus were longitudinally assessed in pediatric de novo kidney allograft recipients during a 6-month period...

..To identify the optimal regimen and dosage of the oral mammalian target of rapamycin inhibitor everolimus (RAD001)...