A Systematic Literature Review Approach to Estimate the Therapeutic Index of Selected Immunosuppressant Drugs After Renal Transplantation

Abstract

Background Drugs that exhibit close margins between therapeutic and toxic blood concentrations are considered to have a narrow therapeutic index (NTI). The Food and Drug Administration has proposed that NTI drugs should have more stringent bioequivalence standards for approval of generic formulations. However, many immunosuppressant drugs do not have a well-defined therapeutic index (TI). Methods We sought to determine whether safety, efficacy, and pharmacokinetic data obtained from the medical literature through a comprehensive literature search could be used to estimate the TI of cyclosporine, tacrolimus, and sirolimus. In this analysis, we considered TI ≤2 as a criterion to define a drug as having an NTI. Results Published literature indicates that cyclosporine has a TI of 2–3, which falls just short of our criteria to be classified as having an NTI. We found sirolimus and tacrolimus to have a therapeutic range of 5–12 ng/mL and of 5–20 ng/mL, respectively, but were unable to calculate the TI. Conclusion Although current literature does not provide a clear indication that these drugs have an NTI, the routine use of therapeutic drug monitoring in clinical practice suggests that more stringent testing of their pharmacokinetic and pharmacodynamic properties should be performed prior to the approval of generic formulations.

Inhibition of Growth of TSC2-Null Cells by a PI3K/mTOR Inhibitor but Not by a Selective MNK1/2 Inhibitor

“…Our in vitro cell studies did not investigate the effect of TSC2+/+ immune cells or stromal cells on the TSC2-null cell growth. We believe inhibition of growth of human LAM cell organoids, in the presence or absence of different human immune or stromal cells, would be more clinically relevant using concentrations of rapamycin that are clinically tolerable, i.e., between 5-25 nM [20].…”

“…Rapamycin was used at a concentration of 10 nM throughout our studies, since this is approximately the clinical blood concentration achieved in patients dosed once daily with 2 mg Sirolimus [8]. However, the pharmacokinetic/efficacy studies with Sirolimus were conducted in combination with other immunosuppressive drugs for transplantation patients with an effective dose range of 0.5-5 mg/day [20]. There has not been a comprehensive study of Sirolimus blood concentrations vs. efficacy in LAM patients.…”

Precision Dosing Priority Criteria: Drug, Disease, and Patient Population Variables

“…These are also called "critical-dose drugs" and often require therapeutic drug monitoring (TDM) and dose individualization based on patientspecific characteristics (Pater, 2004). Values of ≤2 (Bialer et al, 1998;Greenberg et al, 2016;Ericson et al, 2017) or ≤3 (Li et al, 2018) have been considered therapeutic index cut off points for NTI drugs. Examples of drugs that have been specified as NTI by regulatory agencies include anticoagulants (e.g., warfarin), antiarrhythmics (e.g., digoxin, flecainide), antiepileptics (e.g., phenytoin, carbamazepine), hormones (e.g., levothyroxine, ethinyl estradiol), and immunosuppressants (e.g., tacrolimus, sirolimus, cyclosporine) (Yu, 2011).…”

“…This method performed by Ku and colleagues accurately determined the therapeutic index of phenytoin with data that had been collected from patients during standard care (Ku et al, 2016). Systematic review of published data has also been used to estimate the therapeutic index in approved drugs (Greenberg et al, 2016;Ericson et al, 2017). In these studies, safety, efficacy, and therapeutic monitoring data were gathered from published trials and successfully used to estimate the therapeutic index of antiepileptics (phenytoin, phenobarbital, and valproate) (Greenberg et al, 2016) and an immunosuppressant (cyclosporine) (Ericson et al, 2017).…”

“…Systematic review of published data has also been used to estimate the therapeutic index in approved drugs (Greenberg et al, 2016;Ericson et al, 2017). In these studies, safety, efficacy, and therapeutic monitoring data were gathered from published trials and successfully used to estimate the therapeutic index of antiepileptics (phenytoin, phenobarbital, and valproate) (Greenberg et al, 2016) and an immunosuppressant (cyclosporine) (Ericson et al, 2017). However, because patients and physicians are reluctant to collect data that requires frequent monitoring unless it is necessary, many drugs may not have enough TDM data to be able to use this type of method.…”