Update on Pharmacokinetic/Pharmacodynamic Studies With FTY720 and Sirolimus

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Abstract
Expanding the cytokine paradigm beyond the use of calcineurin inhibitors as baseline therapy provides new strategies in immunosuppression. Drugs such as FTY720 alter the sensitivity of lymphocytes to homing chemokines, and agents such as sirolimus (SRL) disrupt downstream cytokine signal transduction. Confirming studies in rodents and nonhuman primates, administration of either FTY720 or both of these drugs afford synergistic interactions with cyclosporine to renal transplant patients to rapidly and dramatically deplete peripheral blood lymphocytes (PBL) but neither granulocytes nor monocytes. Present information suggests that FTY720 facilitates lymphocyte homing mechanisms, leading to T and B cell sequestration in secondary lymphoid structures. Interestingly, FTY720 displays pharmacokinetic characteristics suggesting that therapeutic drug monitoring (TDM) will not be essential for clinical applications. In contrast, SRL is a critical-dose drug that requires TDM. SRL disrupts costimulatory and cytokine-stimulated T cell activation by inhibiting a multifunctional kinase, mammalian target of sirolimus (mTOR). Two pivotal trials including more than 1,300 patients demonstrated that addition of SRL to a CsA-based regimen reduces the incidence, time to onset, and severity of acute rejection episodes. When used alone, SRL seems therapeutically equivalent to CsA. In the coming decade, SRL is likely to be used in a variety of drug combination regimens both simultaneously and sequentially, not only to avert acute rejection episodes, but also to forestall chronic nephropathic processes. These two new agents are likely to usher in a new era of transplant therapy.