PubMed Health⌕ Search

Biomedical subjects

Barry D Kahan

Publications and source records attributed to Barry D Kahan.

At least 37 records · Page 2Linked to original sources
PubMed2003

Pharmacodynamics, pharmacokinetics, and safety of multiple doses of FTY720 in stable renal transplant patients: a multicenter, randomized, placebo-controlled, phase I study.

BACKGROUND: FTY720, a novel immunomodulator, displays potent immunosuppressive activity in a variety of preclinical transplant models. This study examined the safety, pharmacodynamics, and pharmacokinetics of multiple doses of FTY720 in stable renal transplant patients. METHODS: This randomized, multicenter, double-blind, placebo-controlled, phase I study included adults who had been maintained on a regimen of cyclosporine A (CsA) microemulsion and prednisone (or its equivalent) for at least 1 year after renal transplantation. Patients received once-daily doses of 0.125, 0.25, 0.5, 1.0, 2.5, or 5.0 mg FTY720, or placebo for 28 days. After completion of study drug administration, the patients were monitored until day 56 by serial laboratory tests, clinical examinations, and recording of adverse events. The study includes 76 treatment courses (61 FTY720 and 15 placebo), with 65 patients enrolled once and 11 reenrolled. RESULTS: FTY720 doses greater than or equal to 1.0 mg/day produced a significant reduction in peripheral blood lymphocyte count by up to 85%, which reversed within 3 days after discontinuation of study medication. Compared with placebo-treated patients, FTY720 subjects did not show a major increase in adverse events or a change in renal function. Pharmacokinetic measurements revealed that FTY720 displayed linear relations of doses and concentrations over a wide range, but had no effect on CsA exposure. CONCLUSIONS: At doses up to 5.0 mg/day for 28 days, stable renal transplant patients treated with FTY720 in combination with CsA and prednisone displayed a dose-dependent, reversible decline in peripheral blood lymphocytes without an enhanced incidence of collateral toxicities, except possibly bradycardia.

Adult↗
PubMed2003

Sirolimus does not increase the risk for postoperative thromboembolic events among renal transplant recipients.

BACKGROUND: Deep venous thrombosis (DVT) tends to occur in greater frequency among cyclosporine (CsA)-treated renal-transplant recipients. Because administration of sirolimus may increase the whole-blood concentrations of CsA, we sought to assess the impact of the combination regimen on the incidence, predisposing factors, and consequences of postoperative DVT, transplant renal-vein or artery thrombosis, and pulmonary embolus. METHODS: We retrospectively evaluated two cohorts of renal transplant recipients: CsA/prednisone (Pred)+/-azathioprine (n=136, group A) or sirolimus+CsA+Pred (n=354, group B) using Fisher's exact t and chi-square tests, as well as Kaplan-Meier analyses, odds ratios, and multiple logistic regression methods. RESULTS: The 7 of 136 (5.1%) incidence of thrombotic events in group A was similar to the 20 of 354 (5.6%) incidence in group B (P=0.513; NS) and occurred no more frequently ipsilateral to the transplant. Although the occurrence of an acute-rejection episode was not associated with the DVT diagnosis, all affected patients displayed elevated serum creatinine (Scr) values, which remained slightly higher than baseline following recovery (group A 1.63+/-1.22-1.95+/-0.93 mg/dL; group B 1.70+/-1.11-2.01+/-0.88 mg/dL). Renal biopsies failed to show evidence of intrarenal coagulopathy. No patient lost a graft as a complication of DVT, nor did these events produce other lasting adverse effects. Patients in the sirolimus group showed a strong correlation between the occurrence of DVT and the previous existence of an ipsilateral or contralateral lymphocele. CONCLUSION: Addition of sirolimus to a CsA+Pred regimen does not increase the incidence of postoperative thrombotic events among renal transplant recipients.

Adult↗
PubMed2003

Dyslipidemia in renal transplant recipients treated with a sirolimus and cyclosporine-based immunosuppressive regimen: incidence, risk factors, progression, and prognosis.

BACKGROUND: This retrospective study compared the incidence, severity, and predisposing factors for dyslipidemia among renal transplant patients treated for up to 6 years with a cyclosporine +/- prednisone-based concentration-controlled regimen without (n=118) or with (n=280) ascending exposures to sirolimus. METHODS: The diagnosis of dyslipidemia was established when the serum cholesterol value (CHO) was more than 240 mg/dL or serum triglycerides (TG) were more than 200 mg/dL. Generalized estimating equations and mixed-modeling procedures were used for statistical analyses. RESULTS: Hypercholesterolemia was observed in 46% to 80% and hypertriglyceridemia in 43% to 78% of sirolimus-treated patients during the first 6 posttransplantation months. The mean peak serum lipid levels among patients in the sirolimus group (CHO=285.5 mg/dL; TG=322.4 mg/dL) were significantly higher than those in the nonsirolimus group (CHO=250.2 mg/dL and TG=267.6 mg/dL; both P<0.01). The lipid values, which were persistently elevated during the first posttransplantation year, decreased slowly thereafter but remained significantly higher than the pretransplantation levels beyond 4 years after transplantation. The two forms of hyperlipidemia tended to occur in parallel (Pearson's coefficient of correlation, r=0.5, P<0.001), showing a positive predictive value of 0.67 and a negative predictive value of 0.65. However, there was no significant difference in the incidence of cardiovascular events within 4 years after transplantation among patients treated with versus without sirolimus. CONCLUSION: The dyslipidemia associated with sirolimus therapy, albeit persistent, does not seem to represent a major risk factor for the early emergence of cardiovascular complications.

Adult↗
PubMed2003

Thymoglobulin, sirolimus, and reduced-dose cyclosporine provides excellent rejection prophylaxis for pancreas transplantation.

BACKGROUND: We investigated a novel immunosuppressive protocol including thymoglobulin induction in combination with sirolimus and corticosteroids, followed by introduction of markedly reduced exposures to cyclosporine to prevent pancreas-transplant rejection. METHODS: A 7-day course of thymoglobulin (1.5 mg/kg per day) was begun on postoperative day (POD) 0, together with 15 mg of sirolimus on POD 1, and followed by 5 mg per day, targeting these doses to achieve a trough of 10 to 20 ng/mL. When the serum creatinine was below 2.5 mg/dL, cyclosporine was introduced at 50 mg twice daily with dose adjustment to maintain a trough concentration of 100 to 125 ng/mL. RESULTS: The 18 patients included 14 simultaneous pancreas-kidney and 4 pancreas-after-kidney transplant recipients. Two patients were African-American, three patients had a pretransplant panel reactive antibody greater than 20%, and the human leukocyte antigen (HLA) mismatch was 4.5+/-1 (mean+/-standard deviation). With a mean follow-up of 13.6+/-4.7 months, patient, kidney, and pancreas graft survivals are 100%, 100%, and 94%, respectively. A single pancreas graft was lost to thrombosis. There were no acute rejection episodes and no opportunistic infections. Mean hospital stay was 9+/-3 days. At 3 months posttransplantation, the mean value of serum creatinine was 1.2+/-0.3 mg/dL, fasting glucose was 88+/-15 mg/dL, and sirolimus dose at month 3 was 6.3+/-3 mg per day and at month 12 2.7+/-1 mg per day. The average total daily cyclosporine A dose at month 3 was 208+/-62 mg per day and 133+/-13 mg per day at 1 year. CONCLUSIONS: This immunosuppressive regimen provided excellent prophylaxis against acute rejection with no opportunistic infections. We believe that careful monitoring of sirolimus and cyclosporine levels was critical to success of this protocol.

Adult↗
PubMed2003

Pharmacokinetics of an everolimus-cyclosporine immunosuppressive regimen over the first 6 months after kidney transplantation.

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-1 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.

Adult↗
PubMed2003

Individuality: the barrier to optimal immunosuppression.

Immunosuppressive therapy aims to protect transplanted organs from host responses. Individuals have unique repertoires of responses to foreign antigens and toxic reactions to immunosuppressants; the former determining the type or intensity of rejection reactions and the latter influencing the severity of iatrogenic effects. Because existing agents target molecules that are widely distributed in tissues, new strategies must selectively block lymphoid cells only, disrupt alloresponses but not innate immune responses, interact synergistically with other agents, facilitate the homeostatic process that naturally leads to graft acceptance and ideally only interrupt donor-specific responses. Approaches presently under investigation aim to alter cell trafficking, or selectively deviate the maturation of antigen-presenting cells or inhibit lymphocyte-activation cascades - events that are crucial to rejection responses.

Animals↗
PubMed2003

FTY720: A new kid on the block for transplant immunosuppression.

FTY720, a synthetic analogue of myriocin (ISP-1), is derived from culture filtrates of the fungus Isaria sinclairii. As a sphingosine analogue, FTY720 appears to undergo phosphorylation and thereby interact with specific G-protein-linked receptors. In vivo, FTY720 causes emigration of lymphocytes from peripheral blood to secondary lymphoid structures. Thus, the drug is the archetype of a new class of agents that alter cellular homing patterns: the adhesion-migration paradigm. Since FTY720 seems to spare nonspecific elements of host resistance, it may address the not infrequent complications of infections associated with existing therapies. In experimental rodent, canine and non-human primate models, FTY720 produces lymphopenia and immunosuppression, prolonging the survival of allografts. Because of synergistic interactions, it promotes the immunosuppressive effects not only of calcineurin antagonists, but also of proliferation signal inhibitors. These interactions proffer the possibility of large reductions in exposure to and mitigated toxicity of existing drugs. In humans, FTY720 causes dose-dependent peripheral blood lymphopenia, a reduced incidence of acute rejection episodes and only one apparent adverse reaction - a negative chronotropic effect - particularly after the loading dose. While the clinical utility of FTY720 is difficult to predict before completion of Phase III studies that elucidate its benefits versus unanticipated side effects, the initial data suggest several potential advantages: it does not produce hyperlipidaemia, diabetes mellitus, nephrotoxicity, neurotoxicity or myelosuppression, which are characteristic of other immunosuppressants. Furthermore, it displays high oral bioavailability and a low interindividual coefficient of variation. Clearly, structural analogues, as well as other agents that alter the balance of chemokines or affect cellular adhesion to activated endothelium, will represent important components of future regimens.

Animals↗
PubMed2003

Sirolimus: a current perspective.

Sirolimus, a macrocyclic lactone that displays a novel mechanism of immunosuppressive action, is a critical-dose drug requiring therapeutic drug monitoring for optimal outcomes. The compound was documented in two multicenter, blinded clinical trials to reduce the incidence of acute rejection episodes when used in combination with cyclosporine and steroids vs. azathioprine or placebo comparators. Furthermore, studies utilizing cyclosporine withdrawal documented a long-term benefit on renal function of chronic sirolimus therapy, albeit with a modestly enhanced incidence of acute rejection episodes. Although this application may be useful in selected cases, we believe that minimal initial cyclosporine exposures de novo mitigate the need for eventual withdrawal for chronic nephropathy, while preserving the immunosuppressive synergy during the maintenance phase. Recipients treated de novo with a sirolimus-cyclosporine combination tolerate steroid withdrawal at 1 month after living-donor or at 3 to 6 months after cadaveric kidney transplantation with only a 5% risk of acute rejection episodes and 6% incidence of chronic reactions within 3 years. However, sirolimus exacerbates the hypertriglyceridemic and hypercholesterolemic proclivities of transplant recipients, as well as exerts myelosuppressive effects, which are augmented by concomitant therapy with azathioprine or, particularly, with mycophenolate mofetil. Due to its apparent lack of nephrotoxicity, sirolimus has been employed for induction therapy in a calcineurin antagonist-free regimen in combination with either basiliximab or rabbit antilymphocyte sera for weak or strong immune responders, respectively, followed by introduction of a calcineurin antagonist upon resolution of the ischemia-reperfusion injury. Therefore, sirolimus proffers a potent and unique platform for new immunosuppressive strategies in organ transplantation.

Clinical Trials as Topic↗
PubMed2002

Incidence, therapy, and consequences of lymphocele after sirolimus-cyclosporine-prednisone immunosuppression in renal transplant recipients.

BACKGROUND: In a retrospective study we sought to dissect the factors associated with an increased occurrence of clinically significant perinephric fluid collections and lymphoceles among sirolimus-treated renal transplant recipients. METHODS: We compared the incidence, predisposing factors, and consequences of these fluid collections among patients treated with sirolimus-cyclosporine (CsA)-prednisone (Pred) (n=354, group I) versus CsA-Pred with or without azathioprine (n=136, group II). RESULTS: More group I patients (135/354; 38.1%) displayed perinephric fluid collections (denoted as group III) then group II patients (24/136; 17.6%) (denoted as group IV) (P <0.001). In both subgroups the serum creatinine levels were elevated at the time of diagnosis from a nadir of 2.04+/-1.61 to 4.09+/-2.95 mg/dL (group III) and from 2.53+/-2.34 to 4.36+/-2.90 mg/dL (group IV). A significantly greater number of patients required treatment for lymphoceles among group I (56/354; 15.8%) versus group II recipients (6/136; 4.4%; P<0.001). Single or repeated percutaneous drainage procedures successfully treated 35 group I patients versus all 6 group IV patients (P =0.033). No patients in group II versus 21 patients in group I underwent surgical procedures (P <0.001). A significantly higher rate and higher histologic grade of acute rejection episodes, particularly proximate to the onset of the lymphocele, occurred among group IV patients, namely 54.2% (13/24) versus 21.4% (29/135) group III patients (P <0.001). CONCLUSIONS: Addition of sirolimus to a CsA-Pred regimen resulted in both a higher incidence and a requirement for more aggressive treatment of perinephric fluid collections and lymphoceles.

Adult↗
PubMed2002

Allochimeric class I MHC protein-induced tolerance by partial TCR engagement requires activation of both CTL4- and common gamma-chain-dependent cytokine signals.

BACKGROUND: The various toxicities associated with the general immune suppression resulting from current clinical immunosuppressive therapies continue to plague transplant recipients as well as jeopardize allograft survival. METHODS: The present study utilized allochimeric class I MHC antigens (alpha1hu70-77-RT1.Aa) bearing only four donor RT1.Au polymorphic amino acids (a.a.; His70, Val73, Asn74, and Asn77) superimposed on the recipient RT1.Aa background to induce transplantation tolerance in the rat cardiac transplant model. RESULTS: Oral delivery of alpha1hu70-77-RT1.Aa protein alone (days 0-6) induced tolerance, as evidenced by inhibition of both acute and chronic rejection processes. Delivery of alpha1hu70-77-RT1.Aa with therapeutic doses of cyclosporine (CsA) also prevented chronic rejection, otherwise readily developed after treatment with CsA alone. A polymerase chain reaction (PCR)-based analysis showed that tolerant recipients had reduced numbers of interleukin (IL)-2/interferon (IFN)-gamma-producing T helper (Th)1 cells and elevated numbers of IL-4/IL-10-producing Th2 cells. Adoptive transfer experiments revealed that potent regulatory T cells mediated tolerance. The same T cells displayed diminished T cell receptor (TCR)-driven signaling via extracellular regulated kinase, AP-1, and NF-kappaB, as well as the common gamma-chain (gammac) cytokine-receptor-induced signaling by Janus kinase 3 (Jak3)/stimulators and activators of transcription Stat/5 pathways. Tolerance induction was prevented in vivo by inhibition of signal 2 by CTL4Ig or of signal 3 by either rapamycin, which disrupts the mammalian target of rapamycin, or AG490, which inhibits Jak3. Finally, partial or complete tyrosine phosphorylation of Zap70 was observed in alloantigen-specific T cell clones in response to tolerogenic versus immunogenic peptides, respectively. CONCLUSIONS: Tolerance induction by allochimeric proteins is achieved by partial TCR activation in the presence of signals 2 and 3, resulting in a skewed Th2 phenotype.

Abatacept↗
PubMed2002

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

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 <4x10(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 <100x10(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 <3 ng/ml. This is a lower therapeutic concentration limit when everolimus is used with conventionally dosed cyclosporine. Because hyperlipidemias responded to counter-measure therapies and thrombocytopenia had an overall low incidence of 12%, everolimus-related adverse events were manageable up to the highest troughs observed in this population of 15 ng/ml. An upper therapeutic concentration limit is likely more than 15 ng/ml but a precise value could not be derived from these data.

Adrenal Cortex Hormones↗
PubMed2002

De novo hemolytic uremic syndrome after kidney transplantation in patients treated with cyclosporine-sirolimus combination.

OBJECTIVE: We sought to examine factors that predisposed 1.5% (10/672) of renal transplant recipients treated with a cyclosporine (CsA)/sirolimus (SRL)/steroid immunosuppressive regimen to develop hemolytic uremic syndrome (HUS). METHODS: Two cohorts of recipients were treated for 1-212 months (mean: 25.0+/-26.4, median: 18.1) with concentration-control CsA regimens based upon either area under the concentration-time curve (AUC; n=412 patients) or trough measurements (C0; n=260 patients). RESULTS: The only demographic feature more common to affected patients was an original glomerulopathic disease in 7 patients, 4 of whom had displayed IgA glomerulonephritis. All 10 affected patients showed a clinical picture of hemolysis with schistocytes, thrombocytopenia (nadir: 35,000+/-19,600 platelets/mm3), as well as elevated serum levels of lactate dehydrogenase (1697+/-1427 IU) and creatinine (Scr; 2.05+/-1.52 mg/dL prediagnosis to 5.13+/-2.43 mg/dL at diagnosis). Seven patients experienced adverse events concomitant with the bout of HUS, namely, acute rejection episodes prior to (n=2) or during (n=3), and 2 patients, infections (Herpes simplex and pancolitis). The mean values of daily steroid dose and the immunosuppressive drug C0 values were above the putative therapeutic targets: namely, CsA C0=294.9+/-153.2 ng/ml versus 150+/-50 ng/ml and SRL C0=20.1+/-14.0 ng/ml versus 10+/-5 ng/ml, respectively. The therapeutic approach included discontinuation of CsA in 9/10, which was transient in 6/9; discontinuation of SRL in all 10, which was transient in 3, OKT3 for concurrent rejection in 3, and plasmapheresis in 5 patients. At 24 weeks postdiagnosis 9/10 patients have well-functioning kidneys with a mean Scr value of 1.6+/-0.59 mg/dL. One patient who underwent transplant nephrectomy subsequently succumbed due to a cluster of refractory thrombocytopenia, Aspergillus infection, and multiorgan failure. CONCLUSION: This initial experience suggests that a time-limited and reversible de novo HUS syndrome may be less frequent and milder among renal transplant recipients treated with SRL-based immunosuppression.

Adult↗
PubMed2002

Selective inhibitor of Janus tyrosine kinase 3, PNU156804, prolongs allograft survival and acts synergistically with cyclosporine but additively with rapamycin.

Janus kinase 3 (Jak3) is a cytoplasmic tyrosine (Tyr) kinase associated with the interleukin-2 (IL-2) receptor common gamma chain (gamma(c)) that is activated by multiple T-cell growth factors (TCGFs) such as IL-2, -4, and -7. Using human T cells, it was found that a recently discovered variant of the undecylprodigiosin family of antibiotics, PNU156804, previously shown to inhibit IL-2-induced cell proliferation, also blocks IL-2-mediated Jak3 auto-tyrosine phosphorylation, activation of Jak3 substrates signal transducers and activators of transcription (Stat) 5a and Stat5b, and extracellular regulated kinase 1 (Erk1) and Erk2 (p44/p42). Although PNU156804 displayed similar efficacy in blocking Jak3-dependent T-cell proliferation by IL-2, -4, -7, or -15, it was more than 2-fold less effective in blocking Jak2-mediated cell growth, its most homologous Jak family member. A 14-day alternate-day oral gavage with 40 to 120 mg/kg PNU156804 extended the survival of heart allografts in a dose-dependent fashion. In vivo, PNU156804 acted synergistically with the signal 1 inhibitor cyclosporine A (CsA) and additively with the signal 3 inhibitor rapamycin to block allograft rejection. It is concluded that inhibition of signal 3 alone by targeting Jak3 in combination with a signal 1 inhibitor provides a unique strategy to achieve potent immunosuppression.

Administration, Oral↗
PubMed2002

Therapeutic drug monitoring of immunosuppressant drugs in clinical practice.

BACKGROUND: Therapeutic drug monitoring (TDM) is essential to maintain the efficacy of many immunosuppressant drugs while minimizing their toxicity. TDM has become more refined with the development of new monitoring techniques and more specific assays. OBJECTIVE: This article summarizes current data on TDM of the following immunosuppressant drugs used in organ transplantation: cyclosporine, tacrolimus, sirolimus, everolimus, and mycophenolate mofetil. METHODS: Published data were identified by a MEDLINE search of the English-language literature through March 2001 using the terms therapeutic drug monitoring, cyclosporine, tacrolimus, sirolimus, everolimus, and mycophenolate mofetil. Relevant conference abstracts were also included. RESULTS: TDM of cyclosporine has been well studied, and recent findings indicate that monitoring of drug levels 2 hours after dosing is a more sensitive predictor of outcome than trough (C0) monitoring. C0 levels are being used more widely in TDM of tacrolimus; however, the relationship between C0 and area under the curve has varied widely in clinical trials, with correlations ranging from 0.11 to 0.92. The use of TDM of sirolimus, everolimus, and mycophenolate mofetil is evolving rapidly. CONCLUSIONS: TDM of immunosuppressant drugs that have a narrow therapeutic index is an increasingly useful tool for minimizing drug toxicity while maximizing prevention of graft loss and organ rejection.

Drug Monitoring↗
PubMed2002

Update on pharmacokinetic/pharmacodynamic studies with FTY720 and sirolimus.

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.

Animals↗
PubMed2002

Review: metabolism of immunosuppressant drugs.

Pharmacokinetic concepts provide a basis for individualization of drug therapy to optimize outcomes of the critical-dose drugs cyclosporine (CsA), tacrolimus (TRL), sirolimus (SRL), and mycophenolate mofetil (MMF). The therapeutic range of a drug-defined as the concentrations at which the desired pharmacologic effect is produced without adverse effects in most patients-is difficult to achieve given the significant inter-and intrapatient variability of the effects of a given concentration of therapeutic agents. Because of the highly variable rates of absorption of immunosuppressive agents and clinical responses to given concentrations in transplant recipients, individualization of drug regimens by using therapeutic drug monitoring (TDM) is essential to optimize pharmacotherapy Assessing proclivity for acute rejection episodes in transplant recipients currently is attempted by estimating drug exposure using the area under the time-concentration curve (AUC) for MMF and the average concentration (Cav, the quotient of the AUC and the dosing interval) for CsA. These studies have revealed that low oral bioavailability was a more important predictor of rejection than was a rapid clearance rate. In addition, the degree of intra-individual variability of AUC values correlated with the development of chronic rejection in renal transplant recipients. Similarly, TDM of MMF requires AUC determinations. Low mycophenolic acid (MPA) exposure, as estimated by the AUC, demonstrates a significant association with an increased risk of an acute renal transplant rejection episode. The AUC0-2 estimate of MPA shows good agreement with the 12-hr AUC estimate from samples obtained during the entire dosing interval. In contrast, trough levels are utilized during treatment with TRL or SRL, potent new immunosuppressive agents that display a pleiotropic array of side effects. Standard body measures, including weight and body mass index, poorly predict the concentration of SRL in whole blood. Large inter- and intra-individual differences displayed in patients also could not be predicted by demographic features or by laboratory parameters. When SRL is given with other immunosuppressive agents such as CsA, which shares with SRL mutual microsomal metabolism by the cytochrome P450 3A system, pharmacokinetic interactions occur, especially when the agents are administered concomitantly. Because of the critical-dose nature of most of the recent generation of immunosuppressive agents, therapeutic drug monitoring is becoming increasingly important in the selection of doses and treatment regimens.

ATP Binding Cassette Transporter, Subfamily B, Mem↗