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PubMed2004

Exposure-response relationships and drug interactions of sirolimus.

Sirolimus (rapamycin, RAPAMUNE, RAPA) is an immunosuppressive agent used for the prophylaxis of renal allograft rejection and exhibits an immunosuppressive mechanism that is distinct from that for cyclosporine and tacrolimus. The purpose of this manuscript is to discuss the exposure-response relationships and drug interactions of sirolimus. The various factors affecting sirolimus whole blood exposure included first-pass extraction, formulation, food, demographics, liver disease, assay method, and interacting drugs. Clinically significant effects caused by food, pediatric age, hepatic impairment, and interacting drugs require recommendations for the safe and efficacious use of sirolimus in renal allograft patients. An exposure-response model based on multivariate logistic regression was developed using the interstudy data from 1832 renal allograft patients. The analysis revealed an increased probability of acute rejection for sirolimus troughs <5 ng/mL, cyclosporine troughs <150 ng/mL, human leukocyte antigen (HLA) mismatches > or =4, and females. The outcomes suggested that individualization of sirolimus doses immediately after transplantation, based on HLA mismatch and sex, would likely decrease the probability of acute rejections in renal allograft recipients who receive concomitant sirolimus, cyclosporine (full-dose), and corticosteroid therapy. Sirolimus is a substrate for both Cytochrome P450 3A (CYP3A) and P-glycoprotein (P-gp) and undergoes extensive first-pass extraction. Drugs that are known to inhibit or induce these proteins may potentially affect sirolimus whole blood exposure. In healthy volunteers, cyclosporine, diltiazem, erythromycin, ketoconazole, and verapamil significantly increased sirolimus whole blood exposure, and rifampin significantly decreased sirolimus exposure. However, sirolimus whole blood exposure was not affected by acyclovir, atorvastatin, digoxin, ethinyl estradiol/norgestrel, glyburide, nifedipine, or tacrolimus. Among the 15 drugs studied, sirolimus significantly increased the exposures of only erythromycin and S-(-)verapamil.

Adult↗
PubMed2003

The sirolimus-eluting stent: a review of its use in the treatment of coronary artery disease.

UNLABELLED: The sirolimus-eluting stent (CYPHER( trade mark )) is a metal stent coated with 140 micro g/cm(2) of sirolimus blended with synthetic polymers. After stent implantation, sirolimus is slowly released causing localized cytostatic inhibition of proliferation of vascular smooth muscle cells in the peri-stent arterial wall over a period of about 1 month. Only minimal amounts of sirolimus enter the bloodstream and these appear to be insufficient to be of clinical relevance. In clinical trials that evaluated single de novo lesions and in-stent restenosis in patients with coronary artery disease, the sirolimus-eluting stent was associated with minimal neointimal hyperplasia. In four randomized trials in de novo lesions, sirolimus eluting stents produced a significantly lower incidence of major adverse cardiac events (MACE) than that observed in patients with uncoated stents, during periods of up to 2 years (p < 0.05 for all comparisons). The lower incidence of MACE was mostly due to a reduced requirement for repeat target vessel revascularization. At angiographic follow-up at periods of up to 8 months, late luminal loss was significantly smaller in the sirolimus-eluting stent groups than in the uncoated-stent groups (p < 0.001 in all studies). The sirolimus-eluting stent was well tolerated in clinical trials of up to 3 years' follow-up. Because minimal blood levels of sirolimus are achieved, systemic adverse effects appear to be avoided. To date, there has been no evidence of any potential adverse effects resulting from the polymer coating or local drug toxicity. As yet, there is no evidence of an increased risk of subacute or late thrombosis, or aneurysm formation with the sirolimus-eluting stent compared with the uncoated stent. Long-term follow-up is needed to fully assess these theoretical concerns. Cost-effectiveness analyses over 12 months demonstrated a cost advantage for the sirolimus-eluting stent compared with an uncoated stent because of a reduced requirement for repeat target vessel revascularizations. CONCLUSION: Initial clinical trials with the sirolimus-eluting stent in patients with de novo coronary lesions have shown a significantly reduced incidence of MACE and of restenosis compared with a standard stent. Efficacy appears to be maintained throughout follow-up periods of up to 2 years in randomized trials, and to date, systemic or local adverse effects have been avoided. If efficacy and tolerability are consistently demonstrated over the long term, the sirolimus-eluting stent will be a major advance in the control of in-stent restenosis.

Coronary Artery Disease↗
PubMed2004

Sirolimus-eluting stents in the canine cerebral vasculature: a prospective, randomized, blinded assessment of safety and vessel response.

OBJECT: Use of the sirolimus-eluting stent has led to a reduction of in-stent stenosis following treatment of coronary atherosclerosis, whereas treatment of intracranial atherosclerosis with bare-metal stents results in excessive restenosis rates of approximately 40%. Neurotoxicity effects and vessel injury are unknown in the cerebral vasculature. To assess the safety profile and vascular effects of sirolimus-coated stents, the authors conducted a prospective comparative study in which drug-eluting and bare-metal stents were implanted in the canine basilar artery (BA). METHODS: Sixteen mongrel dogs were randomized (eight animals per group) to receive either bare-metal 1.5 x 8-mm (six-cell) stents or sirolimus-eluting stents of the same dimensions. Interventionists, histopathologists, and histopathology technicians who participated in the study were blinded to the stent characteristics. Stents were implanted in the canine BA. Serial peripheral blood samples were obtained during the 1st week after implantation to determine the time-dependent serum concentration of sirolimus. Follow-up angiographic studies were performed 30 days after stent implantation to assess the effects of stent placement on the BA and brainstem perforating vessels. Explantation of the stent and BA was performed immediately after angiography by using a pressurized formalin fixation procedure. Histological and computer-assisted morphometric analyses of specimens obtained in each animal were performed. Sirolimus could not be detected in peripheral blood samples obtained later than 24 hours posttreatment. On follow-up angiography, all perforating vessels observed on initial angiograms remained patent, and no evidence of parent vessel damage or pseudoaneurysm formation was observed. Explanted vessels and brainstem sections did not demonstrate evidence of histological neurotoxicity, such as gliosis or infarction. No significant differences were found in the time to endothelialization of bare-metal and sirolimus-coated stents. Smooth-muscle cell (SMC) proliferation, the putative agent for restenosis, was lower in animals receiving sirolimus-coated stents (p = 0.003). Additionally, intimal fibrin density was increased in the dogs treated with sirolimus-coated stents (p < 0.0001). Histological evidence of an inflammatory response demonstrated a trend toward a reduced response in the sirolimus group (mean 0.58) compared with the bare-metal group (mean 0.83, p = 0.33). CONCLUSIONS: No neurotoxic effects were observed in the intracranial vessel walls or brainstem tissue in which sirolimus-coated stents were implanted. Compared with bare-metal stents, the sirolimus-coated devices did not impair endothelialization and, furthermore, tended to reduce the proliferation of SMCs. These findings indicate that sirolimus-coated devices may inhibit in-stent stenosis. Further studies with longer-term follow up are required to assess the restenosis rates of sirolimus-coated stents implanted in the intracranial vasculature.

Animals↗
PubMed2006

Sirolimus-itraconazole interaction in a hematopoietic stem cell transplant recipient.

Interactions between azole antifungal agents and immunosuppressants that are metabolized by cytochrome P450 3A4 (chiefly calcineurin inhibitors) are well documented. Interactions between itraconazole and sirolimus are known to occur in patients after solid organ transplantation, but interactions in hematopoietic stem cell transplant (HSCT) recipients have yet to be reported in the literature. We describe an allogeneic HSCT recipient who experienced supratherapeutic trough levels of sirolimus as a result of its coadministration with itraconazole. This patient was a 20-year-old African-American man who underwent HSCT for treatment of myelodysplastic syndrome with severe aplastic anemia. After several regimen changes, the patient received oral itraconazole 200 mg every 12 hours and sirolimus at a dosage of 7 mg/day on days 76-80 and 5 mg/day on days 81 and 82. His sirolimus whole blood trough levels were 17.5 and 35.6 ng/ml on days 80 and 82, respectively (therapeutic range 5-15 ng/ml). An interaction between itraconazole and sirolimus was suspected, and sirolimus was withheld on days 83-90. On day 90, the patient's sirolimus trough level had normalized to 4.4 ng/ml. Sirolimus was resumed at 1-2 mg/day, with adjustments as needed to maintain trough levels of 10-15 ng/ml. Both the itraconazole and sirolimus were eventually were discontinued. The patient died, however, from a disseminated adenovirus infection leading to end-organ failure. Sirolimus is extremely sensitive to the inhibitory potential of azole antifungals. We propose that itraconazole also has a potent effect on sirolimus metabolism. Preemptive sirolimus dosage reduction and close monitoring of its whole blood trough levels are required whenever this combination is considered to avoid immunosuppressant toxicity in already critically ill patients.

Adenoviridae Infections↗
PubMed2003

Cardiovascular risk factors of sirolimus compared with cyclosporine: early experience from two randomized trials in renal transplantation.

INTRODUCTION: Renal transplant recipients are at a higher risk of cardiovascular events, including death. This paper examines cardiovascular risk factors in two phase II studies comparing cyclosporine (CsA) with sirolimus-based therapy. METHODS: In two phase II studies, patients (n = 161) were randomized at the time of transplantation to receive either sirolimus or CsA in triple-therapy regimens with either azathioprine (Study A) or mycophenolate mofetil (Study B), and corticosteroids. Sirolimus whole blood trough levels were targeted to 30 ng/mL for 2 months and 15 ng/mL thereafter. Pooled results of the two studies are reported. RESULTS: When patients receiving sirolimus were compared with those receiving CsA, peak cholesterol and trigylcerides at 2 months were markedly and significant higher with sirolimus therapy. The difference between groups decreased thereafter and was not significant from 12 through 24 months. Control of lipid parameters in sirolimus-treated patients was achieved by decreasing the target trough levels after 2 months and by using lipid-lowering agents. Sirolimus-based therapy was associated with a lower incidence of treatment-emergent hypertension (47.5% vs 29.6%, P <.024). At 24 months, the calculated glomerular filtration rate was significantly better with sirolimus (51.3 vs 65.1 mL/min, P <.001). There were no significant differences in the incidences of diabetes or death due to cardiovascular events. CONCLUSION: Patients receiving sirolimus experience an initial increase in lipid levels, but these effects are manageable with the use of lipid-lowering agents. Hypertension was less frequent and renal function was improved with CsA-free, sirolimus-based therapy. Based on this early experience, overall cardiovascular risk does not appear to be increased with sirolimus-based compared with CsA-based therapy.

Cardiovascular Diseases↗
PubMed1998

Sirolimus (rapamycin, Rapamune) and combination therapy with cyclosporin A in the rat developing adjuvant arthritis model: correlation with blood levels and the effects of different oral formulations.

OBJECTIVE AND DESIGN: To determine whole blood levels of sirolimus, a macrolide antibiotic in the rat developing adjuvant arthritis (AA) model after dosing orally with two different vehicles, and whether combinational doses of sirolimus and cyclosporin A (CsA) produced additive or synergistic inhibitory effects in this model. MATERIAL: Male Lewis rats (150-180g). TREATMENT: Arthritis was induced by the injection (0.5 mg/ rat) of heat-killed Mycobacterium butyricum suspended in light mineral oil. Drugs were administered orally either in fine suspension (0.5% Tween 80) or in emulsion (phosal 50 PG in 1% Tween 80) at doses of 0.1 to 5 mg/kg in a 7 day, MWF or daily regimen. METHOD: Paw volumes (ml) were measured by automated mercury plethysmograph and sirolimus concentrations in whole blood were quantitated by liquid chromatography/ mass spectroscopy. RESULTS: At 72h (7 days after adjuvant) after receiving the third oral dose (4.5 mg/kg p.o.), the phosal vehicle resulted in higher sirolimus blood levels (2.5 ng/ml) than in Tween 80 (1.6 ng/ml). After the rats received the last oral dose on day 14, (7 total doses of sirolimus at 4.5 mg/kg) the sirolimus blood levels (2h after the last dose) were about 2 times higher for the phosal dosed rats (9.8 ng/ml) compared to Tween 80 dosed rats (4.6ng/ml). Even 24h after the last dose, sirolimus blood levels were still elevated in the phosal dosed rats (0.8 ng/ml) relative to 0.5% Tween 80 dosed rats (0.5 ng/ml). At day 16 in the rat developing model, sirolimus, when given in phosal vehicle, produced an ED50 of 0.28 mg/ kg (i.e. inhibition of uninjected paw edema) that was about 5.5 times lower than using 0.5% Tween 80 as the suspending agent (ED50 = 1.6mg/kg). When combining sirolimus and CsA using precalculated doses for producing an additive effect in this adjuvant model, an additive inhibitory effect on uninjected paw edema was observed at equal combinational doses of 0.5 and 2 mg/kg, respectively. CONCLUSIONS: The phosal vehicle used in administering sirolimus increases the absorption and whole blood levels in the rat and the elevated blood levels correlated positively with the therapeutic effect in the rat developing AA model. In addition, combination therapy using sirolimus and CsA produced an additive effect in rat developing AA.

Administration, Oral↗
PubMed2006

Differentiation of innovator versus generic cyclosporine via a drug interaction on sirolimus.

OBJECTIVE: Both sirolimus and cyclosporine are immunosuppressants used in a combined regimen after organ transplantation. When coadministered with the innovator formulation of cyclosporine, sirolimus blood levels increase 3.3-fold due to a pharmacokinetic interaction. We assessed this drug interaction for potential differences when the innovator formulation is replaced by a generic cyclosporine. METHODS: In this randomized single-dose crossover study, 28 healthy subjects received 5 mg sirolimus oral solution with 250 mg cyclosporine soft gelatin capsules given as the innovator formulation (reference treatment) versus a generic formulation (test treatment). Sirolimus peak blood concentration (Cmax) and area under the concentration-time curve (AUC) were compared between test and reference treatments by standard bioequivalence testing. RESULTS: Sirolimus Cmax was significantly lower by 17% in the presence of generic versus innovator cyclosporine (p=0.0003) and failed bioequivalence criteria with a test/reference ratio of 0.83 (90% confidence interval, 0.77-0.90). Nearly half of the subjects (46%) had sirolimus Cmax changes which fell outside the bioequivalence window with individual Cmax decreases up to 52% and increases up to 39%. Sirolimus AUC was significantly lower by 11% in the presence of generic versus innovator cyclosporine (p=0.041) but satisfied average bioequivalence criteria with a test/reference ratio of 0.89 (0.83-0.95). Nonetheless, over a third of the subjects (43%) had sirolimus AUC changes outside the standard bioequivalence window with individual AUC decreases up to 39% and increases up to 42%. CONCLUSIONS: Switching between innovator and generic cyclosporine may have a clinically-relevant impact on coadministered sirolimus pharmacokinetics. If such a switch is initiated by the prescriber, follow-up therapeutic monitoring of both cyclosporine and sirolimus blood levels should be performed to guide dose adjustments as necessary. If the switch is made without consulting the prescriber, potentially significant changes in sirolimus exposure could go unnoticed by the clinician and patient.

Adult↗
PubMed2004

Sirolimus in chronic allograft nephropathy.

Chronic allograft nephropathy (CAN) is the most common cause of late renal transplant loss. Calcineurin inhibitor (CNI) nephrotoxicity is known to contribute to CAN. A sirolimus-based regimen way allow for early CNI reduction or elimination. The aim of the present study was to determine the efficacy and safety of a sirolimus-based regimen for CAN. From December 2001 to August 2003, kidney transplant (KTx) recipients with CAN were enrolled for treatment with sirolimus. Among 32 studied patients, 24 (75%) underwent graft biopsy before the initiation of sirolimus. Baseline maintenance immunosuppression consisted of cyclosporine/tacrolimus and prednisone with or without mycophenolate mofetil. The follow-up duration on sirolimus therapy was 8.5 +/- 5.9 months (range: 1 to 22 months). The average dosage of sirolimus was 1.8 +/- 0.5 mg/d at the end of follow-up. The mean trough level of sirolimus was 5.1 +/- 2.1 ng/mL. Sirolimus was effective in 16 (50%) patients while 3 (9.4%) patients improved (serum creatinine [Cr] decrease > 10%) and 13 (40.6%) maintained stable (change of serum Cr within 10%). Sirolimus was effective in 5 (35.7%) patients whose serum Cr was over 3.0 mg/dL but failed to rescue all four patients whose serum Cr was over 4.0 mg/dL. Eleven (68.8%) of 16 responders showed a reduction (29.8% +/- 13.8%) in CNI dosage. The most common adverse events were hyperlipidemia (37.5%), anemia (25%), and diarrhea (21.8%). Twelve patients discontinued sirolimus due to graft failure (4), severe infection (3), stroke related mortality (1), anemia (2), diarrhea (1), and edema (1). In conclusion, sirolimus is effective in 50% of KTx recipients with CAN, especially when the serum Cr is less than 3.0 mg/dL. However, the increased incidence of infection, diarrhea, and hyperlipidemia are of major concern.

Adult↗
PubMed1997

Population pharmacokinetics of sirolimus in kidney transplant patients.

OBJECTIVE: To characterize the dose-related pharmacokinetics of the immunosuppressant agent sirolimus (formerly rapamycin) in kidney transplant patients by use of two-stage and nonlinear mixed-effect model population methods. METHODS: Patients (n = 36) from three centers (Germany, the United Kingdom, and Sweden) who received steady-state oral doses of cyclosporine (ciclosporin) were assessed after single oral administration of sirolimus at doses of 3, 5, 10, and 15 mg/m2. Plasma and whole blood sirolimus samples were analyzed by a high-performance liquid chromatographic/mass spectrophotometric method. Simultaneous fitting used biexponential functions with intercept/slope or clearance/volume terms, as well as first-order absorption (ka) and a lag-time. RESULTS: The nonlinear mixed-effect model method (P-Pharm) provided a better characterization of sirolimus kinetics, especially for the absorption and distribution phases where fewer data were available per patient. Sirolimus distribution between whole blood and plasma was concentration-independent, with a mean blood/plasma ratio (coefficient of variation) of 30.9 (48.5%). Elimination was not influenced by dose, as shown by estimates of the terminal half-life of 63 hours (27.5%) and apparent oral blood clearance of 8.9 L/hr (38.2%). Sirolimus distribution parameters were influenced by body weight and surface area. Sirolimus was rapidly absorbed, as shown by the absorption lag-time of 0.27 hour (35.1%), and ka of 2.77 hr-1 (48.4%). The concomitant administration of sirolimus and cyclosporine did not reveal any pharmacokinetic interactions. CONCLUSION: This report provides an initial population pharmacokinetics of sirolimus in kidney transplant recipients receiving cyclosporine concurrently. Sirolimus blood and plasma pharmacokinetics were biexponential and linear for doses from 3 to 15 mg/m2. No pharmacokinetic interaction was found between sirolimus and cyclosporine.

Adult↗
PubMed2003

Sirolimus changes lipid concentrations and lipoprotein metabolism in kidney transplant recipients.

BACKGROUND: Sirolimus (Rapammune, rapamycin, RAPA) is a strong immunosuppressive agent that reduces kidney transplant rejection. Hyperlipidemia is a significant side effect of sirolimus treatment and often leads to vascular disease. We have studied the repeatability, reversibility, and dose dependence of the plasma lipid and apoprotein changing effects of sirolimus and attempted to determine the mechanism by which sirolimus induces hypertriglyceridemia in some kidney transplant recipients. METHODS: Six patients with renal allografts maintained on cyclosporine A and prednisone were selected on the basis of their previous hyperlipidemic response to short-term (14 days) sirolimus administration. For longer-term treatment, each patient was started on 10 mg/d sirolimus and continued as tolerated for 42 days to reinduce hyperlipidemia. Timed blood samples were analyzed for lipid, apoprotein, and sirolimus levels. RESULTS: During sirolimus administration, mean total plasma cholesterol increased from 214 to 322 mg/dL (+50%); low density lipoprotein-cholesterol levels changed in a similar pattern. Mean triglyceride level rose from 227 to 432 mg/dL (+95%). ApoB-100 concentration rose from 124 to 160 mg/dL (+28%). ApoC-III level increased from 28.9 to 55.5 mg/dL (+92%). These lipid and apoprotein changes were found to be repeatable, reversible, and dose dependent. [(13)C(4)]-palmitate metabolic studies in four patients with hypertriglyceridemia indicated that the free fatty acid pool was expanded by sirolimus treatment (mean = 42.3%). Incorporation of [(13)C(4)]-palmitate into triglycerides of very low density lipoprotien, intermediate density lipoprotein, low density lipoproteins was decreased 38.3%, 42.1%, and 38.4%, respectively, by sirolimus treatment of these patients. CONCLUSIONS: These results suggest that sirolimus alters the insulin signaling pathway so as to increase adipose tissue lipase activity, decrease lipoprotein lipase activity, or both, resulting in increased hepatic synthesis of triglyceride, increased secretion of VLDL, and increased hypertriglyceridemia.

Adult↗
PubMed2003

De novo use of sirolimus in immunosuppression regimens in kidney and kidney-pancreas transplantation at the University of California, San Francisco.

At UCSF, we have used sirolimus in several immunosuppression regimens and protocols, and this article will summarize our experience in four areas. The purpose of the first study was to assess the efficacy of a sirolimus-based, calcineurin inhibitor-free regimen for the first 3 months after transplantation. Patients were treated with a calcineurin inhibitor-free regimen that consisted of daclizumab, sirolimus, mycophenolate mofetil (MMF), and conventional corticosteroids. Of nine patients, one (case #7) had an acute rejection episode (type IA) at 2 months after transplantation, which was fully reversed with corticosteroids. The second study was a prospective trial of calcineurin inhibitor-free regimen in patients with severe delayed graft function (DGF) (requiring dialysis). The immunosuppression regimen consisted of daclizumab, sirolimus, MMF, and corticosteroids. This immunosuppressive regimen was effective in patients with DGF; however, it was effective only in non-African American (non-AA) patients (AA had a significantly higher acute rejection rate at 1 year than non-AA, 63% vs 23%, P =.025). In some patients sirolimus was associated with a prolonged recovery from DGF. The addition of sirolimus to immunosuppressive agents provide the opportunity for safe steroid withdrawal (at day 5). We participated in a sirolimus-based, multicenter open-label trial of very early corticosteroid withdrawal. Primary renal transplant patients were enrolled in an immunosuppression regimen that consisted of basiliximab, sirolimus (target levels 8 to 15 ng/mL, 0 to 5 months, and 6 to 12 ng/mL, 6 to 12 months) and tacrolimus in a dose of 0.05 mg/kg BID (target levels 6 to 9 ng/mL). Two of 14 enrolled patients had an episode of acute rejection before steroids were withdrawn. No acute rejection episodes have occurred after steroids were withdrawn (6-month follow-up). The regimen of sirolimus and tacrolimus was well tolerated. Wound complications were not noted. Another important use of sirolimus has been its incorporation in the immunosuppressive regimens in kidney-pancreas transplantation. Our current protocol consists of thymoglobulin induction, combined with MMF, sirolimus, and low-dose tacrolimus, for maintenance therapy. Steroids are only utilized during the first 5 to 6 days following the transplant. This steroid-free maintenance regimen has been used in the last 30 enteric-drained, simultaneous pancreas-kidney transplants. Using this immunosuppressive approach, rejection rates are less than 10% for either the kidney or the pancreas.

Acute Disease↗
PubMed2001

Pharmacokinetic interaction between single oral doses of diltiazem and sirolimus in healthy volunteers.

AIM AND BACKGROUND: The pharmacokinetic interaction between sirolimus, a macrolide immunosuppressant metabolized by CYP3A4, and the calcium channel blocker diltiazem was studied in 18 healthy subjects. Several clinically important interactions have previously been reported for other immunosuppressive drugs that are metabolized by the same enzyme and for calcium antagonists. METHODS: Healthy subjects who were 20 to 43 years old participated in an open, three-period, randomized, crossover study of the pharmacokinetics of a single 10-mg oral dose of sirolimus, a single oral 120-mg dose of diltiazem, and the two drugs given together. The three study periods were separated by a 21-day washout phase. RESULTS: The geometric mean (90% confidence interval) whole blood sirolimus area under the plasma concentration time-curve increased 60% (35%-90%), from 736 to 1178 ng x h/mL, and maximum concentration increased 43% (14%-81%), from 67 to 96 ng/mL, with diltiazem coadministration, whereas the mean elimination half-life of sirolimus decreased slightly, from 79 to 67 hours. Apparent oral clearance and volume of distribution of sirolimus decreased with 38% and 45%, respectively, when sirolimus was given with diltiazem. The plasma maximum concentration and area under the plasma concentration-time curve of diltiazem, desacetyldiltiazem, and desmethyldiltiazem were unchanged after coadministration of sirolimus, and no potentiation of the effects of diltiazem on diastolic or systolic blood pressure or on the electrocardiographic parameters was seen. CONCLUSIONS: Single-dose diltiazem coadministration leads to higher sirolimus exposure, presumably by inhibition of the first-pass metabolism of sirolimus. Because of the pronounced intersubject variability in the extent of the sirolimus-diltiazem interaction, whole blood sirolimus concentrations should be monitored closely in patients treated with the two drugs.

Administration, Oral↗
PubMed1999

Sirolimus: a potent new immunosuppressant for liver transplantation.

BACKGROUND: Sirolimus (rapamycin) is a new immunosuppressant that appears to be synergistic with cyclosporine in kidney transplantation, but with a different side-effect profile. This pilot study evaluated sirolimus in liver transplantation. METHODS: Patients undergoing orthotopic liver transplantation for primary tumors (8), and later for nonmalignant disease (7), received one of three sirolimus-based immunosuppressive regimens. Protocol A comprised sirolimus, microemulsion cyclosporine (target whole blood concentration: 100 ng/ml), and prednisolone; protocol B omitted prednisolone; and protocol C was sirolimus alone. By 3 months after transplantation, all patients were receiving sirolimus as monotherapy. RESULTS: Fifteen patients were treated with a follow-up of 117-806 days. Rejection was more common on monotherapy than double therapy, and absent on triple therapy. The drug was generally well tolerated, with only three patients discontinuing sirolimus: one for hyperlipidemia, one for pneumocystis pneumonia, and one for inability to tolerate the taste of the drug. Two patients discontinued cyclosporine early, both as a result of neurological complications; they continued on sirolimus monotherapy. Five patients died; one suffered a cardiac arrest, and four died from sepsis in association with graft-versus-host disease, recurrent tumor, a paralyzed right hemidiaphragm, and primary nonfunction. CONCLUSIONS: Sirolimus combined with cyclosporine provided potent immunosuppression of liver allografts, and sirolimus monotherapy was adequate and well tolerated as maintenance therapy. Side effects of sirolimus over the short period of follow-up were uncommon and reversible with dose reduction or cessation of therapy.

Adult↗
PubMed2004

Sirolimus and ketoconazole co-prescription in renal transplant recipients.

Ketoconazole inhibits cytochrome P 3A4, leading to a 10-fold increase in sirolimus blood levels. Although it has not been reported in the clinical setting so far, sirolimus and ketoconazole co-prescription can lead to cost saving by reducing the dose of sirolimus administered. After informed consent was obtained, sirolimus and ketoconazole co-prescription was studied in six patients who could not afford the current recommended doses. Patients received one-eighth to one-fourth of the recommended dose of sirolimus (0.25-0.5 mg) with 100 to 200 mg of ketoconazole. Sirolimus levels were monitored, and the dose of ketoconazole was increased to achieve target levels of sirolimus. The loading dose was 3 mg of sirolimus with 100 mg of ketoconazole. After sirolimus rescue therapy was started, serum creatinine decreased in five patients. The mean serum creatinine for the group decreased from 2.6 +/- 0.3 mg/dL at the initiation of rescue therapy to 2.2 +/- 0.5 mg/dL on the last follow-up. Sirolimus ketoconazole co-prescription with monitoring of sirolimus levels is possible and safe and needs to be explored further.

Adult↗
PubMed2004

Wound-healing complications after kidney transplantation: a prospective, randomized comparison of sirolimus and tacrolimus.

BACKGROUND: Sirolimus has been associated with an increased risk of wound-healing complications in several retrospective analyses. The authors compared the rates of wound-healing complications in renal allograft recipients in a prospective, randomized trial of sirolimus-mycophenolate mofetil-prednisone versus tacrolimus-mycophenolate mofetil-prednisone. METHODS: All patients received antithymocyte globulin induction. In the first phase of the study, patients (n = 77) were included regardless of body mass index (BMI). In the second phase (n = 46 patients), the authors excluded patients with a BMI greater than 32 kg/m2, and the target trough sirolimus level was lowered to 10 to 15 ng/mL (previously 15-20 ng/mL). Multivariate logistic regression analyses were performed to identify predictors of wound complications. RESULTS: Fifty-nine patients received tacrolimus and 64 received sirolimus and were included in subsequent analyses. The incidence of complications was 8% (5 of 59) in the tacrolimus group and 47% (30 of 64) in the sirolimus group (P < 0.0001). Rates of perigraft fluid collections, superficial wound infections, and incisional herniae were significantly higher in the sirolimus group. Multivariate logistic regression showed only sirolimus (P = 0.0001) and BMI (P = 0.0021) to independently correlate with complications. In the first phase of the study, the wound complication rate in the sirolimus group was 55% (21 of 38 patients). After excluding obese recipients and decreasing the target sirolimus level, the wound complication rate in the sirolimus group was 35% (9 of 26 patients; P = 0.1040). CONCLUSIONS: The use of sirolimus-based immunosuppressive regimens leads to a higher incidence of wound-healing complications and will require new approaches to patient selection and management to decrease their incidence.

Acute Disease↗
PubMed2005

Cutaneous adverse events in renal transplant recipients receiving sirolimus-based therapy.

BACKGROUND: Sirolimus is an immunosuppressive drug recently developed for organ transplantation. Its mechanism of action, independent of calcineurin, is different from that of cyclosporine and tacrolimus, two calcineurin inhibitors (CIs). Because the toxicity of CIs is partly the result of calcineurin blockade, sirolimus exhibits a different toxicity profile. In this study, we evaluated the profile, frequency, and severity of cutaneous adverse events in renal transplant recipients receiving sirolimus-based therapy. PATIENTS AND METHODS: A systematic and in-depth evaluation of skin, mucous membranes, nails, and hair was performed in 80 renal transplant recipients receiving sirolimus-based therapy. The mean duration of the graft was 6 years and of sirolimus treatment was 18 months. Mycophenolate mofetil and steroids were combined with sirolimus for 74 patients. Sirolimus was used as first immunosuppressive therapy for 36 patients, and 44 patients were switched from CIs to sirolimus. RESULTS: Seventy-nine patients (99%) experienced cutaneous adverse events. Twenty patients (25%) demonstrated serious adverse events, and six patients (7%) stopped sirolimus during the 3 months after the study because of cutaneous events. The most frequent of these were pilosebaceous apparatus involvement, including acne-like eruptions (46%), scalp folliculitis (26%), and hidradenitis suppurativa (12%); edematous complaints, including chronic edemas (55%) and angioedema (15%); mucous membrane disorders, including aphthous ulceration (60%), epistaxis (60%), chronic gingivitis (20%), and chronic fissure of the lips (11%); and last, nail disorders including chronic onychopathy (74%) and periungual infections (16%). CONCLUSIONS: Skin disorders are frequent in renal transplant recipients receiving sirolimus as a long-term therapy. Despite the usually mild nature of skin events, they are often the reason for stopping sirolimus.

Adult↗
PubMed2004

Sirolimus for pediatric liver transplant recipients with post-transplant lymphoproliferative disease and hepatoblastoma.

Sirolimus is a promising immune suppressive agent, with the potential to reduce calcineurin inhibitor associated nephrotoxicity, halt progression of chronic rejection and prevent tumor proliferation. The aim of this study was to review the experience using sirolimus in pediatric liver transplant recipients at a single center. Database and medical charts of all pediatric liver transplant recipients receiving sirolimus at the Hospital for Sick Children in Toronto were reviewed. Eight patients received sirolimus between October, 2000 and September, 2002. Indications for using sirolimus were post-transplant lymphoproliferative disease (PTLD) (n = 6) and hepatoblastoma (n = 2). Two patients with PTLD concurrently had renal impairment and chronic rejection. Sirolimus dosages ranged between 1.5 and 5 mg once daily. Median duration of follow-up was 17 months. Persistently elevated liver transaminase levels in the two children with chronic rejection decreased during sirolimus therapy. Recurrence of PTLD occurred in one patient. Two patients were diagnosed with acute cellular rejection after transition to maintenance sirolimus monotherapy. Resolution of adverse effects including mouth sores (n = 3), leg swelling (n = 2) and hyperlipidemia (n = 3) occurred either spontaneously or with dose reduction. Sirolimus was discontinued in four patients because of persisting bone marrow suppression, interstitial pneumonitis, life-threatening sepsis and refractory diarrhea. Children with PTLD or hepatoblastoma may benefit from immune suppression with sirolimus after liver transplantation. Further multi-center, prospective, randomized controlled trials will be instrumental to further the knowledge of long-term efficacy, safety and tolerability of sirolimus for selected children following liver transplantation.

Adolescent↗
PubMed2002

Sirolimus oral absorption in rats is increased by ketoconazole but is not affected by D-alpha-tocopheryl poly(ethylene glycol 1000) succinate.

The contributions of cytochrome P450 3A (CYP3A) and P-glycoprotein to sirolimus oral bioavailability in rats were evaluated by coadministration of sirolimus (Rapamune) with the CYP3A inhibitor ketoconazole or the P-glycoprotein inhibitor D-alpha-tocopheryl poly(ethylene glycol 1000) succinate (TPGS). Groups of six male Sprague-Dawley rats (250-300 g) were administered Rapamune (1 mg/kg) by oral gavage, alone and with ketoconazole (30 mg/kg) or TPGS (50 mg/kg). Sirolimus levels were measured in whole blood over a 6-h time course. Sirolimus C(max) (6.6 +/- 1.6 versus 26 +/- 7 ng/ml) and area under the concentration versus time curve from 0 to 6 h (AUC(0-6)) (22 +/- 7 versus 105 +/- 27 ng. h/ml) were increased 3- to 5-fold by ketoconazole. Median T(max) (1.5-2 h) was unchanged. TPGS had no effect on sirolimus absorption. The interaction of sirolimus with P-glycoprotein was also evaluated in vitro using HCT-8 and Caco-2 cell monolayers. Consistent with published reports, sirolimus was a good inhibitor of P-glycoprotein, inhibiting polarized basolateral-to-apical flux of rhodamine 123 with an IC(50) of 0.625 to 1.25 microM (cyclosporine caused >80% inhibition at 5 microM). Sirolimus did not demonstrate significant polarized flux in either direction using the same monolayers (basolateral-to-apical flux was <2 times the apical-to-basolateral). Moreover, sirolimus flux was not impacted by cyclosporine, suggesting that it does not undergo P-glycoprotein-mediated transport in this system. The lack of significant sirolimus transport by P-glycoprotein may, in part, explain the lack of a TPGS effect on sirolimus absorption in rats.

ATP Binding Cassette Transporter, Subfamily B, Mem↗