sirolimus and Liver-Failure

Transplantation is the optimal treatment for end-stage organ failure, and modern immunosuppression has allowed important progress in short-term outcomes. However, immunosuppression poorly influences chronic rejection and elicits chronic toxicity in current clinical practice. Thus, a major goal in transplantation is to understand and induce tolerance. It is well established that human regulatory T cells expressing the transcription factor FoxP3 play important roles in the maintenance of immunological self-tolerance and immune homeostasis. The major regulatory T cell subsets and mechanisms of expansion that are critical for induction and long-term maintenance of graft tolerance and survival are being actively investigated. Likewise, other immune cells, such as dendritic cells, monocyte/macrophages or natural killer cells, have been described as part of the process known as "operational tolerance". However, translation of these results towards clinical practice needs solid tools to identify accurately and reliably patients who are going to be tolerant. In this way, a plethora of genetic and cellular biomarkers is raising and being validated worldwide in large multi-center clinical trials. Few of the studies performed so far have provided a detailed analysis of the impact of immunosuppression withdrawal on pre-existing complications derived from the long-term administration of immunosuppressive drugs and the side effects associated with them. The future of liver transplantation is aimed to develop new therapies which increase the actual low tolerant vs non-tolerant recipients ratio.

Topics: Animals; Biomarkers; Biomarkers, Tumor; Dendritic Cells; Homeostasis; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Killer Cells, Natural; Liver Failure; Liver Transplantation; Macrophages; Sirolimus; T-Lymphocytes, Regulatory; Transplantation Tolerance

In the first five yr after liver transplant, approximately one in 10 pediatric recipients will develop NODAT. Factors associated with higher risk for NODAT have been difficult to identify due to lack of uniformity in reporting and data collection. Limited studies have reported higher risk in those who are at an older age at transplant, those with high-risk ethnic backgrounds, and in those with particular underlying conditions, such as CF and primary sclerosing cholangitis. Immunosuppressive medications, including tacrolimus, cyclosporine A, GC, and sirolimus, have been implicated as contributing to NODAT, to varying degrees. Identifying those at highest risk, appropriately screening, and diagnosing NODAT is critical to initiating timely treatment and avoiding potential complications. In the pediatric population, treatment is limited primarily to insulin, with some consideration for metformin. Children with NODAT should be monitored carefully for complications of DM, including microalbuminuria, hypertension, hyperlipidemia, and retinopathy.

Topics: Albuminuria; Child; Cyclosporine; Diabetes Mellitus; Diabetic Retinopathy; Glucocorticoids; Humans; Hyperlipidemias; Hypertension; Immunosuppressive Agents; Insulin; Liver Failure; Liver Transplantation; Metformin; Pediatrics; Risk Factors; Sirolimus; Tacrolimus

The development of immunosuppression has significantly affected the development of liver transplantation and has helped to switch from the experimental method to a standard treatment of life threatening liver conditions. Tacrolimus is the basic immunosuppressant for patients after a liver transplant and thanks to its prolonged-release dosage form, which due to its simplicity and reliability of use, replaces tacrolimus twice daily early after the transplant and in the longterm administration, will apparently, for a while, defend its position. Other widely used medicines include mycophenolic acid and mTOR inhibitors, sirolimus and everolimus. The induction with antilymphocyte antibodies is used in less than 10% of liver recipients. Only a few new immunosuppresants in this century have passed later stages of clinical studies; the last 2 medicines registered for patients after liver transplantation include Advagraf (Astellas) and Certican (Novartis). Personalised immunosuppression should respect at least the following basic clinical situations: recipients renal function, hepatitis C virus infection, and hepatocellular carcinoma as the liver transplant indication. The results of immunotolerance bio-marker research are necessary for a more successful conduct of protocols minimising immunosuppression and leading to immunotolerance, especially under the efforts of complete withdrawal of immunosupression.

Topics: Antilymphocyte Serum; Carcinoma, Hepatocellular; Everolimus; Graft Rejection; Humans; Immunosuppressive Agents; Liver Diseases; Liver Failure; Liver Neoplasms; Liver Transplantation; Mycophenolic Acid; Reproducibility of Results; Sirolimus; Tacrolimus

An 11-yr-old child presented with acute mental status changes and spastic quadriplegia after orthotopic liver transplantation. Magnetic resonance (MR) imaging findings were consistent with central pontine and EPM. Initial immunosuppression included tacrolimus, mycophenolate mofetil, and corticosteroids. Given that neurotoxicity is a well-established side effect of CNI, the patient was converted to rapamycin and subsequently experienced significant neurologic recovery. The temporal resolution of the patient's symptoms suggests that prompt recognition of central pontine and EPM and conversion from tacrolimus to rapamycin during the early post-operative course may have therapeutic benefits for patients undergoing pediatric transplant with CNI-related neurotoxicity.

Topics: Adrenal Cortex Hormones; Brain; Calcineurin Inhibitors; Child; Humans; Immunosuppressive Agents; Liver Failure; Liver Transplantation; Magnetic Resonance Imaging; Male; Mycophenolic Acid; Myelinolysis, Central Pontine; Sirolimus; Tacrolimus

Castleman disease is a rare hematologic disorder, closely linked to the HHV-8, and most commonly observed in immunocompromised individuals. Thirteen months following a liver transplant for CPS-1 defect, a 15-month-old boy presented with fevers, anemia, and growth retardation. Abdominal CT scan showed splenomegaly and generalized lymphadenopathy. Histology of chest wall lymph nodes revealed a mixed CD3+ T-cell and CD20+ B-cell population with atretic germinal centers consistent with multicentric Castleman disease. Qualitative DNA PCR detected HHV-8 in the resected lymph node and in the blood, supporting the diagnosis. Immunosuppression was tapered, and he was transitioned from tacrolimus to sirolimus. His graft function remained stable, and repeat imaging showed regression of the lymphadenopathy. The child is living one yr after Castleman disease diagnosis with a well-functioning graft. Castleman disease is a potential complication of solid organ transplant and HHV-8 infection. Reduction in immunosuppression and switch to sirolimus may be an effective strategy to treat this condition.

Topics: Adolescent; Adult; Antigens, CD20; B-Lymphocytes; Castleman Disease; CD3 Complex; Graft Survival; Herpesvirus 8, Human; Humans; Immunosuppressive Agents; Infant, Newborn; Liver Failure; Liver Transplantation; Lymphatic Diseases; Male; Middle Aged; Polymerase Chain Reaction; Sirolimus; Splenomegaly; T-Lymphocytes; Tacrolimus; Tomography, X-Ray Computed

Treatment of patients with advanced renal cell carcinoma (RCC) has changed dramatically with the advent of targeted therapeutics. Temsirolimus, an inhibitor of mammalian target of rapamycin (mTOR), has proven beneficial in the treatment of advanced RCC with poor prognosis. The rationale for mTOR inhibitors in treatment of RCC, the pharmacokinetics and toxicities of temsirolimus, landmark clinical trials of temsirolimus in advanced RCC, and the indications for its use in the treatment of RCC are reviewed here. The status of temsirolimus in the rapidly evolving therapeutic landscape of advanced RCC is also discussed.

Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Clinical Trials as Topic; Drug Interactions; Humans; Intracellular Signaling Peptides and Proteins; Liver Failure; Liver Neoplasms; Protein Serine-Threonine Kinases; Renal Insufficiency; Sirolimus; TOR Serine-Threonine Kinases

Everolimus is a novel proliferation signal inhibitor used in immunosuppressive therapies for the prevention of acute and chronic rejection. A role for everolimus drug monitoring has been suggested because of the potential for improving efficacy and reducing adverse effects. Everolimus has proven efficacy for prevention of rejection in adult de novo renal and cardiac transplant recipients. Similar effects have been shown in pediatric renal transplant patients. Several analytic methods are available to quantify everolimus concentrations. A good relationship exists between everolimus concentration and pharmacological response. Mere clinical monitoring of efficacy is insufficient because clinical presentations of graft rejection vary for each patient and are nonspecific. Thus, the authors have used a previously published 9-step decision-making algorithm to evaluate the utility of therapeutic drug monitoring for everolimus. The recommended therapeutic range for everolimus is a trough concentration of 3 to 8 ng/mL, as concentrations over 3 ng/mL have been associated with a decreased incidence of rejection, and concentrations >8 ng/mL with increased toxicity. Everolimus exhibits interindividual pharmacokinetic variability. African American patients have higher apparent clearance, whereas patients with hepatic dysfunction or those on concomitant medications with potent cytochrome P450 (CYP) 3A4 inhibitor or inducer properties have lower or higher apparent clearance, respectively. Solid organ transplant recipients will likely be maintained on immunosuppressant therapy for the life of the graft and/or recipient and thus are likely to benefit from clinical pharmacokinetic monitoring. Based on the available evidence, therapeutic drug monitoring for everolimus may provide additional information on efficacy and safety than sound clinical judgment alone. Patients on everolimus who have problems with absorption, who take concurrent cytochrome P450 inhibitors or inducers, or are noncompliant will attain the greatest benefit from drug monitoring.

Topics: Area Under Curve; Drug Monitoring; Everolimus; Heart Transplantation; Humans; Immunosuppressive Agents; Kidney Transplantation; Liver Failure; Liver Transplantation; Organ Transplantation; Sirolimus

In a prospective, multicenter, open-label study, de novo liver transplant patients were randomized at day 30±5 to (i) everolimus initiation with tacrolimus elimination (TAC Elimination) (ii) everolimus initiation with reduced-exposure tacrolimus (EVR+Reduced TAC) or (iii) standard-exposure tacrolimus (TAC Control). Randomization to TAC Elimination was terminated prematurely due to a higher rate of treated biopsy-proven acute rejection (tBPAR). EVR+Reduced TAC was noninferior to TAC Control for the primary efficacy endpoint (tBPAR, graft loss or death at 12 months posttransplantation): 6.7% versus 9.7% (-3.0%; 95% CI -8.7, 2.6%; p<0.001 for noninferiority [12% margin]). tBPAR occurred in 2.9% of EVR+Reduced TAC patients versus 7.0% of TAC Controls (p = 0.035). The change in adjusted estimated GFR from randomization to month 12 was superior with EVR+Reduced TAC versus TAC Control (difference 8.50 mL/min/1.73 m(2) , 97.5% CI 3.74, 13.27 mL/min/1.73 m(2) , p<0.001 for superiority). Drug discontinuation for adverse events occurred in 25.7% of EVR+Reduced TAC and 14.1% of TAC Controls (relative risk 1.82, 95% CI 1.25, 2.66). Relative risk of serious infections between the EVR+Reduced TAC group versus TAC Controls was 1.76 (95% CI 1.03, 3.00). Everolimus facilitates early tacrolimus minimization with comparable efficacy and superior renal function, compared to a standard tacrolimus exposure regimen 12 months after liver transplantation.

Topics: Adolescent; Adult; Aged; Confidence Intervals; Cross-Over Studies; Dose-Response Relationship, Drug; Drug Administration Schedule; Everolimus; Follow-Up Studies; Glomerular Filtration Rate; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kaplan-Meier Estimate; Kidney; Kidney Function Tests; Liver Failure; Liver Transplantation; Male; Middle Aged; Prospective Studies; Risk Assessment; Sirolimus; Survival Analysis; Tacrolimus; Time Factors; Transplantation Immunology; Treatment Outcome; Young Adult

In an adult healthy liver, hepatocytes are in a quiescent stage unless a physical injury, such as ablation, or a toxic attack occur. Indeed, to maintain their crucial organismal homeostatic role, the damaged or remaining hepatocytes will start proliferating to restore their functional mass. One of the limiting conditions for cell proliferation is amino-acid availability, necessary both for the synthesis of proteins important for cell growth and division, and for the activation of the mTOR pathway, known for its considerable role in the regulation of cell proliferation. The overarching aim of our present work was to investigate the role of amino acids in the regulation of the switch between quiescence and growth of adult hepatocytes. To do so we used non-confluent primary adult rat hepatocytes as a model of partially ablated liver. We discovered that the absence of amino acids induces in primary rat hepatocytes the entrance in a quiescence state together with an increase in Drosha protein, which does not involve the mTOR pathway. Conversely, Drosha knockdown allows the hepatocytes, quiescent after amino-acid deprivation, to proliferate again. Further, hepatocyte proliferation appears to be independent of miRNAs, the canonical downstream partners of Drosha. Taken together, our observations reveal an intriguing non-canonical action of Drosha in the control of growth regulation of adult hepatocytes responding to a nutritional strain, and they may help to design novel preventive and/or therapeutic approaches for hepatic failure.

Topics: Amino Acids; Animals; Autophagy; Cell Proliferation; Cells, Cultured; Disease Models, Animal; Gene Knockdown Techniques; Hepatocytes; Liver Failure; Male; MicroRNAs; Mitochondria; Rats; Rats, Wistar; Ribonuclease III; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Transfection

Sirolimus is an immunosuppressant used to prevent graft versus host disease in allogeneic hematopoietic stem cell transplant recipients. It has a large volume of distribution (12 ± 7.5 l/kg) and within the intravascular space ∼95% of it is bound to red blood cells. Because of potential toxic effects at high trough levels, therapeutic drug monitoring is recommended for sirolimus. We present a case of severe hepatic dysfunction due to Hepatitis B and sirolimus toxicity, in a 51-year-old male stem cell transplant recipient. An automated red cell exchange decreased his blood sirolimus level from 22.6 to 10.3 ng/ml (55% reduction) and improved his liver enzymes. Re-equilibration of sirolimus from other compartments to the blood necessitated a series of four red cell exchanges, after which the sirolimus level was 4.7 ng/ml. Although the patient ultimately succumbed to multiorgan failure, red cell exchange may be considered for acute removal of sirolimus in selected patients.

Topics: Blood Component Removal; Drug Monitoring; Erythrocyte Transfusion; Erythrocytes; Fatal Outcome; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Liver Failure; Male; Middle Aged; Sirolimus

Topics: Age Factors; Child; Child, Preschool; Cyclosporine; Female; Follow-Up Studies; Food Hypersensitivity; Humans; Immunoglobulin E; Infant; Liver Failure; Liver Transplantation; Male; Prognosis; Sirolimus; Tacrolimus; Time Factors

TMA is a rare complication of tacrolimus. Disruption of endothelial cells, platelet aggregation, and intravascular mechanical fragmentation of red cells are core mechanisms of injury; however, exact pathways of toxicity are not clear. The clinical presentation may vary but TMA is a potentially life-threatening condition usually demanding aggressive treatment. We present the case of TMA in a child after living-related liver transplantation (LRLTx) on tacrolimus-based immunosuppressive regiment successfully converted to sirolimus.

Topics: Anemia, Hemolytic; Biopsy; Erythrocytes; Female; Graft Survival; Humans; Immunosuppressive Agents; Infant; Liver Failure; Liver Transplantation; Living Donors; Platelet Aggregation; Sirolimus; Tacrolimus; Thrombotic Microangiopathies; Treatment Outcome

A common situation presented in any clinical facility is a woman with swelling and redness of the breast. Diagnosis upon suspicion is often mastitis or inflammatory breast cancer, which are popular and well-known diseases of the breast. However, there is one main differential diagnosis which has to be taken into consideration: lymphedema of the breast. Twenty patients with internal diseases presented in our Breast Care Unit over a 4-year period with breast-affecting lymphedema. The patients suffered from cardiac failure, nephrotic syndrome, liver failure, lymphadenopathy, and central vein occlusion. Additionally, we identified 5 patients with a history of organ transplantation and under immunosupressive medication with sirolimus or everolimus. These mTor inhibitors are known to have unwanted side effects such as unilateral or bilateral upper/lower extremity peripheral edema or facial/eyelid edema, but as we know, isolated lymphedema of the breast represents a previously unreported complication.

Topics: Adult; Aged; Aged, 80 and over; Breast; Diagnosis, Differential; Everolimus; Female; Heart Failure; Humans; Immunosuppressive Agents; Liver Failure; Lymphatic Diseases; Lymphedema; Middle Aged; Nephrotic Syndrome; Sirolimus; Tissue Transplantation; TOR Serine-Threonine Kinases; Vascular Diseases

  Development of KS in pediatric liver transplant recipients is a rare entity and has dismal prognosis. Latent HHV-8 infection, immunosuppression, and genetic predisposition are possible etiological factors. Decreasing the dose or cessation of immunosuppressive drugs, switching to sirolimus with antiproliferative and antitumor properties, and different chemotherapeutic regimens are the current therapeutic strategies. We herein report a pediatric liver transplant recipient who developed generalized KS at post-transplant fifth month. The disease had an aggressive course despite the highly toxic chemotherapy. On the other hand, a prompt and durable response was provided by paclitaxel with tolerable side effects. The patient is now free of disease for at least 24 months and healthy with good graft function under sirolimus therapy as maintenance immunosuppression. Instead of highly toxic chemotherapy, paclitaxel can be used as therapeutic option in cases with generalized disease and in those who are unresponsive to conventional chemotherapy. However, new studies are needed to assess the efficacy of the paclitaxel therapy in KS in the liver transplant recipients.

Topics: Antineoplastic Agents; Female; Herpesvirus 8, Human; Humans; Immunosuppressive Agents; Infant; Liver Failure; Liver Transplantation; Lymphoproliferative Disorders; Paclitaxel; Prognosis; Sarcoma, Kaposi; Sirolimus; Treatment Outcome

Topics: Bile Duct Diseases; Biopsy; Constriction, Pathologic; Cyclosporine; Humans; Liver; Liver Cirrhosis; Liver Failure; Liver Transplantation; Male; Middle Aged; Postoperative Complications; Sarcoidosis; Sarcoidosis, Pulmonary; Sirolimus; Time Factors; Treatment Outcome

Liver transplantation (OLT) in children has seen significant improvements in recent years. Long-term immunosuppressive strategies have focused on avoiding the risks of long-term immunosuppression, particularly nephrotoxicity, de novo malignancy and late infections. Since its introduction in renal transplantation in 1999, sirolimus (SRL) has been used by an increasing number of liver transplant centers. The aim of this study was to review the experience using SRL in pediatric liver transplant recipients at a single center.. Between 1989 and 2006, 318 children underwent OLT including 13 who were converted to SRL therapy because of tacrolimus-related side effects. The indications were posttransplant lymphoproliferative disease (PTLD; n = 11), nephrotoxicity (n = 1), and de novo autoimmune hepatitis (n = 1). One patient with PTLD previously concurrently displayed chronic rejection. SRL dosages ranged between 0.4 and 5 mg/d. The median duration of follow-up was 18 months.. PTLD recurred in 1 patient. There were no episodes of acute rejection. One child developed hyperlipidemia that resolved with diet and medication.. Conversion from tacrolimus to SRL in selected pediatric liver transplant recipients is safe. Children with PTLD may benefit from immunosuppression with SRL after liver transplantation.

Topics: Adolescent; Cadaver; Child; Child, Preschool; Female; Humans; Immunosuppressive Agents; Infant; Liver Failure; Liver Transplantation; Living Donors; Lymphoproliferative Disorders; Male; Postoperative Complications; Retrospective Studies; Sirolimus; Tacrolimus; Tissue Donors

Experience with sirolimus (SRL)-based immunosuppression following orthotopic liver transplantation (OLT) is rapidly accumulating. In combination with calcineurin inhibitors (CNIs), SRL may reduce the incidence of acute rejection and lower overall required drug levels. This study sought to quantify long-term outcome following OLT in patients with cirrhosis and concomitant hepatocellular carcinoma (HCC) who were treated with an SRL-based regimen as a primary therapy. From January 2000 to June 2007, 97 patients underwent OLT for end-stage liver disease and HCC at the University of Colorado Health Sciences Center. Of those, 45 patients received SRL, in addition to CNIs, as a component of their primary immunosuppression regimen post-OLT. Conversely, 52 patients received the standard immunosuppression regimen including CNIs, mycophenolate mofetil, and corticosteroids. The 2 treatment groups were compared with respect to the following variables: age, gender, tumor stage by explant, grade, size, presence of vascular invasion, focality, Child's class, baseline creatinine, and warm and cold ischemic times. The 2 groups were comparable by all factors save for cold ischemic time, which was significantly longer in the CNI-treated group. Overall survival at 1 and 5 years post-OLT for patients treated with SRL was 95.5% and 78.8%, respectively. Conversely, survival in patients treated with CNIs exclusively at the same time intervals was 83% and 62%. Although there was no difference in the incidence of major complications, the SRL group experienced a modest improvement in renal function. Cumulatively, these data suggest a potential survival benefit with SRL-based therapy in patients undergoing OLT for end-stage liver disease and concomitant malignancy.

Topics: Adrenal Cortex Hormones; Calcineurin Inhibitors; Carcinoma, Hepatocellular; Cyclosporine; Drug Therapy, Combination; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kaplan-Meier Estimate; Kidney Diseases; Liver Failure; Liver Neoplasms; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Neoplasm Recurrence, Local; Proportional Hazards Models; Retrospective Studies; Risk Assessment; Sirolimus; Tacrolimus; Time Factors; Treatment Outcome

Sirolimus, being nonnephrotoxic, is a viable alternative in patients who develop renal insufficiency caused by calcineurin inhibitors (CIs). The aim of this study is to determine whether there is improvement in renal function in liver transplant recipients after switching to sirolimus-based immunosuppression. In this retrospective review, patients who were more than 3 years posttransplantation were selected. Patients who had proteinuria (protein > 300 mg/24 hr), those administered any other nephrotoxic agents, and those with a creatinine clearance (CCr) less than 20 mL/min were excluded. Renal insufficiency was defined as mild (CCr > 70 mL/min), moderate (CCr, 40 to 70 mL/min), or severe (CCr, 20 to 40 mL/min). In the 16 patients studied; there was significant improvement in serum blood urea nitrogen (36 mg/dL; range, 19 to 53 mg/dL; to 25 mg/dL; range, 10 to 37 mg/dL; P =.002) and serum creatinine levels (median, 1.95 mg/dL; range, 1.3 to 2.8 mg/dL; to 1.5 mg/dL; range, 1.0 to 2.4 mg/dL; P =.001) 6 months after switching to sirolimus therapy. There also was a trend in improvement in CCr from 43 mL min (range, 24 to 68 mL/min) to 49 mL/min (range, 22 to 152 mL/min). Among 9 patients with moderate renal insufficiency, 2 patients improved to mild renal insufficiency, 4 patients remained unchanged, and 3 patients deteriorated to severe renal insufficiency. Among 7 patients with severe renal insufficiency, 1 patient improved to mild renal insufficiency, 4 patients improved to moderate renal insufficiency, and 2 patients remained unchanged. No patient developed cellular rejection or other graft-related complications. In liver transplant recipients with chronic renal insufficiency, conversion to sirolimus-based immunosuppression allows complete withdrawal of CIs, leading to some improvement in renal function.

Topics: Aged; Calcineurin Inhibitors; Female; Humans; Immunosuppressive Agents; Kidney; Kidney Failure, Chronic; Liver Failure; Liver Transplantation; Male; Middle Aged; Sirolimus

With the increasing success of liver transplantation and the proven effectiveness of highly active retroviral therapy in HIV-positive patients, liver transplantation has been performed successfully in selected HIV-positive recipients with CD4 and an HIV viral load response to highly active antiretroviral therapy. In these patients, an interaction between a protease inhibitor (nelfinavir) and tacrolimus has been shown. The effect of nelfinavir on the pharmacokinetics of sirolimus, a newer immunosuppressive drug, is currently not known. The goal of the present case report is to document the interaction between sirolimus and nelfinavir in a liver transplantation patient. A 40-year-old woman who was HIV positive underwent a cadaveric liver transplantation for acute fulminant liver failure secondary to nevirapine (a nonnucleoside reverse transcriptase inhibitor). Postoperatively, she was treated with tacrolimus and steroids. She experienced steroid-resistant rejection and was started on sirolimus on the 17th postoperative day. Kinetic parameters were determined after a 2-mg oral dose of sirolimus and 250 mg of nelfinavir by collecting multiple peripheral venous blood samples before and after sirolimus administration. The kinetic parameters were compared with parameters from three liver transplantation patients on sirolimus who were not on nelfinavir. After normalizing the kinetic parameters to sirolimus dose of 1 mg/d, 0-hour and 24-hour trough sirolimus concentrations were nine-fold and five-fold higher for the patient who was on nelfinavir, compared with those who were not on nelfinavir. The maximum concentration was 3.2 times higher, the area under the concentration curve was 1.6 times higher, and the terminal disposition half-life was prolonged by 60%. The time to reach the peak concentration was 1 hour in all patients. Increase in trough concentration, peak concentration area under the curve concentration, and prolongation of half-life of sirolimus has been shown in a patient who was on a low dose (one fifth the recommended dose) of nelfinavir.

Topics: Adult; Female; Graft Rejection; HIV Infections; HIV Protease Inhibitors; Humans; Immunosuppressive Agents; Liver Failure; Liver Transplantation; Nelfinavir; Osmolar Concentration; Sirolimus