Phenytoin decreases the blood concentrations of sirolimus in a liver transplant recipient: a case report.

This report documents that coadministration of phenytoin leads to decreased blood concentrations and area under the blood concentration-time curve of sirolimus in a liver transplant patient. It is essential to monitor the blood concentrations of sirolimus and adjust the sirolimus dosage when phenytoin administration begins or ends.

Conversion from tacrolimus to cyclosporine--a based immunosuppression following liver transplantation.

We examined the frequency, reasons and outcome after conversion from Tacrolimus to Cyclosporine A. From August 1989 to December 1992, 1000 consecutive liver transplantation patients were studied, which included 834 adults (age>18 yr.) and 166 children with mean follow-up of 77 months (range 56 to 96). A prospectively populated electronic database was queried to identify patients that underwent conversion, the clinical indication and outcomes. Thirty-seven out of 834 adult recipients (4.43%), mean age of 48.4+/-12.9 years, 19 male (51.35%) and 18 females (48.64%) required conversion from Tacrolimus to Cyclosporine A baseline immunosuppressive therapy. No pediatric patient required conversion. The mean time interval from liver transplantation to Cyclosporine A conversion was 443.45+/-441.44 days (range 22 to 1641). The clinical indications for conversion included: 20 neurological (54%), 6 gastrointestinal (16%), 5 hematological (14%), and 6 other (16%) scenarios. Seven of the 37 patients (18.9%) died. The causes of death were multi-organ failure (2), sepsis (2), pancreatitis (1), hepatic failure due to relapse of ethanol abuse (1), and unknown cause (1). Nine out of 37 patients (24.32%) had to be reconverted to Tacrolimus (mean 282.22+/-499.79 days; range 15 to 1583 day with a median of 135) after institution of Cyclosporine A; none showed recurrence of the original symptoms. The reasons for these re-conversions were acute cellular rejection (44%, n=4), chronic rejection (11%, n=1), increased hepatic enzymes (33%, n=3) and progressively worsening neurological symptoms (11%, n=1). The frequency of conversion from Tacrolimus to Cyclosporine A was 4.43%. Conversion is safe and efficacious if done in a controlled setting. Additionally, re-conversion to Tacrolimus for lack of efficacy of Cyclosporine A did not appear to be associated with a recurrence of the condition that caused the initial switch.

Nelfinavir, a protease inhibitor, increases sirolimus levels in a liver transplantation patient: a case report.

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.

The interaction between antiretroviral agents and tacrolimus in liver and kidney transplant patients.

Solid organ transplantations have been performed successfully in selected HIV-positive patients with highly active antiretrovirus therapy (HAART). However, some of the medications in the HAART regimen require metabolism via the cytochrome P4503A, the same enzyme complex responsible for clearance of the calcineurin inhibitors cyclosporine and tacrolimus. Several case reports have described significant interactions between the agents used in HAART and immunosuppressive drugs. The goal of this report is to examine the extent of potential drug interactions between antiretroviral agents and tacrolimus after liver and kidney transplantation. Seven liver transplant (LTx) patients (M = 6, F = 1) and four kidney transplant (KTx) patients (M = 4) infected with HIV underwent surgery between September 1997 and January 2001. Initial immunosuppression consisted of tacrolimus and steroids for LTx patients or tacrolimus, steroids, and mycophenolate mofetil for KTx recipients. Their current baseline immunosuppression and HAART regimen were examined retrospectively. Of the seven liver recipients, one (case 4) died 2 weeks after LTx and never received HAART therapy posttransplantation. The remaining six patients were placed on a regimen consisting of two nucleoside reverse transcriptase inhibitors (NRTI) and one protease inhibitor (PI) (nelfinavir in 5, indinavir in 1) based on known viral sensitivities or history of a previous clinical response. Kidney recipients received NRTI and nonnucleoside reverse transcriptase inhibitors (NNRTI). The mean dose of tacrolimus in liver recipients was 0.6 mg/d, with mean trough concentration of 9.7 mg/mL. Compared with historic controls (liver transplant patients not on HAART), the average tacrolimus dose was 16-fold lower in patients on HAART. In contrast to liver recipients, HIV-positive kidney recipients not on PI therapy required a mean tacrolimus dose of 9.5 mg/d to maintain a mean trough concentration of 9.6 ng/mL. Of the two protease inhibitors used, nelfinavir seems to have a more profound effect than indinavir. When patients on nelfinavir alone (n = 5) were compared with a control group not on antiretroviral therapy, the need for a tacrolimus dose was 38 times lower (mean dose, 0.26 mg/d). Profound drug interactions between PI and tacrolimus have been observed requiring up to 50-fold reductions in dosage. This effect seems to be most pronounced with the use of nelfinavir as opposed to indinavir, although further experience is required to confirm this observation. In contrast, HAART using NRTI and NNRTI without the use of PI, as shown in kidney recipients, produces less significant effects on tacrolimus metabolism. Great caution and frequent drug level monitoring are necessary when HAART is introduced or withdrawn in HIV-positive recipients of organ transplants.