Use of FK 506 in pediatric patients

Transplantation proceedings, 1991

FK 506 therapy with low doses of steroids was adequate to control rejection in most liver recipients. Rejection episodes were readily reversed with single IV doses of methylprednisone or hydrocortisone. Short courses of OKT3 (3 to 5 days 5-10 mL) controlled severe rejections. The rate of retransplantation directly due to rejection was low (1.6%). There was a limited need for steroids either early or out to 6 to 12 months.

Transplantation proceedings, 1991

Journal of Gastroenterology and Hepatology, 1992

Immunosuppressive regimens are usually required for patients receiving organ transplants. The development of a post-transplant lymphoproliferative disorder is an infrequent complication of such therapy. FK 506 is a new immunosuppressant agent that has recently been used in patients receiving organ transplantation. This report describes a 20 month old Saudi child who developed post-transplant lymphoproliferative disorder while receiving FK 506 following liver transplantation. Such a complication has been recognized with cyclosporine but has not been well addressed as yet with FK 506. The child also developed progressive renal complications. There was also a difficulty in interpreting the results for IgM antibodies to different viruses. The overall features of progressive renal toxicity and those of lymphadenopathy, hepatosplenomegaly, fever, neutropenia and thrombocytopenia reversed following discontinuation of FK 506 therapy. It is concluded that all the above complications, though reversible, may well be linked to the new immunosuppressant agent FK 506.

Transplantation proceedings, 1993

Transplantation proceedings, 1991

ESPITE improvements in operative techniques. or• .... preservation. and the inuodUdion of OKn, the incidence of retranspianWion (RET,,) under cyclosporine (CyA).based therapy hu changed litde since our initial repon. I-J Approximately 15% to 20% of all CyA•treated recipients require RET". with a I•year mortality rate of 5095. The purpose of this study was to evaluate the impact of FK 506 on the incidence of RETx and on the cause of graft loss. CASE MATERIALS CyAGroup Between October 25. 1987 and September 5. 1989. 631 adult patients 118 years or older) received their first orthotopic: liver transplantation IOLTx) underCyA-steroid therapy at the Univer• sity Health Center of Pillsbul'lh. Within the first 6 months followinlthe OLT. 97 adults patients had required 118 retrans• plantations (RETx) (97 second. 19 third. and 2 fourth). Median follow-up in this group was 27 months. Four patients initially treated with CyA had unsuccessful at• tempts at rescue with FK 506 before RETx. Followinl RETx. 18 patients were switched to FK 506. For the purpose of analysis. these patients were included in the CyA RrOuP. FK 506 Group Between AUIUSl 19. 1989 and September 30. 1990. 409 adults received primary liver gratts under FK 506 and low-dose steroid therapy. Thiny-tive pallents required 39 RETxs 135 second. " thirdl within the first 6 months followlftlthe pnrnary transplanta• lion. Median follow-up 1ft this IrouP was 13 months.

Clinical …, 1993

1994

Transplantation proceedings, 1991

No group of patients is likely to benefit more by improvements in immunosuppression than the pediatric transplant recipients who face lifelong treatment. The advent of cyclosporine (CyA) has transformed liver transplantation into the preferred treatment modality for chronic liver failure. 1 Its effect on pediatric liver transplantation was profound, allowing for acceptable patient and graft survival when used with steroids at a fraction of the dose necessary under previous immunosuppressive regimens. 2-8 Complications included renal toxicity, hypertension, gum hyperplasia, hirsutism, and an uncommon but very troubling syndrome of facial disfigurement. FK 506, a new immunosuppressive agent derived from Streptomyces tsukubaensis, was first shown to be efficacious in experimental 9 and clinical primary liver transplantation, 10-12 and also in reversing rejection in patients who failed CyA treatment. 13 Additional indications for use in pediatrics were its apparent simplicity of use, low toxicity, and independence from adjuvant steroid therapy. 9-14 This report summarizes our clinical experience with FK 506 from a prospective study of children who underwent primary liver transplantation at the Children's Hospital of

Transplant International, 1994

FK 506 plasma levels were analyzed in 89 liver-grafted patients under FK 506-based immunosuppression. Plasma levels were found to be influenced by the patients' liver function: compared to patients without major liver dysfunction, those with cholestasis had higher plasma levels and these plasma levels were able to differentiate between rejection and toxicity. In patients with stable liver function, no clear difference was observed with regard to the plasma levels detectable during toxicity or rejection. We conclude that plasma levels can be used to determine the FK 506 dose but only in patients with cholestasis (i. e., during the early post-transplant course, or in patients with cholestatic rejection). In patients with stable liver function, plasma levels are only of limited clinical relevance.

Therapeutic Drug Monitoring, 1995

is a new immunosuppressive agent. recently approved for use in solid organ transplants. The first use of FK506 was for the indication of refractory liver allograft rejection. This revealed a marked ability to reverse ongoing rejection. even in cases where chronic changes were observed. Between 50 and 70% of patients converted to FK506 had shown improvement. In long-term follow-up of patients with chronic rejection. 75% of patients were still alive at 3 years following FK506 conversion. and 65% of liver allografts were still functioning. FK506 has been compared to cyclosporine in primary liver transplantation. In the three randomized trials. freedom from rejection was statistically greater in the FK506-treated group, as compared to the cyclosporine-treated group. By intent-to-treat analysis, the patient and graft survival in the FK506 group was the same or better than the cyclosporine group. The good results in the cyclosporine limb was due. in part, to the ability of FK506 to treat rejection in the cyclosporine group. Freedom from steroid use, and the lower incidence of hypertension, were prominent features of FK506 patients. FK506 has been used for rescue of rejecting kidney allografts, with results similar to the liver transplant trials. When used as primary immunosuppression. FK506 was shown to be effective. as measured by graft survival. FK506-based immunosuppression has also been used in primary heart transplantation. as well as for primary adult pulmonary transplantation. Results from these small series of patients are equally encouraging. The results . of these studies suggest that FK506 is effective for solid organ transplantation. Both FK506 and cyclosporine administration have been associated with side effects. many of which are similar. and some of which are peculiar to a given organ transplant.

Transplantation Proceedings, 2002

Transplant International, 1993

Thirty-seven liver-grafted patients with steroidresistant acute or chronic graft rejection or with cyclosporin-related complications were c o n v e r t e d from C y A to F K 506. The clinical o u t c o m e of the patients primarily d e p e n d e d on the d e g r e e of liver dysfunction present at initiation of F K 506 t r e a t m e n t. In patients switched to F K 506 for t r e a t m e n t of acute or early chronic graft rejection, C y A nephrotoxicity, or C y A m a l a b s o r p t i o n , the F K 506 t h e r a p y was associated with a clear i m p r o v e m e n t in the clinical course. I n contrast, in patients with advanced chronic graft rejection, a lower response rate to the conversion in i m m u n o s u p p r e s s i o n was observed. The lower response rate was associated with a higher p a t i e n t mortality. T h e s e studies d e m o n s t r a t e that F K 506 represents a v a l u a b l e alternative i m m u n o s u p p r e s s a n t for livergrafted patients. The conversion from C y A to F K 506 should t a k e place before serious-and potentially irreversible-disturbances in liver function are observed.

The Journal of Clinical Pharmacology, 1993

The fIrst•dose pharmacokinetics of FK506 was studied in nine orthotopic liver transplant patients receiving continuous intravenous infusion of O.lS mg/kg/dav. lvlultiple blood samples were obtained during the infusion and plasma FK506 concentrations were measured by enzyme-linked immunosorbent assay. The plasma clearance ranged from 0.47 to 5.B L/minute, and the half-life ranged from 4.5 hours to 33.1 hours. These results indicate the pharmacokinetics of FK506 to be highly variable between patients. FKS06 is extensively distributed outside the plasma compartment. FK506 is extensively metabolized in the body, with less than 1 %) of the administered dose being excreted in the urine as unchanged FK506. The large variability in FKS06 kinetics during the immediate post• operative period is attributed to the variability in the functional status of the liver in the transplant patients. Because of the long half-life of FKS06, it takes more than 45 hours to reach steady-state concentrations after continuous infusion. Based on the estimated kinetic parameters, it appears that a combination of a bolus or a rapid infusion of .02 mg/kg with a continuous infusion of o.os mg/kg/day will provide and maintain a concentration of more than 2 ng/mL from the beginning of the drug treatment. F K506 is a macrolide isolated from the fungus Streptomyces tsukubaensis. 1 It is nearly 100 times more potent than cyclosporine (CsA) in inhibiting lymphocyte proliferation in mixed lymphocyte cultures. 2 FKS06 has been shown to prevent or reverse the rejection of heart. liver, kidney. pancreas. lung, intestine, and skin grafts in mice. rats. dogs. monkeys, and baboons. 3 FKS06 has been in clinical use since March 1989 at the University of Pittsburgh. It was used initially for rescuing livers that have failed under conventional immunosuppression and later as the primary immunosuppressant for liver, kidney, and heart transplantation. 4-6 Current results indicate that FKS06 provides better immunosuppression in From the Schools of Pharmacy (Drs. Venkataramanan and Abdallah) and Medicine (Drs.

Transplantation proceedings, 1990

THE introduction of Cya was a major breakthrough in organ transplantation. However, side effects of the drug, such as frequent episodes of rejection, nephrotoxicity, and hypertension, stimulated a search for agents devoid of such effects. A recently developed drug, FK 506, appears to be superior to CyA in immunosuppression, with an advantage in humans of minimal side effects. 1 Its reported effects on the cardiovascular system are variable, ranging from no organic change 2-4 to vasculitis and myocardial necrosis. 5 The organic changes seen in animal studies may have been species specific. This study was designed to investigate the acute hemodynamic effects of FK 506 in patients receiving a large loading dose followed by a maintenance dose. MATERIALS AND METHODS This study was approved by the Institutional Research Review Board, and informed consent was obtained from the patients. Sixteen adult patients undergoing primary orthotopic liver transplantation were studied. Anesthetic management followed the standard care at Presbyterian-University Hospital (Pittsburgh, PA). Anesthesia was induced with thiopental and maintained with isoflurane and fentanyl. Electrocardiograms (ECGs) were continuously recorded by a data acquisition system. Complete hemodynamic profile and biochemical variables, including arterial blood gas tensions, electrolytes, ionized calcium, glucose, and lactate, were measured. In addition, right ventricular ejection fraction was measured with a REF-ejection fraction/cardiac output computer (Baxter, Irvine, CA). Standard surgical procedure was followed, including the use of veno-venous bypass. Methylprednisolone (1 g) was given after reperfusion of the grafted liver. During biliary reconstruction, a loading dose of FK 506 (0.15 mg/kg) was infused over 1 hour. This was the first dose of intravenous FK 506 given, as well as the largest. Postoperatively, maintenance doses of FK 506 (0.075 mg/kg) were administered over 1 hour, every 12 hours. Intraoperatively, a complete hemodynamic profile and set of biochemical measurements were obtained 5 miriutes and 1 minute before, and 15 minutes (FK + 15), 30 minutes (FK + 30), 45 minutes (FK + 45), 60 minutes (FK + 60), 90 minutes (FK + 90), and 120 minutes (FK + 120) after the start of the first FK 506 infusion. Postoperatively, a hemodynamic profile was measured prior to and immediately after a maintenance dose of FK 506 infusion.