Protopic
Improvement in renal function and rejection control in pediatric liver transplant recipients with the introduction of sirolimus.

Casas-Melley AT, Falkenstein KP, Flynn LM, Ziegler VL, Dunn SP.

Division of Solid Organ Transplantation, Nemours Children's Clinic-Wilmington, Alfred I. duPont Hospital for Children, Wilmington, DE 19899, USA. acasas nemours.org

Calcineurin inhibitors have dramatically improved the outcomes of pediatric liver transplantation. However, calcineurin inhibitor use is associated with a 50% reduction in glomerular filtration rate in the first year post-transplant. Nephrotoxicity can be difficult to manage, especially in the pediatric population. We hypothesized that the addition of an mTOR inhibitor with decreased calcineurin inhibitor levels might improve or prevent renal insufficiency and improve control of rejection. A retrospective chart review was performed on the patients treated with sirolimus who had undergone an orthotopic liver transplant between January 2000 and February 2003. Thirty-eight patients were identified. Mean age was 8.6 yr. Fourteen patients were male and 24 were female. Mean weight was 30.3 kg. The most common indications for starting sirolimus were rejection (42%) and renal impairment (29%). Seventy-three percent of patients begun on sirolimus remain on the medication. Those with renal impairment (11 patients) showed improvement in their creatinine levels from a mean baseline of 1.3 to 0.8 mg/dL. Their calculated creatinine clearance (Schwartz formula) improved from 63.7 to 84.8 mL/min (p = 0.03). Patients started on sirolimus for rejection showed significant improvement in hepatocellular enzymes despite a reduction in the tacrolimus level from 12.2 to 7.5 ng/mL. The mean alanine aminotransferase level improved from 221 to 100 units/L (p = 0.02), and the mean aspartate aminotransferase improved from 121 to 99 units/L (p = 0.59). Addition of sirolimus to a tacrolimus-based regimen with lower target tacrolimus levels improved liver function in patients with rejection. Addition of sirolimus significantly improved renal function as shown by creatinine level and calculated creatinine clearance in those children with renal impairment. The effect of combined immunosuppressant treatment with tacrolimus and sirolimus on long-term renal function needs to be evaluated. Copyright 2004 Blackwell Munksgaard

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15265163&dopt=Abstract tacrolimus Protopic



Protopic
The rate of gastric emptying determines the timing but not the extent of oral tacrolimus absorption: simultaneous measurement of drug exposure and gastric emptying by carbon-14-octanoic acid breath test in stable renal allograft recipients.

Kuypers DR, Claes K, Evenepoel P, Maes B, Vanrenterghem Y.

Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Herestraat 49, B-3000 Leuven, Belgium. Dirk.Kuypers uz.kuleuven.ac.be

Tacrolimus is characterized by a highly variable oral bioavailability and narrow therapeutic window. Tacrolimus absorption from the gastrointestinal tract is to a large extent determined by the genotypic, phenotypic, and functional expression of P-glycoprotein and CYP3A in the gut wall and liver. It is disputed whether the gastric emptying rate per se is important for determining oral bioavailability of tacrolimus and whether delayed gastric emptying is clinically relevant for therapeutic drug dosing. We conducted a pharmacokinetic study in 50 renal recipients, measuring simultaneously the rate of gastric emptying using a carbon-14-octanoic acid breath test and quantifying drug exposure by area under the concentration-time curve sampling. Gastric half emptying time (t1/2) significantly correlated with time to reach maximum blood tacrolimus (tmax) concentration (r2 = 0.30; p < 0.0001), whereas the gastric emptying coefficient, reflecting the overall gastric emptying rate, showed a weak inverse correlation with tmax (r2 = 0.14; p = 0.007). The time-dependent rate of gastric emptying strongly correlated with the simultaneously measured blood tacrolimus concentration over the first 4 h after oral drug administration (r2 = 0.96; p < 0.0001). Comparison between patients with and without delayed gastric emptying confirmed that maximum blood tacrolimus concentration was reached significantly more slowly in the former group (tmax, 2 +/- 1 h versus 1.48 +/- 0.68 h; p = 0.04), whereas the extent of tacrolimus absorption was not different. Despite a strong association between gastric emptying rate and the timing of tacrolimus absorption from the gut in stable recipients, gastric emptying rate does not affect the total extent of drug absorption and is not responsible for significant alterations in drug exposure, even in situations of delayed gastric emptying.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15383495&dopt=Abstract tacrolimus Protopic



Protopic
Effect of oral tacrolimus (FK 506) on steroid-refractory moderate/severe ulcerative colitis.

Hogenauer C, Wenzl HH, Hinterleitner TA, Petritsch W.

Department of Internal Medicine, Division of Gastroenterology, Karl Franzens University Graz, Austria.

BACKGROUND: Steroid refractory ulcerative colitis is most commonly treated with intravenous ciclosporin to avoid colectomy. In search for an alternative drug that can be administered orally we investigated oral tacrolimus (FK 506) for this indication. METHODS: Nine patients with active, moderate/severe steroid refractory UC were treated with oral tacrolimus with a daily dose of 0.15 mg/kg body weight. After patients had responded azathioprine was added for long-term immunosuppression. RESULTS: All patients responded within 1-2 weeks. After 12 weeks of tacrolimus therapy six patients (67%) were in complete remission, two patients (22%) had mild to moderate disease activity, and one patient (11%) underwent colectomy. After a mean follow up of 21 months six of the nine patients (67%) had their colon in situ. Two patients developed severe side-effects, one thrombopenia with intestinal bleeding, and one bicytopenia. Mild side-effects were common. CONCLUSION: Oral tacrolimus may be an effective alternative to intravenous ciclosporin for the therapy of steroid-refractory ulcerative colitis. Patients receiving tacrolimus need to be watched carefully for side-effects.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12940927&dopt=Abstract tacrolimus Protopic



Protopic
Distinct inhibitory effects of tacrolimus and cyclosporin a on calcineurin phosphatase activity.

Fukudo M, Yano I, Masuda S, Okuda M, Inui K.

Department of Pharmacy, Kyoto University Hospital, Sakyo-ku, Kyoto 606-8507, Japan.

We have compared the pharmacodynamic properties of calcineurin inhibitors tacrolimus and cyclosporin A in rats to clarify the different therapeutic drug monitoring strategy of both drugs in a clinical situation. In various tissue extracts, the inhibition of calcineurin activity by cyclosporin A was significantly greater than that by tacrolimus at the same drug concentration (1 microM) in the thymus, heart, liver, spleen, kidney, and testis (p < 0.05). The time profiles of blood concentrations and calcineurin activity in whole blood were examined after single or repeated administration of each drug in rats. A substantial time delay in the inhibition was observed following the single administration of tacrolimus or cyclosporin A, resulting in an anticlockwise hysteresis in the relationship between blood concentrations and calcineurin inhibition in whole blood. In contrast, such a hysteresis loop diminished after the repeated administration of each drug, and the recovery rate of calcineurin activity was greater for the inhibition induced by cyclosporin A than by tacrolimus. Furthermore, tacrolimus produced a comparable inhibition of calcineurin activity in whole blood at lower blood concentrations than cyclosporin A. Overall, the effect compartment model well described the time profiles of calcineurin activity in whole blood after the single and repeated administrations of each drug. These findings suggest that the properties of calcineurin inhibition differ between tacrolimus and cyclosporin A. Distinct pharmacodynamics may partly contribute to the therapeutic drug monitoring strategy in transplant patients receiving calcineurin inhibitors.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15383634&dopt=Abstract tacrolimus Protopic



Protopic
Long-term changes in mycophenolic acid exposure in combination with tacrolimus and corticosteroids are dose dependent and not reflected by trough plasma concentration: a prospective study in 100 de novo renal allograft recipients.

Kuypers DR, Claes K, Evenepoel P, Maes B, Coosemans W, Pirenne J, Vanrenterghem Y.

Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Herestraat 49, B-3000 Leuven, Belgium.

Tacrolimus and cyclosporine A have different effects on exposure to concomitantly administered mycophenolate mofetil (MMF), measured as the mycophenolic acid (MPA) dose interval area under the plasma concentration versus time curve (AUC0-12 h) or the plasma MPA predose concentration (C0). This has led to recommendations in using a 50% lower dose of MMF in combination with tacrolimus compared to cyclosporin A. At present, no long-term data are available regarding the pharmacokinetics (PK) of different dosages of MMF in combination with tacrolimus and the clinical variables that influence the dose-exposure relationship of MPA. A prospective 12-month pharmacokinetic study was performed in 100 de novo renal transplant recipients treated with two different MMF dosages (1 g/day vs. 2 g/day) in combination with tacrolimus and corticosteroids. MPA AUC data were collected 7 days, 6 weeks, and 3 and 12 months posttransplantation, and model-independent PK parameters were calculated. Clinical variables that could possibly influence MPA PK were evaluated. The MPA AUC0-12 h significantly increased toward 6 weeks (p < 0.05) but only in the 2-g MMF dosing group. The MPA AUC0-12 h in the 1-g MMF group reached its nadir at 3 months, while in the 2-g MMF group, it remained elevated until 3 months, returning to baseline values by 12 months. This differential evolution in exposure was not only inadequately reflected by the corresponding MPA C0 concentrations, but the MPA C0 concentrations also were not significantly different between the two dosing groups at early postgrafting (day 7) and at 12 months. Using multiple stepwise regression analysis, C0 (r = 0.51, p < 0.0001) and end-of-dose interval MPA plasma concentration (C12: r2 = 0.61, p < 0.0001) were found to poorly predict MPA AUC0-12 h, while MPA plasma concentrations at 4 hours (C4: r2 = 0.85, p < 0.0001) and 6 hours postdosing (C6: r2 = 0.83, p < 0.0001) were superior but hampered by a large prediction bias and imprecision. An abbreviated 2-hour AUC measurement (r2 = 0.78), using three sampling points (C0, C40 [MPA plasma concentration 40 min postdosing], C2), provided the best compromise between a monitoring tool that is theoretically ideal and practically feasible. MPA pharmacokinetics were not influenced by recipient age, gender, and body weight or by serum albumin concentrations, allograft function, or corticosteroid or tacrolimus dose. Mild hepatic dysfunction early after grafting did result in significantly reduced MPA exposure (MPA AUC0-12 h, p = 0.01 and C0, p = 0.03). In this study, it was demonstrated for the first time that the dynamics of long-term MPA pharmacokinetics in combination with tacrolimus differ according to the daily MMF dose and that this effect is not adequately reflected by MPA trough concentrations. Using the latter as a routine measure for therapeutic drug monitoring might mislead clinicians into drawing wrong conclusions in terms of relating questions of efficacy or toxicity to MPA exposure.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12953344&dopt=Abstract tacrolimus Protopic



Protopic
Daclizumab induction as an immunosuppressive regimen for renal transplant recipients from non-heart-beating donors.

Sanchez-Fructuoso AI, Prats D, Marques M, Ridao N, Conesa J, Garcia Mena M, Torrente J, Barrientos A.

Department of Nephrology, Hospital Clinico San Carlos, Madrid, Spain. sanchezfruct telefonica.net

BACKGROUND: Recent reports have demonstrated the efficacy of interleukin-2-receptor blockers in lowering the incidence of early acute rejection. The present study aimed to test the hypothesis that the use of daclizumab induction (DAC) plus low-dose tacrolimus, mycophenolate mofetil, and steroid diminishes the incidence of delayed graft function (DGF) in renal transplants from non-heart-beating donors (NHBD). METHODS: We compared the incidence of DGF and rejection in 185 renal transplants from NHBD treated as follows: Group-I: quadruple sequential therapy with antithymocyte globulin, cyclosporine, azathioprine, and steroids (n=22); Group-II: cyclosporine (8 mg/kg/d) plus azathioprine plus steroid (n=26); Group-III: low-dose cyclosporine (5 mg/kg/d) plus mycophenolate mofetil plus steroid (n=68); Group-IV: low-dose tacrolimus (0.1 mg/kg/d) plus mycophenolate mofetil plus steroid (n=17); and Group-V: DAC plus low-dose tacrolimus plus mycophenolate mofetil plus steroid (n=43). RESULTS: The incidences of DGF were 72.7% in Group-I, 73.1% in Group-II, 69.1% in Group-III, 76.5% in Group-IV, and 44.2% in Group-V. Acute rejection was higher in Group-IV. CONCLUSIONS: The combination of DAC, low-dose tacrolimus, mycophenolate mofetil, and steroids is effective in lowering the incidence of DSF in NHBD kidney transplant recipients without any increase in acute rejection.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12962759&dopt=Abstract tacrolimus Protopic



Protopic
High incidence of severe infections in heart transplant recipients receiving tacrolimus.

Peraira JR, Segovia J, Arroyo R, Ortiz P, Fuertes B, Monivas V, Burgos R, Alonso-Pulpon L.

Cardiology Department, Hospital Universitario Puerta de Hierro, Madrid, Spain.

BACKGROUND: Tacrolimus (FK) is being increasingly used as an alternative to cyclosporine (CyA) in heart transplantation (HTx). It is believed to engender slightly more powerful protection against acute rejection. However, the increased immunosuppression could result in an excess of infectious complications. METHODS: Our study compared the incidence of major infections (MInf), defined as life-threatening infectious episodes requiring admission and intravenous (IV) antimicrobial therapy, among a series of HTx recipients treated with either FK (n=30) or CyA (n=84). RESULTS: A total of 21 patients received FK in an elective protocol and 9 patients initially treated with CyA were converted to FK. Tacrolimus was combined with azathioprine and prednisone in 21 cases, and with mycophenolate mofetil and steroids in 8 recipients. After a follow-up between 6 and 37 months, 11 patients (37%) in the FK group developed 13 episodes of MInf, most (85%) occurring during the first posttransplant year. Conversely, CyA patients (n=84), a group with similar characteristics and follow-up, showed a MInf incidence of 12% (P<.05). Among the FK group, the most common site of MInf was pulmonary (69%). A variety of opportunistic agents caused MInf in 54% of cases, whereas the remaining ones were attributed to nosocomial bacteria. There were three deaths (27% of all MInf), all in azathioprine-treated patients with initial FK therapy. CONCLUSIONS: Tacrolimus therapy seems to be associated with an increased incidence of severe infections in HTx recipients. We recommend aggressive diagnostic and therapeutic approaches for patients on FK who develop signs or symptoms of infection in the first year after HTx.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12962875&dopt=Abstract tacrolimus Protopic