Kristine S. Schonder

The impact of conversion from prograf to generic tacrolimus in liver and kidney transplant recipients with stable graft function.

Bioequivalence of the recently available generic tacrolimus formulation, manufactured by Sandoz, to the reference product (Prograf; Astellas Pharma, Tokyo, Japan) has been demonstrated in healthy subjects. However, the safety and efficacy of substitution with generic tacrolimus in transplant patients have not been evaluated. Tacrolimus trough concentrations and indices of liver and kidney function were recorded before and after generic substitution in 48 liver and 55 kidney transplant recipients. In liver transplant patients, the mean tacrolimus concentration/dose (C/D) ratio (±SD) was 184.1 (±123.2) ([ng/mL]/[mg/kg/day]) for the reference product and 154.7 (±87.8) ([ng/mL]/[mg/kg/day]) for the generic product (p < 0.05). The mean C/D‐ratios in kidney transplant patients were 125.3 (±92.7) and 110.4 (±79.2) ([ng/mL]/[mg/kg/day]) for the reference and generic products, respectively (p < 0.05). Actual trough concentrations declined by an average of 1.98 ng/mL in liver and 0.87 ng/mL in kidney transplant patients following the switch, after accounting for all significant covariates. No change was observed in biochemical indices of liver or kidney function and no cases of acute rejection occurred following the substitution. These results suggest that transplant patients currently taking the reference tacrolimus formulation may be safely switched to the Sandoz‐generic product provided trough concentrations are closely monitored following the substitution.

Polyomavirus BK Neutralizing Activity in Human Immunoglobulin Preparations

Background. Polyomavirus BK (BKV) infection can cause nephropathy in the allograft kidney. No well-established drug treatment is available at this time. Human intravenous immunoglobulins (IVIG) have been used as an empiric therapy without proof of effectiveness. Methods. We tested five lots of commercially available IVIG preparations from two different suppliers for polyomavirus neutralizing activity. BKV and mouse polyomavirus were used to infect human and murine host cells, respectively, with or without prior treatment with IVIG. Neutralization activity was measured by quantitation of viral DNA after 7 days in culture. Results. Coincubation of BKV but not mouse polyomavirus with clinically relevant concentrations of IVIG derived from healthy and hepatitis B vaccinated subjects caused more than 90% inhibition of viral DNA yield after 7 days in culture. Consistent with a direct neutralizing mechanism, this effect was significantly diminished if viral infection was performed in immunoglobulin pretreated cells or if immunoglobulin treatment was delayed 2 hr after addition of infectious virus. Conclusion. Human IVIG preparations contain BKV neutralizing antibodies. Data on neutralizing capacity of these antibodies are presented to aid dose exploration in clinical trials seeking to validate the use of IVIG in patients with BKV infection.

Adverse Effects of Immunosuppression in Pediatric Solid Organ Transplantation

Solid organ transplantation is a life-saving treatment for end-stage organ failure in children. Immunosuppressant medications are used to prevent rejection of the organ transplant. However, these medications are associated with significant adverse effects that impact growth and development, quality of life (QOL), and sometimes long-term survival after transplantation. Adverse effects can differ between the immunosuppressants, but many result from the overall state of immunosuppression. Strategies to manage immunosuppressant adverse effects often involve minimizing exposure to the drugs while balancing the risk for rejection. Early recognition of immunosuppressant adverse effects may help to reduce morbidities associated with solid organ transplantation, improve QOL, and possibly increase overall patient survival.

Pharmacokinetics of low-dose cidofovir in kidney transplant recipients with BK virus infection

BK virus (BKV) infection in kidney transplant recipients is associated with progressive graft dysfunction and graft loss. Cidofovir, an antiviral agent with known nephrotoxicity, has been used in low doses to treat BKV infections. However, the systemic exposure and disposition of the low‐dose cidofovir regimen are not known in kidney transplant recipients.

Determination of cidofovir in human plasma after low dose drug administration using high-performance liquid chromatography–tandem mass spectrometry

A sensitive and specific method for the determination of cidofovir (CDV) in human plasma using high-performance liquid chromatography with tandem mass spectrometry (LC-MS/MS) was developed and validated. Plasma samples were processed by a solid phase extraction (SPE) procedure using Varian SAX extraction cartridges prior to chromatography. The internal standard was (13)C5-Folic acid ((13)C5-FA). Chromatography was performed using a Luna C8(2) analytical column, 5 microm, 150 mm x 3.0 mm, using an isocratic elution with a mobile phase consisting of 43% methanol in water containing 12 mM ammonium acetate, at a flow rate of 0.3 mL/min. The retention times of CDV and (13)C5-FA were 2.1 min and 1.9 min, respectively, with a total run time of 5 min. The analytes were detected by a Micromass Quattro Micro triple quadrupole mass spectrometer in positive electron spray ionization (ESI) mode using multiple reaction monitoring (MRM). The extracted ions monitored following MRM transitions were m/z 280.0-->262.1 for CDV and m/z 447.0-->294.8 for (13)C5-FA (IS). The assay was linear over the range 20-1000 ng/mL. Accuracy (101.6-105.7%), intra-assay precision (4.1-5.4%), and inter-assay precision (5.6-6.8%) were within FDA limits. No significant variation in the concentration of CDV was observed with different sample storage conditions. This method is simple, adaptable to routine application, and allows easy and accurate measurement of CDV in human plasma.

Effect of long-term tacrolimus immunosuppression on renal function in liver transplant recipients

Study Objectives. To describe changes in renal function occurring after long‐term treatment with tacrolimus in clinically stable liver transplant recipients, and to identify risk factors for a clinically significant decline in renal function in these patients.

Terbutaline for Chronotropic Support in Heart Transplantation

OBJECTIVE To report the use of oral terbutaline for chronotropic support in a patient who had undergone heart transplantation. CASE SUMMARY A 54-year-old white man received a heart transplant secondary to ischemic dilated cardiomyopathy. His clinical course was uncomplicated until postoperative day 10, when he became hemodynamically compromised despite inotropic therapy (BP 88/53 mm Hg, mean HR 80 beats/min) secondary to stage IIIa rejection. Although a continuous intravenous infusion of dobutamine was maintained, therapy with oral terbutaline 2.5 mg every 6 hours was initiated. Because the patient remained bradycardic on postoperative day 11 (HR 64 beats/min; mean 75), terbutaline was titrated to a dosage of 5 mg every 8 hours. Subsequently, an improvement in the hemodynamic profile (BP 140/78 mm Hg, mean HR 91 beats/min) was noted. Treatment with terbutaline was continued for 13 days and was well tolerated. DISCUSSION As of February 11, 2004, this is the first case, to our knowledge, to describe the use of oral terbutaline therapy for chronotropic support in the setting of acute rejection after heart transplantation. Terbutaline is a β2-adrenergic agonist that may mediate its effects via direct β2-receptor stimulation, baroreceptor-mediated increases in sympathetic tone, or via presynaptic β2-stimulation. Although isoproterenol has been the mainstay of therapy for chronotropic support in this setting, its availability has been an issue in recent years. Terbutaline, therefore, may represent a useful alternative for chronotropic support in the setting of heart transplantation. CONCLUSIONS Terbutaline therapy did not appear to be associated with any significant adverse effects and warrants further application and study in this setting.

Pharmacology of Immunosuppressive Medications in Solid Organ Transplantation

The multitude of immunosuppressants available for solid organ transplantation allows for many combinations of immunosuppressive therapies that can be tailored to a patient’s specific lifestyle and immunosuppression needs. Newer agents currently being studied offer even more possibilities for the future to further reduce the incidence of acute rejection and prolong graft and patient survival.

Advances in Anemia Management in Chronic Kidney Disease

The prevalence of chronic kidney disease (CKD) is increasing in the United States. Efforts to promote earlier intervention to screen for CKD and manage secondary complications are of paramount importance to improve overall care of this population. Anemia is a secondary complication of CKD that develops as kidney function declines. Historically, anemia management efforts have been primarily emphasized in patients with end-stage renal disease; however, early detection and treatment of anemia in the early stages of the disease are essential to prevent negative consequences of anemia such as reduced quality of life, left ventricular hypertrophy and mortality. With the increased prevalence of CKD and efforts focused on identifying this disorder early in its course, it is likely that more pharmacists will be involved in the management of CKD and secondary complications such as anemia. Treatment approaches must also be based on the more recently advocated guidelines from the National Kidney Foundation’s Kidney Disease Outcomes Quality Initiative (NKF-K/DOQI). This article reviews therapeutic issues of anemia of CKD, new agents for management, and the NKF-K/DOQI anemia management guidelines from a clinical perspective that will assist pharmacists involved in the care of these patients.

Early risk factors for persistent anemia after kidney transplantation.

Study Objective. To identify predictors of persistent posttransplant anemia that appear within the first week after kidney transplantation in order to determine the high‐risk patients who might receive the most benefit from erythropoiesis‐stimulating agents.