Jeong M. Park

Effects of St. John's Wort (Hypericum perforatum) on Tacrolimus Pharmacokinetics in Healthy Volunteers

Tacrolimus is an immunosuppressant approved for the prevention of rejection following transplantation and is a substrate for CYP3A and P‐glycoprotein. A pharmacokinetic interaction between St. Johns wort (antidepressant herbal product and inducer of CYP3A and P‐glycoprotein) and tacrolimus was evaluated in 10 healthy volunteers. The pharmacokinetics of tacrolimus were obtained from serial blood samples collected following single oral doses (0.1 mg/kg) prior to and during an 18‐day concomitant St. Johns wort dosing phase (300 mg orally three times daily). Coadministration of St. Johns wort significantly decreased tacrolimus AUC (306.9 μg•h/L ±175.8 μg•h/L vs. 198.7 μg•h/L ± 139.6 μg•h/L; p = 0.004) and increased apparent oral clearance (349.0 mL/h/kg ± 126.0 mL/h/kg vs. 586.4 mL/h/kg ± 274.9 mL/h/kg; p = 0.01) and apparent oral volume of distribution at steady state (11.5 L/kg ± 4.3 L/kg vs. 17.6 L/kg ± 9.6 L/kg; p = 0.04). St. Johns wort appears to induce tacrolimus metabolism, most likely through induction of CYP3A and P‐glycoprotein.

Efficacy and Safety of Low-Dose Valganciclovir in the Prevention of Cytomegalovirus Disease in Adult Liver Transplant Recipients

The efficacy and safety of valganciclovir (VGCV) for cytomegalovirus (CMV) prophylaxis in liver transplant recipients has not been established. We retrospectively compared the efficacy and safety of low‐dose oral VGCV (450 mg once daily for 90 days) and standard oral ganciclovir (1 g three times a day for 90 days, GCV) in preventing CMV disease in 109 adult liver transplant recipients who survived at least 1 month between January 2001 and April 2003 (49 GCV and 60 VGCV). The incidence of CMV disease at 1 year post‐transplant was similar among patients treated with VGCV and GCV (3% and 4%, respectively). Three of the four CMV disease cases occurred in high‐risk recipients with CMV serotype of donor+/recipient− (D+/R−) and all cases presented after completion of CMV prophylaxis, ranging 114‐152 days post‐transplant. Severe neutropenia was rare, and thrombocytopenia and anemia occurred at similar frequencies with both prophylaxis regimens. In conclusion, a 90‐day regimen of low‐dose oral VGCV has a similar efficacy and safety profile to high‐dose oral GCV in adult liver transplant recipients. D+/R− liver transplant recipients remain at risk of developing CMV disease after completion of antiviral prophylaxis. Additional prospective studies with close monitoring for CMV viremia and drug resistance are needed to further establish the optimal dose and duration of VGCV in liver transplant recipients. Liver Transpl 12:112–116, 2006.

Six-Month Prophylaxis Is Cost Effective in Transplant Patients at High Risk for Cytomegalovirus Infection

The risk of late-onset cytomegalovirus (CMV) infection remains a concern in seronegative kidney and/or pancreas transplant recipients of seropositive organs despite the use of antiviral prophylaxis. The optimal duration of prophylaxis is unknown. We studied the cost effectiveness of 6- versus 3-mo prophylaxis with valganciclovir. A total of 222 seronegative recipients of seropositive kidney and/or pancreas transplants received valganciclovir prophylaxis for either 3 or 6 mo during two consecutive time periods. We assessed the incidence of CMV infection and disease 12 mo after completion of prophylaxis and performed cost-effectiveness analyses. The overall incidence of CMV infection and disease was 26.7% and 24.4% in the 3-mo group and 20.9% and 12.1% in the 6-mo group, respectively. Six-month prophylaxis was associated with a statistically significant reduction in risk for CMV disease (HR, 0.35; 95% CI, 0.17 to 0.72), but not infection (HR, 0.65; 95% CI, 0.37 to 1.14). Cost-effectiveness analyses showed that 6-mo prophylaxis combined with a one-time viremia determination at the end of the prophylaxis period incurred an incremental cost of

Pharmacokinetics of Tacrolimus in Kidney Transplant Recipients: Twice Daily Versus Once Daily Dosing

34,362 and

Choice of induction regimens on the risk of cytomegalovirus infection in donor‐positive and recipient‐negative kidney transplant recipients

16,215 per case of infection and disease avoided, respectively, and

Tacrolimus Toxicity Associated with Concomitant Metoclopramide Therapy

8,304 per one quality adjusted life-year gained. Sensitivity analyses supported the cost effectiveness of 6-mo prophylaxis over a wide range of valganciclovir and hospital costs, as well as variation in the incidence of CMV disease. In summary, 6-mo prophylaxis with valganciclovir combined with a one-time determination of viremia is cost effective in reducing CMV infection and disease in seronegative recipients of seropositive kidney and/or pancreas transplants.

Transiently altered acetaminophen metabolism after liver transplantation

Tacrolimus a macrolide immunosuppressant that is routinely given in two equally divided doses every 12 h. However, the time‐dependent pharmacokinetics of tacrolimus suggest that once daily morning administration of tacrolimus may produce appropriate drug exposure. The purpose of this pilot study was to compare the pharmacokinetics and safety of twice vs. once daily administration of tacrolimus in stable kidney transplant recipients. Steady‐state tacrolimus pharmacokinetic parameters were estimated on two occasions in an open‐label, three‐arm, two‐period sequential study: twice daily dosing (Phase I) and once daily dosing (Phase II). In phase II, 18 patients were assigned to one of three arms: those taking 67%, 85% and 100% of their total twice daily dose once in the morning. In phase I, the mean area under the blood concentration–time curve (AUC) was higher after the morning dose, AUC0–12 117 ± 40 vs. AUC12–24 97 ± 30 ng/h/mL, p = 0.012. In the 85% Group, the mean AUC ratio between twice and once daily was 1.0 (95% CI, 0.9–1.1) which predicted the best conversion ratio. Tacrolimus given once daily in the morning, at 85% of the twice daily dose, provides safe and equivalent drug exposure to twice daily dosing. This convenient dosing schedule may help to increase compliance and lower costs.

Clinical and Economic Outcomes of Rabbit Antithymocyte Globulin Induction in Adults Who Received Kidney Transplants from Living Unrelated Donors and Received Cyclosporine-Based Immunosuppression

F.L. Luan, M. Samaniego, M. Kommareddi, J.M. Park, A.O. Ojo. Choice of induction regimens on the risk of cytomegalovirus infection in donor‐positive and recipient‐negative kidney transplant recipients.
Transpl Infect Dis 2010: 12: 473–479. All rights reserved

Valganciclovir: therapeutic role in pediatric solid organ transplant recipients

Subtherapeutic tacrolimus trough concentrations were noted in a 52‐year‐old woman who had undergone liver transplantation. Her tacrolimus dosage was increased from 7 to 28 mg twice/day, and ketoconazole therapy was added; however, her tacrolimus concentration remained undetectable. Metoclopramide 10 mg 4 times/day was begun to control the patients new‐onset nausea and vomiting. Within 48 hours of increasing the dosage to 20 mg 4 times/day, her tacrolimus trough concentration exceeded 30 ng/ml. Signs and symptoms were suggestive of tacrolimus nephrotoxicity and neurotoxicity. According to the Naranjo scale, this adverse drug event was probably the result of improved absorption of tacrolimus secondary to metoclopramide therapy. The patients subtherapeutic tacrolimus concentration at baseline was probably secondary to poor absorption due to impaired gastric emptying. Coadministration of metoclopramide significantly improved gastric motility and delivery of tacrolimus to the small intestine, increasing tacrolimus bioavailability, thus resulting in acute‐onset tacrolimus toxicity. When tacrolimus is administered with metoclopramide in patients with gastric dysmotility, tacrolimus concentrations should be monitored closely to minimize the risk of toxicity.

Impact of Changing From Cyclosporine to Tacrolimus on Pharmacokinetics of Mycophenolic acid in Renal Transplant Recipients With Diabetes

Background and objectives: Acetaminophen (INN, paracetamol) is metabolized to N‐acetyl‐p‐benzoquinone imine (NAPQI), a hepatotoxic metabolite, predominantly by cytochrome P450 (CYP) 2E1. Alterations in drug metabolism occur after organ transplantation. This study was designed to characterize acetaminophen disposition during the first 6 months after liver transplantation.