Contribution of Population Pharmacokinetics to Dose Optimization of Ganciclovir-Valganciclovir in Solid-Organ Transplant Patients.

Treatment of solid-organ transplant (SOT) patients with ganciclovir (GCV)-valganciclovir (VGCV) according to the manufacturer's recommendations may result in over- or underexposure. Bayesian prediction based on a population pharmacokinetics model may optimize GCV-VGCV dosing, achieving the area under the curve (AUC) therapeutic target. We conducted a two-arm, randomized, open-label, 40% superiority trial in adult SOT patients receiving GCV-VGCV as prophylaxis or treatment of cytomegalovirus infection. Group A was treated according to the manufacturer's recommendations. For group B, the dosing was adjusted based on target exposures using a Bayesian prediction model (NONMEM). Fifty-three patients were recruited (27 in group A and 26 in group B). About 88.6% of patients in group B and 22.2% in group A reached target AUC, achieving the 40% superiority margin (P< 0.001; 95% confidence interval [CI] difference, 47 to 86%). The time to reach target AUC was significantly longer in group A than in group B (55.9 ± 8.2 versus 15.8 ± 2.3 days,P< 0.001). A shorter time to viral clearance was observed in group B than in group A (12.5 versus 17.6 days;P= 0.125). The incidences of relapse (group A, 66.67%, and group B, 9.01%) and late-onset infection (group A, 36.7%, and group B, 7.7%) were higher in group A. Neutropenia and anemia were related to GCV overexposure. GCV-VCGV dose adjustment based on a population pharmacokinetics Bayesian prediction model optimizes GCV-VGCV exposure. (This study has been registered at ClinicalTrials.gov under registration no. NCT01446445.).

Determination of ganciclovir in human plasma by ultra performance liquid chromatography-UV detection.

OBJECTIVES: Implement a sensitive UHPLC method for the assay of ganciclovir in human plasma. DESIGN AND METHODS: We developed and validated a chromatographic method coupled to ultraviolet detection for quantification of ganciclovir, with a short run time using a small volume of human plasma. Comparison of system performance was made with respect to analysis time, efficiency and sensitivity. RESULTS: Correlation coefficients (r) of the calibration curves ranged from 0.999744 to 0.999784. Within-day and between-day imprecision and inaccuracy, specificity and recovery were also evaluated for validation. The method was precise and accurate and the retention time was 0.7 min. The calibration curves were linear between 0.5 and 30 µg/mL. There was a good correlation between HPLC and UHPLC techniques. CONCLUSIONS: We developed a method that is currently applied in a clinical study assessing GCV plasma concentration variability after ganciclovir and valganciclovir administration.

Sequential treatment of cytomegalovirus infection or disease with a short course of intravenous ganciclovir followed by oral valganciclovir: efficacy, safety, and pharmacokinetics.

Oral (p.o.) or intravenous (IV) ganciclovir (GCV) has been the first-line agent for prevention and treatment of cytomegalovirus (CMV) infection and disease in solid organ transplantation (SOT). The introduction of p.o. valganciclovir, with higher bioavailability than p.o. GCV, has proven to be a suitable approach toward outpatient p.o. therapy for CMV infection/disease. The present single-arm, exploratory pilot trial performed with 21 patients investigates the efficacy and safety of a short therapeutic course (21 days) based on an initial IV treatment with GCV (5 mg/kg twice daily, for 5 days) followed by p.o. valganciclovir (900 mg twice daily, for 16 days) for CMV infection/disease in SOT patients. In all cases, doses were adjusted for renal function. Moreover, the study allowed comparison of exposure to GCV after p.o. valganciclovir with respect to IV GCV in the same patients. Response to treatment was monitored until day 180. Viral load eradication was achieved in 66.7% of patients, on day 21. Although not statistically significant, a trend was seen toward increased persistence of viral load on day 21 for patients with donor positive/recipient negative CMV serostatus or receiving either anti-rejection therapy or polyclonal anti-thymocyte globulin. CMV clinical infection recurred in 14.3% of patients, with higher recurrence rates in patients with risk factors for persistence of viremia. Exposures to GCV after using IV GCV or p.o. valganciclovir showed comparable values (P=0.054). This short course, combining initial IV GCV and subsequent p.o. valganciclovir, may provide effective exposure and therapeutic response in the treatment of CMV infection in SOT patients with adequate drug exposure and with the additional potential benefit of shortening the length of hospital stay, which may result in cost reduction and improved patient comfort.

Impact of health related quality of life in Catalonia liver transplant patients.

OBJECTIVE: Our aim was to study the changes in the Health Related Quality of Life (HRQoL) during the first year following liver transplantation. MATERIALS AND METHODS: Among 159 patients awaiting orthotopic liver transplantation (OLT) who were prospectively studied at 4 hospitals in Catalonia, 108 actually obtained an organ. HRQoL over time, namely, before, as well as at 3 and 12 months after transplantation, was recorded using the Short Form-36 (SF-36) and the Liver Disease Quality of Life (LDQOL 1.0). After we searched medical, clinical, and sociodemographic records to examine the studied variables on the HRQoL at each moment, the significance was explored using t tests and one-way analysis of variance (ANOVA). RESULTS: Comparison of the SF-36 dimensions before and at 3 months after transplantation revealed almost all domains to show significant improvements (P < .01), except bodily pain, role-physical, social functioning, and PCS. Comparisons between 3 and 12 months after transplantation showed only significant improvements in role-physical, physical functioning, and PCS (P < .05). The other dimensions showed similar or slightly better scores, but the differences were not significant. For LDQOL 1.0 before and 3 months after transplantation, the dimensions with significant differences (P < .01) were: effects of liver disease on activities of daily living; concentration; health distress; sleep problems; stigmata of liver disease; and sexual function. Comparing 3 and 12 months posttransplantation, no dimension showed a significant improvement. A negative correlation existed between hypertensive patients and PCS on the SF-36 (P < .001). The clinical diagnosis of alcoholic liver disease showed better scores in some dimensions of the LDQOL than the other diagnoses. Female subjects showed significantly worse HRQoL than men (P < .001). Child-Pugh and Model for End-Stage Liver Disease (MELD) classifications were not associated with the HRQoL either before or after transplantation. CONCLUSIONS: The most important finding in this study was that all domains showed significant improvements in HRQoL at 3 months after transplantation with only slight improvements at 12 months.

Population pharmacokinetics of ganciclovir after intravenous ganciclovir and oral valganciclovir administration in solid organ transplant patients infected with cytomegalovirus.

A population pharmacokinetics analysis was performed after intravenous ganciclovir and oral valganciclovir in solid organ transplant patients with cytomegalovirus. Patients received ganciclovir at 5 mg/kg of body weight (5 days) and then 900 mg of valganciclovir (16 days), both twice daily with dose adjustment for renal function. A total of 382 serum concentrations from days 5 and 15 were analyzed with NONMEM VI. Renal function given by creatinine clearance (CL(CR)) was the most influential covariate in CL. The final pharmacokinetic parameters were as follows: ganciclovir clearance (CL) was 7.49.(CL(CR)/57) liter/h (57 was the mean population value of CL(CR)); the central and peripheral distribution volumes were 31.9 liters and 32.0 liters, respectively; intercompartmental clearance was 10.2 liter/h; the first-order absorption rate constant was 0.895 h(-1); bioavailability was 0.825; and lag time was 0.382 h. The CL(CR) was the best predictor of CL, making dose adjustment by this covariate important to achieve the most efficacious ganciclovir exposure.

Sirolimus in heart transplantation: a single center initial experience.

Sirolimus (SRL) is a potent non-nephrotoxic immunosuppressant. In our unit, SRL was administered to 17 heart transplant (HT) recipients at 1770+/-1234 days' posttransplant surgery, for the following reasons: (1) calcineurin inhibitor (CI) withdrawal due to renal insufficiency (RI; n=6); (2) neurotoxicity (n=1) and pancytopenia (n=1); (3) vascular graft disease (VGD) treatment (n=5); (4) immunosuppression optimization due to lung cancer (n=2); (5) CI use was delayed due to postsurgery RI (n=2). The mean follow-up was 190+/-165 days. Mean SRL doses (mg)/concentrations (ng/mL) at 7 (n=17), 30 (n=14), and 180 (n=8) days were: 1.2+/-0.6/5.9+/-6; 1.6+/-0.8/4.8+/-3.1; and 1.7+/-1.0/5.2+/-3.7. Among group 1, CI patients were discontinued without favorable functional impact. Neurotoxicity and pancytopenia improved, but there were no major clinical events in the VGD group. One "bridge" to CI was successfully performed (postsurgery RI). Total leukocyte count fell while hemoglobin, platelet, and cholesterol profiles were not affected. Ten of 15 patients (67%) were discontinued from CI without rejection and with a dose reduction of mycophenolate mofetil. There were 8 episodes (47%) of SRL-related toxicity, leading to 4 discontinuations (23%); 8 patients (47%) have died during follow-up. This retrospective analysis of outcomes in the context of severe complicated patients suggests that more premature introduction SRL is preferable, particularly in a large patient cohort.