Though an important cause of morbidity and mortality in solid organ transplantation (SOT), the long‐term outcomes of cytomegalovirus (CMV) disease treatment have not been well studied. In a randomized trial, 321 SOT recipients with CMV disease were followed 1 year after treatment with either twice daily intravenous ganciclovir or oral valganciclovir (for 21 days) followed by once daily valganciclovir until day 49 in all patients. Clinical and viral eradication of CMV disease was similar between groups. Clinical recurrence beyond day 49 was found in 15.1% and virological recurrence in 30.0%, no difference between groups (p > 0.77). In a multivariable logistic regression analysis, the only independent predictor for recurrence was failure to eradicate DNAemia by day 21 (clinical: OR 3.9 [1.3–11.3], p = 0.012; virological: OR 5.6 [2.5–12.6], p < 0.0001). Eight patients developed ganciclovir resistance, with no difference between groups (p = 0.62). Twenty patients (valganciclovir: 11, ganciclovir: 9, p = 0.82) died, 12 due to infections, two involving CMV disease. There were no differences in long‐term outcomes between treatment arms, further supporting the use of oral valganciclovir for treatment of CMV disease. Persistent DNAemia at day 21, CMV IgG serostatus and development of resistance may be relevant factors for further individualization of treatment.

Background Early after renal transplantation, it is often challenging to achieve and maintain tacrolimus concentrations within the target range. Computerized dose individualization using population pharmacokinetic models may be helpful. The objective of this study was to prospectively evaluate the target concentration achievement of tacrolimus using computerized dosing compared with conventional dosing performed by experienced transplant physicians. Methods A single-center, prospective study was conducted. Renal transplant recipients were randomized to receive either computerized or conventional tacrolimus dosing during the first 8 weeks after transplantation. The median proportion of tacrolimus trough concentrations within the target range was compared between the groups. Standard risk (target, 3-7 μg/L) and high-risk (8-12 μg/L) recipients were analyzed separately. Results Eighty renal transplant recipients were randomized, and 78 were included in the analysis (computerized dosing (n = 39): 32 standard risk/7 high-risk, conventional dosing (n = 39): 35 standard risk/4 high-risk). A total of 1711 tacrolimus whole blood concentrations were evaluated. The proportion of concentrations per patient within the target range was significantly higher with computerized dosing than with conventional dosing, both in standard risk patients (medians, 90% [95% confidence interval {95% CI}, 84-95%] vs 78% [95% CI, 76-82%], respectively, P < 0.001) and in high-risk patients (medians, 77% [95% CI, 71-80%] vs 59% [95% CI, 40-74%], respectively, P = 0.04). Conclusions Computerized dose individualization improves target concentration achievement of tacrolimus after renal transplantation. The computer software is applicable as a clinical dosing tool to optimize tacrolimus exposure and may potentially improve long-term outcome.

Atorvastatin is increasingly used as a cholesterol‐lowering agent in solid organ transplant recipients receiving cyclosporine A (CsA). However, the potential bilateral pharmacokinetic interaction bet...

Background. Cytomegalovirus (CMV) infections in kidney transplant recipients are in most cases successfully treated with oral valganciclovir (VGCV). However, in a few percent of patients, mutations in the UL 97 or UL 54 gene lead to drug resistance. Methods. We investigated the incidence and outcomes of ganciclovir-resistant CMV viremia in all 1244 kidney recipients transplanted at our center from 2004 through 2008. CMV DNAemia was monitored in all patients at least weekly, and patients who were positive were treated preemptively with VGCV (900 mg once daily). Results. Ganciclovir-resistant mutations were detected in 27 patients (2.2%), of which 26 occurred in the 209 CMV IgG-negative recipients receiving a CMV-positive kidney (12.5%). All had UL97 gene mutations, and none had UL54 gene mutations. Mean DNAemia half-life for the first (nonresistance) episode of CMV viremia was 3.8±1.2 days. After established resistance, 25 of 27 patients had their mycophenolate mofetil dose reduced by approximately 50%, and 10 of these were also treated with intravenous foscarnet. The DNAemia half-life was 3.7±1.4 days in the foscarnet-treated patients, significantly shorter than in the other 17 patients, 10.8±6.7 days (P=0.001). Time to DNAemia eradication was 30±16 and 81±51 days in the two groups, respectively (P=0.001). Conclusion. Use of 900 mg VGCV once daily for preemptive CMV treatment is associated with a high incidence of CMV UL97-resistance gene mutations in D+/R− patients. Foscarnet treatment rapidly and safely eradicated CMV DNAemia, and also patients who only reduced the immunosuppression and continued on VGCV treatment eventually cleared the virus.

Aims: The aim was to develop a theory‐based population pharmacokinetic model of tacrolimus in adult kidney transplant recipients and to externally evaluate this model and two previous empirical models.Methods: Data were obtained from 242 patients with 3100 tacrolimus whole blood concentrations. External evaluation was performed by examining model predictive performance using Bayesian forecasting.Results: Pharmacokinetic disposition parameters were estimated based on tacrolimus plasma concentrations, predicted from whole blood concentrations, haematocrit and literature values for tacrolimus binding to red blood cells. Disposition parameters were allometrically scaled to fat free mass. Tacrolimus whole blood clearance/bioavailability standardized to haematocrit of 45% and fat free mass of 60 kg was estimated to be 16.1 l h⁻¹ [95% CI 12.6, 18.0 l h⁻¹]. Tacrolimus clearance was 30% higher (95% CI 13, 46%) and bioavailability 18% lower (95% CI 2, 29%) in CYP3A5 expressers compared with non‐expressers. An E_max model described decreasing tacrolimus bioavailability with increasing prednisolone dose. The theory‐based model was superior to the empirical models during external evaluation displaying a median prediction error of −1.2% (95% CI −3.0, 0.1%). Based on simulation, Bayesian forecasting led to 65% (95% CI 62, 68%) of patients achieving a tacrolimus average steady‐state concentration within a suggested acceptable range.Conclusion: A theory‐based population pharmacokinetic model was superior to two empirical models for prediction of tacrolimus concentrations and seemed suitable for Bayesian prediction of tacrolimus doses early after kidney transplantation.