Dr Liset Pengel, Centre for Evidence in Transplantation, The Royal College of Surgeons of England.
Conclusion:
The RCT compared the efficacy of two treatment strategies for solid organ transplant recipients with CMV infection. Sixty kidney, liver and heart transplant recipients received ganciclovir-valganciclovir according to the manufacturer’s dosing recommendations (based on Cockcroft-Gault-calculated creatinine clearance and body weight) or according to a pharmacokinetics (PPK) modelling approach which did not include body weight. The primary endpoint was defined as a 40% or higher superiority margin in the number of patients reaching the AUC target of 40–50 µg·h/ml. The sample size was sufficient to provide 80% power. There was no description of how patients were allocated to groups and whether allocation was concealed. The PKK modelling approach led to a significantly higher percentage of AUC values within target range (65.9% versus 19.2%) and the time to reach target AUC was also significantly shorter.
Expert Review
Reviewer:
Professor Jan Ijzermans, Erasmus Medical Center, Rotterdam, The Netherlands
Conflicts of Interest:
No
Clinical Impact Rating
4
Review:
The paper describes the outcome of a personalized approach to optimize anti-CMV management in transplant recipients for prevention as well as treatment of viral disease. In a two-arm, randomized, open-label, single-center trial organ recipients were either treated with ganciclovir (GCV)-valganciclovir (VGCV) according to normal dosing recommendations based on Cockcroft calculated clearance and body weight (controls), or with GCV-VGCV as calculated by a previously developed population pharmacokinetic model (PPK). The primary endpoint of the study was defined as a pharmacological parameter including the percentage of patients achieving the target therapeutic exposure. Using the PPK model as a tool for Bayesian prediction the authors demonstrate that the target AUC values of the experimental group were superior to those of controls, and that the time to reach these values were significantly shorter as well. A trend toward reduced time to viral clearance was found but no significant difference. However, as stated by the authors, it should be noted that the study was powered on a pharmacodynamic endpoint and not on viral clearance, leading to a smaller number of inclusions. This study is of great interest as it demonstrates the feasibility of a personalized approach to optimize anti-CMV drug exposure in transplant recipients. It should be noted that the primary outcome was defined as a pharmacological parameter and a more effective and earlier viral clearance in these patients still has to be demonstrated. In addition, it will be of interest to investigate whether the efficacy in viral clearance will be the same for prophylaxis as well as treatment of CMV disease as suggested by the pharmacological outcome of this paper. Before wider application of this approach can be realized some issues need to be addressed to facilitate implementation, such as the intensity of the blood sampling collection which is quite intensive. Nevertheless, this study has clearly demonstrated the feasibility of personalized therapeutic drug monitoring and calls for new studies demonstrating the clinical benefits of this approach for CMV management.
Aims:
To investigate whether a Bayesian prediction model can optimize Ganciclovir-Valganciclovir (GCV-VGCV) dosing in solid organ transplant recipients.
Interventions:
Patients were randomized to receive either GCV-VGCV according to the manufacturer’s dosing recommendations (group A), versus adjusted dosing based on target exposures using a Bayesian prediction model (group B).
Participants:
60 kidney, liver, and heart transplant recipients aged ≥18 years of age, treated with GCV or VGCV as either prophylaxis or treatment of cytomegalovirus (CMV) infection.
Outcomes:
The primary outcomes measured were the percentage of patients achieving target area under the curve (AUC) values between 40-50µg.h/ml, exposures on days 30, 60, and 90, and the time needed to achieve target AUC values. Secondary measured outcomes were measurements of time to viral clearance, recurrence of CMV infection, and incidence of late-onset CMV infection.
Follow Up:
6 months
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.).
Sir Peter Morris, Centre for Evidence in Transplantation, The Royal College of Surgeons of England.
Conclusion:
In this study patients who were receiving sirolimus with reduced dose tacrolimus had inferior graft and patient survival to those patients allocated to standard dose tacrolimus. The adverse events occurring in the reduced dose tacrolimus and sirolimus arm lead to discontinuation of the study after 21 months. It was also noted that in addition to a higher graft loss and patient death in the interventional arm there was a higher rate of hepatic artery thrombosis and portal vein thrombosis in the patients on sirolimus and reduced dose tacrolimus. Furthermore there was essentially no difference in renal function in the interventional arm. Thus the data from this study does not suggest that this is an appropriate protocol in liver transplantation.
Expert Review
Reviewer:
Professor Christopher Watson, University of Cambridge, Department of Surgery, United Kingdom.
Conflicts of Interest:
I have received honoraria, sponsorship to attend transplant congresses, and my department has received funds for clinical trials from Wyeth (then makers of sirolimus) and Astellas (makers of tacrolimus). My unit was one of the sites participating in the trial.
Clinical Impact Rating
5
Review:
This report represents a milestone for the investigators who participated in this study, but then saw the trial halted due to complications with few details being made available for external scrutiny, and with the knowledge that the FDA had cautioned against the use of sirolimus immediately after liver transplantation. This paper reports the results of the trial, some 10 years after it was halted. The combination of tacrolimus and sirolimus given immediately post liver transplantation was associated with significantly more adverse events, sufficient to warrant premature termination of the study. In particular the incidence of thrombosis, including graft threatening hepatic artery (HAT) and portal venous (PVT) thromboses (8.3% vs 2.7%), were much higher and translated into higher rates of graft loss and death in the sirolimus/tacrolimus arm. There was no difference in acute rejection rates, but more significant complications including bile leaks and wound healing problems, as well as “kidney failure”. Dosage of the drugs was high, with a mean sirolimus level of 8ng/ml at 14 days and tacrolimus level of 6.6ng/ml in the combination arm, compared to 10.9ng/ml at one month in the tacrolimus arm. Sirolimus was also loaded at the onset of administration, together with high initial dose until levels were available. Today no loading would be given, and initial immunosuppressive load would be much reduced; the adverse consequences of the sirolimus on wound healing, recovery from acute tubular necrosis and other early adverse effects would probably lead to delayed introduction of the drug, as has been done with the other mTOR licensed in transplantation, everolimus. The detail of the complications, particularly the thrombosis, makes interesting reading and highlights why the data should have been made available for scrutiny sooner. Of the 9 thrombotic events in the combination arm 4 had mitigating circumstances, including ligation of the right hepatic artery in one, thrombosis in the native PV in another, presence of PV in a third before they received any sirolimus, and in the fourth a diagnosis of HAT in someone who had already lost two previous grafts from HAT. Allowing for those, there is still an excess of thrombotic events (5 vs 3), and other adverse events in sirolimus treated patients. Other studies have not shown such an excess of HAT or PVT with early sirolimus use, although lower doses have been employed. Pharmaceutical companies are slow to publish trials showing their drugs in an adverse light, and, in spite of pressure at the time, this was the case with this study. Credit should be given to Pfizer who have supported this late publication of the study which is as educational now as it would have been at the time.
We studied whether the use of sirolimus with reduced-dose tacrolimus, as compared to standard-dose tacrolimus, after liver transplantation is safe, tolerated and efficacious. In an international multicenter, open-label, active-controlled randomized trial (2000-2003), adult primary liver transplant recipients (n=222) were randomly assigned immediately after transplantation to conventional-dose tacrolimus (trough: 7-15 ng/mL) or sirolimus (loading dose: 15 mg, initial dose: 5 mg titrated to a trough of 4-11 ng/mL) and reduced-dose tacrolimus (trough: 3-7 ng/mL). The study was terminated after 21 months due to imbalance in adverse events. The 24-month cumulative incidence of graft loss (26.4% vs. 12.5%, p=0.009) and patient death (20% vs. 8%, p=0.010) was higher in subjects receiving sirolimus. A numerically higher rate of hepatic artery thrombosis/portal vein thrombosis was observed in the sirolimus arm (8% vs. 3%, p=0.065). The incidence of sepsis was higher in the sirolimus arm (20.4% vs. 7.2%, p=0.006). Rates of acute cellular rejection were similar between the two groups. Early use of sirolimus using a loading dose followed by maintenance doses and reduced-dose tacrolimus in de novo liver transplant recipients is associated with higher rates of graft loss, death and sepsis when compared to the use of conventional-dose tacrolimus alone.
CET Conclusion