Valganciclovir: Dosing Strategies for Effective Cytomegalovirus Prevention

Trends in Transplantation 2007;1:35-43 Mark D. Pescovitz: Valganciclovir Dosing Strategies Valganciclovir: Dosing Strategies for Effective Cytomegalovirus Prevention Mark D. Pescovitz Department of Surgery and Department of Microbiology/Immunology Indiana University, Indianapolis, IN, USA Abstract Valganciclovir has widely become the agent of choice for the prevention of cytomegalovirus in recipients of organ transplants. Optimal dosing is needed to achieve efficacy and avoid toxicity. For subjects at high risk of cytomegalovirus, it is strongly suggested that full-dose (based on renal function) valganciclovir be used. While low-dose valganciclovir appears to be efficacious in some reports, the recommendations are based on inadequate- ly designed trials and must be taken with caution. Unfortunately, because of the sample size needed, it is not likely that the efficacy of reduced-dose valganciclovir will be ade- quately tested in well-controlled trials. The duration of prophylaxis, particularly whether prophylaxis should be extended beyond three months, continues to be an important ques- tion and is the subject of a well-designed clinical trial of which we anxiously await the results. (Trends in Transplant 2007;1:35-43) Corresponding author: Mark D. Pescovitz, [email protected] Key words Valganciclovir. Ganciclovir. Transplant. Cytomegalovirus. Children. Pharmacokinetics. Correspondence to: Mark D. Pescovitz Indiana University Medical Center Department of Surgery UH 4601 550 N University Blvd Indianapolis, IN 46202, USA Mark D. Pescovitz is a consultant to Roche and received honoraria E-mail: [email protected] for speaking and also research grants. 35 Trends in Transplantation 2007;1 ported in 1995, CMV disease developed in only ntroduction I one of 124 patients (0.8%) treated with intra- Cytomegalovirus (CMV) is the cause of venous ganciclovir (6 mg/kg/d IV for 30 days substantial morbidity in solid-organ transplant after transplantation followed by 6 mg/kg/d recipients1,2. Since the field of CMV is so five days per week until day 100) compared large, this review will have a limited scope, to 48 of 126 patients (38%) treated with acy- addressing only the issues of dosing for effec- clovir (10 mg/kg IV every 8 hours while hos- tive prophylaxis of CMV in recipients of organ pitalized followed by 800 mg 4/d orally until 10 transplantation. Because of differences in patho- day 100) . Many but not all of the logistic physiology, dosing in patients with HIV and problems with intravenous ganciclovir for pro- following bone-marrow or stem-cell transplan- phylaxis were substantially alleviated by the 11 tation will not be addressed in this review. development of an oral formulation . In a study in liver-transplant recipients, 100 days of oral ganciclovir 1 g 3/d were better than Cytomegalovirus prophylaxis placebo in preventing CMV disease12. In the high-risk group, i.e. CMV donor serology pos- Ganciclovir, in its several forms (oral, itive/recipient serology negative (D+/R–), the intravenous), or the recently approved pro- rate of CMV disease in the placebo-treated drug valganciclovir, has emerged as the prin- group was 44 vs. 14.8% in the ganciclovir- ciple drug for CMV prophylaxis3. Ganciclovir, treated group. This rate of CMV disease in the an acyclic nucleoside analog of 2’-deoxy- placebo group is important to remember when guanosine, requires tri-phosphorylation to ex- considering the frequency of late CMV that ert its antiviral activity, the first phosphorylation occurs after completion of prophylaxis. While of which is mediated by the virally encoded late CMV does occur after completion of pro- kinase, UL97; this leads to the specificity of phylaxis, particularly in the high-risk group, the drug for infected cells. Cellular enzymes the rate is substantially lower than if no pro- complete the activation to ganciclovir triphos- phylaxis were provided; therefore, while not phate, which is then able to inhibit the CMV perfect, prophylaxis does have a long-term viral DNA polymerase (UL54). The actual an- benefit in the prevention of CMV disease. tiviral activity is prolonged beyond ganciclovir contained in the blood because of the long For prophylaxis, the utility of intrave- intracellular half-life of the triphosphate (6-24 nous ganciclovir is limited by the risk of line hours)4. Ganciclovir is excreted unchanged in infections, and the utility of oral ganciclovir is the urine by both glomerular filtration and net limited by the poor oral bioavailability requir- active tubular secretion and therefore dose ing frequent large daily doses, and the devel- modifications based on renal function are re- opment of resistance and breakthrough CMV quired5. Ganciclovir shows potent antiviral ac- disease9,12,13. These limitations stimulated the tivity against all known human herpes viruses6. search for an improved version of ganciclovir, For most sensitive strains of CMV the IC50 is the result of which was valganciclovir. in the range of 0.08-14 µM (0.02-3.58 mg/ml). Viral resistance to ganciclovir is well-docu- mented including transplant recipients and is Valganciclovir primarily by mutations in the UL97 gene but occasionally in the UL54 gene7-9. Valganciclovir is the L-valine ester of ganciclovir (Fig. 1). It was originally studied in In the first large, randomized, controlled the setting of HIV-associated CMV retinitis for trial of ganciclovir in organ transplantation re- which it was first approved by the FDA14. Only 36 Mark D. Pescovitz: Valganciclovir Dosing Strategies O N HN N H2N N O Cl– + H3N HO O O Figure 1. Schematic diagram of valganciclovir. The bold part on the right of the molecule is the amino acid valine that is conjugated to the ganciclovir portion by an ester linkage. after this approval was it studied in transplant little intact valganciclovir is detectable in the patients. Valganciclovir is rapidly converted to circulation16,17,22. Plasma concentrations of ganciclovir and the amino acid valine after ganciclovir reach maximal concentrations with- oral absorption. There are no other metabo- in 2-3 hours after dosing. Dosing valganciclo- lites. Once converted to ganciclovir, the mech- vir with food leads to an increased ganciclovir anism of antiviral activity and clearance is the exposure of about 30% (p < 0.001)16. Mean 3,15 same as that described for ganciclovir . Be- Cmax values of ganciclovir also increase but cause of the long intracellular half-life of gan- less so (p = 0.079). The manufacturer recom- ciclovir as noted above, there is probably little mends that valganciclovir be given with food. rationale to split the daily dose of valganciclovir in the hope of reducing toxicity; however, The first trial with valganciclovir in organ this has not been formally tested. transplantation was a phase II pharmacoki- netic study in 28 stable liver-transplant pa- The 60% absorption of valganciclovir tients17. This open-label study was conducted (as measured by ganciclovir blood concentra- to confirm dosing recommendations determined tions) is linear over the normal dosing range, originally in HIV subjects. The subjects re- indicating that the absorption pathway is not ceived a single dose/day of oral ganciclovir saturated16,17. The addition of the amino acid 1000 mg 3/d, valganciclovir 450 mg 1/d and valine to ganciclovir therefore increases the 900 mg 1/d , and intravenous ganciclovir 5 absorption from 6% as seen with the parent mg/kg, in random order. The fact that these ganciclovir, a factor of approximately 10-fold18,19. were not at steady state is important to con- Although the valine is attached to ganciclovir sider when comparing actual drug exposure. by an ester linkage, valganciclovir takes ad- The study suggested that the total drug expo- vantage of the peptide transport mechanism sure of valganciclovir 450 mg was equivalent of the small intestine, similar to what occurs to oral ganciclovir, and that valganciclovir 900 with valacyclovir19-21. Valganciclovir is then mg was similar to but slightly less than intra- rapidly hydrolyzed to ganciclovir, such that venous ganciclovir. The study set the stage 37 Trends in Transplantation 2007;1 for the international, multicenter, randomized, ease usually occurs during that period”. Fol- double-blind, double-dummy phase III pivotal lowing on the success of this protocol, Winston, trial of 364 CMV-seronegative recipients of et al.10 compared 100 days of intravenous gan- hearts, livers, or kidneys from seropositive do- ciclovir to 100 days of acyclovir, with improved nors (D+/R–)23. Based on the standard of care efficacy. In the placebo-controlled trial of oral for duration of prophylaxis, 100 days of valganciclovir in liver-transplant recipients, again ganciclovir 900 mg 1/d were compared to 100 100 days was the selected time for prophy- days of oral ganciclovir 1 g 3/d for the preven- laxis12. Since this was now the indicated time tion of CMV disease, with the primary efficacy for oral ganciclovir, the time of prophylaxis was endpoint at six months and a secondary effi- set for valganciclovir. But is this sufficient pro- cacy endpoint at one year. The results dem- phylaxis? Is it too long? Is it not long enough? onstrated that valganciclovir was equal (i.e. non-inferior) to oral ganciclovir at six and 12 In the study of Paya, et al. with either months. Since the efficacy was demonstrated oral ganciclovir or valganciclovir, while there in patients prohibited from initial use of IV were no cases of CMV disease on treatment, therapy (oral therapy had to be started within after treatment stopped approximately 18% 10 days posttransplantation), it is reasonable of patients developed CMV during the first to wait for up to ten days before starting pro- year posttransplantation23. As noted above, in phylaxis, thus avoiding the need for any IV the placebo-controlled trial with oral ganciclo- ganciclovir. These efficacy results have been vir the rate of CMV in absence of any prophy- confirmed in an open-label trial24.

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