TY - JOUR
AU1 - Cochrane, Adam, B.
AB - Abstract Purpose. The implications of the findings from clinical studies and pharmacokinetic analyses of the antiviral agent valganciclovir for dosing of the drug to prevent cytomegalovirus (CMV) disease in solid organ transplant recipients are reviewed. Summary. Valganciclovir, an oral prodrug of ganciclovir, is as effective as oral ganciclovir for preventing CMV disease, although prophylaxis with either agent may delay CMV disease. Dosage reduction is required for both drugs in patients with renal impairment to prevent high plasma ganciclovir concentrations and toxicity. A valganciclovir dosage of 900 mg/day is required in patients with normal renal function, especially those at high risk for CMV disease, to provide adequate systemic ganciclovir exposure. Some studies suggest that a lower dosage might suffice for patients at a low risk for CMV disease. Conclusion. Valganciclovir dosing should be based on renal function to avoid toxicity. Antivirals, Blood levels, Cytomegalovirus infections, Dosage, Drugs, Ganciclovir, Kidney failure, Metabolism, Pharmacokinetics, Toxicity, Transplantation, Valganciclovir The development of antiviral drug therapies to prevent cytomegalovirus (CMV) disease has been a major accomplishment in the transplant community because of the morbidity and mortality associated with CMV disease in solid organ transplant recipients.1 The introduction of the antiviral agent acyclovir had a favorable impact on morbidity and mortality from CMV in solid organ transplant recipients (see the article by Baillie in this supplement), despite its limited activity against the virus because no other antiviral therapy was available at the time.2 The development of valacyclovir, the l-valyl ester of acyclovir with oral bioavailability three to five times greater than that of acyclovir, was not a major advance in preventing CMV in solid organ transplant recipients because the activity of this prodrug against CMV is no different from that of acyclovir.3 Ganciclovir Ganciclovir has greater antiviral activity against CMV than acyclovir and valacyclovir.3 Ganciclovir is approved by the Food and Drug Administration (FDA) for the prevention of CMV disease in solid organ transplant recipients and in individuals with advanced human immunodeficiency virus (HIV) infection who are at risk for developing CMV disease.4 Ganciclovir also is approved by FDA for the treatment of CMV retinitis in immunocompromised patients, including patients with the acquired immunodeficiency syndrome (AIDS). Renal excretion of unchanged drug by glomerular filtration and active tubular secretion is the major route of elimination for ganciclovir. 4 Therefore, dosage reduction is required for patients with renal impairment. The benefit of oral ganciclovir for CMV prophylaxis after liver transplantation was demonstrated in a multicenter, randomized, double-blind, placebo-controlled trial of 304 patients (see the article by Baillie in this supplement).5 In this study, the incidence of CMV infection during the 6-month period after transplantation was 25% (76 patients) with ganciclovir (1 g orally three times daily, with dosage reductions for renal impairment, until day 98 after transplantation) and 52% (158 patients) with placebo, a difference that is significant (p < 0.001). More patients in the placebo group than in the ganciclovir group (31% versus 16%) discontinued the study drug prematurely, primarily because of CMV disease. Twenty-seven (93%) of 29 placebo-treated patients with CMV disease were diagnosed during the 98-day treatment period after transplantation, but 4 (57%) of the 7 ganciclovir-treated patients with CMV disease were not diagnosed until after the treatment period. Thus, ganciclovir delayed the onset of CMV infection in some patients. No differences in outcome were observed in patients whose doses were adjusted for renal function. Resistance to ganciclovir is a potential problem when the drug is used for prophylaxis in solid organ transplant recipients, especially if the duration of therapy is long. In 240 liver, kidney, or pancreas transplant recipients who received ganciclovir 1 g orally three times daily for 100 days after transplantation, the incidence of resistance to ganciclovir was 2% (5 patients) in the year following transplantation.6 In 197 patients with AIDS who received ganciclovir 1 g orally three times daily and were followed for a median of 9.2 months, 15 (8%) patients developed resistance to ganciclovir.7 Valganciclovir Valganciclovir, a prodrug, is the l-valyl ester of ganciclovir (Figure 11).8 It is rapidly converted to ganciclovir by intestinal and hepatic esterases and then to ganciclovir triphosphate, which is the active form.8 The major route of elimination of valganciclovir is renal excretion as ganciclovir by glomerular filtration and active tubular secretion.9 Therefore, dosage reduction is required for patients with renal impairment. Figure 1. Open in new tabDownload slide Chemical Structures of Ganciclovir and Valganciclovir. Figure 1. Open in new tabDownload slide Chemical Structures of Ganciclovir and Valganciclovir. Valganciclovir is approved by FDA for the prevention of CMV disease in kidney, heart, and kidney–pancreas transplant patients at high risk (i.e., CMV-seronegative recipients of organs from seropositive donors, D+/R−). Valganciclovir does not carry an FDA-approved indication for use in high-risk liver transplant recipients because of concerns that arose from a noninferiority study known as PV16000 (see the Baillie article in this supplement).10 In this study, a significantly higher incidence (p value not reported) of tissue-invasive CMV disease was observed in a subgroup analysis of liver transplant recipients treated with valganciclovir (14%) than in liver transplant recipients treated with ganciclovir (3%), although the study was not powered to detect differences in subgroups.9 The safety and efficacy of the drug for prevention of CMV disease in recipients of other solid organ transplants (e.g., lung) have not been established. (Valganciclovir also is indicated for the treatment of CMV retinitis in patients with AIDS.) Dosing. Pescovitz et al. conducted an open-label, four-way, randomized, crossover study in 28 liver transplant recipients to identify the dosage of oral valganciclovir that would provide a systemic ganciclovir exposure that is lower than that provided by i.v. ganciclovir to avoid toxicity but higher than that provided by oral ganciclovir to ensure efficacy.11 Patients were randomized to receive oral ganciclovir 1 g three times at six-hour intervals on one day, oral valganciclovir 450 mg as a single dose, oral valganciclovir 900 mg as a single dose, and i.v. ganciclovir as a single 5-mg/kg infusion over one hour, with a 3–7-day washout period between the four treatments. Maintenance immunosuppressive therapy was continued throughout the study with no changes. Valganciclovir 450 mg provided a systemic ganciclovir exposure (24-hour area under the plasma concentration–time curve) comparable to that produced by oral ganciclovir (21.1 μg·hr/mL and 20.7 μg·hr/mL, respectively).11 The systemic ganciclovir exposure was comparable with valganciclovir 900 mg (41.7 μg·hr/mL) and i.v. ganciclovir (48.2 μg·hr/mL). The absolute bioavailability of valganciclovir 450 mg (60%) and valganciclovir 900 mg (59%) was nearly 10 times higher than that of oral ganciclovir (6.3%). The investigators concluded that because the systemic ganciclovir exposure of the 900-mg dose of valganciclovir did not exceed that of i.v. ganciclovir, both valganciclovir doses should be at least as safe as i.v. ganciclovir in transplant recipients.11 They also concluded that because the systemic ganciclovir exposure of the 450-mg dose of valganciclovir was not less than that of oral ganciclovir, the efficacy of either valganciclovir dose should be at least as great as that associated with oral ganciclovir in transplant recipients. Because the cost of the drug and dose-related toxicity are considerations in using antiviral therapy, the feasibility of using low valganciclovir doses for CMV prophylaxis without compromising efficacy has been explored in solid organ transplant patients. In a retrospective analysis of 58 recipients of kidney transplants (a type of organ transplant associated with a relatively low risk for CMV) who were treated with valganciclovir 450 mg/day for 6 months after transplantation, 3 (5%) patients developed CMV disease after a median follow up of 20 months after transplantation.12 All three patients were CMV-seronegative recipients of cadaveric kidneys from CMV-seropositive donors (D+/R−) and had received antithymocyte globulin induction. One patient developed CMV disease during the 6-month prophylaxis period, and the other 2 patients developed CMV disease 10 days and 60 days after the end of prophylaxis, respectively. The investigators concluded that low-dose valganciclovir 450 mg/day is effective for preventing CMV disease in renal transplant patients. A risk-stratified approach to valganciclovir dosing for CMV prophylaxis based on donor–recipient CMV serostatus was examined in a retrospective analysis of 80 African American renal transplant patients who were followed for an average of 22 months.13 In the 90-day period after transplantation, 12 high-risk patients (D+/R−) received valganciclovir 900 mg/day, 60 moderate-risk seropositive recipients of kidneys from a seropositive or seronegative donor (D+/R+ or D−/R+) received valganciclovir 450 mg/day, and 8 low-risk seronegative recipients of kidneys from a seronegative donor (D−/R−) received no prophylaxis. Symptomatic CMV infection (diagnosed using the CMV phosphoprotein 65 antigenemia assay) developed in 3 (25%) patients in the high-risk group and 3 (5%) patients in the moderate-risk group (p = 0.02). In all three cases in the high-risk group and two of the three cases in the moderate-risk group, symptomatic CMV infection developed after the end of prophylaxis, reflecting a delayed onset. There were no cases of tissue-invasive disease. These findings demonstrate that risk-stratified valganciclovir dosing according to donor–recipient CMV serostatus is effective for preventing CMV disease in African American renal transplant recipients. A retrospective analysis was conducted of 129 transplant recipients of a kidney, pancreas, or both.14 Fourteen low-risk seronegative recipients of organs from seronegative donors (D−/R−) who did not receive induction therapy were treated with acyclovir 400 mg orally twice daily. All other patients received i.v. ganciclovir followed by oral ganciclovir (1 g three times daily) or valganciclovir (450 mg orally once daily) for 90 days as CMV prophylaxis. Oral ganciclovir was used during the time before valganciclovir became available, at which time the treatment protocol was changed. Patients were not randomly assigned to one of the two drugs. The median follow up was 12 months. Eighteen (14%) of the 129 patients, including 10 (15%) of 68 ganciclovir-treated patients and 8 (17%) of 47 valganciclovir-treated patients, developed CMV disease within the 1-year period after transplantation. 14 One of the 18 patients with CMV disease developed CMV disease during prophylaxis and the other 17 developed it after a median of 8 weeks had elapsed since the end of prophylaxis, reflecting a delayed onset. Resistance was not observed to either drug. One patient developed recurrent CMV disease. Thus, valganciclovir 450 mg/day was as effective as oral ganciclovir for CMV prophylaxis in kidney and pancreas transplant recipients. Noninferiority study. In the noninferiority study known as PV16000, 364 recipients of kidney, liver, heart, or pancreas transplants who were at high risk for CMV disease (i.e., D+/R−) were randomly assigned in a 2:1 ratio to receive valganciclovir 900 mg orally once daily or oral ganciclovir 1000 mg 3 times daily beginning within 10 days after transplantation and continuing through day 100 after transplantation (see the article by Baillie in this supplement). 10 The multicenter, double-blind, double-dummy study had a one year follow-up. There was no difference between valganciclovir and ganciclovir in the incidence of CMV disease 6 months after transplantation (12% and 15%, respectively) or 12 months after transplantation (17% and 18%, respectively).10 Only 4 cases of CMV disease (2 in each group) developed during the 100-day prophylaxis period. The median time to viremia (a CMV viral load above the level of quantification) was slightly longer in the valganciclovir group (357 days) than in the ganciclovir group (282 days).10 The peak viral load at the time of suspected CMV disease tended to be lower in valganciclovir-treated patients than in ganciclovir-treated patients. The overall rate of acute graft rejection appeared to be lower with valganciclovir than ganciclovir. Only seven patients with CMV disease (five receiving valganciclovir and two receiving ganciclovir) experienced acute graft rejection after CMV infection, and five patients (three receiving valganciclovir and two receiving ganciclovir) lost the graft. Two of the three patients who experienced graft loss in the valganciclovir group had liver invasive disease. The safety profiles of valganciclovir and ganciclovir were similar. 10 The incidence of investigator- reported leukopenia and neutropenia tended to be higher in valganciclovir-treated patients than in ganciclovir-treated patients, but the percentage of patients discontinuing the study because of these effects was similar (2.0% with valganciclovir and 2.4% with ganciclovir). The percentage of patients with at least one opportunistic infection during the prophylaxis period was similar (7.4% with valganciclovir and 8.7% with ganciclovir). The mortality rate was low during the prophylaxis period (2.0% of valganciclovir-treated patients and 1.6% of ganciclovir-treated patients). In the valganciclovir group, there were nine deaths, including one due to CMV disease, within the first six months after transplantation and 15 deaths within 1 year after transplantation. In the ganciclovir group, there were two deaths, including one due to CMV disease, within the first six months after transplantation and eight deaths within one year after transplantation. Pharmacokinetics. A pharmacokinetic model was developed using data from the PV16000 study.15 The 24-hour systemic exposure to ganciclovir (area under the serum concentration–time curve) was 1.65 times higher after valganciclovir administration (46.3 μg·hr/mL) than after oral ganciclovir administration (28.0 μg·hr/mL). Systemic ganciclovir exposure after valganciclovir administration was similar for kidney, liver, and heart transplant recipients. The systemic ganciclovir exposure after oral ganciclovir administration observed in the PV16000 study (28.0 μg·hr/mL) was higher than that observed in the Pescovitz study (20.7 μg·hr/mL). The discrepancy may be attributed to the fact that the values in the PV16000 study were measured at steady state and those in the Pescovitz study were not because they were measured after only three doses on a single day. Valganciclovir 900 mg/day is the recommended dosage for solid organ transplant recipients with normal renal function because at steady state, a valganciclovir dosage of 450 mg/day can be expected to result in a systemic ganciclovir exposure substantially lower than that associated with oral ganciclovir 1 g three times daily (the standard regimen). This recommendation is particularly important for patients at high risk for CMV disease. A pharmacokinetic study of valganciclovir was conducted in 18 patients with mild, moderate, or severe renal impairment; 6 patients with end-stage renal disease requiring dialysis; 8 patients with normal renal function who were seropositive for HIV and CMV; and 12 healthy subjects. 16 Hemodialysis reduced plasma ganciclovir concentrations by about 50%. The 24-hour area under the plasma ganciclovir concentration–time curve (i.e., daily systemic ganciclovir exposure) after single oral 900- mg valganciclovir doses increased with worsening renal function from 27.1 μg·hr/mL in HIV/CMV-positive patients with normal renal function and 28.1 μg·hr/mL in healthy subjects to 100 μg·hr/mL, 252 μg·hr/mL, and 407 μg·hr/mL in patients with a creatinine clearance of 21–50 mL/min, 11–20 mL/min, and less than 10 mL/min, respectively. Therefore, valganciclovir dosage adjustment is required for patients with impaired renal function (e.g., renal transplant recipients with delayed graft function) to prevent drug accumulation and toxicity.16 Lung transplants. Data from randomized controlled trials of CMV prophylaxis in lung transplant patients are limited. The use of valganciclovir 900 mg orally once daily for 12 weeks was studied prospectively in 40 D+/R− or D+/R+ lung transplant recipients and compared with retrospective data from a cohort of 40 historical controls who received 12 weeks of daily i.v. ganciclov ir 5 mg/kg daily (for high-risk D+/R− patients) or oral ganciclovir 1 g three times daily (for CMV-seropositive recipients D+/R+).17 CMV viral load testing was done at two-week intervals until six months had elapsed since transplantation. None of the valganciclovir-treated patients and 2 (5%) of the 40 ganciclovir-treated patients developed CMV viremia during prophylaxis. One patient in each group developed ganciclovir- resistant CMV infection. Thus, valganciclovir 900 mg/day for 100 days is an option for CMV prophylaxis in lung transplant patients.18 Conclusion Valganciclovir is as effective as oral ganciclovir for preventing CMV disease, although prophylaxis with either agent may delay CMV disease. Dosage reduction is required for both drugs in patients with renal impairment to prevent high plasma ganciclovir concentrations and toxicity. A valganciclovir dosage of 900 mg/day is required in patients with normal renal function, especially those at high risk for CMV disease, to provide adequate systemic ganciclovir exposure. Some studies suggest that a lower dosage might suffice for patients at a low risk for CMV disease, but no randomized prospective studies have validated this dosing schedule. Footnotes Based on the proceedings of a symposium held December 6, 2005, during the ASHP Midyear Clinical Meeting in Las Vegas, NV, and supported by an educational grant from Roche Laboratories, Inc. Dr. Cochrane received an honorarium for his participation in the symposium and for the preparation of this manuscript. Dr. Cochrane reports that he served on an advisory board for Roche Laboratories. References 1 Patel R, Paya CV. Infections in solid-organ transplant recipients. Clin Microbiol Rev . 1997 ; 10 : 86 –124. Crossref Search ADS PubMed 2 Balfour HH Jr, Chace BA, Stapleton JT et al. A randomized, placebo-controlled trial of oral acyclovir for the prevention of cytomegalovirus disease in recipients of renal allografts. N Engl J Med . 1989 ; 320 : 1381 –7. Crossref Search ADS PubMed 3 Balfour HH Jr. Antiviral drugs. N Engl J Med . 1999 ; 340 : 1255 –68. Crossref Search ADS PubMed 4 Cytovene package insert. Nutley, NJ: Roche Laboratories Inc.; 2000 Sep. 5 Gane E, Saliba F, Valdecasas GJ et al. Randomised trial of efficacy and safety of oral ganciclovir in the prevention of cytomegalovirus disease in liver-transplant recipients. The Oral Ganciclovir International Transplantation Study Group. Lancet . 1997 ; 350 : 1729 –33. Crossref Search ADS PubMed 6 Limaye AP, Corey L, Koelle DM et al. Emergence of ganciclovir-resistant cytomegalovirus disease among recipients of solid-organ transplants. Lancet . 2000 ; 356 : 645 –9. Crossref Search ADS PubMed 7 Jabs DA, Martin BK, Forman MS et al. Cytomegalovirus resistance to ganciclovir and clinical outcomes of patients with cytomegalovirus retinitis. Am J Ophthalmol . 2003 ; 135 : 26 –34. Crossref Search ADS PubMed 8 McEvoy GK, ed. Valganciclovir hydrochloride. In: AHFS drug information 2006. Bethesda, MD: American Society of Health-System Pharmacists; 2006 :843–5. 9 Valcyte package insert. Nutley, NJ: Roche Laboratories Inc.; 2003 Sep. 10 Paya C, Humar A, Dominguez E et al. Valganciclovir Solid Organ Transplant Study Group. Efficacy and safety of valganciclovir vs. oral ganciclovir for prevention of cytomegalovirus disease in solid organ transplant recipients. Am J Transplant . 2004 ; 4 : 611 –20. Crossref Search ADS PubMed 11 Pescovitz MD, Rabkin J, Merion RM et al. Valganciclovir results in improved oral absorption of ganciclovir in liver transplant recipients. Antimicrob Agents Chemother . 2000 ; 44 : 2811 –5. Crossref Search ADS PubMed 12 Gabardi S, Magee CC, Baroletti SA et al. Efficacy and safety of low-dose valganciclovir for prevention of cytomegalovirus disease in renal transplant recipients: a single-center, retrospective analysis. Pharmacotherapy . 2004 ; 24 : 1323 –30. Crossref Search ADS PubMed 13 Gruber SA, Garnick J, Morawski K et al. Cytomegalovirus prophylaxis with valganciclovir in African-American renal allograft recipients based on donor/recipient serostatus. Clin Transplant . 2005 ; 19 : 273 –8. Crossref Search ADS PubMed 14 Akalin E, Sehgal V, Ames S et al. Cytomegalovirus disease in high-risk transplant recipients despite ganciclovir or valganciclovir prophylaxis. Am J Transplant . 2003 ; 3 : 731 –5. Crossref Search ADS PubMed 15 Wiltshire H, Hirankarn S, Farrell C et al. Pharmacokinetic profile of ganciclovir after its oral administration and from its prodrug, valganciclovir, in solid organ transplant recipients. Clin Pharmacokinet . 2005 ; 44 : 495 –507. Crossref Search ADS PubMed 16 Czock D, Scholle C, Rasche FM et al. Pharmacokinetics of valganciclovir and ganciclovir in renal impairment. Clin Pharmacol Ther . 2002 ; 72 : 142 –50. Crossref Search ADS PubMed 17 Humar A, Kumar D, Preiksaitis J et al. A trial of valganciclovir prophylaxis for cytomegalovirus prevention in lung transplant recipients. Am J Transplant . 2005 ; 5 : 1462 –8. Crossref Search ADS PubMed 18 Zamora MR, Davis RD, Leonard C et al. Management of cytomegalovirus infection in lung transplant recipients: evidence-based recommendations. Transplantation . 2005 ; 80 (2): 157 –63. Crossref Search ADS PubMed Copyright © 2006. American Society of Health-System Pharmacists, Inc. All rights reserved.
TI - Antiviral dosing and efficacy for prophylaxis of cytomegalovirus disease in solid organ transplant recipients
JF - American Journal of Health-System Pharmacy
DO - 10.2146/ajhp060379
DA - 2006-10-01
UR - https://www.deepdyve.com/lp/oxford-university-press/antiviral-dosing-and-efficacy-for-prophylaxis-of-cytomegalovirus-dvHpqWBxsU
SP - S17
VL - 63
IS - 19_Supplement_5
DP - DeepDyve
ER -