Valganciclovir: therapeutic role in pediatric solid organ transplant recipients
2.Introduction to valganciclovir
Marie A Yu & Jeong M Park†
†University of Michigan, College of Pharmacy, Ann Arbor, MI, USA
5.Pharmacokinetics and metabolism
7.Safety and tolerability
Introduction: Cytomegalovirus (CMV) infection is a common infectious complication after solid organ transplantation (SOT) and is associated with the increased risk of opportunistic infections and allograft rejection, as well as decreased patient survival. Ganciclovir has been the mainstay antiviral agent for prevention and treatment of CMV; however, its clinical use is hampered by the poor oral bioavailability and the need for intravenous access. Valganciclovir, an oral prodrug of ganciclovir, is up to 10 times more bioavailable than oral ganciclovir and has replaced ganciclovir as a first-line agent in the management of CMV in adult SOT patients.
Areas covered: This article examines the safety and efficacy of valganciclovir in pediatric SOT patients, with a particular focus on prophylaxis of CMV infec- tions. An in-depth review of the literature, including pertinent data from the adult SOT population, and a discussion of unmet needs are provided. The pharmacokinetics and pharmacodynamics of valganciclovir in the pediatric population are also discussed.
Expert opinion: Existing evidence supports the use of valganciclovir in pediatric SOT patients for CMV prophylaxis. Although comprehensive data are lacking, valganciclovir is a treatment option for CMV infection in pediatric SOT patients. The role of valganciclovir in pediatrics is expected to grow given its demonstrated efficacy in a variety of clinical settings and its advantages over ganciclovir.
Keywords: cytomegalovirus, ganciclovir, pediatrics, solid organ transplantation, valganciclovir Expert Opin. Pharmacother. (2013) 14(6):807-815
1.1Cytomegalovirus in pediatric solid organ transplantation Cytomegalovirus (CMV) is a ubiquitous human herpes virus that infects people of all ages. Defense against CMV is mediated by host cytotoxic T-cell responses, which are impaired in solid organ transplant (SOT) recipients. SOT patients with CMV infections can present with asymptomatic viremia, CMV syndrome (viremia with fever, malaise, and/or myelosuppression), and end-organ disease such as colitis, pneumonitis, or hepatitis. Differences in CMV between pediatric and adult SOT patients are not well described. In the general pediatric population, newborns are at risk of congenital CMV infections, which may lead to mental retardation and hearing loss . In SOT patients, indirect effects of CMV infections include allograft injury with increased risk of rejection, increased risk of opportunistic infections including Epstein-Barr virus (EBV), and negative impacts on allograft and patient survival [2-4].
Rates of CMV infection vary among the transplant population due to differences in predisposing factors and immunosuppression use. For adults, the incidence of CMV infection in lung transplant recipients can reach 53 — 75%, 5 — 10% in liver transplant, 5 — 23% in kidney transplant, and 30 — 40% in heart transplant .
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Box 1. Drug summary.
Drug name Valganciclovir
Phase Phase IV
Indication Prevention of CMV
Pharmacology description/mechanism of action Valganciclovir is a
in CMV-infected cells, inhibiting viral DNA
Route of administration Oral (tablets and
Chemical structure OH
pediatric SOT recipients
ester prodrug of ganciclovir. After phosphorylation ganciclovir triphosphate inhibits viral replication by
NH2 · HCl
Pivotal trials [29,42]
Incidences of CMV end-organ disease also vary among organ type and are lower than reported incidences of CMV infec- tion. Data on precise incidences of CMV infection and dis- ease are lacking in pediatric SOT populations. Similarly to adults, pediatric SOT patients who received anti-lymphocyte therapy and CMV seronegative recipients receiving organs from seropositive donors (D+/R-) are at higher risk for devel- oping CMV infection and disease . Given many pediatric SOT recipients are CMV seronegative at the time of trans- plant, appropriate prevention and treatment of CMV infec- tion following transplant may have significant impacts on transplant outcomes.
1.2Overview of the market
Four antiviral agents with activity against CMV are currently licensed for systemic use: ganciclovir, valganciclovir, foscar- net, and cidofovir. Only valganciclovir is approved for use in pediatric patients for the prevention of CMV disease in D+/R- kidney or heart transplant recipients.
In adult and pediatric SOT patients, valganciclovir is considered the primary CMV prophylactic agent in high and moderate risk patients. Oral ganciclovir is also available for CMV prophylaxis. Intravenous (IV) ganciclovir and valganciclovir are both first line agents for the treatment of CMV infection and disease. Foscarnet and cidofovir are typically reserved to treat CMV infections in patients with ganciclovir-resistant CMV or intolerances to ganciclovir or valganciclovir.
Acyclovir has a limited role in prevention and treatment of CMV in adults and children [7-9]. Valacyclovir has demon- strated some effect in preventing CMV, but it is not widely used in clinical practice . CMV immunoglobulin
(CMV-IG) is approved for CMV prevention in SOT patients and studies evaluating its effects have yielded conflicting results, especially in conjunction with antiviral prophylaxis. Very limited data support the use of CMV-IG alone for pro- phylaxis. Experience with CMV-IG in the pediatric transplant population was recently summarized .
There are only a few published studies describing pre- emptive therapy (antiviral therapy is initiated after detection of viral replication over a pre-determined threshold during periods of serial monitoring) for CMV in pediatric SOT patients [12-14]. All studies utilized ganciclovir and most stud- ies also employed universal prophylaxis for a period of time. There are no studies comparing universal prophylaxis versus pre-emptive therapy in pediatric SOT patients.
Maribavir, an investigational antiviral agent, was found to be inferior to ganciclovir as a CMV prophylactic agent at 100 mg twice daily in SOT patients in a Phase III trial and its development was halted in 2009 . However, mar- ibavir may still be considered as a treatment option for multi-drug resistant CMV infections as it has a different mechanism of action compared to currently available agents. Maribavir was recently granted orphan status by European Medicines Agency and the U.S. Food and Drug Administra- tion. Positive experience with maribavir has prompted ongo- ing studies evaluating higher doses. These new Phase II studies may help clarify its role as a potential CMV prophy- lactic and treatment agent . CMX-001, an ester formu- lation of cidofovir, and AIC 246, which has a novel mechanism targeting the viral terminase, are in the early phases of clinical trials [17,18]. Several CMV vaccine candi- dates (CMV gB vaccine, VCL-CB01, CMV pp65 peptide, ALVAC-CMV, and VCL-CT02) are also under investigation
808 Expert Opin. Pharmacother. (2013) 14(6)
in healthy volunteers, stem cell transplant patients, and SOT recipients [19-24].
Most practice guidelines on the management of CMV in SOT patients were developed prior to the approval of valgan- ciclovir oral solution in 2010 [25-28]. Therefore, the guidelines list IV ganciclovir as the first-line agent for prevention and treatment of CMV infection in pediatric SOT patients and often do not address the therapeutic role of valganciclovir.
2.Introduction to valganciclovir
Valganciclovir was initially approved in 2001 for the treatment of CMV retinitis in adult patients with acquired immunodeficiency syndrome (AIDS) and then for the prevention of CMV disease in adult D+/R- kidney, heart, or kidney– pancreas transplant recipients for 3 — 6 months post- transplant. Valganciclovir is not licensed for use in adult liver transplant recipients as a greater incidence of CMV disease was observed in a subgroup analysis of the Phase III clinical trial . In practice, valganciclovir is often used as universal prophylaxis or preemptive therapy in all adult SOT including liver transplant. Present practice guidelines recommend val- ganciclovir for 3 — 6 months to minimize the risk of CMV disease in adult SOT patients [25-28].
In pediatrics, valganciclovir is approved to be used begin- ning within 10 days of organ transplantation until 100 days posttransplantation to reduce the risk of CMV disease in D+/R– kidney or heart transplant patients between 4 months and 16 years of age . Safety and efficacy in children younger than 4 months old have not been established.
Valganciclovir is the valine ester prodrug of ganciclovir, and exists as a mixture of two diastereomers (Box 1). Valganciclovir was engineered to improve the poor oral bioavailability of oral ganciclovir from 6 — 9% up to 60%. It is a hydrophilic com- pound with the molecular formula of C14H22N6O5HCl and molecular weight of 390.83 Da. Valganciclovir HCl is a whitish crystalline powder that is freely soluble at pH of 7 and has a pKa of 7.6. Valganciclovir is commercially available in 450 mg oral tablets and 50 mg/ml oral solution [30,31].
Valganciclovir is converted to ganciclovir after absorption. Ganciclovir is a synthetic nucleoside analog of deoxyguano- sine. It is initially phosphorylated by viral protein kinase, UL97, and further phosphorylated to ganciclovir triphosphate by host cellular kinases. Ganciclovir triphosphate competi- tively inhibits viral replication by inhibiting viral DNA poly- merase, UL54. Ganciclovir triphosphate is slowly metabolized intracellularly, prolonging its effects. As the initial activation step requires viral UL97, ganciclovir exerts its antiviral effects preferentially in virus-infected cells. Ganciclovir, and
therefore valganciclovir, has activity against all human herpes viruses in vitro. However, clinical efficacy against certain herpes viruses (e.g., HHV-6) is limited. Other pharmaco- dynamic properties of valganciclovir are similar to that of ganciclovir .
Available data from adults and older children do not sup- port routine therapeutic drug monitoring in SOT patients on valganciclovir or ganciclovir therapy [32-34]. No strong correlations between ganciclovir concentrations and either efficacy or toxicity have been established during therapy with IV ganciclovir or valganciclovir [32,34]. Plasma ganciclovir levels may have clinical utility in subsets of patients where ganciclovir resistance, prophylactic or treatment failure, or malabsorption of valganciclovir is suspected. Low ganciclovir levels (trough concentration < 0.5 mg/l) have been implicated in treatment failure in several cases of liver transplant, hematopoietic stem cell transplant, and AIDS patients [34-36]. The probability of developing CMV viremia during and after valganciclovir prophylaxis was higher with underexposure to ganciclovir . Because inter- and intrapatient variability of ganciclovir levels appears to be higher and low ganciclovir levels were more frequent in younger children, this patient population may benefit from therapeutic drug monitoring of ganciclovir levels if efficacy and toxicity targets can be established [37,38]. 5.Pharmacokinetics and metabolism After oral administration, valganciclovir is well absorbed from the gastrointestinal tract and rapidly converted to ganciclovir by intestinal and hepatic esterases. Systemic exposure to valganciclovir is limited to 1 -- 2% [30,39]. The drug is then eliminated essentially unchanged and almost exclusively by renal excretion in the form of ganciclovir. As in adult patients, the absolute bioavailability of ganciclovir from valganciclovir is approximately 40 -- 60% in children and similar across organ types and age ranges . Valganciclovir oral solution is bioequivalent to tablets . In a pharmacokinetic study of kidney (n = 26) and liver (n = 20) transplant patients, pediatric doses of 200 mg/m2 for IV ganciclovir and 520 mg/m2 for oral valganciclovir solution were derived based on dose normalization for body surface area (BSA), using reference doses of 5 mg/kg IV gan- ciclovir and 900 mg oral valganciclovir for a 70-kg adult with a BSA of 1.73 m2 . In patients aged between 6 and 16 years, this dosing scheme resulted in ganciclovir exposures that were comparable to that observed in adult patients. However, exposure to ganciclovir in children £ 5 years old was notice- ably lower. This finding called for a new approach to pediatric dosing of valganciclovir. The current pediatric dosing algorithm for valganciclovir (Box 2) was derived from a pharmacokinetic study of ganciclo- vir following oral administration of valganciclovir in pediatric kidney, liver, and heart transplant patients (aged 4 months to 16 years; n = 63) for prevention of CMV infection. The Expert Opin. Pharmacother. (2013) 14(6) 809 Box 2. Pediatric dose calculation of valganciclovir for prevention of CMV disease. Valganciclovir dose (mg/day)* = 7 ti BSA ti CrCL Mosteller BSA (m2) = Height (cm) × Weight (kg) 3600 2 Schwartz CrCL (ml / min / 1.73 m ) = k ×Height (cm) Serum creatinine (mg / dl) k = 0.45 for patients aged 4 months to < 2 years k = 0.55 for girls aged 2 -- 16 years and boys aged 2 -- 12 years k = 0.7 for boys aged 13 -- 16 years Refer to adult dosing for patients older than 16 years of age *A max CrCL of 150 ml/min/1.73 m2 should be used. equation employs BSA and creatinine clearance (CrCL) as calculated by the modified Schwartz formula . If the calcu- lated CrCL exceeds 150 ml/min/1.73 m2, then a maximum value of 150 ml/min/1.73 m2 should be used. Doses should be rounded to the nearest 25 mg and not exceed 900 mg per day for prevention of CMV infection . 6.Clinical efficacy 6.1Valganciclovir for prevention of CMV The efficacy of valganciclovir in preventing CMV disease in adult SOT recipients by universal prophylactic or preemptive strategies has been well documented [5,29,39]. In pediatric SOT recipients, supportive literature is relatively lacking, especially among young children. Although preemptive therapy with valganciclovir has been studied in pediatric allogeneic stem cell transplant patients with promising results [43,44], the majority of published studies in pediatric SOT patients employed universal prophylaxis with valganciclovir. One small study found valganciclovir at 15 -- 18 mg/kg daily to be safe and effective as prophylaxis against CMV in 10 non-high-risk (CMV D+/R+, D-- /R+, D-- /R-- ) pediatric liver transplant patients with a mean age of 5 years old . One Phase II/III prospective noncomparative study also found valganciclovir to be safe and effective in 63 pediatric SOT recipients . Only two patients developed CMV viremia and none developed CMV tissue-invasive disease. A retrospective study examined the incidence of CMV dis- ease in 111 pediatric renal transplant recipients with a median age of 14.5 years old after receiving prophylaxis with valganci- clovir at 15 mg/kg daily up to 900 mg per day . Patients of all CMV serologic status combinations were included and received valganciclovir for a mean duration of 5.9 months (range 0.5 -- 24 months). The overall incidence of CMV infection and disease was 27 and 4.5%, respectively. Of the patients with viremia, 9 patients were observed to have detect- able CMV viral load while on prophylaxis and 18 patients developed viremia after prophylaxis ended. All patients with CMV disease were CMV D+/R-- and were diagnosed after prophylaxis ended. Patients who received shorter durations of prophylaxis with valganciclovir had a trend toward a higher cumulative CMV viremia rate at 6 months, but the association was not statistically significant. A retrospective study compared valganciclovir and oral ganciclovir for CMV prophylaxis in 92 pediatric recipients of kidney and/or liver transplants . The study included all CMV serologic status combinations except for D-- /R-- . All patients received IV ganciclovir initially at 5 mg/kg every 12 hours for the first 2 weeks posttransplant followed by oral ganciclovir at 30 mg/kg 3 times daily up to 1 g per dose or valganciclovir once daily at the dose calculated by the manufacturer’s equation (Box 2) up to 900 mg per day. Patients with CMV D+/R-- received therapy for 6 months, while D-- /R+ and D+/R+ patients received therapy for 3 months, all with a follow-up period of 1 year. The mean age of patients was approximately 10 years old. The overall incidence of CMV infection was 16% and the incidences were comparable between the valganciclovir and ganciclovir arms (13.7 vs. 19.5%, respectively; p = 0.573). The time to CMV infection was similar between groups, and five and four episodes occurred while receiving valganciclovir and ganciclovir prophylaxis, respectively. It is unclear why the rate of CMV infection occurring during prophylaxis reported in this study is higher compared to other pediatric and adult studies. All patients with CMV infection or disease responded to treatment with IV ganciclovir, making resistance less likely. Other possible causes include adherence and inadequate absorption, which were not assessed. The rate of acute allograft rejection was similar between study groups. A retrospective study of 56 pediatric liver transplant recipients comparing the rates of early-onset and late-onset CMV infection and disease reported similar findings and found no differences in the safety and efficacy between oral ganciclovir and valganciclovir prophylaxis for a duration of 120 days . Additional clinical trials of valganciclovir are ongoing to evaluate a longer duration (200 days) of CMV prophylaxis in 810 Expert Opin. Pharmacother. (2013) 14(6) pediatric kidney transplant recipients and a younger age group (£ 4 months old) in pediatric heart transplant patients [48,49]. Patients who develop CMV infection or disease while on valganciclovir prophylaxis should be treated and possibly eval- uated for potential ganciclovir resistance. Pediatric and adult patients have been successfully treated with IV ganciclovir . Monitoring the plasma level of ganciclovir may be considered to evaluate possible inadequate absorption or dosing. 6.2Valganciclovir for treatment of CMV Valganciclovir is not licensed for treatment of CMV infection in any age group of SOT patients. IV ganciclovir and valgan- ciclovir are approved for the treatment of CMV retinitis in AIDS patients. IV ganciclovir has been the “gold standard” treatment for CMV infections in SOT patients. Recently, the VICTOR trial demonstrated that valganciclovir is nonin- ferior to IV ganciclovir in the treatment of CMV disease in adult SOT patients . Studies in the pediatric SOT popula- tion are lacking, but some clinicians support upfront treat- ment with valganciclovir in pediatric SOT patients with mild to moderate CMV infections in whom absorption is not a concern by extrapolating from the adult data. However, lack of established pediatric dosing guidelines for valganciclo- vir induction therapy may prohibit the use of this approach in younger children. As an off-label use in neonates, several stud- ies documented the safety and efficacy of valganciclovir for the treatment of congenital CMV disease [31,51-54]. 6.3Valganciclovir for prevention of EBV EBV infection increases the risk of developing posttransplant lymphoproliferative disorder (PTLD), but there is no estab- lished prevention regimen. A recent prospective trial utilizing ganciclovir or valganciclovir as CMV prophylaxis showed promising results in their ability to also reduce the risk of EBV infection. In EBV D+/R-- pediatric renal transplant recip- ients, a cohort on chemoprophylaxis with ganciclovir or valgan- ciclovir was associated with a significantly decreased incidence of EBV primary infection compared to a control group without chemoprophylaxis (45 vs. 100%, respectively; p < 0.001) . An earlier study also supported the beneficial effects of antiviral prophylaxis by documenting a 83% relative risk reduction of developing PTLD in SOT patients who received ganciclovir compared to no antiviral prophylaxis . The effect of antiviral prophylaxis with valganciclovir on EBV infection and PTLD has not been evaluated in prospective randomized trials. 7.Safety and tolerability The overall safety profile of valganciclovir in pediatric patients is similar to that in adult patients. The commonly reported adverse events occurring in > 10% of pediatric transplant patients treated with valganciclovir were diarrhea, pyrexia, upper respiratory infection, hypertension, vomiting, cytope- nias, nausea, and constipation . Leucopenia and neutropenia were the most frequently reported clinically relevant adverse
events in pediatric studies. Patients experiencing persistent leucopenia may require discontinuation of therapy and use of alternative agents. Use of granulocyte colony-stimulating factor (G-CSF) in adult SOT patients have reversed valganciclovir- related leucopenia and even allowed continued use of ganciclovir, leading to successful prophylaxis against and treatment of CMV [57,58]. Although the use of G-CSF is well documented in the pediatric oncology literature, supportive evidence in pediatric SOT patients is lacking.
Data on the safety and efficacy of valganciclovir for the treat- ment of CMV infection or end-organ disease are lacking in pediatric SOT recipients, and IV ganciclovir remains a primary first-line agent [25-28]. One may extrapolate the positive results documented in adult SOT patients and neonates with congen- ital CMV, but high-quality studies are needed to determine dosage, safety, and efficacy in pediatric SOT patients.
Widespread and prolonged use of valganciclovir prophylaxis raises concerns for the development of ganciclovir-resistant CMV. Ganciclovir-resistant CMV is a clinical challenge among patients infected with human immunodeficiency virus partly due to the limited number of alternative CMV antiviral agents . Mutations in the UL97-encoded CMV phospho- transferase responsible for the initial phosphorylation of ganciclovir are a common mechanism of resistance. Other mechanisms include alterations in the viral DNA polymerase, UL54, which results in impaired inhibition of viral replication by ganciclovir triphosphate . Studies in adult SOT patients report low rates of ganciclovir resistance in patients who received valganciclovir prophylaxis, with incidence rates rang- ing from 0 to 5% [61,62]. The reported rates of resistance in pediatric SOT patients are lacking. Routine testing for CMV resistance is not commonly practiced. Viral sensitivity testing has not been standardized, but genetic testing for the presence of UL97 and UL54 mutations should be considered in patients failing valganciclovir or ganciclovir prophylaxis or treatment.
Antiviral agents with activity against ganciclovir-resistant CMV either have serious toxicities (e.g., foscarnet, cidofovir) or lack strong supportive data documenting its efficacy (e.g., leflunomide, maribavir). Foscarnet and cidofovir do not rely on UL97 to exert their antiviral activity, but are extremely neph- rotoxic and can lead to permanent renal failure. Leflunomide has an unclear mechanism of antiviral action and has been used successfully in a small cohort of patients with ganciclovir- resistant CMV . Unfortunately, its immunosuppressive effects may increase the risk of other infections in SOT patients.
Late-onset CMV occurring after prophylactic therapy with valganciclovir or ganciclovir is a growing clinical problem. Clinical monitoring of transplant patients tapers off as time lapses posttransplant, which poses a surveillance challenge, and late-onset CMV has been shown to increase the risk of allograft failure and mortality . No consensus currently exists regarding appropriate monitoring for late-onset CMV,
Expert Opin. Pharmacother. (2013) 14(6) 811
but it may be prudent to routinely monitor high-risk D+/R– patients postprophylaxis. In the adult transplant literature, studies comparing different durations of valganciclovir pro- phylaxis have found that longer durations may be associated with reduced CMV infection and disease [65,66]. No data have been published in pediatrics regarding the impact of lon- ger prophylactic durations compared to 3 months on late- onset CMV disease. Head-to-head trials evaluating the impact of preemptive therapy versus prophylaxis on late-onset CMV are also lacking in the pediatric SOT literature.
The availability of oral formulations and its higher bioavail- ability make valganciclovir an attractive alternative to ganci- clovir in multiple clinical settings in pediatrics. The safety and efficacy of valganciclovir in prophylaxis and treatment of CMV infection are well documented in adult SOT popula- tions. In the pediatric SOT population, valganciclovir is only approved for the prevention of CMV in kidney or heart trans- plant recipients. However, multiple studies and clinical expe- rience support its safe and efficacious use for CMV prophylaxis in other pediatric SOT populations and in the treatment of congenital CMV infection. Like adults, cytope- nias are the most commonly reported adverse events in chil- dren. Additional studies are needed to further elucidate the appropriate use of valganciclovir for the treatment of CMV infection in pediatric SOT recipients.
The approval of valganciclovir for pediatric use has changed the landscape of CMV prophylaxis in pediatric transplantation. Ganciclovir is a valuable antiviral agent for prophylaxis and treat- ment of CMV, but the IV formulation is hampered by the need for venous access while oral ganciclovir is challenged by poor bio- availability. Pharmacokinetic studies demonstrate that dosing valganciclovir using BSA and CrCL in pediatric patients can yield safe and effective serum levels of ganciclovir similar to what can be achieved with IV ganciclovir. The availability of valganciclovir oral suspension accommodates a wide range of pediatric doses and also negates the need for extemporaneous preparations from valganciclovir tablets.
The higher bioavailability of valganciclovir may provide more consistent viral suppression and the once daily prophy- lactic dosing compared to 3 times daily dosing of oral ganci- clovir can improve patient adherence. These advantages simplify clinical management of CMV prevention and lower associated costs. It has been proposed that valganciclovir may improve patient adherence and decrease the development of CMV resistance compared to oral ganciclovir; however, these potential benefits need to be further studied. These ben- efits must be balanced against the risks associated with valgan- ciclovir, especially its myelosuppressive effects. Opportunistic infections attributed to valganciclovir-related neutropenia are difficult to quantify, but it is a clinical concern. Valganciclo- vir’s purported superior ability to suppress CMV replication may blunt a host’s immune response, potentially leading to late-onset CMV disease, which has been linked to negative outcomes in transplant patients. Valganciclovir is also more costly than other agents or preventative measures.
While valganciclovir is approved for CMV prophylaxis only in pediatric kidney and heart transplant patients, the role of valganciclovir in pediatric populations will likely expand. Studies have already demonstrated the benefits of val- ganciclovir in additional clinical scenarios such as prevention of CMV infection in pediatric liver transplant recipients and treatment of congenital CMV infection. Valganciclovir has also shown potential to reduce EBV infection and possibly decrease the risk of EBV-related PTLD. Ongoing clinical tri- als are also examining the effects of prolonged valganciclovir exposure on the incidence of late-onset CMV infection and the safety and efficacy of valganciclovir prophylaxis in youn- ger children. However, the exact role of valganciclovir in the pediatric SOT population cannot be determined without comparative studies against other antiviral agents and pre- emptive strategies. Comprehensive safety and efficacy data for valganciclovir for the treatment of CMV infection are also needed along with an appropriate pediatric dosing strat- egy for treatment scenarios.
Declaration of interest
J Park has received a research grant from Roche. M Yu has no financial or other conflict of interest to disclose.
812 Expert Opin. Pharmacother. (2013) 14(6)
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†Author for correspondence
1Infectious Diseases Clinical Pharmacist, Sharp Grossmont Hospital,
Department of Pharmacy, La Mesa, CA, USA 2Clinical Associate Professor,
Transplant Clinical Specialist, University of Michigan, College of Pharmacy,
Victor Vaughan Building – Room 306, 1111 Catherine St.,
Ann Arbor, MI 48109-2054, USA Tel: +1 734 647 4711;
Fax: +1 734 615 2314;
E-mail: [email protected]
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