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American Journal of Transplantation :... Feb 2013Cytomegalovirus (CMV) is the most common infection after organ transplantation and has a major impact on morbidity, mortality and graft survival. Optimal prevention,... (Review)
Review
Cytomegalovirus (CMV) is the most common infection after organ transplantation and has a major impact on morbidity, mortality and graft survival. Optimal prevention, diagnosis and treatment of active CMV infection enhance transplant outcomes, and are the focus of this section. Methods to prevent CMV include universal prophylaxis and preemptive therapy; each has its merits, and will be compared and contrasted. Diagnostics have improved substantially in recent years, both in type and quality, allowing for more accurate and savvy treatment; advances in diagnostics include the development of an international standard, which should allow comparison of results across different methodologies, and assays for cellular immune function against CMV. Therapy primarily involves ganciclovir, now rendered more versatile by data suggesting oral therapy with valganciclovir is not inferior to intravenous therapy with ganciclovir. Treatment of resistant virus remains problematic, but is enhanced by the availability of multiple novel therapeutic agents.
Topics: Administration, Oral; Antiviral Agents; Cytomegalovirus; Cytomegalovirus Infections; Drug Resistance, Viral; Ganciclovir; Graft Survival; Humans; Organ Transplantation; Valganciclovir
PubMed: 23347212
DOI: 10.1111/ajt.12006 -
Expert Review of Clinical Pharmacology 2023Infants and immunocompromised children with cytomegalovirus (CMV) infection have significant morbidity and mortality. Ganciclovir (GCV) and its oral prodrug... (Review)
Review
INTRODUCTION
Infants and immunocompromised children with cytomegalovirus (CMV) infection have significant morbidity and mortality. Ganciclovir (GCV) and its oral prodrug valganciclovir (VGCV) are the major antiviral options of choice for the prophylaxis and treatment of CMV infection. However, with the currently recommended dosing regimens used in pediatric patients, large intra- and inter-individual variability of pharmacokinetic (PK) parameters and exposure are observed.
AREAS COVERED
This review describes the PK and pharmacodynamic (PD) characteristics of GCV and VGCV in pediatrics. Moreover, the role of therapeutic drug monitoring (TDM) and current clinical practice for GCV and VGCV dosing regimens optimization in pediatrics are discussed.
EXPERT OPINION
GCV/VGCV TDM has shown the potential value to improve the benefit/risk ratio in pediatrics when using the therapeutic ranges derived from adults. However, well-designed studies are required to evaluate the relationship of TDM with clinical outcomes. Furthermore, studies to explore the children-specific dose-response-effect relationships will be helpful to facilitate the TDM practice. In the clinical setting, optimal sampling methods such as limited sampling strategies for pediatrics can be used in TDM and intracellular ganciclovir triphosphate may be used as an alternative TDM marker.
Topics: Child; Humans; Infant; Antiviral Agents; Cytomegalovirus Infections; Drug Monitoring; Ganciclovir; Valganciclovir
PubMed: 36794592
DOI: 10.1080/17512433.2023.2181161 -
Journal of Pharmacy & Pharmaceutical... 2017Valganciclovir 900 mg/day is approved for cytomegalovirus (CMV) prophylaxis, but 450 mg/day is seems also effective. We systematically reviewed the efficacy and safety... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVES
Valganciclovir 900 mg/day is approved for cytomegalovirus (CMV) prophylaxis, but 450 mg/day is seems also effective. We systematically reviewed the efficacy and safety of low-dose versus high-dose valganciclovir prophylaxis in renal transplantation recipients.
METHODS
An electronic search was conducted up to November 29, 2016. The primary outcomes were incidences of CMV, CMV disease, mortality and opportunistic infection. The second outcomes were acute rejection, allograft loss, adverse drug reaction (ADR).
RESULTS
7 cohort studies, all with high quality involving (1431 patients) were included. There was no significant difference of the incidence of following CMV disease (1271 patients, odds ratio [OR] 0.74, 95% confidence interval [CI], 0.38-1.43, p=0.36), acute rejection (1343 patients, OR 0.77, 95%CI 0.53-1.14, p=0.19), allograft loss (1271 patients, OR 0.64, 95%CI 0.31-1.35, p=0.24), mortality (1271 patients, OR 0.55, 95%CI 0.20-1.47, p=0.23) and opportunistic infections (OI) (985 patients, OR 0.76, 95%CI 0.52-1.10, p=0.14) between the low-dose and the high-dose valganciclovir prophylaxis. And no significant difference was observed for premature valganciclovir discontinuation (1010 patients, OR 0.81, 95%CI 0.52-1.25, p=0.33) and the incidence of leukopenia (1082 patients, OR 0.65, 95%CI 0.34-1.22, p=0.18) between the two regimens.
CONCLUSION
450 mg and 900 mg doses of valganciclovir are equipotent for CMV universal prophylaxis. CMV 450 mg prophylaxis should be used for renal transplant recipients. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.
Topics: Antibiotic Prophylaxis; Antiviral Agents; Cytomegalovirus; Cytomegalovirus Infections; Dose-Response Relationship, Drug; Ganciclovir; Humans; Kidney Transplantation; Valganciclovir
PubMed: 28719361
DOI: 10.18433/J3805B -
Clinical Cancer Research : An Official... Aug 2020Several groups have reported a prevalence of human cytomegalovirus (CMV) in glioblastoma close to 100%. Previously, we reported that treatment with the antiviral drug...
PURPOSE
Several groups have reported a prevalence of human cytomegalovirus (CMV) in glioblastoma close to 100%. Previously, we reported that treatment with the antiviral drug valganciclovir as an add-on to standard therapy significantly prolonged survival in 50 patients with glioblastoma. Here, we present an updated retrospective analysis that includes an additional 52 patients.
EXPERIMENTAL DESIGN
From December 2006 to November 2019, 102 patients with newly diagnosed glioblastoma received valganciclovir as an add-on to standard therapy. No additional toxicity was observed. Contemporary controls were 231 patients with glioblastoma who received similar baseline therapy.
RESULTS
Patients with newly diagnosed glioblastoma receiving valganciclovir had longer median overall survival (OS 24.1 vs. 13.3 months, < 0.0001) and a 2-year survival rate (49.8% vs. 17.3%) than controls. Median time-to-tumor progression was also longer than in controls; 9.9 (0.7-67.5 months) versus 7.3 (1.2-49 months), = 0.0003. Valganciclovir improved survival in patients with radical or partial resection and an unmethylated or methylated promoter gene.
CONCLUSIONS
Valganciclovir prolonged median OS of patients with newly diagnosed glioblastoma (with methylated or unmethylated promoter gene) and was safe to use.
Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; DNA Methylation; DNA Modification Methylases; DNA Repair Enzymes; Disease Progression; Female; Glioblastoma; Humans; Male; Middle Aged; Prognosis; Promoter Regions, Genetic; Retrospective Studies; Survival Rate; Time Factors; Treatment Outcome; Tumor Suppressor Proteins; Valganciclovir; Young Adult
PubMed: 32423968
DOI: 10.1158/1078-0432.CCR-20-0369 -
Clinical Pharmacokinetics 2009Valganciclovir and ganciclovir are widely used for the prevention of cytomegalovirus (CMV) infection in solid organ transplant recipients, with a major impact on... (Review)
Review
Valganciclovir in adult solid organ transplant recipients: pharmacokinetic and pharmacodynamic characteristics and clinical interpretation of plasma concentration measurements.
Valganciclovir and ganciclovir are widely used for the prevention of cytomegalovirus (CMV) infection in solid organ transplant recipients, with a major impact on patients' morbidity and mortality. Oral valganciclovir, the ester prodrug of ganciclovir, has been developed to enhance the oral bioavailability of ganciclovir. It crosses the gastrointestinal barrier through peptide transporters and is then hydrolysed into ganciclovir. This review aims to describe the current knowledge of the pharmacokinetic and pharmacodynamic characteristics of this agent, and to address the issue of therapeutic drug monitoring. Based on currently available literature, ganciclovir pharmacokinetics in adult solid organ transplant recipients receiving oral valganciclovir are characterized by bioavailability of 66 +/- 10% (mean +/- SD), a maximum plasma concentration of 3.1 +/- 0.8 mg/L after a dose of 450 mg and of 6.6 +/- 1.9 mg/L after a dose of 900 mg, a time to reach the maximum plasma concentration of 3.0 +/- 1.0 hours, area under the plasma concentration-time curve values of 29.1 +/- 5.3 mg.h/L and 51.9 +/- 18.3 mg.h/L (after 450 mg and 900 mg, respectively), apparent clearance of 12.4 +/- 3.8 L/h, an elimination half-life of 5.3 +/- 1.5 hours and an apparent terminal volume of distribution of 101 +/- 36 L. The apparent clearance is highly correlated with renal function, hence the dosage needs to be adjusted in proportion to the glomerular filtration rate. Unexplained interpatient variability is limited (18% in apparent clearance and 28% in the apparent central volume of distribution). There is no indication of erratic or limited absorption in given subgroups of patients; however, this may be of concern in patients with severe malabsorption. The in vitro pharmacodynamics of ganciclovir reveal a mean concentration producing 50% inhibition (IC(50)) among CMV clinical strains of 0.7 mg/L (range 0.2-1.9 mg/L). Systemic exposure of ganciclovir appears to be moderately correlated with clinical antiviral activity and haematotoxicity during CMV prophylaxis in high-risk transplant recipients. Low ganciclovir plasma concentrations have been associated with treatment failure and high concentrations with haematotoxicity and neurotoxicity, but no formal therapeutic or toxic ranges have been validated. The pharmacokinetic parameters of ganciclovir after valganciclovir administration (bioavailability, apparent clearance and volume of distribution) are fairly predictable in adult transplant patients, with little interpatient variability beyond the effect of renal function and bodyweight. Thus ganciclovir exposure can probably be controlled with sufficient accuracy by thorough valganciclovir dosage adjustment according to patient characteristics. In addition, the therapeutic margin of ganciclovir is loosely defined. The usefulness of systematic therapeutic drug monitoring in adult transplant patients therefore appears questionable; however, studies are still needed to extend knowledge to particular subgroups of patients or dosage regimens.
Topics: Adult; Cytomegalovirus Infections; Ganciclovir; Humans; Organ Transplantation; Transplantation; Valganciclovir
PubMed: 19650679
DOI: 10.2165/00003088-200948060-00006 -
Archives of Disease in Childhood Aug 2023Congenital human cytomegalovirus (CMV) infection is the most common congenital infection, affecting around 1 in 200 infants in high-income settings. It can have... (Review)
Review
Congenital human cytomegalovirus (CMV) infection is the most common congenital infection, affecting around 1 in 200 infants in high-income settings. It can have life-long consequences for up to one in four children, including sensorineural hearing loss and neurodisability. Despite the frequency of congenital CMV and the severity for some children, it is a little-known condition by pregnant women, families and healthcare providers. Timely diagnosis of CMV infection in pregnancy is important to facilitate consideration of treatment with valaciclovir, which may reduce the risk of transmission to the fetus or reduce the severity of the outcomes for infected infants. Recognition of features of congenital CMV is important for neonatologists, paediatricians and audiologists to prompt testing for congenital CMV within the first 21 days of life. Early diagnosis gives the opportunity for valganciclovir treatment, where appropriate, to improve outcomes for affected infants. Further research is urgently needed to inform decisions about antenatal and neonatal screening, long-term outcomes for asymptomatic and symptomatic infants, predictors of these outcomes and optimal treatment for women and infants.
Topics: Infant; Infant, Newborn; Child; Female; Pregnancy; Humans; Cytomegalovirus Infections; Valganciclovir; Pregnancy Complications, Infectious; Valacyclovir; Fetal Diseases; Hearing Loss, Sensorineural
PubMed: 36442957
DOI: 10.1136/archdischild-2022-323809 -
Pediatrics International : Official... Dec 2021
Topics: Antiviral Agents; Cytomegalovirus; Cytomegalovirus Infections; Humans; Infant, Newborn; Pneumonia; Valganciclovir
PubMed: 34399019
DOI: 10.1111/ped.14636 -
Medical Microbiology and Immunology Oct 2017Congenital cytomegalovirus (CMV) infection is the leading cause for sensorineural hearing loss and mental retardation in children without genetic diseases worldwide.... (Review)
Review
Congenital cytomegalovirus (CMV) infection is the leading cause for sensorineural hearing loss and mental retardation in children without genetic diseases worldwide. There is little evidence guiding therapeutic strategies during pregnancy when intrauterine fetal CMV infection is confirmed. We provide a systematic review of the use of ganciclovir (GCV) or VGCV during pregnancy discussing safety of its use for mother and fetus and describe two cases of intrauterine therapy of fetal CMV infection with valganciclovir (VGCV). A PubMed database search was done up to November 16, 2016 without any restrictions of publication date or journal, using the following keywords: "valganciclovir" or "ganciclovir" and "pregnan*". Furthermore, citations were searched and expert references were obtained. Reported cases were considered if therapy was in humans and initiation of treatment of the CMV infection was during pregnancy. In total, seven case reports were retrieved which described GCV or VGCV use during pregnancy for fetal or maternal CMV infection. In the four cases of treatment for maternal CMV infection, no negative effects on the fetus were reported. Three cases of GCV administration to pregnant woman with the intention of fetal treatment after proven fetal infection were found. We additionally present two cases of VGCV treatment in pregnancy from our center of tertiary care. VGCV seems to be a safe treatment for congenital CMV infection for the mother and the fetus. Therapeutic concentrations can be achieved in the fetus by oral intake of the mother and CMV replication can be suppressed. Larger studies are needed to evaluate this therapeutic intervention and the long-term effects.
Topics: Antiviral Agents; Cytomegalovirus Infections; Drug-Related Side Effects and Adverse Reactions; Female; Fetal Diseases; Ganciclovir; Humans; Pregnancy; Pregnancy Complications, Infectious; Treatment Outcome; Valganciclovir
PubMed: 28733760
DOI: 10.1007/s00430-017-0512-3 -
Clinical Infectious Diseases : An... Jul 2021Optimal valganciclovir dosing for cytomegalovirus (CMV) prophylaxis in solid-organ transplant (SOT) patients on continuous veno-venous hemodialysis (CVVHD) is not known.... (Clinical Trial)
Clinical Trial
BACKGROUND
Optimal valganciclovir dosing for cytomegalovirus (CMV) prophylaxis in solid-organ transplant (SOT) patients on continuous veno-venous hemodialysis (CVVHD) is not known. Ganciclovir trough concentrations ≥0.60 μg/mL have been suggested for CMV prophylaxis. This study was conducted to determine if valganciclovir 450 mg enterally every 24 hours achieves ganciclovir trough concentrations ≥0.60 μg/mL in patients on CVVHD.
METHODS
This single-center, prospective, open-label, pharmacokinetic study included adult SOT patients admitted to an intensive care unit from March 2018 to June 2019 on CVVHD. All patients were receiving valganciclovir 450 mg enterally every 24 hours for CMV prophylaxis prior to enrollment. Each patient had a peak and trough sample drawn at steady state.
RESULTS
Ten SOT patients were included in the study (6 liver, 1 simultaneous liver-kidney, 2 bilateral lung, 1 heart). The mean ± SD age was 51.8 ± 14.0 years, and average body mass index was 27 ± 6.9 kg/m2. Ganciclovir trough concentrations ranged from 0.31 to 3.16 μg/mL, and 80% of participants have trough concentrations ≥0.60 μg/mL. No patients had documented neutropenia while on valganciclovir and CVVHD; 60% of patients had significant thrombocytopenia.
CONCLUSIONS
Valganciclovir 450 mg enterally every 24 hours achieved ganciclovir trough concentrations ≥0.60 μg/mL in most patients on CVVHD, similar to those reported with intravenous ganciclovir for prophylaxis in this population. Based on these data, valganciclovir may require dosing every 24 hours to achieve concentrations equivalent to ganciclovir. Neutropenia did not occur in the study period. Thrombocytopenia was common and likely multifactorial.
Topics: Adult; Aged; Antiviral Agents; Continuous Renal Replacement Therapy; Cytomegalovirus; Cytomegalovirus Infections; Ganciclovir; Humans; Middle Aged; Organ Transplantation; Prospective Studies; Transplant Recipients; Valganciclovir
PubMed: 32379860
DOI: 10.1093/cid/ciaa537 -
Drugs 2005Valganciclovir (Valcyte) is an orally administered prodrug of the standard anti-cytomegalovirus (CMV) drug ganciclovir. Valganciclovir is as effective as intravenous... (Review)
Review
Valganciclovir (Valcyte) is an orally administered prodrug of the standard anti-cytomegalovirus (CMV) drug ganciclovir. Valganciclovir is as effective as intravenous ganciclovir for the treatment of AIDS-related CMV retinitis, and oral ganciclovir for the prophylaxis of CMV infection and disease in high-risk solid organ transplant recipients. The drug is generally well tolerated and has a similar tolerability profile to that of oral or intravenous ganciclovir, but is devoid of adverse events related to intravenous or indwelling catheter access associated with the use of intravenous ganciclovir, cidofovir and foscarnet. The simple and convenient once-daily valganciclovir regimen offers potential for improved patient compliance. It provides greater systemic ganciclovir exposure than oral ganciclovir, thus reducing the risk of viral resistance when used for prophylaxis in high-risk solid organ transplant recipients. Furthermore, the use of valganciclovir instead of intravenous ganciclovir may provide significant cost savings, based on data comparing oral versus intravenous regimens for the treatment of AIDS-related CMV retinitis. Overall, valganciclovir appears to have some advantages over ganciclovir. Therefore, when used as prophylaxis against CMV infection and disease in high-risk solid organ transplant recipients or as induction and maintenance therapy of CMV retinitis in patients with AIDS, oral valganciclovir is an attractive alternative to other available anti-CMV drugs.
Topics: Antiviral Agents; Cytomegalovirus Infections; Ganciclovir; Humans; Immunocompromised Host; Opportunistic Infections; Valganciclovir
PubMed: 15819597
DOI: 10.2165/00003495-200565060-00012