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CPT: Pharmacometrics & Systems... Mar 2019Intravenous ganciclovir and oral valganciclovir are effective in the prevention and treatment of pediatric cytomegalovirus (CMV) infection but various dosing regimens...
Intravenous ganciclovir and oral valganciclovir are effective in the prevention and treatment of pediatric cytomegalovirus (CMV) infection but various dosing regimens are used in medical practice. Population pharmacokinetic (PopPK) model-based simulations were used to propose a new ganciclovir pediatric dosing algorithm for regulatory review and to evaluate the approved valganciclovir pediatric dosing algorithm against published dosing recommendations derived from quantitative approaches. Oral valganciclovir (mg = 7 × body surface area (BSA) × creatinine clearance according to the Schwarz formula (CrCLS) daily) and i.v. ganciclovir (mg = 3 × BSA × CrCLS daily) are effective in reaching ganciclovir target exposure for the prevention of CMV (area under the concentration-time curve (AUC) 40-60 μg ∙ hour/mL) in most pediatric patients across the full pediatric age range. In contrast, ganciclovir and valganciclovir dosing based on body weight, as commonly used in medical practice, leads to underexposure, particularly in younger pediatric patients. This example shows that model-based dosing algorithms built on clinical pharmacology and implemented using good modeling practice can prevent underexposure and reduce the risk of treatment failure in pediatric patients.
Topics: Adolescent; Algorithms; Antiviral Agents; Child; Child, Preschool; Computer Simulation; Cytomegalovirus Infections; Ganciclovir; Humans; Infant; Infant, Newborn; Models, Biological; Treatment Failure; Valganciclovir
PubMed: 30354026
DOI: 10.1002/psp4.12363 -
Journal of Clinical and Experimental... Jun 2017Cytomegalovirus (CMV) infection is the most common viral infection in liver transplant recipients, affecting post-transplant patients and graft survival. Recent advances... (Review)
Review
Cytomegalovirus (CMV) infection is the most common viral infection in liver transplant recipients, affecting post-transplant patients and graft survival. Recent advances in diagnosis and management of CMV have led to marked reduction in incidence, severity, and its associated morbidity and mortality. CMV DNA assay is the most commonly used laboratory parameter to diagnose and monitor CMV infection. Current evidence suggests that both pre-emptive and universal prophylaxis approaches are equally justified in liver transplant recipients. Intravenous ganciclovir and oral valganciclovir are the most commonly used drugs for treatment of CMV disease. Most of the centre use valganciclovir prophylaxis for prevention of CMV disease in liver trasplant recipient. The aim of this article is to review the current standard of care for diagnosis and management of CMV disease in liver transplant recipients.
PubMed: 28663679
DOI: 10.1016/j.jceh.2017.05.011 -
Journal of Transplantation 2018Organ transplant recipients receive immunosuppressive regimens to prevent transplant rejection, which put them at increased risk for opportunistic infections like...
OBJECTIVE
Organ transplant recipients receive immunosuppressive regimens to prevent transplant rejection, which put them at increased risk for opportunistic infections like cytomegalovirus (CMV). Ganciclovir and Valganciclovir are mostly used to prevent or treat CMV. Any incorrect use of the drug may have serious consequences for patients. In this study, the outcome of transplant recipients was assessed in relation to the optimal or suboptimal use of Ganciclovir or Valganciclovir.
METHODS
This study was performed on 148 hospitalized patients who received Ganciclovir or Valganciclovir in the nephrology and kidney transplantation departments of our university hospitals, from March 2012 to December 2016. Patients' demographic and clinical data including dose and duration of treatment were collected and then analyzed in comparison with the standard CMV treatment protocols.
FINDINGS
About 94.6% of patients received Ganciclovir or Valganciclovir therapy consistent with the standard defined indications. The mean ratio of prescribed daily dose to the optimal dose was 2.9 in the first dose, 2.0 in the second dose, 1.3 in the third dose, and 1.5 in the fourth dose. From 148 included patients, 26.5% experienced CMV infection once, 7.2% experienced CMV infection twice, and 1.2% had CMV infection for 3 times, within six-month follow-up after first episode of antiviral therapy during hospitalization.
CONCLUSION
In this study, empiric anti-CMV therapy was initially given. The doses used were generally higher than recommended but we could not find more adverse events in the patients receiving high initial doses. In any case, it seems necessary to advocate use of standard treatment guidelines to avoid adverse outcomes.
PubMed: 30319817
DOI: 10.1155/2018/8414385 -
American Journal of Transplantation :... Dec 2022Prophylaxis with valganciclovir (VGCV) is used routinely to prevent cytomegalovirus (CMV) infections in at-risk pediatric solid organ transplant (SOT) recipients....
Prophylaxis with valganciclovir (VGCV) is used routinely to prevent cytomegalovirus (CMV) infections in at-risk pediatric solid organ transplant (SOT) recipients. However, the rate and factors associated with toxicities in this population are not well-described. We conducted a retrospective cohort study of children undergoing SOT at our hospital from January 2012-June 2018. We evaluated the frequency of hematologic and renal toxicities from day 15 through 1-year post-SOT in relation to antiviral exposures, focused on VGCV prophylaxis. Marginal rate models were used to determine the risk of kidney injury and neutropenia in relation to VGCV prophylaxis. Among 281 SOTs, VGCV prophylaxis was administered on 20.1% of all follow-up days. The incidence rates of kidney injury, leukopenia, and neutropenia were significantly higher during VGCV prophylaxis compared to when no antiviral agents were given. Using multivariable marginal rate models, receipt of VGCV prophylaxis was associated with development of kidney injury (rate ratio [RR] 1.79, 95% confidence interval [CI]: 1.22-2.65) and neutropenia (RR 4.82, 95% CI: 3.08-7.55). VGCV dosing did not impact the development of kidney injury or neutropenia. Toxicities are common with VGCV prophylaxis in pediatric SOT recipients.
Topics: Humans; Child; Antiviral Agents; Ganciclovir; Retrospective Studies; Valganciclovir; Transplant Recipients; Cytomegalovirus Infections; Kidney Transplantation; Neutropenia
PubMed: 35971847
DOI: 10.1111/ajt.17171 -
World Journal of Gastroenterology Aug 2008Cytomegalovirus (CMV) is a common viral pathogen that influences the outcome of liver transplantation. In addition to the direct effects of CMV syndrome and... (Review)
Review
Cytomegalovirus (CMV) is a common viral pathogen that influences the outcome of liver transplantation. In addition to the direct effects of CMV syndrome and tissue-invasive diseases, CMV is associated with an increased predisposition to acute and chronic allograft rejection, accelerated hepatitis C recurrence, and other opportunistic infections, as well as reduced overall patient and allograft survival. Risk factors for CMV disease are often interrelated, and include CMV D+/R- serostatus, acute rejection, female gender, age, use of high-dose mycophenolate mofetil and prednisone, and the overall state of immunity. In addition to the role of CMV-specific CD4+ and CD8+ T lymphocytes, there are data to suggest that functionality of the innate immune system contributes to CMV disease pathogenesis. In one study, liver transplant recipients with a specific polymorphism in innate immune molecules known as Toll-like receptors were more likely to develop higher levels of CMV replication and clinical disease. Because of the direct and indirect adverse effects of CMV disease, its prevention, whether through antiviral prophylaxis or preemptive therapy, is an essential component in improving the outcome of liver transplantation. In the majority of transplant centers, antiviral prophylaxis is the preferred strategy over preemptive therapy for the prevention of CMV disease in CMV-seronegative recipients of liver allografts from CMV-seropositive donors (D+/R-). However, the major drawback of antiviral prophylaxis is the occurrence of delayed-onset primary CMV disease. In several prospective and retrospective studies, the incidence of delayed-onset primary CMV disease ranged from 16% to 47% of CMV D+/R- liver transplant recipients. Current data suggests that delayed-onset CMV disease is associated with increased mortality after liver transplantation. Therefore, optimized strategies for prevention and novel drugs with unique modes of action are needed. Currently, a randomized controlled clinical trial is being performed comparing the efficacy and safety of maribavir, a novel benzimidazole riboside, and oral ganciclovir as prophylaxis against primary CMV disease in liver transplant recipients. The treatment of CMV disease consists mainly of intravenous (IV) ganciclovir, and if feasible, a reduction in the degree of immunosuppression. A recent controlled clinical trial demonstrated that valganciclovir is as effective and safe as IV ganciclovir for the treatment of CMV disease in solid organ (including liver) transplant recipients. In this article, the author reviews the current state and the future perspectives of prevention and treatment of CMV disease after liver transplantation.
Topics: Acyclovir; Antiviral Agents; Benzimidazoles; Cytomegalovirus; Cytomegalovirus Infections; Drug Resistance, Viral; Ganciclovir; Graft Rejection; Humans; Immunity, Cellular; Immunity, Innate; Immunosuppressive Agents; Liver Transplantation; Ribonucleosides; Risk Factors; Treatment Outcome; Valganciclovir; Virus Replication
PubMed: 18756591
DOI: 10.3748/wjg.14.4849 -
Biochemical Society Transactions Apr 2020Solute carrier (SLC) transporters play important roles in regulating the movement of small molecules and ions across cellular membranes. In mammals, they play an... (Review)
Review
Solute carrier (SLC) transporters play important roles in regulating the movement of small molecules and ions across cellular membranes. In mammals, they play an important role in regulating the uptake of nutrients and vitamins from the diet, and in controlling the distribution of their metabolic intermediates within the cell. Several SLC families also play an important role in drug transport and strategies are being developed to hijack SLC transporters to control and regulate drug transport within the body. Through the addition of amino acid and peptide moieties several novel antiviral and anticancer agents have been developed that hijack the proton-coupled oligopeptide transporters, PepT1 (SCL15A1) and PepT2 (SLC15A2), for improved intestinal absorption and renal retention in the body. A major goal is to understand the rationale behind these successes and expand the library of prodrug molecules that utilise SLC transporters. Recent co-crystal structures of prokaryotic homologues of the human PepT1 and PepT2 transporters have shed important new insights into the mechanism of prodrug recognition. Here, I will review recent developments in our understanding of ligand recognition and binding promiscuity within the SLC15 family, and discuss current models for prodrug recognition.
Topics: Animals; Biological Transport; Crystallography, X-Ray; Drug Design; Humans; Oligopeptides; Peptide Transporter 1; Prodrugs; Symporters; Valacyclovir; Valganciclovir
PubMed: 32219385
DOI: 10.1042/BST20180302 -
American Journal of Transplantation :... Dec 2019
Topics: BK Virus; Cytomegalovirus; Cytomegalovirus Infections; Humans; Kidney Diseases; Polyomavirus Infections; Valganciclovir; Viremia
PubMed: 31400049
DOI: 10.1111/ajt.15562 -
Viruses Mar 2015Adenovirus infections of immunocompromised pediatric hematopoietic stem cell transplant patients can develop into serious and often deadly multi-organ disease. There are...
Adenovirus infections of immunocompromised pediatric hematopoietic stem cell transplant patients can develop into serious and often deadly multi-organ disease. There are no drugs approved for adenovirus infections. Cidofovir (an analog of 2-deoxycytidine monophosphate) is used at times but it can be nephrotoxic and its efficacy has not been proven in clinical trials. Brincidofovir, a promising lipid-linked derivative of cidofovir, is in clinical trials. Ganciclovir, an analog of 2-deoxyguanosine, has been employed occasionally but with unknown efficacy in the clinic. In this study, we evaluated valganciclovir against disseminated adenovirus type 5 (Ad5) infection in our permissive immunosuppressed Syrian hamster model. We administered valganciclovir prophylactically, beginning 12 h pre-infection or therapeutically starting at Day 1, 2, 3, or 4 post-infection. Valganciclovir significantly increased survival, reduced viral replication in the liver, and mitigated the pathology associated with Ad5 infection. In cultured cells, valganciclovir inhibited Ad5 DNA replication and blocked the transition from early to late stage of infection. Valganciclovir directly inhibited Ad5 DNA polymerase in vitro, which may explain, at least in part, its mechanism of action. Ganciclovir and valganciclovir are approved to treat infections by certain herpesviruses. Our results support the use of valganciclovir to treat disseminated adenovirus infections in immunosuppressed patients.
Topics: Adenovirus Infections, Human; Adenoviruses, Human; Animals; Antiviral Agents; Cell Line; DNA-Directed DNA Polymerase; Disease Models, Animal; Epithelial Cells; Female; Ganciclovir; Humans; Immunocompromised Host; Liver; Male; Mesocricetus; Survival Analysis; Treatment Outcome; Valganciclovir; Viral Load; Virus Replication
PubMed: 25807051
DOI: 10.3390/v7031409 -
PloS One 2023High HHV-8 viral load (VL) in Kaposi Sarcoma (KS) has been associated with Severe Immune Reconstitution Inflammatory Syndrome (Severe-IRIS-KS), which can occur after... (Randomized Controlled Trial)
Randomized Controlled Trial
INTRODUCTION
High HHV-8 viral load (VL) in Kaposi Sarcoma (KS) has been associated with Severe Immune Reconstitution Inflammatory Syndrome (Severe-IRIS-KS), which can occur after initiating cART, and leads to high mortality, particularly in patients with pulmonary involvement. We investigate if valganciclovir (as an anti-HHV-8 agent) initiated before cART reduces the mortality associated with Severe-IRIS-KS and the incidence of Severe-IRIS-KS.
METHODS
Open-label parallel-group randomized clinical trial in AIDS cART naïve patients with disseminated KS (DKS) as defined by at least two of the following: pulmonary, lymph-node, or gastrointestinal involvement, lymphedema, or ≥30 skin lesions. In the experimental group (EG), patients received valganciclovir 900 mg BID four weeks before cART and continued until week 48; in the control group (CG), cART was initiated on week 0. Non-severe-IRIS-KS was defined as: an increase in the number of lesions plus a decrease of ≥one log10 HIV-VL, or an increase of ≥50cells/mm3 or ≥2-fold in baseline CD4+cells. Severe-IRIS-KS was defined as abrupt clinical worsening of KS lesions and/or fever after ruling out another infection following cART initiation, and at least three of the following: thrombocytopenia, anemia, hyponatremia, or hypoalbuminemia.
RESULTS
40 patients were randomized and 37 completed the study. In the ITT analysis, at 48 weeks, total mortality was the same in both groups (3/20), severe-IRIS-KS attributable mortality was 0/20 in the EG, compared with 3/20 in the CG (p = 0.09), similar to the per-protocol analysis: 0/18 in the EG, and 3/19 in the control group (p = 0.09). The crude incidence rate of severe-IRIS-KS was four patients developed a total of 12 episodes of Severe-IRIS-KS in the CG and two patients developed one episode each in the EG. Mortality in patients with pulmonary KS was nil in the EG (0/5) compared with 3/4 in the CG (P = 0.048). No difference was found between groups in the number of non-S-IRIS-KS events. Among survivors at week 48, 82% achieved >80% remission.
CONCLUSIONS
Although mortality attributable to KS was lower in the EG the difference was not statistically significant.
Topics: Humans; Sarcoma, Kaposi; HIV Infections; Valganciclovir; Herpesvirus 8, Human; Antiretroviral Therapy, Highly Active; Anemia
PubMed: 37195970
DOI: 10.1371/journal.pone.0280209 -
Journal of Veterinary Pharmacology and... Oct 2013Equine herpes myeloencephalopathy, resulting from equine herpes virus type 1 (EHV-1) infection, is associated with substantial morbidity and mortality in the horse. As...
Equine herpes myeloencephalopathy, resulting from equine herpes virus type 1 (EHV-1) infection, is associated with substantial morbidity and mortality in the horse. As compared to other antiviral drugs, such as acyclovir, ganciclovir has enhanced potency against EHV-1. This study investigated the pharmacokinetics of ganciclovir and its oral prodrug, valganciclovir, in six adult horses in a randomized cross-over design. Ganciclovir sodium was administered intravenously as a slow bolus at a dose of 2.5 mg/kg, and valganciclovir was administered orally at a dose of 1800 mg per horse. Intravenously administered ganciclovir disposition was best described by a three-compartment model with a prolonged terminal half-life of 72 ± 9 h. Following the oral administration of valganciclovir, the mean observed maximum serum ganciclovir concentration was 0.58 ± 0.37 μg/mL, and bioavailability of ganciclovir from oral valganciclovir was 41 ± 20%. Superposition predicted that oral dosing of 1800-mg valganciclovir two times daily would fail to produce and maintain effective plasma concentrations of ganciclovir. However, superposition suggested that i.v. administration of ganciclovir at 2.5 mg/kg every 8 h for 24 h followed by maintenance dosing of 2.5 mg/kg every 12 h would maintain effective ganciclovir serum concentrations in most horses throughout the dosing interval.
Topics: Administration, Oral; Animals; Antiviral Agents; Female; Ganciclovir; Horses; Injections, Intravenous; Male; Valganciclovir
PubMed: 23301502
DOI: 10.1111/jvp.12029