Valganciclovir: oral prevention and treatment of cytomegalovirus in the immunocompromised host

Herpes virus infections, particularly those caused by cytomegalovirus (CMV), lead to significant and, sometimes severe, clinical problems for the immunocompromised host. As effective agents have become available, several treatment and prevention strategies have evolved over the past decade, first in intra-venous form and more recently, as oral preparations. Valganciclovir, the valine ester of ganciclovir, is an orally administered, potent, antiviral agent active against all herpes viruses. When taken orally, valganciclovir has much-improved bioavailability compared with oral ganciclovir and achieves ganciclovir exposures similar to intravenous ganciclovir. Clinical trials evaluating the safety and efficacy of valganciclovir for the treatment of new AIDS-associated CMV retinitis showed equivalency to intravenous ganciclovir and prevented progression of quiescent disease. In solid organ recipients, once-daily valganciclovir has been proven equivalent to oral ganciclovir for the prevention of CMV infection. The high bioavailability and convenient dosing formulation make valganciclovir an attractive option for these indications.     

Valganciclovir: oral prevention and treatment of cytomegalovirus in the immunocompromised host

Herpes virus infections, particularly those caused by cytomegalovirus (CMV), lead to significant and, sometimes severe, clinical problems for the immunocompromised host. As effective agents have become available, several treatment and prevention strategies have evolved over the past decade, first in intra-venous form and more recently, as oral preparations. Valganciclovir, the valine ester of ganciclovir, is an orally administered, potent, antiviral agent active against all herpes viruses. When taken orally, valganciclovir has much-improved bioavailability compared with oral ganciclovir and achieves ganciclovir exposures similar to intravenous ganciclovir. Clinical trials evaluating the safety and efficacy of valganciclovir for the treatment of new AIDS-associated CMV retinitis showed equivalency to intravenous ganciclovir and prevented progression of quiescent disease. In solid organ recipients, once-daily valganciclovir has been proven equivalent to oral ganciclovir for the prevention of CMV infection. The high bioavailability and convenient dosing formulation make valganciclovir an attractive option for these indications.     

Valganciclovir: new preparation. CMV retinitis: a simpler,oral treatment

For AIDS patients with cytomegalovirus (CMV) retinitis, the standard initial treatment has so far been ganciclovir or foscarnet, both of which are infused intravenously. The choice between these two antiviral agents is based on their differing side effects. Maintenance treatment is based on ganciclovir or foscarnet, but both these drugs must be given as daily intravenous infusions. Oral ganciclovir is less effective. Intraocular maintenance treatment in appropriate only for patients with localised infections and a low risk of relapse. Valganciclovir can be taken orally for both initial and maintenance treatment of CMV retinitis. Valganciclovir has good bioavailability and is rapidly metabolised into ganciclovir. A comparative randomised trial in 160 patients showed that oral valganciclovir is as effective as intravenous ganciclovir when used as an initial treatment. There are no comparative trials of oral valganciclovir as a maintenance treatment, but non comparative data and pharmacokinetic studies suggest that oral valganciclovir is about as effective as intravenous ganciclovir. The adverse effects of oral valganciclovir are similar to those of intravenous ganciclovir, except that the oral route avoids the risk of local complications at the infusion site. Valganciclovir causes more frequent diarrhoea and oral candidosis than intravenous ganciclovir. In practice, for patients with CMV retinitis who require systemic treatment, oral valganciclovir is easier to use and, in our opinion, should now replace IV ganciclovir for both initial and maintenance treatment. The convenience of oral valganciclovir should also limit the use of purely intraocular treatment of CMV retinitis.     

Oral valganciclovir: a new option for treatment of cytomegalovirus infection and disease in immunocompromised hosts

Immunocompromised hosts are at increased risk of cytomegalovirus (CMV) infection and serious CMV disease. CMV infection is an important cause of morbidity among patients infected with HIV and after solid organ transplantation (SOT) and may cause life-threatening disease in allogeneic stem cell transplant (SCT) recipients. The introduction into clinical use of potent antiviral compounds and of rapid detection assays for CMV during the past two decades has allowed development of strategies for the prevention and treatment of disease caused by CMV in these groups of immunocompromised patients. At present, the antiviral drugs ganciclovir, foscarnet and cidofovir are commonly used in the treatment of CMV infection and disease. However, these agents have a poor oral bioavailability and, for systemic use, require iv. administration for most indications. Valganciclovir is an oral prodrug of ganciclovir, with a 10-fold greater bioavailability than oral ganciclovir. Studies of the pharmacokinetics of valganciclovir among HIV-infected CMV-seropositive patients and liver transplant recipients suggest that this oral compound has the potential to replace both oral and iv. ganciclovir in many situations if it is shown to be as efficacious and safe as those ganciclovir formulations in immunodeficient patients. In the first part of this review, currently established approaches to the management of CMV infection and disease in SCT and SOT recipients and HIV-infected patients are discussed to highlight possible indications for future valganciclovir use; in the second part, data from human studies of valganciclovir are presented.     

Pharmacokinetic profile of ganciclovir after its oral administration and from its prodrug, valganciclovir, in solid organ transplant recipients

BACKGROUND: Valganciclovir (Valcyte) has recently been approved for the prevention of cytomegalovirus (CMV) disease in high-risk (CMV donor positive [D+]/recipient negative [R-]) solid organ transplant (SOT) recipients. Large-scale studies describing the pharmacokinetics of valganciclovir in SOT recipients are lacking. A recent randomised, double-blind study of valganciclovir in 364 D+/R- (intent-to-treat population) SOT recipients provided valuable data on which a population pharmacokinetic analysis was performed. METHODS: The pharmacokinetics of ganciclovir from oral ganciclovir (Cymevene, 1000 mg three times daily) and from valganciclovir (900 mg once daily) were described with plasma levels from 240 patients (1181 datapoints describing 449 pharmacokinetic profiles) using nonlinear mixed-effects modelling (NONMEM) software. A two-compartment pharmacokinetic model with separate absorption/metabolism and absorption parameters for valganciclovir and ganciclovir, respectively, was developed. RESULTS: Exposure to ganciclovir from valganciclovir averaged 1.65-fold greater than that from oral ganciclovir (95% CI 1.58, 1.81); respective daily area under the plasma concentration-time curve values were 46.3 +/- 15.2 microg . h/mL and 28.0 +/- 10.9 microg . h/mL. The relative systemic exposure of ganciclovir was approximately 8-fold higher from valganciclovir than oral ganciclovir. Exposure to ganciclovir from valganciclovir was similar among liver, heart and kidney transplant recipients (46.0 +/- 16.1, 40.2 +/- 11.8 and 48.2 +/- 14.6 microg . h/ mL, respectively). Adherence to the prescribed dosing regimens, which were reduced for renal impairment, gave consistent exposure to ganciclovir. CONCLUSION: Oral valganciclovir produces exposures of ganciclovir exceeding those attained with oral ganciclovir, but in line with those reported after standard intravenous administration of ganciclovir. This indicates that oral valganciclovir is suitable in circumstances requiring prophylactic use of ganciclovir and allows for more convenient management of patients at risk of CMV disease.     

Valganciclovir

Valganciclovir is a prodrug of ganciclovir which has been developed for the treatment of cytomegalovirus (CMV) retinitis in patients with AIDS. Oral valganciclovir is rapidly absorbed and hydrolysed to ganciclovir. The oral bioavailability of ganciclovir after oral valganciclovir administration is high. Oral valganciclovir 900 mg provides a daily exposure of ganciclovir comparable to that of intravenous ganciclovir 5 mg/kg. A single, randomised, nonblind study indicated that oral valganciclovir (900mg twice daily for 3 weeks then 900 mg once daily) and intravenous ganciclovir (5 mg/kg twice daily for 3 weeks then 5 mg/kg once daily) were equally effective in the treatment of newly diagnosed CMV retinitis in 160 patients with AIDS. Valganciclovir appears to have a similar tolerability profile to intravenous ganciclovir during induction therapy in patients with AIDS and newly diagnosed CMV retinitis. During maintenance therapy with valganciclovir, the most commonly reported adverse events included neutropenia, anaemia, thrombocytopenia, gastrointestinal (including diarrhoea, nausea, vomiting and abdominal pain), fever, headache, insomnia, peripheral neuropathy, paraesthesia and retinal detachment.     

Valganciclovir: A new oral alternative for cytomegalovirus retinitis in human immunodeficiency virus-seropositive individuals

Oral valganciclovir recently was approved by the Food and Drug Administration for treatment of cytomegalovirus (CMV) retinitis. We performed MEDLINE (June 1998-May 2002) and AIDSLINE (June 1998-December 2000) searches of available information on valganciclovir, and the drug's prescribing information was used to identify relevant articles. Additional studies, case reports, reviews, and abstracts were identified from references in the reviewed literature. Most of the information was obtained from abstracts or product labeling, since few trials have been published in the medical literature. Valganciclovir is a prodrug of ganciclovir and has been shown to have significantly higher oral absorption than ganciclovir capsules. One short-term study found valganciclovir to be as effective as intravenous ganciclovir in treating CMV retinitis. Recommended dosages for patients with normal renal function are valganciclovir 900 mg twice/day for induction and 900 mg once/day for maintenance. Side effects are similar to those of intravenous ganciclovir and require periodic monitoring of complete blood count and renal function. Given the need for lifelong therapy for CMV retinitis in some human immunodeficiency virus-positive patients, valganciclovir is a welcome alternative to long-term administration of intravenous antivirals.     

Antiviral drugs for cytomegalovirus diseases

Cytomegalovirus infections are associated with severe morbidity and mortality is patients at risk for disease because of immune system disabilities; in particular, recipients of stem cell (HSCT) or solid organ (SOT) transplants. There are three systemic drugs approved for CMV treatment: ganciclovir, or its prodrug valganciclovir, foscarnet, and cidofovir. An anti-sense therapeutic, ISIS 2922, is also approved specifically as in intravitreal treatment for CMV retinitis. Ganciclovir, and more recently, valganciclovir, have been useful in proactive approaches of CMV disease management; in both prophylactic and preemptive regimens in HSCT and SOT populations. The major anti-herpes agent valacyclovir has also been approved for prophylaxis of renal transplant recipients, or SOTs outside of the US. These drugs have provided major advances in CMV disease management, although they are limited by intolerable toxicities, oral bioavailability and efficacy, and risk of drug resistance with extended use. Several drugs are in early clinical development which may address these limitations; this review will provide an overview of our current arsenal of available drugs, and of those in the early clinical development pipeline.     

Pharmacokinetics of valganciclovir and ganciclovir following multiple oral dosages of valganciclovir in HIV- and CMV-seropositive volunteers.

OBJECTIVE: Ganciclovir is commonly used in the treatment of cytomegalovirus (CMV) disease in patients who are immunocompromised and for the prevention of CMV disease in solid organ transplant recipients. Owing to limited bioavailability and saturable absorption, the use of oral ganciclovir in CMV retinitis is restricted to maintenance therapy only. As induction therapy must be given intravenously, an oral formulation which could be used for induction would offer significant benefits. A previous study of valganciclovir, a valyl ester prodrug of ganciclovir showed a 10-fold increase in plasma ganciclovir concentrations compared with the oral formulation. However, before studies can be conducted to confirm the utility of oral valganciclovir for the treatment and prevention of CMV disease, a dose must be selected for use in these studies. This study was designed to investigate the pharmacokinetics of ganciclovir and valganciclovir. DESIGN AND PARTICIPANTS: The study was an open-label, randomised, 4-way crossover, dose-ranging pharmacokinetic study, conducted in 39 patients who were HIV- and CMV-seropositive. The participants were randomised to one of 2 groups: fasted (n = 19) and fed (n = 20). In both groups, participants received 450, 875, 1750 and 2625 mg oral valganciclovir once daily for 3 days in a randomised order. RESULTS: In the 32 participants who completed the study, valganciclovir was rapidly absorbed and converted into ganciclovir (maximum ganciclovir concentrations occurred after 1.0 to 1.75 hours in the fasted group and 1.5 to 2.0 hours in the fed group). Systemic exposure to valganciclovir was low [with an area under the concentration-time curve to 24 hours (AUC24) of 1.3 to 2.5% that of ganciclovir]. The mean plasma concentrations of ganciclovir were dose-related. Peak concentrations of ganciclovir were achieved approximately 30 minutes after those for valganciclovir. In the fed state, the AUC24 of ganciclovir increased proportionally with dose. The mean AUC24 values for ganciclovir were slightly higher following food (24 to 56%) than in the fasted state. Based on linear regression of AUC24 values from the fed group, a dose of valganciclovir of 900 mg/day is expected to produce a daily exposure (AUC24) comparable with an intravenous dose of ganciclovir 5 mg/kg/day. CONCLUSIONS: These results show that once daily oral valganciclovir can produce exposures of ganciclovir (AUC24) exceeding those attained using intravenous ganciclovir 10 mg/kg. This suggests that oral valganciclovir may be suitable in many circumstances currently requiring intravenous ganciclovir, allowing for more convenience in the management of patients with CMV retinitis by utilising a 2 or 4 tablet daily regimen to cover all phases of treatment.     

Cytomegalovirus infection in solid organ transplantation: economic implications

Cytomegalovirus (CMV) is a pathogen, commonly encountered in the recipients of solid organ transplantation and is an important cause of morbidity and mortality in these patients. CMV infection and disease have been shown to increase the cost of care in transplant recipients and several different strategies of prevention have been shown to be effective in clinical trials. A systematic review of published information on the economic impact of CMV in solid organ transplantation was performed; both clinical- and decision-analysis-based studies were reviewed. Clinical studies have shown that CMV infection and disease is associated with increased length of hospital stay and overall costs. Decision-analysis-based studies suggest that in general, antiviral chemoprophylaxis against CMV in transplant recipients is a cost-effective intervention compared with other established healthcare interventions such as strategies for colorectal cancer screening. Prophylaxis with oral or parenteral ganciclovir is probably the most cost-effective strategy; however, restricting prophylaxis to high-risk groups (such as donor seropositive/recipient seronegative status and the use of an antilymphocyte antibody) or chemoprophylaxis for an extended period does not improve cost effectiveness. Pre-emptive therapy is an evolving strategy for prevention of CMV disease in transplant recipients and is rapidly gaining in popularity. Well-designed trials incorporating prospective cost data and comparing pre-emptive therapy versus conventional antiviral prophylaxis are needed to establish the superiority of one strategy over the other.     

Current management strategies for the prevention and treatment of cytomegalovirus infection in pediatric transplant recipients

Cytomegalovirus (CMV) is a significant cause of morbidity and mortality following transplantation, especially in the pediatric population, who remain at high risk of primary infection. The availability of effective antiviral therapy has led to dramatic improvements in the outcome of CMV infection in patients undergoing transplantation. In recent years, three major strategies have been developed for the prevention of CMV disease in this population: reduction of risk of viral acquisition or reactivation by management of risk factors; prophylaxis of all 'at-risk' patients using prophylactic strategies for a defined period of time, initiated at or near the time of transplant; and pre-emptive treatment with ganciclovir of selected 'at-risk' patients, guided by either laboratory markers indicative of subclinical infection or the presence of specific risk factors. In general, well designed comparative studies of one or more antiviral agents for the prevention of CMV have not been carried out. While ganciclovir appears to be more effective than aciclovir, its tolerability profile is less optimal. The use of foscarnet avoids myelosuppresions, but is associated with significant nephrotoxicity. Its use should be reserved for patients unable to tolerate ganciclovir or with ganciclovir-resistant CMV disease. Similar to foscarnet, the high frequency of nephrotoxicity associated with the use of cidofovir limits its use to clinical scenarios suggestive of ganciclovir resistance. Newer options, such as valaciclovir and valganciclovir, are currently under investigation and preliminary experience has been promising. Finally, passive immunoprophylaxis has been shown to prevent CMV disease after solid organ transplantation, but its use in bone marrow transplantation is controversial. Essentially, pre-emptive strategies have relied on the quantitation in the peripheral blood of CMV phosphoprotein pp65 antigen and/or the polymerase chain reaction assay. Strict guidelines for the use of those assays as a guide to pre-emptive therapy have not been standardized. Prospective trials comparing pre-emptive therapy using either intravenous or oral ganciclovir, and now oral valganciclovir or valaciclovir, are necessary to determine the relative cost effectiveness and efficacy of these alternative strategies. Finally, it remains controversial as to whether prophylaxis or pre-emptive therapy is the optimal strategy for preventing CMV disease. While a growing body of literature describes these approaches in adult transplant recipients, published experience in children has been much more limited.     

Ganciclovir: an update of its use in the prevention of cytomegalovirus infection and disease in transplant recipients

Ganciclovir is a nucleoside guanosine analogue which incorporates ganciclovir triphosphate (the active moiety) into DNA during elongation, thereby inhibiting viral replication. Comparative studies of pre-emptive and prophylactic ganciclovir therapies in bone marrow transplant (BMT) recipients have shown similar rates of cytomegalovirus (CMV) infection, disease and patient mortality. Long term prophylaxis with either oral, or sequential intravenous/oral, ganciclovir has shown efficacy in renal allograft recipients, including high risk patients or those receiving antilymphocyte antibody therapy. A preliminary study indicates that ganciclovir is more efficacious than aciclovir in paediatric patients. Both oral and intravenous prophylactic ganciclovir regimens have shown efficacy compared with no antiviral treatment in lung transplant recipients; initial reports have shown similar efficacy between pre-emptive and prophylactic ganciclovir. Oral ganciclovir monotherapy is as efficacious as sequential intravenous/oral ganciclovir therapy in liver transplant recipients. Pre-emptive treatment was equally as effective as long term ganciclovir prophylaxis in high risk patients. Ganciclovir prophylaxis for 4 weeks appears ineffective in heart allograft recipients treated with antithymocyte globulin. Long term sequential intravenous/ oral ganciclovir therapy has shown greater efficacy in preventing CMV disease than sequential ganciclovir/aciclovir therapy. in these patients. Initial reports indicate that pre-emptive therapy may be beneficial in this patient group. although this remains to be determined. Ganciclovir in therapeutic dosage regimens generally has acceptable tolerability with adverse effects usually of a haematological or neurological nature. Neutropenia, thrombocytopenia and anaemia are the primary dose-limiting toxicities associated with ganciclovir therapy. Overall, neutropenia occurs less frequently with administration of oral ganciclovir than with intravenous ganciclovir. Monitoring of renal function is recommended as serum creatinine levels may rise during ganciclovir therapy. In addition, ganciclovir prophylaxis appears more cost effective than the majority of other currently available therapies for CMV with oral ganciclovir more cost effective than intravenous ganciclovir. In conclusion, it is unlikely that a single strategy will be able to be applied to all transplant patients for the prevention of CMV disease. An optimal strategy will probably be arisk-adapted approach. Prophylactic treatment with ganciclovir appears the best strategy to implement in high risk patients: oral ganciclovir formulations may be best employed where lower toxicity is required. Pre-emptive treatment with ganciclovir appears most efficacious in patients identified as lower risk or, in the case of BMT recipients, where lower toxicity may be desirable. Ganciclovir remains an important therapeutic option for the prevention and treatment of CMV disease in transplant recipients.     

口服抗病毒新药——缬更昔洛韦

缬更昔洛韦 (valganciclovir)是抗病毒药更昔洛韦的前体药物 ,用于治疗AIDS病人发生的巨细胞病毒 (CMV)视网膜炎。缬更昔洛韦口服后迅速吸收 ,并水解为更昔洛韦 ,其口服给药的生物利用度较高 (60 % )。试验表明 ,口服缬更昔洛韦 (90 0mg)与静脉注射更昔洛韦 (5mg·kg-1) ,bid,3wk后改为 qd ,治疗 1 60例AIDS病人发生的CMV视网膜炎有相同疗效 ,且耐受性相似。缬更昔洛韦维持治疗中最常见的不良反应为中性粒细胞减少症、贫血、胃肠道反应 (腹泻、恶心、呕吐 )、发热、头痛和失眠等     

HIV/AIDS感染型的巨细胞病毒视网膜炎药物治疗研究

巨细胞病毒(Cytomegalovirus,CMV)视网膜炎是AIDS患者中最普遍的视觉损伤,严重危害着人们的健康,所有年龄段的人群都可能感染CMV病毒,尤其是新生儿、器官移植者和免疫功能缺损者如HIV/AIDS患者等。感染CMV初期,一般呈无症状或隐性感染,一旦免疫功能缺损时将导致发生严重疾病如视网膜脱落、失明等。目前CMV视网膜炎的治疗药物有更昔洛韦,膦甲酸,西多福韦,缬更昔洛韦,更昔洛韦埋植剂,其中更昔洛韦埋植剂、口服缬更昔洛韦已经广泛用于治疗CMV视网膜炎。     

Viral prophylaxis in organ transplant patients

Viral pathogens have emerged as the most important microbial agents having deleterious effects on solid organ transplant (SOT) recipients. Antiviral chemoprophylaxis involves the administration of medications to abort transmission of, avoid reactivation of, or prevent progression to disease from, active viral infection. Cytomegalovirus (CMV) is the major microbial pathogen having a negative effect on SOT recipients. CMV causes infectious disease syndromes, augments iatrogenic immunosuppression and is commonly associated with opportunistic superinfection. CMV has also been implicated in the pathogenesis of rejection. Chemoprophylactic regimens for CMV have included oral aciclovir (acyclovir) at medium and high doses, intravenous and oral ganciclovir, and the prodrugs valaciclovir (valacyclovir) and valganciclovir. CMV prophylactic strategies should be stratified, with the highest-risk patients receiving the most 'potent' prophylactic regimens. Herpes simplex virus (HSV) reactivation in SOT recipients is more frequent, may become more invasive, takes longer to heal, and has greater potential for dissemination to visceral organs than it does in the immunocompetent host. Prophylactic regimens for CMV are also effective chemoprophylaxis against HSV; in the absence of CMV prophylaxis, aciclovir, valaciclovir or famciclovir should be used as HSV prophylaxis in seropositive recipients. Primary varicella-zoster virus (VZV) after SOT is rare and most commonly seen in the paediatric transplant population because of VZV epidemiology. Zoster occurs in 5-15% of patients, usually after the sixth post-transplant month. Prophylactic regimens for zoster are neither practical nor cost effective after SOT because of the late onset of disease and low proportion of affected individuals. All SOT recipients should receive VZV immune globulin after contact with either varicella or zoster. Epstein-Barr virus has its most significant effect in SOT as the precipitating factor in the development of post-transplant lymphoproliferative disorders. Antiviral agents that could be effective are the same as those used for CMV, but indications for and effectiveness of prophylaxis are poorly established. Hepatitis B virus (HBV) and hepatitis C virus (HCV) are important pathogens in the SOT population as indications for transplantation. So-called 'prophylaxis' for recurrent HBV and HCV after liver transplantation is controversial, suppressive rather than preventive, and potentially lifelong. Influenza infection after SOT is acquired by person-to-person contact. During epidemic periods of influenza, transplant populations experience a relatively high frequency of infection, and influenza may affect immunosuppressed SOT recipients more adversely than immunocompetent individuals. Antiviral medications for prevention of influenza are administered as post-exposure prophylaxis to SOT recipients, in addition to yearly vaccine, in circumstances such as influenza epidemics and nosocomial outbreaks, and after exposure to a symptomatic individual during 'flu season'.     

Efficacy and safety of low-dose valganciclovir for prevention of cytomegalovirus disease in renal transplant recipients: a single-center, retrospective analysis

STUDY OBJECTIVE: To evaluate the safety and efficacy of valganciclovir 450 mg/day for 6 months for cytomegalovirus (CMV) prophylaxis in renal transplant recipients. DESIGN: Single-center, retrospective analysis. SETTING: Urban, academic medical center. PATIENTS: Fifty-eight patients who received de novo renal transplants from August 1, 2001-November 21, 2002. INTERVENTION: Valganciclovir 450 mg/day was administered to all renal transplant recipients at risk for CMV disease. Therapy was begun postoperatively and was dose adjusted to renal function. MEASUREMENTS AND MAIN RESULTS: Data collected from renal transplant recipients were demographics, immunosuppressive and antiviral drug therapy, and occurrence of CMV disease, acute rejection, allograft loss, and hematologic adverse events. Donor (D)/recipient (R) CMV serostatus was 37.9% D+/R+, 29.3% D-/R+, 17.3% D+/R-, and 15.5% D-/R-. Antithymocyte globulin (ATG) was administered to 62.1% of patients. Most of the transplant recipients received triple immunosuppression as maintenance therapy. Median follow-up was 20 months. The frequency of CMV disease was 1.7% within 6 months after transplantation and 5.2% at any point after transplantation. All patients who developed CMV disease were D+/R- and had received ATG. Leukopenia and thrombocytopenia associated with valganciclovir were seen in 28% and 24% of patients, respectively. One patient developed acute cellular rejection. No graft losses or deaths occurred. Early discontinuation of valganciclovir occurred in 20% of patients secondary to severe, persistent leukopenia, thrombocytopenia, and/or diarrhea. None of these patients developed CMV disease. CONCLUSION: A high rate of CMV disease was noted among the D+/R- population. Administration of ATG as an induction agent also increased the frequency of CMV disease. Despite the low dosage of valganciclovir, hematologic adverse events were common. However, valganciclovir, administered at 450 mg/day for 6 months, was effective and relatively safe for prophylaxis of CMV disease in renal transplant recipients.     

Single-dose pharmacokinetics of valganciclovir in HIV- and CMV-seropositive subjects.

As a result of the low oral bioavailability of ganciclovir, a prodrug was developed to improve the bioavailability of ganciclovir. This study was designed to investigate the fasting, single-dose pharmacokinetics as well as the absolute and relative bioavailability of a valine ester prodrug of ganciclovir, valganciclovir, as compared to oral and intravenous ganciclovir in asymptomatic HIV+ and CMV+ subjects. In this open-label, randomized, three-period crossover study, 18 subjects received, in random order, single oral doses of valganciclovir 360 mg and ganciclovir 1000 mg and an intravenous infusion of ganciclovir 5 mg/kg over 1 hour. Valganciclovir was rapidly and extensively hydrolyzed to ganciclovir, resulting in significantly greater bioavailability compared to 1000 mg oral ganciclovir (60.9% vs. 5.6%, respectively). Higher peak serum concentrations were reached earlier following valganciclovir (ganciclovir [2.98 +/- 0.77 micrograms/mL at 1.0 +/- 0.3 h]) than following oral ganciclovir (0.47 +/- 0.17 microgram/mL and 2.2 +/- 1.0 h). Mean total ganciclovir AUCs following oral ganciclovir (1000 mg) and 360 mg valganciclovir (3.8 +/- 1.2 and 10.8 +/- 1.9 micrograms-h/mL) were less than that following a standard 5 mg/kg intravenous infusion of ganciclovir (25.1 +/- 3.8 micrograms-h/mL). In summary, valganciclovir is a prodrug with a favorable safety profile with enhanced bioavailability and significantly higher serum concentrations of ganciclovir than following oral administration of ganciclovir itself.     

Ganciclovir in solid organ transplant recipients: is there a role for clinical pharmacokinetic monitoring?

The authors use a previously published decision-making algorithm to address the role of clinical pharmacokinetic monitoring of ganciclovir, the drug of choice for prophylaxis and treatment of cytomegalovirus (CMV) in solid organ transplant recipients. Ganciclovir pharmacokinetics have been studied in solid organ transplant recipients with a wide range of peak and trough concentrations reported. Numerous assays are available to measure plasma concentrations of ganciclovir, but no clear correlation has been established between peak or trough concentrations and either efficacy or toxicity of the drug. For patients receiving treatment, the pharmacological response of ganciclovir is assessed initially by clinical response. Monitoring prophylactic therapy in asymptomatic patients poses a greater challenge. Although monitoring of antigenemia or polymerase chain reaction (PCR) deoxyribonucleic acid (DNA) is not yet part of routine clinical practice, studies have shown a role for these techniques in monitoring response to antiviral therapy. Studies of subpopulations of renal failure patients show a prolonged ganciclovir half-life that requires dosage adjustments. However, ganciclovir clearance is closely correlated with creatinine clearance, which is an appropriate approach to adjusting dosages. Studies in pediatric patients also demonstrate a close correlation between dose per kilogram and AUC, suggesting that monitoring of ganciclovir levels may not be necessary. Based on the evidence presented in this review, routine clinical pharmacokinetic monitoring of ganciclovir does not appear to be warranted in solid organ transplant recipients.     

AIDS-related cytomegalovirus retinitis

Until recently, chronic daily intravenous infusions of ganciclovir or foscarnet were the only available treatment regimens for cytomegalovirus (CMV) retinitis, a sight-threatening complication that has historically affected approximately one-third of all AIDS patients in industrialized countries. In recent years, results of many randomized clinical trials of new treatments for AIDS-related CMV retinitis have been disseminated. These trials have involved four novel treatment modalities (i.e., an oral formulation of ganciclovir, a ganciclovir intraocular device, a combined intravenous ganciclovir/foscarnet regimen and a new agent, cidofovir) that offer better efficacy and/or less inconvenience than standard daily intravenous therapy with either ganciclovir or foscarnet. This review summarizes the main points clinicians should know about the available treatments for CMV disease.     

Cidofovir: a review of its use in cytomegalovirus retinitis in patients with AIDS.

Cidofovir is an antiviral nucleotide analogue with significant activity against cytomegalovirus (CMV) and other herpesviruses. The drug is indicated for the treatment of CMV retinitis, a sight-threatening condition, in patients with AIDS. Cidofovir has a long intracellular half-life which allows for a prolonged interval (2 weeks) between maintenance doses. In contrast, other intravenous treatment options for patients with CMV retinitis (i.e. ganciclovir and foscarnet) must be administered on a daily basis. The efficacy of intravenous cidofovir has been demonstrated in patients with AIDS and previously untreated CMV retinitis in multicentre randomised trials, and in a dose-finding study of cidofovir in patients with AIDS and previously treated relapsing CMV retinitis. Clinical trials have been relatively small (n < or = 100 patients) and no studies have been conducted directly comparing intravenous cidofovir with the more established intravenous agents, ganciclovir or foscarnet. Indirect comparisons of clinical trial data suggest that intravenous cidofovir may have similar efficacy to intravenous ganciclovir or foscarnet in delaying progression of CMV retinitis. However, such comparisons must be made with caution because of potential differences in patient populations, data analysis techniques and interobserver variability in the masked assessment of retinal photographs. Nevertheless, intravenous cidofovir offers a less intrusive administration regimen than intravenous ganciclovir or foscarnet because of its prolonged dosage interval. Since therapy is life-long, patients receiving daily intravenous ganciclovir or foscarnet (but not cidofovir) usually require an indwelling central venous catheter and are therefore at increased risk of serious infection. The relatively long dosage interval for cidofovir may also have favourable implications in terms of overall treatment costs and patient quality of life, although specific data are very limited. Potentially irreversible nephrotoxicity is the major treatment-limiting adverse event associated with intravenous cidofovir in patients with AIDS-related CMV retinitis. Anterior uveitis/iritis has been reported frequently with intravenous cidofovir in postmarketing reports and a small number of patients have developed hypotony. Other treatment options for CMV retinitis are also associated with serious adverse events, and selection of pharmacotherapy will depend on a number of factors including retinitis lesion characteristics, patient quality-of-life issues and efficacy and tolerability profiles of available therapies. CONCLUSION: Although the extent of its use may be limited by its adverse event profile, cidofovir offers a useful addition to the limited number of drugs available for the treatment of CMV retinitis in patients with AIDS.