Intravitreal Ganciclovir Concentration after Intravenous Administration in AIDS Patients with Cytomegalovirus Retinitis: Implications for Therapy

Kuppermann, Baruch D.; Quiceno, José I.; Flores-Aguilar, Marisa; Connor, James D.; Capparelli, Edmund V.; Sherwood, Charles H.; Freeman, William R.

doi:10.1093/infdis/168.6.1506

Cited by 93 publications

(23 citation statements)

References 12 publications

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“…The limited performance of CMV load in the prediction of CMV retinitis progression might have been predicted, since most patients receiving systemic anti-CMV therapy suffer relapse of retinitis because of the limited intraocular penetration of systemic anti-CMV drugs, and not because of resistance [26,43,44]. Therefore, events occurring in the blood may be less relevant for CMV retinitis progression.…”

Section: Discussionmentioning

confidence: 99%

“…Time-dependent analyses were performed for the association of CMV load with CMV retinitis progression and with occurrence of resistant CMV, for the following reasons: (1) CMV retinitis progression occurs in nearly all patients treated with systemic anti-CMV therapy [1,26,42], because of the limited intraocular penetration of these drugs [43,44], even without the occurrence of resistance; and (2) regardless of whether a patient harbors a resistant virus, treatment regimens and CMV load may change over time [15,27]. Patient follow-up was divided into 3-month blocks centered on the collection of specimens for CMV culture and CMV load measurement.…”

Section: Patientsmentioning

confidence: 99%

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Cytomegalovirus (CMV) Blood DNA Load, CMV Retinitis Progression, and Occurrence of Resistant CMV in Patients with CMV Retinitis

et al. 2005

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The amount of cytomegalovirus (CMV) DNA in the blood (CMV load) may be a marker for detection of resistant CMV.METHODS. A total of 165 patients with AIDS and CMV retinitis had CMV load measurements (plasma and leukocyte) and cultures performed every 3 months; these measurements were correlated with CMV resistance to antiviral drugs and CMV retinitis progression (from masked readings of retinal photographs).RESULTS. Detectable plasma and leukocyte CMV loads were associated with CMV retinitis progression (odds ratios [OR], 6.3; P<.0001 and OR, 6.6; P<.0001, respectively), phenotypic resistance (OR, 6.1; P<.0001 and OR, 23.4; P=.0002, respectively), and genotypic resistance (OR, 17.5; P<.0001 and OR, 51.6; P=.0004, respectively). The sensitivity, specificity, and positive and negative predictive values of plasma CMV loads were 0.47, 0.86, 0.36, and 0.91, respectively, for progression and 0.59, 0.81, 0.07, and 0.99, respectively, for resistance; those of leukocyte CMV loads were 0.52, 0.83, 0.35, and 0.91, respectively, for progression and 0.82, 0.78, 0.08, and 0.99, respectively, for resistance. A detectable plasma CMV load at the time of diagnosis of CMV retinitis was associated with mortality (median survival time, 13.6 vs. 29.7 months; P=.007).CONCLUSIONS. CMV load has limited clinical utility, because of its low positive predictive value. Its high negative predictive value for occurrence of resistant CMV suggests that it may have utility as a screening tool to exclude resistance.

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Section: Discussionmentioning

confidence: 99%

Section: Patientsmentioning

confidence: 99%

Cytomegalovirus (CMV) Blood DNA Load, CMV Retinitis Progression, and Occurrence of Resistant CMV in Patients with CMV Retinitis

et al. 2005

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“…Intravenous administration of antiviral agents has been the conventional mode of administration in AIDS patients. Kuppermann et al, (1993) reported a mean intravitreal GCV concentration of 0.93 Ϯ 0.39 g/ml from a daily dose of 6.1 Ϯ 2.0 mg/kg i.v. for a period of 3 months, which falls within the borderline or subtherapeutic levels.…”

Section: Discussionmentioning

confidence: 99%

Ocular Disposition of Ganciclovir and Its Monoester Prodrugs following Intravitreal Administration Using Microdialysis

Macha¹,

Mitra²

2002

Drug Metabolism and Disposition

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ABSTRACT:The present study was carried out to delineate the ocular pharmacokinetics of ganciclovir (GCV) following intravitreal administration. Another objective was to achieve sustained therapeutic concentrations of GCV in the vitreous over a prolonged period of time using its acyl monoester prodrugs (acetate, propionate, butyrate, and valerate). New Zealand albino male rabbits (2-2.5 kg) were kept under anesthesia. A concentric microdialysis probe was implanted in the vitreous using a 21-guage needle, and a linear microdialysis probe was implanted in the anterior chamber across the cornea using a 25-guage needle. The probes were perfused with isotonic phosphate buffer saline (pH 7.4) at a flow rate of 2 l/min. The drugs were administered (0.2 moles) intravitreally and the samples were collected every 20 min over a period of 10 h. The vitreal terminal elimination half-life (t 1/2 ␤) of GCV was found to be 426 ؎ 109 min. The hydrolysis rate and vitreal clearance of the prodrugs increased with the ascending ester chain length. The vitreal elimination half-lives (t 1/2k10 ) of GCV, acetate, propionate, butyrate, and valerate esters of GCV were 170 ؎ 37, 117 ؎ 50, 122 ؎ 13, 55 ؎ 26, and 107 ؎ 14 min, respectively. A parabolic relationship was observed between the vitreal elimination rate constant and the ester chain length. Mean residence time (MRT) of the regenerated GCV following prodrug administration was found to be three to four times the value obtained after GCV injection. In conclusion, these studies have shown that the ester prodrugs generated therapeutic concentrations of GCV in vivo, and the MRT of GCV could be enhanced by 3-to 4-fold through prodrug modification.

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“…At the University of Minnesota, samples were collected and well documented at irregular intervals. Serum samples were assayed for ganciclovir by two previously validated high-performance liquid chromatographic (HPLC) assays (6,7). The patients at the University of Minnesota all had their samples assayed by one method (6).…”

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confidence: 99%

Population differences in ganciclovir clearance as determined by nonlinear mixed-effects modelling

Yuen

Drusano

Fletcher

et al. 1995

Antimicrob Agents Chemother

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We examined the pharmacokinetics of ganciclovir in different populations of cytomegalovirus (CMV)-infected patients through the use of nonlinear mixed-effects modelling. As expected, patient weight and estimated creatinine clearance were shown to be important covariates in the serum ganciclovir clearance. Unexpectedly, major differences in ganciclovir clearance between different populations of patients were found. Human immunodeficiency virus (HIV)-infected patients with CMV retinitis cleared ganciclovir 41% faster than HIV-infected patients only shedding CMV into the urine. Solid-organ transplant patients had a serum clearance one-fourth that of HIV-infected patients, even with correction for creatinine clearance. These findings require prospective validation and may have important implications for ganciclovir dosing in different populations of CMV-infected patients.Ganciclovir is an acyclic nucleoside analog with efficacy in patients with serious cytomegalovirus (CMV) infections (3-5, 8, 10). The utility of the drug has been demonstrated in human immunodeficiency virus (HIV)-positive patients with CMV retinitis, as well as with other serious CMV disease (3, 10). Other patient populations such as transplant recipients suffering from CMV disease have also demonstrated therapeutic benefit of ganciclovir (4,5,8).In addition to therapeutic effectiveness, many antiviral drugs also have exposure-related toxicities. For ganciclovir, the most common dose-limiting toxicity is granulocytopenia (1). As there are now multiple different populations of patients receiving ganciclovir (e.g., patients with AIDS, solid-organ transplant patients, and bone marrow transplant patients), it is important to determine if these patient populations handle ganciclovir differently. This is of consequence if efficacy or toxicity is related to some measure of exposure (peak concentration, trough concentration, or area under the concentration-time curve. As a first step toward developing optimal dosing schedules for this agent, we examined the pharmacokinetics of ganciclovir in different patient populations employing the population modelling tool NONMEM (nonlinear mixed-effects modelling) (9).Patients were studied at six different medical centers. One of the centers (University of Minnesota) was examining the use of ganciclovir in CMV-infected renal-transplant patients. The other centers examined HIV-positive patients either with shedding of CMV into the urine or with CMV retinitis. The ganciclovir was administered intravenously as a 1-h constant-rate infusion. The dosage range was from 1.2 to 5.0 mg/kg of body weight. Blood was collected for serum from all patients, except for those studied at the University of Minnesota, at 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 12.0, 15.0, and 24.0 h after the initiation of the infusion. At the University of Minnesota, samples were collected and well documented at irregular intervals. Serum samples were assayed for ganciclovir by two previously validated high-performance liquid chromatographic (HPLC) assays (...

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Intravitreal Ganciclovir Concentration after Intravenous Administration in AIDS Patients with Cytomegalovirus Retinitis: Implications for Therapy

Cited by 93 publications

References 12 publications

Cytomegalovirus (CMV) Blood DNA Load, CMV Retinitis Progression, and Occurrence of Resistant CMV in Patients with CMV Retinitis

Cytomegalovirus (CMV) Blood DNA Load, CMV Retinitis Progression, and Occurrence of Resistant CMV in Patients with CMV Retinitis

Ocular Disposition of Ganciclovir and Its Monoester Prodrugs following Intravitreal Administration Using Microdialysis

Population differences in ganciclovir clearance as determined by nonlinear mixed-effects modelling

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