Pharmacokinetics of intermittently administered intravenous foscarnet in the treatment of acquired immunodeficiency syndrome patients with serious cytomegalovirus retinitis

Aweeka, Francesca; Gambertoglio, John G.; Mills, John; Jacobson, Mark A.

doi:10.1128/aac.33.5.742

Cited by 60 publications

(20 citation statements)

References 11 publications

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“…Because of poor oral absorption, foscarnet is administered intravenously (20). Pharmacokinetic parameters of this drug have been established after either continuous intravenous infusion (15,19,20) or intermittent administration at a dosage of 60 mg/kg of body weight every 8 h (1,7). Clinical experience suggests that the twice-daily administration of 90 mg/kg was as effective as the threetimes-daily administration of 60 mg/kg (5,12).…”

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confidence: 99%

Pharmacokinetics of foscarnet after twice-daily administrations for treatment of cytomegalovirus disease in AIDS patients

Taburet

Katlama

Blanshard

et al. 1992

Antimicrob Agents Chemother

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The pharmacokinetics of foscarnet were evaluated in 11 AIDS patients with cytomegalovirus disease after twice-daily infusion of 90 mg/kg of body weight for 2 weeks. All patients were hydrated during foscarnet infusion. Blood and urine samples were collected on days 1, 7, and 14 of therapy. Foscarnet concentrations were measured by high-pressure liquid chromatography. Despite large interindividual variations, no significant differences were seen between day 1, day 7, and day 14 concentrations in plasma. Mean peak and trough concentrations on day 14 of therapy were 605 ± 118 and 52 ± 59 ,uM, respectively. In all patients, peak concentrations were well above those necessary to inhibit cytomegalovirus. Pharmacokinetic parameters remained stable throughout the study. On day 14, the mean half-life was 3.4 h, total and renal clearances were 118 and 92 ml/min, respectively, and the volume of distribution was 0.6 liter/kg. These data and previous clinical trials demonstrate that this more convenient dosage regimen can be safel used for patients with cytomegalovirus disease. The side effects were comparable to those reported with other dosage regimens, although no renal impairment was seen in this study, probably because of the hydration.Foscarnet, a PPi analog (trisodium phosphonoformate hexahydrate), selectively inhibits the DNA polymerase of human herpesviruses, including cytomegalovirus and the reverse transcriptase of human immunodeficiency virus (HIV) (2). Clinical studies have demonstrated the role of foscarnet in the treatment of cytomegalovirus disease complicating immunodeficiency diseases, including HIV infection (8,11,18,21). Because of poor oral absorption, foscarnet is administered intravenously (20). Pharmacokinetic parameters of this drug have been established after either continuous intravenous infusion (15,19,20) or intermittent administration at a dosage of 60 mg/kg of body weight every 8 h (1, 7). Clinical experience suggests that the twice-daily administration of 90 mg/kg was as effective as the threetimes-daily administration of 60 mg/kg (5, 12).The aim of this study was to evaluate the pharmacokinetic properties of foscarnet after single and repeated administrations of the twice-daily dosage regimen, which is more convenient than the currently used continuous intravenous infusion or the three-times-daily regimen. MATERIALS AND METHODSPatients. Eleven AIDS patients were included in the study: five patients with cytomegalovirus retinitis, five with cytomegalovirus gastrointestinal disease, and one with biopsyproven cytomegalovirus pneumonitis. Nine were Caucasian males, one was a black male, and one was a Caucasian female. The median age was 34 years, (range, 22 to 44 years), the mean weight was 61 + 9 kg, and the mean serum creatinine level was 86 ± 21 ,uM. Mean creatinine clearance calculated by the method of Cockcroft and Gault (3) was 94

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confidence: 99%

Pharmacokinetics of foscarnet after twice-daily administrations for treatment of cytomegalovirus disease in AIDS patients

Taburet

Katlama

Blanshard

et al. 1992

Antimicrob Agents Chemother

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“…Additionally, serial CD4+ cell counts obtained during induction therapy were analyzed by a normalized (adjusted for baseline) area-under-the-curve (NAUC) method; Induction phase concentration-time data were fit to a twocompartment pharmacokinetic model by a Bayesian estimation strategy (13). The a priori population parameters used were taken from the data for foscarnet in the literature (2,14,15). These parameters correspond to a typical half-life at ox phase of 0.31 h, a half-life at X phase of 4.4 h, and a clearance of 0.11 liter/kg/h.…”

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confidence: 99%

Foscarnet for suppression of human immunodeficiency virus replication

Fletcher

Collier

Rhame

et al. 1994

Antimicrob Agents Chemother

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The effect of foscarnet against human immunodeficiency virus (H1V) was evaluated in nine HIV-infected individuals; six completed 28 days of induction therapy. The overall mean increase in CD4+ lymphocytes was 64 cells per mm3. The mean decline in the HIV antigen concentration was 108 pg/ml (P = 0.03), and suppression was related to systemic foscarnet exposure by a maximum-effect pharmacodynamic model.Foscarnet has in vitro activity against a broad spectrum of viruses, including herpes simplex virus, varicella-zoster virus, cytomegalovirus (CMV), hepatitis B virus, and human immunodeficiency virus (HIV) (8,12). Several investigations of foscarnet therapy for CMV retinitis in patients with AIDS have described a decrease in the concentration of HIV antigen in serum (6,9,11). The present study (designated protocol 028 by the AIDS Clinical Trials Group [ACTG]) was designed to evaluate the safety, pharmacokinetic disposition, and anti-HIV effect of foscarnet in HIV-infected individuals.The criteria for participation in this trial included confirmed HIV infection with CD4+ lymphocyte count of less than 500/mm3 (on two separate occasions), detectable concentration of HIV antigen in serum equal to or greater than 25 pg/ml, age of .12 years, Karnofsky performance status of at least 60%, granulocyte count of >1,000 cells per mm3, platelet count of >75,000/mm3, hemoglobin concentration of .9 g/dl, and serum creatinine and bilirubin levels within the normal range. Primary and secondary chemoprophylaxis of Pneumocystis carinii pneumonia was permitted but not required; antiretroviral agents were not allowed. This investigation was approved by the institutional review board of each participating site, and all subjects gave written consent before participation.Study participants were randomly assigned to groups given 12.5, 25, or 50 mg of foscarnet per kg of body weight every 8 h for the first 28 days. Individuals who were clinically stable after 28 days had the option of receiving maintenance therapy that consisted of a dose of 50 mg/kg given once daily 5 days per week for an indefinite period. During the 28-day induction period, foscarnet was administered in a double-blind manner. The dose was adjusted in any participant whose estimated creatinine clearance was .1.3 ml/min/kg. Study participants were required to spend a minimum of 48 h after initiation of therapy as inpatients, after which they were monitored as outpatients.Patients responses to therapy. CD4+ lymphocyte cell counts were obtained at screening, entry into study, the second and fourth week of treatment, and then monthly. Serum HIV antigen tests were collected weekly during induction but were otherwise obtained according to the same schedule as that for CD4+ lymphocyte counts. Serum HIV antigen levels were measured with an enzyme-linked immunosorbent assay kit (Abbott Laboratories, North Chicago, Ill.), using purified virion p24 (ACTG Virology Reference Laboratory) as the calibration standard; the limit of detection was 10 pg/ml. All serum samples were stored at -...

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“…The lowest concentration offoscarnet detectable by this assay is 33 umol/L. Calculation of plasma half-lives (t I / 2 ) of foscarnet was done as described [27].…”

Section: Methodsmentioning

confidence: 99%

Phase I-II Trial of Foscarnet for Prevention of Cytomegalovirus Infection in Autologous and Allogeneic Marrow Transplant Recipients

Reusser

Gambertoglio

Lilleby

et al. 1992

Journal of Infectious Diseases

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The safety and efficacy of foscarnet for prevention of cytomegalovirus (CMV) infection was evaluated in 19 CMV-seropositive bone marrow transplant (BMT) recipients. All patients received intermittent intravenous (iv) foscarnet: 40 mg/kg every 8 h from 7 days before to day 30 after BMT, then 60 mg/kg once a day until day 75. The main toxicity was transient renal dysfunction, with a >50 pmol/L increase in serum creatinine above baseline in 5 of the 7 autograft recipients and in 6 of the 12 allograft recipients. Only 4 allograft recipients developed CMV infection during foscarnet prophylaxis, and no patient showed evidence ofCMV disease. Because 3 allograft recipients receiving concomitant iv amphotericin B showed rapid impairment of renal function, foscarnet prophylaxis should not be given to allograft recipients requiring amphotericin B; otherwise, foscarnet prophylaxis at this dose appears safe after BMT.Infection due to cytomegalovirus (CMV) causes significant morbidity and mortality among bone marrow transplant (BMT) recipients [1]. In two published series, the probability ofCMV infection within the first 100 days after BMT among patients who were CMV-seropositive before transplant was up to 80%and 60%for allograft and autograft recipients, respectively [2,3]. Mortality was primarily related to CMV pneumonia, which developed in 37% of allograft and in 22% of autograft recipients who had evidence of active CMV infection [2,3]. Thus, the prevention of CMV infection and disease after BMT is of foremost importance.Antiviral chemotherapy aimed at preventing reactivation of latent virus may be the most promising approach to CMV prophylaxis both among CMV-seropositive autograft and allograft recipients and among seronegative allograft recipients who have a seropositive marrow donor. CMV drug prophylaxis should cover the early period after BMT in which a deficiency in CMV-specific immunity can contribute to the risk of severe CMV disease [4].The antiviral agent acyclovir given intravenously at high doses was shown to be partially effective in preventing CMV infection and disease among seropositive BMT recipients [5].

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Pharmacokinetics of intermittently administered intravenous foscarnet in the treatment of acquired immunodeficiency syndrome patients with serious cytomegalovirus retinitis

Cited by 60 publications

References 11 publications

Pharmacokinetics of foscarnet after twice-daily administrations for treatment of cytomegalovirus disease in AIDS patients

Pharmacokinetics of foscarnet after twice-daily administrations for treatment of cytomegalovirus disease in AIDS patients

Foscarnet for suppression of human immunodeficiency virus replication

Phase I-II Trial of Foscarnet for Prevention of Cytomegalovirus Infection in Autologous and Allogeneic Marrow Transplant Recipients

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