RESUMO
Smallpox, caused by Variola virus (VARV), was eradicated in 1980; however, VARV bioterrorist threats still exist, necessitating readily available therapeutics. Current preparedness activities recognize the importance of oral antivirals and recommend therapeutics with different mechanisms of action. Monkeypox virus (MPXV) is closely related to VARV, causing a highly similar clinical human disease, and can be used as a surrogate for smallpox antiviral testing. The prairie dog MPXV model has been characterized and used to study the efficacy of antipoxvirus therapeutics, including recently approved TPOXX (tecovirimat). Brincidofovir (BCV; CMX001) has shown antiviral activity against double-stranded DNA viruses, including poxviruses. To determine the exposure of BCV following oral administration to prairie dogs, a pharmacokinetics (PK) study was performed. Analysis of BCV plasma concentrations indicated variability, conceivably due to the outbred nature of the animals. To determine BCV efficacy in the MPXV prairie dog model, groups of animals were intranasally challenged with 9 × 105 plaque-forming units (PFU; 90% lethal dose [LD90]) of MPXV on inoculation day 0 (ID0). Animals were divided into groups based on the first day of BCV treatment relative to inoculation day (ID-1, ID0, or ID1). A trend in efficacy was noted dependent upon treatment initiation (57% on ID-1, 43% on ID0, and 29% on ID1) but was lower than demonstrated in other animal models. Analysis of the PK data indicated that BCV plasma exposure (maximum concentration [Cmax]) and the time of the last quantifiable concentration (AUClast) were lower than in other animal models administered the same doses, indicating that suboptimal BCV exposure may explain the lower protective effect on survival.IMPORTANCE Preparedness activities against highly transmissible viruses with high mortality rates have been highlighted during the ongoing coronavirus disease 2019 (COVID-19) pandemic. Smallpox, caused by variola virus (VARV) infection, is highly transmissible, with an estimated 30% mortality. Through an intensive vaccination campaign, smallpox was declared eradicated in 1980, and routine smallpox vaccination of individuals ceased. Today's current population has little/no immunity against VARV. If smallpox were to reemerge, the worldwide results would be devastating. Recent FDA approval of one smallpox antiviral (tecovirimat) was a successful step in biothreat preparedness; however, orthopoxviruses can become resistant to treatment, suggesting the need for multiple therapeutics. Our paper details the efficacy of the investigational smallpox drug brincidofovir in a monkeypox virus (MPXV) animal model. Since brincidofovir has not been tested in vivo against smallpox, studies with the related virus MPXV are critical in understanding whether it would be protective in the event of a smallpox outbreak.
Assuntos
Citosina/análogos & derivados , Monkeypox virus/efeitos dos fármacos , Organofosfonatos/farmacologia , Organofosfonatos/farmacocinética , Varíola/tratamento farmacológico , Animais , Antivirais/farmacocinética , Antivirais/farmacologia , Benzamidas/farmacocinética , Benzamidas/farmacologia , Citosina/farmacocinética , Citosina/farmacologia , Modelos Animais de Doenças , Cães , Feminino , Isoindóis/farmacocinética , Isoindóis/farmacologia , Masculino , Vírus da Varíola/efeitos dos fármacosRESUMO
Brincidofovir (BCV) is an investigational lipid conjugate of the nucleotide analog cidofovir (CDV), which is being developed as a medical countermeasure for the treatment of smallpox. BCV is active against double-stranded DNA viruses including BK and JC viruses. Here, we validated procedures for quantifying BCV and its pharmacologically active moiety cidofovir diphosphate (CDV-PP) in mouse kidney, brain and spleen tissue homogenates. Following homogenization, BCV and CDV-PP were extracted from the tissues by protein precipitation with their stable, isotopically labeled internal standards, BCV-d6 and 13 C3 15 N2 -CDV-PP. Then, samples were analyzed for BCV by reverse-phase chromatography on a Waters Xterra MS C18 (50 × 2.1 mm, 3.5 µm particle size) column while CDV-PP was analyzed on a Thermo BioBasic AX (50 × 2.1 mm, 5 µm particle size) column using anion exchange chromatography. Detection was achieved by electrospray ionization in positive ion mode on an AB Sciex API-5000 triple quadrupole mass spectrometer. The calibration curves were linear over a range of 1.00-1,000 ng/ml homogenate and 0.050-50.0 ng/ml homogenate for BCV and CDV-PP, respectively. These methods were validated according to US Food and Drug Administration guidance for industry and may be used to characterize the tissue pharmacology of both analytes to advance its preclinical development.
Assuntos
Antivirais , Química Encefálica , Cidofovir , Citosina/análogos & derivados , Rim/química , Organofosfonatos , Baço/química , Animais , Antivirais/análise , Antivirais/farmacocinética , Cromatografia Líquida de Alta Pressão/métodos , Cidofovir/análise , Cidofovir/farmacocinética , Citosina/análise , Citosina/farmacocinética , Camundongos , Camundongos Endogâmicos C57BL , Organofosfonatos/análise , Organofosfonatos/farmacocinética , Infecções por Polyomavirus/tratamento farmacológico , Espectrometria de Massas em Tandem/métodosRESUMO
Brincidofovir (BCV) is a lipid conjugate of cidofovir with good oral bioavailability, enabling optimal intracellular levels of the active drug. Lower rates of nephrotoxicity and myelotoxicity make it a favorable alternative. Despite a greater safety profile among pediatric hematopoietic cell transplant recipients, the oral formulation has been associated with increased gastrointestinal toxicity in adult hematopoietic cell transplant recipients. Oral BCV continues to be developed as a countermeasure against smallpox, while a potentially safer intravenous preparation has been out licensed to another company. BCV has demonstrated great in vitro potency against double-stranded DNA viruses, especially adenovirus. Because of its importance for immunocompromised patients, this review aims to evaluate BCV's clinical and safety profile to support its continued development.
Assuntos
Infecções por Adenovirus Humanos/tratamento farmacológico , Antivirais , Citosina/análogos & derivados , Infecções por Vírus de DNA/tratamento farmacológico , Vírus de DNA/efeitos dos fármacos , Organofosfonatos , Infecções por Adenovirus Humanos/virologia , Animais , Antivirais/efeitos adversos , Antivirais/farmacocinética , Antivirais/farmacologia , Antivirais/uso terapêutico , Ensaios Clínicos como Assunto , Citosina/efeitos adversos , Citosina/farmacocinética , Citosina/farmacologia , Citosina/uso terapêutico , Infecções por Vírus de DNA/virologia , Humanos , Hospedeiro Imunocomprometido , Organofosfonatos/efeitos adversos , Organofosfonatos/farmacocinética , Organofosfonatos/farmacologia , Organofosfonatos/uso terapêuticoRESUMO
MDH-7 (2,3,9-tri-O-acetyl-5,6-dideoxy-1,10-di-[N4'-pentoxycarbonyl-5'-fluoro cytosine]-4-ulose 1,4: 7,10-difuranose-4,8-pyranose) is a novel anti-tumor drug candidate. To study the pharmacokinetic interaction between MDH-7 and 5-fluorouracil (5-FU), a sensitive and rapid liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed to simultaneously determine the concentrations of MDH-7 and 5-fluorouracil (5-FU) in rat plasma. Plasma samples were prepared by simple liquid-liquid extraction with ethyl acetate. Chromatographic separation was performed on a Waters XBridge™ C18 column (5⯵m, 2.1â¯mmâ¯×â¯150â¯mm) with the mobile phase of methanol and H2O (80:20, v/v). The ESI positive and negative ion switch was operated in the multiple reactions monitoring (MRM) mode. The calibration curves showed good linearity (r2â¯>â¯0.99) over the ranges of 50-8000â¯ng/mL for MDH-7 and 10-2000â¯ng/mL for 5-FU, respectively. The lower limit of quantitations (LLOQs) was 50â¯ng/mL (MDH-7) and 10â¯ng/mL (5-FU) with relative standard deviation (RSD)â¯<â¯13.0%. The proposed method was successfully applied to simultaneous assessment of pharmacokinetic drug-drug interaction between MDH-7 and 5-FU in rats.
Assuntos
Antimetabólitos Antineoplásicos/sangue , Cromatografia Líquida/métodos , Citosina/análogos & derivados , Fluoruracila/sangue , Nucleosídeos de Pirimidina/sangue , Espectrometria de Massas em Tandem/métodos , Animais , Antimetabólitos Antineoplásicos/química , Antimetabólitos Antineoplásicos/farmacocinética , Citosina/sangue , Citosina/química , Citosina/farmacocinética , Estabilidade de Medicamentos , Feminino , Fluoruracila/química , Fluoruracila/farmacocinética , Modelos Lineares , Masculino , Nucleosídeos de Pirimidina/química , Nucleosídeos de Pirimidina/farmacocinética , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
OBJECTIVES: The primary objective was to evaluate the safety and local tolerance of a topical 2% (w/w) cidofovir gel, applied directly to the cervices of women with high-grade cervical intraepithelial neoplasia (CIN 2+). The secondary objective was to evaluate the pharmacokinetics of cidofovir during the treatment. MATERIALS AND METHODS: Nine women with CIN 2+, were treated with a course of 3 g of cidofovir gel, applied locally once per week for 3 weeks in total (9 g). The treatment was administered in a cervical cap, applied to the cervix for 5 or 10 hours (n = 6 and 3 patients, respectively). Follow-up included a structured questionnaire, a gynecological examination, blood analysis for hematology, C-reactive protein (CRP), and renal function assessment plus pharmacokinetic analyses of cidofovir after each treatment and at the end of the full course. RESULTS: No clinically significant hematological/biochemical abnormalities or serious adverse events (SAE) were reported, although 6 mild to moderate adverse events (AE) occurred in relation to the study drug: 1 flu-like syndrome and 5 local AEs. Plasma concentrations of cidofovir were very low (mean Cmax of 103.0 and 99.2 ng/mL after 5 and 10 hours of exposure, respectively). CONCLUSION: Cidofovir, directly applied on CIN 2+, is reasonably well tolerated and the systemic exposure following topical application is much lower than that seen with intravenous administration, at the approved dose.â©.
Assuntos
Antivirais/administração & dosagem , Proteína C-Reativa/metabolismo , Citosina/análogos & derivados , Organofosfonatos/administração & dosagem , Displasia do Colo do Útero/tratamento farmacológico , Administração Tópica , Adulto , Antivirais/efeitos adversos , Antivirais/farmacocinética , Cidofovir , Citosina/administração & dosagem , Citosina/efeitos adversos , Citosina/farmacocinética , Feminino , Seguimentos , Géis , Humanos , Organofosfonatos/efeitos adversos , Organofosfonatos/farmacocinética , Inquéritos e Questionários , Fatores de Tempo , Adulto JovemRESUMO
ABT-072 is a non-nucleoside HCV NS5B polymerase inhibitor that was discovered as part of a program to identify new direct-acting antivirals (DAAs) for the treatment of HCV infection. This compound was identified during a medicinal chemistry effort to improve on an original lead, inhibitor 1, which we described in a previous publication. Replacement of the amide linkage in 1 with a trans-olefin resulted in improved compound permeability and solubility and provided much better pharmacokinetic properties in preclinical species. Replacement of the dihydrouracil in 1 with an N-linked uracil provided better potency in the genotype 1 replicon assay. Results from phase 1 clinical studies supported once-daily oral dosing with ABT-072 in HCV infected patients. A phase 2 clinical study that combined ABT-072 with the HCV protease inhibitor ABT-450 provided a sustained virologic response at 24 weeks after dosing (SVR24) in 10 of 11 patients who received treatment.
Assuntos
Citosina/análogos & derivados , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Hepacivirus/enzimologia , Estilbenos/química , Sulfonamidas/síntese química , Sulfonamidas/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Administração Oral , Disponibilidade Biológica , Técnicas de Química Sintética , Citosina/síntese química , Citosina/química , Citosina/farmacocinética , Citosina/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Humanos , Permeabilidade , Estereoisomerismo , Sulfonamidas/química , Sulfonamidas/farmacocinética , Distribuição Tecidual , Proteínas não Estruturais Virais/químicaRESUMO
Smallpox (variola) virus is considered a Category A bioterrorism agent due to its ability to spread rapidly and the high morbidity and mortality rates associated with infection. Current recommendations recognize the importance of oral antivirals and call for having at least two smallpox antivirals with different mechanisms of action available in the event of a smallpox outbreak. Multiple antivirals are recommended due in large part to the propensity of viruses to become resistant to antiviral therapy, especially monotherapy. Advances in synthetic biology heighten concerns that a bioterror attack with variola would utilize engineered resistance to antivirals and potentially vaccines. Brincidofovir, an oral antiviral in late stage development, has proven effective against orthopoxviruses in vitro and in vivo, has a different mechanism of action from tecovirimat (the only oral smallpox antiviral currently in the US Strategic National Stockpile), and has a resistance profile that reduces concerns in the scenario of a bioterror attack using genetically engineered smallpox. Given the devastating potential of smallpox as a bioweapon, preparation of a multi-pronged defense that accounts for the most obvious bioengineering possibilities is strategically imperative.
Assuntos
Antivirais/uso terapêutico , Armas Biológicas , Citosina/análogos & derivados , Surtos de Doenças/prevenção & controle , Organofosfonatos/uso terapêutico , Varíola/prevenção & controle , Varíola/terapia , Animais , Antivirais/farmacocinética , Benzamidas/uso terapêutico , Citosina/farmacocinética , Citosina/uso terapêutico , Bases de Dados de Produtos Farmacêuticos , Farmacorresistência Viral/efeitos dos fármacos , Farmacorresistência Viral/genética , Quimioterapia Combinada , Humanos , Isoindóis/uso terapêutico , Modelos Animais , Organofosfonatos/farmacocinética , Vírus da Varíola/efeitos dos fármacos , Vírus da Varíola/genéticaRESUMO
BACKGROUND: Brincidofovir (BCV) is an orally bioavailable lipid conjugate of cidofovir (CDV) with increased in vitro potency relative to CDV against all 5 families of double-stranded DNA viruses that cause human disease. After intravenous (IV) administration of CDV, the organic anion transporter 1 (OAT1) transports CDV from the blood into the renal proximal tubule epithelial cells with resulting dose-limiting nephrotoxicity. OBJECTIVE: To study whether OAT1 transports BCV and to evaluate the pharmacokinetic and renal safety profile of oral BCV compared with IV CDV. METHODS: The cellular uptake of BCV and its major metabolites was assessed in vitro. Renal function at baseline and during and after treatment in subjects in BCV clinical studies was examined. RESULTS: In OAT1-expressing cells, uptake of BCV and its 2 major metabolites (CMX103 and CMX064) was the same as in mock-transfected control cells and was not inhibited by the OAT inhibitor probenecid. In human pharmacokinetic studies, BCV administration at therapeutic doses resulted in detection of CDV as a circulating metabolite; peak CDV plasma concentrations after oral BCV administration in humans were <1% of those observed after IV CDV administration at therapeutic doses. Analysis of renal function and adverse events from 3 BCV clinical studies in immunocompromised adult and pediatric subjects indicated little to no evidence of associated nephrotoxicity. Over 80% of subjects who switched from CDV or foscarnet to BCV experienced an improvement in renal function as measured by maximum on-treatment estimated glomerular filtration rate. CONCLUSIONS: The lack of BCV uptake through OAT1, together with lower CDV concentrations after oral BCV compared with IV CDV administration, likely explains the superior renal safety profile observed in immunocompromised subjects receiving BCV compared with CDV.
Assuntos
Antivirais/efeitos adversos , Antivirais/farmacocinética , Citosina/análogos & derivados , Túbulos Renais Proximais/efeitos dos fármacos , Proteína 1 Transportadora de Ânions Orgânicos/metabolismo , Organofosfonatos/efeitos adversos , Organofosfonatos/farmacocinética , Adolescente , Adulto , Idoso , Animais , Transporte Biológico/fisiologia , Linhagem Celular , Criança , Citosina/efeitos adversos , Citosina/farmacocinética , Cães , Feminino , Taxa de Filtração Glomerular/efeitos dos fármacos , Humanos , Túbulos Renais Proximais/metabolismo , Células Madin Darby de Rim Canino , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
ABT-072 is a candidate drug evaluated for treatment of hepatitis C virus. It is an acidic compound with extremely low intrinsic aqueous solubility. An in vitro dissolution-partition system, referred as biphasic test method, was used to characterize ABT-072 prototype formulations. This test used 2 aqueous dissolution media of pH 2 and 6.5 in a sequential manner to simulate the transition of drug in gastrointestinal tract. The biphasic test used in this work effectively differentiated various ABT-072 formulations derived from conventional and enabling technologies. In vitro profiles of these formulations indicate a complex interplay among the 3 competitive kinetic processes including dissolution, precipitation, and partition in the aqueous media. The relative amount of drug partitioned into the organic phase (i.e., octanol) from different formulations was found to be directly related to their in vivo exposures observed in both dogs and human subjects, respectively. An in vitro-in vivo relationship was obtained between ABT-072 concentrations in octanol at t = 2 h from these formulations and the relative bioavailabilities in dogs and human subjects. This work revealed the significance of polymeric precipitation inhibition by sustaining a supersaturated state of ABT-072 and its impact on in vivo exposure in human subjects.
Assuntos
Antivirais/química , Antivirais/farmacocinética , Citosina/análogos & derivados , Sulfonamidas/química , Sulfonamidas/farmacocinética , Animais , Disponibilidade Biológica , Estudos Cross-Over , Citosina/química , Citosina/farmacocinética , Cães , Composição de Medicamentos , Excipientes , Humanos , Concentração de Íons de Hidrogênio , Solubilidade , Comprimidos , ÁguaRESUMO
OBJECTIVES: The objective of this study was to evaluate the pharmacokinetics and safety of cidofovir administered via the intravesicular route to patients with haemorrhagic cystitis following allogeneic HSCT (allo-HSCT). METHODS: Patients with gross haematuria and confirmed BK or adenovirus viruria following allo-HSCT were prospectively enrolled in an open-label pharmacokinetic study (ClinicalTrials.gov registration: NCT01816646). Three hours after an oral probenecid dose (2 g), cidofovir (2.5-5 mg/kg in 50-100 mL of normal saline) was given via a transurethral catheter for up to 2 h of dwell time. Serial plasma samples were obtained over 24 h and assayed for cidofovir concentrations using LC-MS/MS. A custom pharmacokinetic model with a time-limited absorption compartment was fitted to the concentration-time profile of each patient. Systemic drug exposure was expressed as AUC0-24, by integrating the best-fit profile with respect to time. RESULTS: Six subjects (meanâ±âSD ageâ=â38â±â21 years) with baseline serum creatinine <1.4 mg/dL were enrolled. Mean values for volume of distribution, clearance and elimination half-life were 19.5 L, 5.6 L/h and 2.8 h, respectively. Compared with the reported AUC0-24 for an equivalent intravenous dose, intravesicular instillation of cidofovir resulted in 1%-74% of the corresponding systemic exposure. Owing to primarily lower abdominal pain, only two patients were able to tolerate a 2 h dwell time. One patient developed a >50% increase in serum creatinine within 7 days of administration. CONCLUSIONS: Intravesicular administration of cidofovir resulted in highly variable systemic exposures. The safety and efficacy of intravesicular cidofovir should be further evaluated before routine use.
Assuntos
Infecções por Adenoviridae/tratamento farmacológico , Antivirais/efeitos adversos , Antivirais/farmacocinética , Cistite/tratamento farmacológico , Citosina/análogos & derivados , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Organofosfonatos/efeitos adversos , Organofosfonatos/farmacocinética , Administração Intravesical , Adolescente , Idoso , Antivirais/administração & dosagem , Cidofovir , Citosina/administração & dosagem , Citosina/efeitos adversos , Citosina/farmacocinética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Organofosfonatos/administração & dosagem , Plasma/química , Estudos Prospectivos , Transplante Homólogo/efeitos adversos , Adulto JovemRESUMO
PURPOSE OF REVIEW: The mainstay of antiviral therapy for the alpha-herpesviruses [herpes simplex virus (HSV)-1, HSV-2, and varicella zoster virus (VZV)] over the past 40 years has been the nucleoside analogues such as aciclovir. Although conventional antiviral therapy has reduced mortality in severe disease, novel agents are needed to address the emergence of resistance and toxicity associated with current second-line therapy. Treatment and prophylaxis of VZV and HSV reactivations remains a challenge. RECENT FINDINGS: A number of compounds have recently been evaluated in human clinical trials, amongst them brincidofovir, an intracellularly acting derivative of cidofovir currently undergoing phase III trials. The helicase-primase inhibitors are a new class of antiviral agent and may circumvent resistance to existing agents. Amenamevir and pritelivir are two examples of these agents that have been evaluated clinically along with novel nucleoside analogues such as valomaciclovir and FV-100. Tenofovir, an agent used in HIV and hepatitis B therapy, may also have a role in the prevention of HSV-2 acquisition and reduce viral shedding. SUMMARY: Although several novel antiviral agents have undergone clinical trials in recent years, all are yet to gain licensure. Brincidofovir appears to be the candidate with most promise for adoption into routine practice in the near future.
Assuntos
Antivirais/uso terapêutico , Citosina/análogos & derivados , Farmacorresistência Viral/efeitos dos fármacos , Herpes Simples/tratamento farmacológico , Herpes Zoster/tratamento farmacológico , Organofosfonatos/uso terapêutico , Antivirais/farmacocinética , Antivirais/farmacologia , Ensaios Clínicos como Assunto , Citosina/farmacocinética , Citosina/farmacologia , Citosina/uso terapêutico , Descoberta de Drogas , Avaliação de Medicamentos , Herpes Simples/imunologia , Herpes Zoster/imunologia , Humanos , Testes de Sensibilidade Microbiana , Organofosfonatos/farmacocinética , Organofosfonatos/farmacologia , Resultado do Tratamento , Replicação Viral/efeitos dos fármacosRESUMO
Brincidofovir (BCV) has broad-spectrum in vitro activity against dsDNA viruses, including smallpox, and is being developed as a treatment for smallpox as well as infections caused by other dsDNA viruses. BCV has previously been shown to be active in multiple animal models of smallpox. Here we present the results of a randomized, blinded, placebo-controlled study of the efficacy and pharmacokinetics of a novel, "humanized" regimen of BCV for treatment of New Zealand White rabbits infected with a highly lethal inoculum of rabbitpox virus, a well characterized model of smallpox. Compared with placebo, a dose-dependent increase in survival was observed in all BCV-treatment groups. Concentrations of cidofovir diphosphate (CDV-PP), the active antiviral, in rabbit peripheral blood mononuclear cells (PBMCs) were determined for comparison to those produced in humans at the dose proposed for treatment of smallpox. CDV-PP exposure in PBMCs from rabbits given BCV scaled to human exposures at the dose proposed for treatment of smallpox, which is also currently under evaluation for other indications. The results of this study demonstrate the activity of BCV in the rabbitpox model of smallpox and the feasibility of scaling doses efficacious in the model to a proposed human dose and regimen for treatment of smallpox.
Assuntos
Citosina/análogos & derivados , Modelos Animais de Doenças , Organofosfonatos/farmacocinética , Organofosfonatos/uso terapêutico , Coelhos , Varíola/tratamento farmacológico , Vaccinia virus/efeitos dos fármacos , Vacínia/tratamento farmacológico , Animais , Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Antivirais/farmacocinética , Antivirais/uso terapêutico , Cidofovir , Citosina/administração & dosagem , Citosina/farmacocinética , Citosina/farmacologia , Citosina/uso terapêutico , Humanos , Injeções Intradérmicas , Organofosfonatos/administração & dosagem , Organofosfonatos/farmacologia , Distribuição Aleatória , Vacínia/virologia , Vaccinia virus/crescimento & desenvolvimento , Vírus da Varíola/efeitos dos fármacos , Vírus da Varíola/crescimento & desenvolvimentoRESUMO
Children undergoing hematopoietic stem cell transplantation (HSCT) are at risk for life-threatening viral infections. Cidofovir is often used as a first-line agent for adenovirus infections, despite the absence of randomized controlled trials with HSCT patients, and as a second-line agent for resistant herpesvirus infections. The frequency and severity of adverse effects, particularly nephrotoxicity, in pediatric HSCT recipients are unclear, and pharmacokinetics (PK) of cidofovir in children have not previously been reported. This study was an open-label, nonrandomized, single-dose pilot study to determine the safety and PK of cidofovir in pediatric HSCT recipients with symptomatic adenovirus, nucleoside-resistant cytomegalovirus (CMV) or herpes simplex virus (HSV), and/or human papovavirus infections. Subsequent dosing and frequency were determined by clinical response and side effects, as assessed by the treating physician. Blood and urine samples were obtained from patients for PK studies and assessment of toxicity and virologic response. Twelve patients were enrolled (median age, 9 years; 33.5 days posttransplantation). Four of seven patients with adenovirus infection were successfully treated and eventually cleared their infections. Four of twelve patients died of disseminated viral disease and multiorgan failure. Two of twelve patients had evidence of acute kidney injury after the first dose, and one of these patients developed chronic kidney disease; two other patients developed late nephrotoxicity. The mean drug half-life was 9.5 h. There was no correlation between nephrotoxicity and plasma maximum concentration, clearance, or half-life. PK were similar to those reported for adults, although the drug half-life was significantly longer than that for adults. Cidofovir was well tolerated in the majority of patients. However, effective therapeutic strategies are urgently needed to support patients until immune reconstitution is achieved.
Assuntos
Infecções por Adenovirus Humanos/tratamento farmacológico , Infecções por Citomegalovirus/tratamento farmacológico , Citosina/análogos & derivados , Infecções por Herpesviridae/tratamento farmacológico , Organofosfonatos , Infecções por Polyomavirus/tratamento farmacológico , Injúria Renal Aguda/induzido quimicamente , Infecções por Adenovirus Humanos/mortalidade , Adolescente , Antivirais/efeitos adversos , Antivirais/farmacocinética , Antivirais/uso terapêutico , Vírus BK/efeitos dos fármacos , Criança , Pré-Escolar , Cidofovir , Citosina/efeitos adversos , Citosina/farmacocinética , Citosina/uso terapêutico , Feminino , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Masculino , Organofosfonatos/efeitos adversos , Organofosfonatos/farmacocinética , Organofosfonatos/uso terapêutico , Projetos Piloto , Viremia/tratamento farmacológico , Viremia/virologiaRESUMO
Dosage recommendations for cidofovir are available for renally competent as well as impaired patients; however, there are no data for patients undergoing continuous renal replacement therapy. We determined the single-dose concentration-versus-time profile of cidofovir in a critically ill patient undergoing continuous venovenous hemofiltration (CVVH). One dose of 450 mg cidofovir (5 mg/kg) was administered intravenously due to a proven cytomegalovirus (CMV) infection and failure of first-line antiviral therapy. Additionally, 2 g of probenecid was administered orally 3 h prior to and 1 g was administered 2 h as well as 8 h after completion of the infusion. The concentrations of cidofovir in serum and ultrafiltrate were assessed by high-performance liquid chromatography. The peak serum concentration measured at 60 min postinfusion was 28.01 mg/liter at the arterial port. The trough serum level was 19.33 mg/liter at the arterial port after 24 h. The value of the area under the concentration-versus-time curve from 0 to 24 h was 543.8 mg·h/liter. The total body clearance was 2.46 ml/h/kg, and the elimination half-life time was 53.32 h. The sieving coefficient was 0.138±0.022. Total removal of the drug was 30.99% after 24 h. Because of these data, which give us a rough idea of the concentration profile of cidofovir in patients undergoing CVVH, a toxic accumulation of the drug following repeated doses may be expected. Further trials have to be done to determine the right dosage of cidofovir in patients undergoing CVVH to avoid toxic accumulation of the drug.
Assuntos
Antivirais/farmacocinética , Citosina/análogos & derivados , Hemofiltração , Organofosfonatos/farmacocinética , Antivirais/administração & dosagem , Antivirais/uso terapêutico , Cidofovir , Estado Terminal , Citosina/administração & dosagem , Citosina/farmacocinética , Citosina/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Organofosfonatos/administração & dosagem , Organofosfonatos/uso terapêutico , Probenecid/uso terapêuticoRESUMO
A convenient and efficient in vitro diffusion cell method to evaluate formulations for inner ear delivery via the intratympanic route is currently not available. The existing in vitro diffusion cell systems commonly used to evaluate drug formulations do not resemble the physical dimensions of the middle ear and round window membrane. The objectives of this study were to examine a modified in vitro diffusion cell system of a small diffusion area for studying sustained release formulations in inner ear drug delivery and to identify a formulation for sustained drug delivery to the inner ear. Four formulations and a control were examined in this study using cidofovir as the model drug. Drug release from the formulations in the modified diffusion cell system was slower than that in the conventional diffusion cell system due to the decrease in the diffusion surface area of the modified diffusion cell system. The modified diffusion cell system was able to show different drug release behaviors among the formulations and allowed formulation evaluation better than the conventional diffusion cell system. Among the formulations investigated, poly(lactic-co-glycolic acid)-poly(ethylene glycol)-poly(lactic-co-glycolic acid) triblock copolymer systems provided the longest sustained drug delivery, probably due to their rigid gel structures and/or polymer-to-cidofovir interactions.
Assuntos
Citosina/análogos & derivados , Portadores de Fármacos/química , Orelha Interna/metabolismo , Orelha Média/metabolismo , Modelos Biológicos , Organofosfonatos/administração & dosagem , Polietilenoglicóis/química , Poliglactina 910/química , Química Farmacêutica/métodos , Cidofovir , Simulação por Computador , Citosina/administração & dosagem , Citosina/química , Citosina/farmacocinética , Preparações de Ação Retardada , Liberação Controlada de Fármacos , Orelha Interna/efeitos dos fármacos , Orelha Média/efeitos dos fármacos , Membranas Artificiais , Organofosfonatos/química , Organofosfonatos/farmacocinéticaRESUMO
BACKGROUND: BK virus (BKV) infection in kidney transplant recipients is associated with progressive graft dysfunction and graft loss. Cidofovir, an antiviral agent with known nephrotoxicity, has been used in low doses to treat BKV infections. However, the systemic exposure and disposition of the low-dose cidofovir regimen are not known in kidney transplant recipients. METHODS: We investigated the pharmacokinetics (PK) of low-dose cidofovir (0.24 - 0.62 mg/kg) both without and with oral probenecid in 9 transplant patients with persistent BK viremia without nephropathy in a crossover design. RESULTS: The mean estimated glomerular filtration rate (eGFR) of the study participants was 46.2 mL/min/1.73 m(2) (range: 17-75 mL/min/1.73 m(2) ). The contribution of active renal secretion to cidofovir total body clearance was assessed by evaluating the effect of probenecid on cidofovir PK. Maximum cidofovir plasma concentrations, which averaged approximately 1 µg/mL, were significantly below the 36 µg/mL 50% effective concentration in vitro for cidofovir against BKV. The plasma concentration of cidofovir declined with an overall disposition half-life of 5.1 ± 3.5 and 5.3 ± 2.9 h in the absence and in the presence of probenecid, respectively (P > 0.05). CONCLUSIONS: Cidofovir clearance and eGFR were linearly related irrespective of probenecid administration (r(2) = 0.8 without probenecid; r(2) = 0.7 with probenecid). This relationship allows for the prediction of systemic cidofovir exposure in individual patients and may be utilized to evaluate exposure-response relationships to optimize the cidofovir dosing regimen for BKV infection.
Assuntos
Antivirais/farmacocinética , Vírus BK/efeitos dos fármacos , Citosina/análogos & derivados , Nefropatias/metabolismo , Transplante de Rim , Organofosfonatos/farmacocinética , Infecções por Polyomavirus/metabolismo , Infecções Tumorais por Vírus/metabolismo , Adjuvantes Farmacêuticos/farmacocinética , Adulto , Idoso , Área Sob a Curva , Cidofovir , Estudos Cross-Over , Citosina/farmacocinética , Relação Dose-Resposta a Droga , Feminino , Taxa de Filtração Glomerular , Meia-Vida , Humanos , Nefropatias/virologia , Masculino , Pessoa de Meia-Idade , Probenecid/farmacocinética , Viremia/metabolismoAssuntos
Antivirais/uso terapêutico , Citosina/análogos & derivados , Herpesvirus Humano 6/efeitos dos fármacos , Organofosfonatos/uso terapêutico , Infecções por Roseolovirus/tratamento farmacológico , Antivirais/farmacocinética , Antivirais/farmacologia , Linhagem Celular , Citosina/farmacocinética , Citosina/farmacologia , Citosina/uso terapêutico , Humanos , Testes de Sensibilidade Microbiana , Organofosfonatos/farmacocinética , Organofosfonatos/farmacologiaRESUMO
CMX001 is a novel, broad-spectrum lipid antiviral conjugate (LAC) that produces high intracellular levels of the active antiviral agent cidofovir diphosphate (CDV-PP). Study CMX001-102 was a randomized, double-blind, placebo-controlled, parallel group, dose-escalating study in healthy volunteers. The objectives of the study were to evaluate the safety and pharmacokinetic parameters of CMX001 after single and multiple doses. Single doses ranging from 0.25 to 2.0 mg/kg of body weight and multiple doses ranging from 0.1 to 1.0 mg/kg (3 total doses, administered every 6 days) were given orally. Safety was assessed using comprehensive clinical and laboratory evaluations, including enhanced monitoring for potential gastrointestinal (GI) effects using wireless capsule endoscopy (WCE). Serial plasma and pooled urine samples were collected to estimate pharmacokinetic parameters for both CMX001 and cidofovir (CDV). No adverse events occurred that prevented dose escalation. No clinically significant drug-related changes in blood chemistry, hematology, renal function, or intraocular pressure were observed. No CMX001-related gastrointestinal mucosal changes were observed by WCE. CMX001 was absorbed rapidly, with maximum plasma concentrations observed 2 to 3 h postdose. Maximum plasma drug concentration and systemic exposure of CMX001 increased approximately in proportion to dose following single and multiple doses; no significant accumulation of CMX001 or CDV was observed following multiple doses. We conclude that CMX001 is orally bioavailable and well tolerated in healthy volunteers at doses up to 2 mg/kg, approximately 140 mg in a typical adult. This is the first demonstration of the use of phospholipid conjugation technology to achieve plasma drug exposures that are expected to result in activity against multiple double-stranded DNA viruses.
Assuntos
Antivirais/farmacocinética , Citosina/análogos & derivados , Vírus de DNA/efeitos dos fármacos , Organofosfonatos/farmacocinética , Administração Oral , Adolescente , Adulto , Antivirais/sangue , Antivirais/urina , Área Sob a Curva , Disponibilidade Biológica , Endoscopia por Cápsula , Cidofovir , Citosina/sangue , Citosina/farmacocinética , Citosina/urina , Método Duplo-Cego , Esquema de Medicação , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Feminino , Humanos , Pressão Intraocular/efeitos dos fármacos , Testes de Função Renal , Masculino , Pessoa de Meia-Idade , Organofosfonatos/sangue , Organofosfonatos/urina , Placebos , Estados UnidosRESUMO
PURPOSE: To evaluate the intraocular safety and pharmacokinetics of hexadecyloxypropyl-cidofovir (HDP-CDV), the hydrolysis product of HDP-cyclic-CDV, a long-lasting intravitreal cidofovir prodrug for cytomegalovirus (CMV) retinitis. METHODS: HDP-cyclic-CDV was suspended in phosphate-buffered saline (PBS) at 37°C and formation of HDP-CDV was monitored by high-performance liquid chromatography (HPLC) analysis for 30 weeks. The safety and pharmacokinetics of HDP-CDV intravitreal injections were studied using New Zealand Red rabbits and (14)C labeled HDP-CDV. Ocular tissues from five time points (1, 3, 7, 14, and 35 days) were analyzed by scintillation counting and HPLC to characterize the pharmacokinetics. RESULTS: During the hydrolysis study, approximately 35% of the HDP-cyclic-CDV was converted to HDP-CDV. Evaluation of safety found no toxicity after intravitreal injection of HDP-CDV up to 28 µg/eye. Intravitreal pharmacokinetics of HDP-CDV in the retina, choroid, and vitreous followed a two-phase elimination process and elimination half-lives of 8.4 days (retina), 6.9 days (choroid), and 6.2 days (vitreous). In the retina, cidofovir and an unknown metabolite were detected in the first 2 weeks, and the maximum metabolite concentrations were present 48 hours after the maximum HDP-CDV concentration. CONCLUSIONS: HDP-cyclic CDV, under simulated physiologic conditions, slowly converts to HDP-CDV, another potent anti-CMV prodrug that may be taken up by retinal cells and metabolized further to the active antiviral metabolite, cidofovir diphosphate. Taken together, these observations help to explain the ability of a single intravitreal dose of HDP-cyclic-CDV to prevent viral retinitis for up to 68 days in a rabbit model.
Assuntos
Corpo Ciliar/metabolismo , Retinite por Citomegalovirus/tratamento farmacológico , Citosina/análogos & derivados , Organofosfonatos/farmacocinética , Retina/metabolismo , Corpo Vítreo/metabolismo , Animais , Cromatografia Líquida de Alta Pressão , Corpo Ciliar/efeitos dos fármacos , Retinite por Citomegalovirus/metabolismo , Citosina/administração & dosagem , Citosina/farmacocinética , Preparações de Ação Retardada , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Seguimentos , Hidrólise , Injeções Intravítreas , Organofosfonatos/administração & dosagem , Coelhos , Retina/efeitos dos fármacos , Corpo Vítreo/efeitos dos fármacosRESUMO
Eight novel single amino acid (6-11) and dipeptide (12, 13) tyrosine P-O esters of cyclic cidofovir ((S)-cHPMPC, 4) and its cyclic adenine analogue ((S)-cHPMPA, 3) were synthesized and evaluated as prodrugs. In vitro IC(50) values for the prodrugs (<0.1-50 µM) vs vaccinia, cowpox, human cytomegalovirus, and herpes simplex type 1 virus were compared to those for the parent drugs ((S)-HPMPC, 2; (S)-HPMPA, 1; IC(50) 0.3-35 µM); there was no cytoxicity with KB or HFF cells at ≤100 µM. The prodrugs exhibited a wide range of half-lives in rat intestinal homogenate at pH 6.5 (<30-1732 min) with differences of 3-10× between phostonate diastereomers. The tyrosine alkylamide derivatives of 3 and 4 were the most stable. (l)-Tyr-NH-i-Bu cHPMPA (11) was converted in rat or mouse plasma solely to two active metabolites and had significantly enhanced oral bioavailability vs parent drug 1 in a mouse model (39% vs <5%).