RESUMEN
ATI-2173 is an active site polymerase inhibitor nucleotide in development as part of a potentially curative regimen for chronic hepatitis B virus (HBV) infection. This study evaluated the safety, tolerability, pharmacokinetics (PK) and antiviral activity of ATI-2173. This was a phase 1b, randomized, double-blind, placebo-controlled trial in treatment-naive adults with chronic HBV infection conducted in the Republic of Moldova and Ukraine (ClinicalTrials.gov: NCT04248426). Patients positive for hepatitis B surface antigen were randomized 6:2 to receive once-daily oral doses of ATI-2173 10, 25, or 50 mg (n = 6 per dose) or placebo (n = 7) for 28 days, with off-treatment monitoring for 24 weeks. Endpoints included PK parameters of ATI-2173 and its metabolite clevudine, maximum reduction from baseline in HBV DNA, and safety and tolerability. Treatment-emergent adverse events occurred in eight patients (47%) receiving ATI-2173 and five (71%) receiving placebo; headache was the most common (n = 4). ATI-2173 PK was generally dose proportional. Systemic clevudine exposure with ATI-2173 dosing was substantially reduced compared with historical values observed with clevudine administration. On Day 28, mean changes from baseline in HBV DNA were -2.72 to -2.78 log10 IU/ml with ATI-2173 and +0.17 log10 IU/ml with placebo. Off-treatment sustained viral suppression and decreases in covalently closed circular DNA biomarkers were observed in most patients; one maintained undetectable HBV DNA at 24 weeks off treatment. In this 28-day monotherapy study, ATI-2173 demonstrated safety and antiviral activity, with sustained off-treatment effects and substantially reduced systemic clevudine exposure. These results support evaluation of ATI-2173 with tenofovir disoproxil fumarate in phase 2 studies.
Asunto(s)
Hepatitis B Crónica , Adulto , Humanos , Nucleótidos/uso terapéutico , ADN Viral , Dominio Catalítico , Antígenos e de la Hepatitis B , Antivirales/efectos adversos , Virus de la Hepatitis B/genéticaRESUMEN
ATI-2173 is a novel liver-targeted molecule designed to deliver the 5'-monophosphate of clevudine for the treatment of chronic hepatitis B infection. Unlike other nucleos(t)ides, the active clevudine-5'-triphosphate is a noncompetitive, non-chain-terminating inhibitor of hepatitis B virus (HBV) polymerase that delivers prolonged reduction of viremia in both a woodchuck HBV model and in humans for up to 6 months after cessation of treatment. However, long-term clevudine treatment was found to exhibit reversible skeletal myopathy in a small subset of patients and was subsequently discontinued from development. ATI-2173 was designed by modifying clevudine with a 5'-phosphoramidate to deliver the 5'-monophosphate to the liver. Bypassing the first phosphorylation step of clevudine, the 5'-monophosphate is converted to the active 5'-triphosphate in the liver. ATI-2173 is a selective inhibitor of HBV with an anti-HBV 50% effective concentration (EC50) of 1.31 nM in primary human hepatocytes, with minimal to no toxicity in hepatocytes, skeletal muscle, liver, kidney, bone marrow, and cardiomyocytes. ATI-2173 activity was decreased by viral polymerase mutations associated with entecavir, lamivudine, and adefovir resistance, but not capsid inhibitor resistance mutations. A single oral dose of ATI-2173 demonstrated 82% hepatic extraction, no food effect, and greatly reduced peripheral exposure of clevudine compared with equimolar oral dosing of clevudine. Despite reduced plasma clevudine exposure, liver concentrations of the 5'-triphosphate were equivalent following ATI-2173 versus clevudine administration. By selectively delivering the 5'-monophosphate to the liver, while retaining the unique anti-HBV activity of the 5'-triphosphate, ATI-2173 may provide an improved pharmacokinetic profile for clinical use, reducing systemic exposure of clevudine and potentially eliminating skeletal myopathy.
Asunto(s)
Hepatitis B Crónica , Hepatitis B , Antivirales/farmacología , Antivirales/uso terapéutico , Hepatitis B/tratamiento farmacológico , Virus de la Hepatitis B/genética , Hepatitis B Crónica/tratamiento farmacológico , Humanos , Nucleótidos/uso terapéuticoRESUMEN
BACKGROUND: Three perioperative factors impair host defence against recurrence during cancer surgery: the surgical stress response, use of volatile anaesthetic, and opioids for analgesia. All factors are ameliorated by regional anaesthesia-analgesia. We tested the primary hypothesis that breast cancer recurrence after potentially curative surgery is lower with regional anaesthesia-analgesia using paravertebral blocks and the anaesthetic propofol than with general anaesthesia with the volatile anaesthetic sevoflurane and opioid analgesia. A second hypothesis was that regional anaesthesia-analgesia reduces persistent incisional pain. METHODS: We did a randomised controlled trial at 13 hospitals in Argentina, Austria, China, Germany, Ireland, New Zealand, Singapore, and the USA. Women (age <85 years) having potentially curative primary breast cancer resections were randomised by computer to either regional anaesthesia-analgesia (paravertebral blocks and propofol) or general anaesthesia (sevoflurane) and opioid analgesia. The primary outcome was local or metastatic breast cancer recurrence. The secondary outcome was incisional pain at 6 months and 12 months. Primary analyses were done under intention-to-treat principles. This trial is registered with ClinicalTrials.gov, NCT00418457. The study was stopped after a preplanned futility boundary was crossed. FINDINGS: Between Jan 30, 2007, and Jan 18, 2018, 2132 women were enrolled to the study, of whom 24 were excluded before surgery. 1043 were assigned to regional anaesthesia-analgesia and 1065 were allocated to general anaesthesia. Baseline characteristics were well balanced between study groups. Median follow-up was 36 (IQR 24-49) months. Among women assigned regional anaesthesia-analgesia, 102 (10%) recurrences were reported, compared with 111 (10%) recurrences among those allocated general anaesthesia (hazard ratio 0·97, 95% CI 0·74-1·28; p=0·84). Incisional pain was reported by 442 (52%) of 856 patients assigned to regional anaesthesia-analgesia and 456 (52%) of 872 patients allocated to general anaesthesia at 6 months, and by 239 (28%) of 854 patients and 232 (27%) of 852 patients, respectively, at 12 months (overall interim-adjusted odds ratio 1·00, 95% CI 0·85-1·17; p=0·99). Neuropathic breast pain did not differ by anaesthetic technique and was reported by 87 (10%) of 859 patients assigned to regional anaesthesia-analgesia and 89 (10%) of 870 patients allocated to general anaesthesia at 6 months, and by 57 (7%) of 857 patients and 57 (7%) of 854 patients, respectively, at 12 months. INTERPRETATION: In our study population, regional anaesthesia-analgesia (paravertebral block and propofol) did not reduce breast cancer recurrence after potentially curative surgery compared with volatile anaesthesia (sevoflurane) and opioids. The frequency and severity of persistent incisional breast pain was unaffected by anaesthetic technique. Clinicians can use regional or general anaesthesia with respect to breast cancer recurrence and persistent incisional pain. FUNDING: Sisk Healthcare Foundation (Ireland), Eccles Breast Cancer Research Fund, British Journal of Anaesthesia International, College of Anaesthetists of Ireland, Peking Union Medical College Hospital, Science Fund for Junior Faculty 2016, Central Bank of Austria, and National Healthcare Group.
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Anestesia de Conducción/métodos , Anestesia General/métodos , Neoplasias de la Mama/cirugía , Recurrencia Local de Neoplasia/prevención & control , Adulto , Anciano , Anciano de 80 o más Años , Analgésicos Opioides/efectos adversos , Analgésicos Opioides/uso terapéutico , Anestesia de Conducción/efectos adversos , Anestesia General/efectos adversos , Anestésicos por Inhalación/efectos adversos , Neoplasias de la Mama/patología , Femenino , Estudios de Seguimiento , Humanos , Estimación de Kaplan-Meier , Metástasis Linfática , Mastectomía/métodos , Persona de Mediana Edad , Clasificación del Tumor , Recurrencia Local de Neoplasia/etiología , Estadificación de Neoplasias , Bloqueo Nervioso/métodos , Dolor Postoperatorio/prevención & control , Sevoflurano/efectos adversosRESUMEN
BACKGROUND: Intraoperative hypotension is associated with complications that might be ameliorated by earlier intervention. We therefore tested the primary hypothesis that a supplemental decision support alert for critically low systolic blood pressure (SBP) decreases the duration of intraoperative hypotension. METHODS: We enrolled adults having surgery and anesthetized by attending anesthesiologists or nurse anesthetists under attending supervision. When invasive SBP <80 mmHg was detected for 3 consecutive minutes or any oscillometric SBP <80 mmHg, patients were randomly assigned to routine management or a visual alert and pager notification. Clinicians who received alerts were free to act on the alert or not. The primary outcome was time to return to SBP ≥ 80 mmHg. Secondary outcomes were time until SBP remained ≥ 80 mmHg for at least 10 minutes and the duration of hospitalization. RESULTS: One thousand five hundred ninety-eight patients were randomly assigned to the hypotension alerts and 1567 to no alerts. Randomized groups did not differ on time to return to SBP ≥ 80 mmHg after the first alert, with estimated adjusted hazard ratio of 0.99 (95% confidence interval, 0.92-1.06; P = 0.69). The median time [quartiles] to return to SBP ≥ 80 mmHg was 1 [0, 3] minutes in each group and 1 [0, 3] minutes in the nonalert group (P = 0.69). Hospital length of stay was also similar, with the median [quartiles] lengths of stay being 2 [1, 4] days in the alert group and 2 [1,5] in the nonalert group (P = 0.35). CONCLUSIONS: An additional warning for severe hypotension did not reduce the duration of hypotension or hospitalization. Decision support alerts may be more useful for more complicated situations.
Asunto(s)
Presión Sanguínea , Alarmas Clínicas , Sistemas de Apoyo a Decisiones Clínicas , Hipotensión/diagnóstico , Hipotensión/prevención & control , Monitoreo Intraoperatorio/métodos , Adulto , Anciano , Presión Sanguínea/fisiología , Alarmas Clínicas/estadística & datos numéricos , Sistemas de Apoyo a Decisiones Clínicas/estadística & datos numéricos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proyectos PilotoRESUMEN
BACKGROUND & AIMS: Samatasvir is a pan-genotypic inhibitor of the hepatitis C (HCV) non-structural protein 5A (NS5A). This study evaluated the antiviral activity, pharmacokinetics and safety of samatasvir monotherapy in treatment-naïve subjects infected with HCV genotype 1-4. METHODS: Thirty-four genotype 1 and thirty genotype 2, 3 or 4 subjects were randomized to receive for 3days placebo or samatasvir 25-100mg per day. Plasma samples for HCV RNA, pharmacokinetics and sequencing were collected up to day 10. RESULTS: Samatasvir achieved potent antiviral activity across genotypes: mean maximum reductions from baseline were 3.2-3.6 (genotype 1a), 3.0-4.3 (genotype 1b), 3.2-3.4 (genotype 3), and 3.6-3.9 (genotype 4) log10/ml respectively; no viral rebound was observed during the 3-day treatment period. For genotype 2 HCV, samatasvir was active in subjects with NS5A L31 polymorphism at baseline (individual range 2.5-4.1 log10/ml), but showed minimal activity in those with baseline M31 polymorphism. Samatasvir exhibited a long plasma half-life of approximately 20h which supports once daily dosing. Samatasvir was well tolerated in all subjects with no safety-related discontinuations or serious adverse events. The most common adverse events included constipation, nausea and headache and occurred at similar frequency in active and placebo subjects. All events were mild or moderate in intensity. There were no patterns or dose dependence of adverse events, vital signs, laboratory parameters or electrocardiograms. CONCLUSIONS: Samatasvir 25-100mg monotherapy for 3days was well tolerated and induced a rapid and profound reduction in plasma HCV RNA in subjects infected with HCV genotype 1-4. Samatasvir is being evaluated in combination with other direct-acting antiviral agents in subjects with HCV infection.
Asunto(s)
Antivirales/administración & dosificación , Bencimidazoles/administración & dosificación , Carbamatos/administración & dosificación , Hepacivirus/genética , Hepatitis C Crónica/tratamiento farmacológico , Hepatitis C Crónica/virología , Proteínas no Estructurales Virales/antagonistas & inhibidores , Adulto , Antivirales/efectos adversos , Antivirales/farmacocinética , Bencimidazoles/efectos adversos , Bencimidazoles/farmacocinética , Carbamatos/efectos adversos , Carbamatos/farmacocinética , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Esquema de Medicación , Femenino , Genotipo , Semivida , Hepacivirus/efectos de los fármacos , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo Genético , ARN Viral/sangre , ARN Viral/genética , Proteínas no Estructurales Virales/genéticaRESUMEN
IDX184 is a liver-targeted prodrug of 2'-methylguanosine (2'-MeG) monophosphate. This study investigated the safety, tolerability, antiviral activity, and pharmacokinetics of IDX184 as a single agent in treatment-naïve patients with genotype-1 chronic hepatitis C virus (HCV) infection. Forty-one patients with baseline HCV RNA ≥ 5 log(10) IU/ml, alanine aminotransferase (ALT) ≤ 2.5× the upper limit of normal, and compensated liver disease were dosed. Sequential cohorts of 10 patients, randomized 8:2 (active:placebo), received 25, 50, 75, and 100 mg of IDX184 once daily for 3 days, with a 14-day follow-up. There were no safety-related treatment discontinuations or serious adverse events. The adverse events and laboratory abnormalities observed for IDX184- and placebo-treated patients were similar. At the end of the 3-day treatment period, changes from baseline in HCV RNA levels (means ± standard deviations) were -0.5 ± 0.6, -0.7 ± 0.2, -0.6 ± 0.3, and -0.7 ± 0.5 log(10) for the 25-, 50-, 75-, and 100-mg doses, respectively, while viral load remained unchanged for the pooled placebo patients (-0.05 ± 0.3 log(10)). Patients with genotype-1a and patients with genotype-1b responded similarly. Serum ALT levels decreased, especially at daily doses ≥ 75 mg. During the posttreatment period, plasma viremia and serum aminotransferase levels returned to near pretreatment levels. No resistance mutations associated with IDX184 were detected. Plasma exposure of IDX184 and its nucleoside metabolite 2'-MeG was dose related and low. Changes in plasma viral load correlated with plasma exposure of 2'-MeG. In conclusion, the results from this proof-of-concept study show that small doses of the liver-targeted prodrug IDX184 were able to deliver significant antiviral activity and support further clinical evaluation of the drug candidate.
Asunto(s)
Antivirales/uso terapéutico , Guanosina Monofosfato/análogos & derivados , Hepatitis C Crónica/tratamiento farmacológico , Hígado/efectos de los fármacos , Inhibidores de la Síntesis del Ácido Nucleico , Adolescente , Adulto , Anciano , Alanina Transaminasa/sangre , Antivirales/efectos adversos , Antivirales/farmacocinética , Área Bajo la Curva , Demografía , Método Doble Ciego , Sistemas de Liberación de Medicamentos , Femenino , Guanosina Monofosfato/efectos adversos , Guanosina Monofosfato/farmacocinética , Guanosina Monofosfato/uso terapéutico , Semivida , Hepatitis C Crónica/virología , Humanos , Hígado/metabolismo , Masculino , Persona de Mediana Edad , Profármacos , ARN Viral/sangre , ARN Viral/genética , Carga Viral , Adulto JovenRESUMEN
GSK2248761 is a novel, once-daily (QD), next-generation nonnucleoside reverse transcriptase inhibitor (NNRTI) with activity against efavirenz-resistant strains. Two phase I/IIa, double-blind, randomized, placebo-controlled studies investigated the antiviral activity, safety, and pharmacokinetics (PK) of several doses of GSK2248761 monotherapy in treatment-naive HIV-infected subjects. In the initial study, 10 subjects (8 active and 2 placebo) per dose received sequentially descending GSK2248761 monotherapy regimens of 800, 400, 200, and 100 mg QD for 7 days. Because a dose-response relationship was not identified, a second study examined a lower, 30-mg QD dose in 8 subjects (6 active and 2 placebo). Adverse events, viral load (VL), PK, and reverse transcriptase mutations were assessed and combined for analysis. Treatment with GSK2248761 for 7 days was well tolerated with no serious adverse events or discontinuations. The mean VL reductions from baseline on day 8 were 0.97, 1.87, 1.84, 1.81, and 1.78 log(10) copies/ml for GSK2248761 doses of 30, 100, 200, 400, and 800 mg QD, respectively. GSK2248761 PK (maximum drug concentration in serum [C(max)], area under the plasma concentration-time curve from 0 h to the end of the dosing interval [AUC(0-τ)], and concentration at the end of the dosing interval [C(τ)]) increased proportionally over the dose range of 30 to 800 mg QD. The relationship between short-term VL change and GSK2248761 PK was best described by a maximum-effect (E(max)) model using C(τ) (E(max) = 2.0; 50% effective concentration [EC(50)] = 36.9 ng/ml). No NNRTI resistance mutations emerged during the study. GSK2248761 at 100 to 800 mg QD for 7 days was well tolerated, demonstrated potent antiviral activity in treatment-naive HIV-infected subjects, and had favorable PK and resistance profiles. GSK2248761 is no longer in clinical development.
Asunto(s)
Fármacos Anti-VIH/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Transcriptasa Inversa del VIH/antagonistas & inhibidores , VIH-1/efectos de los fármacos , Indoles/uso terapéutico , Ácidos Fosfínicos/uso terapéutico , Inhibidores de la Transcriptasa Inversa/uso terapéutico , Adulto , Alquinos , Fármacos Anti-VIH/administración & dosificación , Fármacos Anti-VIH/síntesis química , Argentina , Benzoxazinas , Ciclopropanos , Método Doble Ciego , Esquema de Medicación , Farmacorresistencia Viral , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Femenino , Infecciones por VIH/virología , VIH-1/enzimología , VIH-1/genética , Humanos , Indoles/administración & dosificación , Indoles/síntesis química , Masculino , Mutación , Ácidos Fosfínicos/administración & dosificación , Ácidos Fosfínicos/síntesis química , Placebos , Inhibidores de la Transcriptasa Inversa/administración & dosificación , Inhibidores de la Transcriptasa Inversa/síntesis química , Carga Viral/efectos de los fármacosRESUMEN
AIM: To evaluate potential drug interactions with antiretroviral therapies or supportive therapies for use in conjunction with the once daily, next generation non-nucleoside reverse transcriptase inhibitor GSK2248761 in patients with HIV-1 infection. METHODS: A series of phase I drug interaction studies was conducted. RESULTS: GSK2248761 was shown to be a weak CYP3A4 and CYP2D6 inhibitor in a clinical study with a probe cocktail. Mean plasma concentration-time profiles for atazanavir, tenofovir disoproxil fumarate/emtricitabine (TDF/FTC), darunavir (DRV, administered with ritonavir [RTV]), and drospirenone/ethinylestradiol were similar following co-administration of GSK2248761. Plasma raltegravir AUC(0,τ) and C(max) increased by 18% with no change in Cτ when raltegravir was co-administered with GSK2248761. Lopinavir (LPV) plasma AUC(0,τ), C(max) and Cτ decreased by 23%, 14% and 40%, respectively, following administration of lopinavir/ritonavir with GSK2248761. Atorvastatin, rosuvastatin and simvastatin AUC(0,∞) and C(max) increased following co-administration with GSK2248761, with the largest changes observed for simvastatin (3.7-fold and 4.3-fold). Changes in maximum and extent of GSK2248761 exposure were marginal after co-administration with atazanavir, TDF/FTC and raltegravir compared with GSK2248761 administered alone. Co-administration of GSK2248761 with DRV/RTV and LPV/RTV increased plasma GSK2248761 exposures by 1.25- to ≤2-fold compared with GSK2248761 administered alone, and increases in GSK2248761 exposure were higher following single dose co-administration of DRV/RTV or LPV/RTV compared with multiple doses. There were few drug-related AEs, and no treatment-related trends in blood chemistry, haematology, urinalysis, vital signs or ECG findings. CONCLUSIONS: These studies indicate that GSK2248761 was safe and well tolerated in healthy adults treated in these studies at the doses and duration of therapy evaluated.
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Fármacos Anti-VIH/farmacocinética , Indoles/farmacocinética , Ácidos Fosfínicos/farmacocinética , Inhibidores de la Transcriptasa Inversa/farmacocinética , Adenina/administración & dosificación , Adenina/análogos & derivados , Adenina/farmacocinética , Androstenos/administración & dosificación , Androstenos/farmacocinética , Fármacos Anti-VIH/administración & dosificación , Sulfato de Atazanavir , Atorvastatina , Anticonceptivos Orales/administración & dosificación , Anticonceptivos Orales/farmacocinética , Estudios Cruzados , Citocromo P-450 CYP2D6/metabolismo , Inhibidores del Citocromo P-450 CYP2D6 , Citocromo P-450 CYP3A/metabolismo , Inhibidores del Citocromo P-450 CYP3A , Darunavir , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacocinética , Método Doble Ciego , Combinación de Medicamentos , Interacciones Farmacológicas , Emtricitabina , Etinilestradiol/administración & dosificación , Etinilestradiol/farmacocinética , Femenino , Fluorobencenos/administración & dosificación , Fluorobencenos/farmacocinética , Ácidos Heptanoicos/administración & dosificación , Ácidos Heptanoicos/farmacocinética , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/administración & dosificación , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacocinética , Indoles/administración & dosificación , Análisis de los Mínimos Cuadrados , Modelos Lineales , Lopinavir/administración & dosificación , Lopinavir/farmacocinética , Masculino , Oligopéptidos/administración & dosificación , Oligopéptidos/farmacocinética , Organofosfonatos/administración & dosificación , Organofosfonatos/farmacocinética , Seguridad del Paciente , Ácidos Fosfínicos/administración & dosificación , Piridinas/administración & dosificación , Piridinas/farmacocinética , Pirimidinas/administración & dosificación , Pirimidinas/farmacocinética , Pirroles/administración & dosificaciónRESUMEN
Chronic hepatitis B virus (HBV) infection affects 240 to 300 million people worldwide. In the nucleus of infected hepatocytes, the HBV genome is converted to covalently closed circular DNA (cccDNA), which persists and serves as a transcriptional template for viral progeny. Therefore, a long-term cure for chronic HBV infection will require elimination of cccDNA. Although currently available nucleos(t)ide analogues (eg, tenofovir disoproxil fumarate, tenofovir alafenamide, entecavir) effectively control HBV replication, they are seldom curative (functional cure rate â¼10%) and require lifelong treatment for most patients. As such, antiviral agents with novel mechanisms of action are needed. Active site polymerase inhibitor nucleotides (ASPINs) noncompetitively distort the HBV polymerase active site to completely inhibit all polymerase functions, unlike traditional chain-terminating nucleos(t)ide analogues, which only target select polymerase functions and are consumed in the process. Clevudine, a first-generation ASPIN, demonstrated potent and prolonged HBV suppression in phase 2 and 3 clinical studies, but long-term treatment was associated with reversible myopathy in a small number of patients. ATI-2173, a novel next-generation ASPIN, is structurally similar to clevudine but targets the liver and demonstrates potent anti-HBV activity on and off treatment, and may ultimately demonstrate an improved pharmacokinetic and safety profile by significantly reducing systemic clevudine exposure. Thus, ATI-2173 is currently in clinical development as an agent for HBV cure. Here, we review the mechanism of action and preclinical and clinical profiles of clevudine and ATI-2173 to support the role of ASPINs as part of curative regimens for chronic HBV infection.
Asunto(s)
Hepatitis B Crónica , Humanos , Hepatitis B Crónica/tratamiento farmacológico , Nucleótidos/farmacología , Virus de la Hepatitis B , Dominio Catalítico , ADN Viral/genética , ADN Circular/farmacología , ADN Circular/uso terapéutico , Nucleotidiltransferasas/genética , Nucleotidiltransferasas/farmacología , Nucleotidiltransferasas/uso terapéuticoRESUMEN
IDX184 is a nucleotide prodrug designed to enhance formation in the liver of the active triphosphate of 2'-methylguanosine (2'-MeG), a potent and specific polymerase inhibitor of the hepatitis C virus (HCV). In the present study, single ascending oral doses of 5, 10, 25, 50, 75, and 100 mg IDX184 were administered sequentially to cohorts of 8 healthy subjects, randomized 6:2, active/placebo. Plasma and urine pharmacokinetic sampling was performed over a period of 120 h after dosing. Upon absorption, IDX184 rapidly disappeared from plasma, with a mean half-life (t(1/2)) of approximately 1 h, while plasma concentrations of 2'-MeG gradually increased. Consistent with a liver-targeting approach, plasma exposure of IDX184 and 2'-MeG was low and was also dose related: the mean maximum concentrations ranged from 1.1 to 17 ng/ml for IDX184 and 1.7 to 19 ng/ml for 2'-MeG, and the respective mean total area under the curve ranged from 1.2 to 22.7 and 17.3 to 334 ng·h/ml. Mean 2'-MeG plasma concentrations 24 h after dosing were 0.6 to 3 ng/ml for the 25- to 100-mg doses. Mean 2'-MeG t(1/2) values ranged from 18 to 43 h for doses of 25 mg and above. Mean cumulative urine excretion was 0.2% and 12 to 20% of administered doses for the unchanged IDX184 and 2'-MeG, respectively. IDX184 was safe and well tolerated; no serious adverse events (SAEs), dose-dependent adverse events (AEs), or dose-limiting toxicities were observed. The incidence of AEs and laboratory abnormalities was low and was similar among subjects receiving IDX184 or a placebo. All AEs were mild to moderate and resolved at the end of study. The favorable safety and pharmacokinetic profiles support further clinical evaluation of IDX184 in HCV-infected patients.
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Antivirales/farmacocinética , Antivirales/uso terapéutico , Guanosina Monofosfato/análogos & derivados , Hepacivirus/enzimología , Hepatitis C/tratamiento farmacológico , Hepatitis C/virología , Adulto , Anciano , Antivirales/efectos adversos , Femenino , Guanosina Monofosfato/efectos adversos , Guanosina Monofosfato/farmacocinética , Guanosina Monofosfato/uso terapéutico , Hepacivirus/efectos de los fármacos , Hepatitis C/sangre , Humanos , Masculino , Persona de Mediana Edad , Placebos , Adulto JovenRESUMEN
BACKGROUND: Single-dose nevirapine (sdNVP)-which prevents mother-to-child transmission of HIV-selects non-nucleoside reverse-transcriptase inhibitor (NNRTI) resistance mutations in the majority of women and HIV-infected infants receiving it. This open-label, randomised trial examined the efficacy of short-course zidovudine (AZT) and lamivudine (3TC) with sdNVP in reducing NNRTI resistance in mothers, and as a secondary objective, in infants, in a setting where sdNVP was standard-of-care. METHODS AND FINDINGS: sdNVP alone, administered at the onset of labour and to the infant, was compared to sdNVP with AZT plus 3TC, given as combivir (CBV) for 4 (NVP/CBV4) or 7 (NVP/CBV7) days, initiated simultaneously with sdNVP in labour; their newborns received the same regimens. Women were randomised 1ratio1ratio1. HIV-1 resistance was assessed by population sequencing at: baseline, 2, and 6 wk after birth. An unplanned interim analysis resulted in early stopping of the sdNVP arm. 406 pregnant women were randomised and took study medication (sdNVP 74, NVP/CBV4 164, and NVP/CBV7 168). HIV-1 resistance mutations emerged in 59.2%, 11.7%, and 7.3% of women in the sdNVP, NVP/CBV4, and NVP/CBV7 arms by 6 wk postpartum; differences between NVP-only and both NVP/CBV arms were significant (p<0.0001), but the difference between NVP/CBV4 and NVP/CBV7 was not (p = 0.27). Estimated efficacy comparing combined CBV arms with sdNVP was 85.6%. Similar resistance reductions were seen in infants who were HIV-infected by their 6-wk visit. CONCLUSIONS: A short course of AZT plus 3TC, supplementing maternal and infant sdNVP, reduces emergent NNRTI resistance mutations in both mothers and their infants. However, this trial was not powered to detect small differences between the CBV arms. TRIAL REGISTRATION: www.ClinicalTrials.govNCT 00144183.
Asunto(s)
Fármacos Anti-VIH/administración & dosificación , Infecciones por VIH/prevención & control , Transmisión Vertical de Enfermedad Infecciosa/prevención & control , Lamivudine/administración & dosificación , Complicaciones Infecciosas del Embarazo/prevención & control , Zidovudina/administración & dosificación , Adulto , Recuento de Linfocito CD4 , Farmacorresistencia Viral/efectos de los fármacos , Farmacorresistencia Viral/genética , Farmacorresistencia Viral/fisiología , Quimioterapia Combinada , Femenino , Estudios de Seguimiento , VIH-1/genética , Humanos , Mutación/genética , Nevirapina/uso terapéutico , Embarazo , Resultado del Tratamiento , Carga ViralRESUMEN
IDX899 is a novel nonnucleoside reverse transcriptase inhibitor (NNRTI) with potent in vitro activity against wild-type and NNRTI-resistant strains of human immunodeficiency virus type 1 (HIV-1) and with a high genetic barrier to resistance. Single rising doses of 50 and 100 (given by use of a 50-mg capsule) and 200, 400, 800, and 1,200 mg (given by use of a 200-mg capsule) of IDX899 or matching placebo were administered sequentially to cohorts of healthy male subjects, followed by the administration of multiple doses of 800 mg once daily (QD) or 400 mg twice daily (BID) for 7 days. A single dose of 400 mg was also administered to a cohort of females. IDX899 was administered orally under fasted (50- to 400-mg doses) and then fed (> or = 200-mg doses) conditions. Exposure to IDX899 was dose proportional and comparable in males and females. With a different drug-to-excipient ratio, the 50-mg capsule led to a higher exposure but a shorter mean terminal half-life (t(1/2)) of 6.2 to 6.8 h. The 200-mg capsule resulted in a more sustained exposure with a longer mean t(1/2) of 7.9 to 14.6 h. Food enhanced absorption by approximately twofold, while it delayed the time to the maximum concentration. The mean concentration at 24 h following the administration of a single 200-mg dose under fed conditions exceeded the in vitro protein binding-adjusted 90% inhibitory concentration by fourfold. The levels of plasma exposure were similar between the single dosing and the repeat dosing with 800 mg QD and was approximately twofold higher with 400 mg BID. Mean steady-state trough levels were 0.9 microg/ml (range, 0.2 to 2.5 microg/ml) and 2.1 microg/ml (range, 0.5 to 4.5 microg/ml) for the 800-mg QD and 400-mg BID regimens, respectively. The level of excretion of unchanged drug in urine was negligible. IDX899 was well tolerated; and no serious adverse events, dose-dependent adverse events, or laboratory abnormalities were detected. These favorable safety and pharmacokinetic results support further clinical studies with patients with HIV-1 infection by the use of a QD regimen.
Asunto(s)
Fármacos Anti-VIH , Transcriptasa Inversa del VIH/antagonistas & inhibidores , VIH-1/efectos de los fármacos , Indoles , Ácidos Fosfínicos , Inhibidores de la Transcriptasa Inversa/administración & dosificación , Adolescente , Adulto , Anciano , Fármacos Anti-VIH/administración & dosificación , Fármacos Anti-VIH/antagonistas & inhibidores , Fármacos Anti-VIH/química , Fármacos Anti-VIH/farmacocinética , Método Doble Ciego , Esquema de Medicación , Femenino , Humanos , Indoles/administración & dosificación , Indoles/efectos adversos , Indoles/química , Indoles/farmacocinética , Masculino , Persona de Mediana Edad , Ácidos Fosfínicos/administración & dosificación , Ácidos Fosfínicos/efectos adversos , Ácidos Fosfínicos/química , Ácidos Fosfínicos/farmacocinética , Inhibidores de la Transcriptasa Inversa/efectos adversos , Inhibidores de la Transcriptasa Inversa/química , Inhibidores de la Transcriptasa Inversa/farmacocinética , Resultado del Tratamiento , Adulto JovenRESUMEN
Telbivudine is a new nucleoside analog indicated for the treatment of chronic hepatitis B infection. A population pharmacokinetic model was developed based on data pooled from 16 early phase studies in 363 healthy participants and patients. Telbivudine was administered as single and/or multiple doses of 25 to 1800 mg daily for up to 28 days. A 2-compartment model with first-order input and lag time provided the best fit to the data. A final model was built with identified covariates, including creatinine clearance on plasma clearance, dose and race on bioavailability fraction, and body weight on central volume of distribution. The final model was applied to simulate steady-state exposure for patients with impaired renal function for various dosing regimens. Results from these simulation analyses support that in patients with moderate to severe renal impairment or end-stage renal disease, reduced daily doses of telbivudine could be an alternative to interval adjustment to achieve exposure comparable to patients with normal renal function or mild renal impairment treated with the full clinical dose.
Asunto(s)
Antivirales/administración & dosificación , Antivirales/farmacocinética , Enfermedades Renales/metabolismo , Nucleósidos/administración & dosificación , Nucleósidos/farmacocinética , Pirimidinonas/administración & dosificación , Pirimidinonas/farmacocinética , Adulto , Anciano , Disponibilidad Biológica , Femenino , Humanos , Masculino , Persona de Mediana Edad , Modelos Biológicos , Telbivudina , Timidina/análogos & derivadosRESUMEN
The massive outbreak of Ebola virus disease in west Africa between 2013 and 2016 resulted in intense efforts to evaluate the efficacy of several specific countermeasures developed through years of preclinical work, including the first clinical trials for therapeutics and vaccines. In this Review, we discuss how the experience and data generated from that outbreak have helped to advance the understanding of the use of these countermeasures for post-exposure prophylaxis against Ebola virus infection. In future outbreaks, post-exposure prophylaxis could play an important part in reducing community transmission of Ebola virus by providing more immediate protection than does immunisation as well as providing additional protection for health-care workers who are inadvertently exposed over the course of their work. We propose provisional guidance for use of post-exposure prophylaxis in Ebola virus disease and identify the priorities for future preparedness and further research.
Asunto(s)
Antivirales/farmacología , Vacunas contra el Virus del Ébola/inmunología , Fiebre Hemorrágica Ebola/prevención & control , Profilaxis Posexposición , Desarrollo de Medicamentos , HumanosRESUMEN
BACKGROUND: Treatment options for HIV-1 infected individuals who have received extensive previous antiretroviral therapy are limited. We compared efficacy and safety of the novel non-peptidic protease inhibitor tipranavir co-administered with ritonavir plus an optimised background regimen with that of an investigator-selected ritonavir-boosted comparator protease inhibitor (CPI-ritonavir) in such patients. METHODS: We did a combined analysis of 48-week data from two ongoing, randomised, open-label, multinational, phase III, RESIST studies. HIV-1-infected adults with 3 months or longer previous triple antiretroviral class experience, two or more previous protease inhibitor regimens, HIV-1 RNA 1000 copies per mL or greater, and genotypically demonstrated primary resistance to protease inhibitor, were eligible. Primary endpoints were proportion of treatment responders (with reduction in viral load of 1 log(10) copies per mL or greater below baseline without treatment change) at 48 weeks and time to treatment failure through 48 weeks (intention-to-treat analysis). The RESIST studies are registered with ClinicalTrials.gov, numbers NCT00054717 (RESIST-1) and NCT00144170 (RESIST-2). FINDINGS: 3324 patients were screened; 746 received tipranavir-ritonavir and 737 CPI-ritonavir. 486 (65.1%) patients on tipranavir-ritonavir and 192 (26.1%) on CPI-ritonavir remained on assigned treatment until week 48. At week 48, more patients achieved and maintained treatment response in the tipranavir-ritonavir group than in the CPI-ritonavir group (251 [33.6%] vs 113 [15.3%]; p<0.0001). Median time to treatment failure was significantly longer in the tipranavir-ritonavir group than in the CPI-ritonavir group (113 days vs 0 days; p<0.0001). Gastrointestinal system disorders and raised transaminase, cholesterol, and triglycerides were more frequent in the tipranavir-ritonavir group than in the CPI-ritonavir group. INTERPRETATION: Compared with CPI-ritonavir, tipranavir-ritonavir with an optimised background regimen provides better virological and immunological responses over 48 weeks in patients who have received extensive previous antiretroviral treatment.
Asunto(s)
Infecciones por VIH/tratamiento farmacológico , Inhibidores de la Proteasa del VIH/uso terapéutico , VIH-1/genética , Piridinas/uso terapéutico , Pironas/uso terapéutico , Ritonavir/uso terapéutico , Adulto , Farmacorresistencia Viral/genética , Quimioterapia Combinada , Enfuvirtida , Femenino , Proteína gp41 de Envoltorio del VIH/uso terapéutico , Inhibidores de Fusión de VIH/uso terapéutico , Inhibidores de la Proteasa del VIH/administración & dosificación , Humanos , Modelos Logísticos , Masculino , Estudios Multicéntricos como Asunto , Fragmentos de Péptidos/uso terapéutico , Piridinas/administración & dosificación , Pironas/administración & dosificación , Ensayos Clínicos Controlados Aleatorios como Asunto , Ritonavir/administración & dosificación , Sulfonamidas , Factores de Tiempo , Insuficiencia del Tratamiento , Carga ViralRESUMEN
BACKGROUND: We compared two strategies for treating patients infected with multidrug-resistant human immunodeficiency virus (HIV). METHODS: Patients with multidrug-resistant HIV and HIV RNA levels of more than 5000 copies per milliliter were randomly assigned to a four-month structured interruption of treatment followed by a change in antiretroviral regimen (treatment-interruption group) or to an immediate change in regimen (control group). Genotypic and phenotypic resistance testing was performed. Disease progression, death, and changes in genotypic resistance, CD4 cell counts, HIV RNA levels, and quality of life were assessed. RESULTS: After a median follow-up of 11.6 months, disease progression or death occurred in 22 of the 138 patients in the treatment-interruption group and in 12 of the 132 patients in the control group (P=0.01), with a hazard ratio of 2.57 (95 percent confidence interval, 1.2 to 5.5) for the treatment-interruption group. There were eight deaths in each group. In the treatment-interruption group, the mutant HIV populations completely or partially reverted to wild type by four months in 64.0 percent of patients. As compared with the control group, the treatment-interruption group had a mean CD4 cell count that was 85 cells per cubic millimeter lower from months 0 through 4 (P<0.001), 47 cells per cubic millimeter lower from months 5 through 8 (P<0.001), and 31 cells per cubic millimeter lower after eight months (P=0.11). The mean HIV RNA levels were 1.2 log copies per milliliter higher (on a base-10 scale) in the treatment-interruption group during months 0 through 4 (P<0.001), but they were not significantly different from those in the control group after month 4. The overall quality of life was similar in the two groups. CONCLUSIONS: In patients infected with multidrug-resistant HIV, structured interruption of treatment was associated with greater progression of disease and did not confer immunologic or virologic benefits or improve the overall quality of life.
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Fármacos Anti-VIH/administración & dosificación , Infecciones por VIH/tratamiento farmacológico , Infecciones Oportunistas Relacionadas con el SIDA/epidemiología , Adulto , Recuento de Linfocito CD4 , Progresión de la Enfermedad , Esquema de Medicación , Farmacorresistencia Viral Múltiple , Femenino , VIH/efectos de los fármacos , VIH/genética , VIH/aislamiento & purificación , Infecciones por VIH/mortalidad , Humanos , Masculino , Persona de Mediana Edad , Análisis Multivariante , ARN Viral/sangreRESUMEN
The efficacy, safety, and pharmacokinetics of three doses of tipranavir/ritonavir (TPV/r) in highly treatment-experienced human immunodeficiency virus (HIV)-1-infected patients with protease inhibitor (PI)-resistant isolates were evaluated. A 24-week multicenter, double-blind, randomized, dose-finding trial was conducted. All patients were three-drug class experienced and had taken at least two PI-based regimens. All had at least one primary PI mutation and had plasma HIV-RNA > 1000 copies/ml. Patients remained on their background non-PI antiretroviral medications for the first 14 days. After this 14-day period of functional TPV/r monotherapy, the background antiretroviral medications were optimized based on treatment history and the screening genotype. A total of 216 patients were randomized. All groups [TPV/r 500 mg/100 mg (n = 73), 500 mg/200 mg (n = 72), and 750 mg/200 mg (n = 71) twice daily] achieved an approximate 1 log10 reduction in the median HIV-RNA at week 2. A significant reduction was sustained through 24 weeks in the TPV/r 500 mg/200 mg and 750 mg/200 mg groups. The 500 mg/200 mg dose achieved optimal median TPV trough concentrations and lower interpatient variability. The most frequently reported adverse events (AEs) were diarrhea, nausea, vomiting, fatigue, and headache. The TPV/r 750 mg/200 mg group had the highest rate of grade 3 or 4 laboratory abnormalities and study discontinuations due to AEs. All doses of TPV/r tested in this study were associated with HIV-1 viral load reductions through 24 weeks. The 500 mg/200 mg dose achieved the best efficacy, safety, and pharmacokinetic profile in this highly treatment-experienced population and was selected for the pivotal phase 3 studies.
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Fármacos Anti-VIH/administración & dosificación , Farmacorresistencia Viral Múltiple/efectos de los fármacos , Infecciones por VIH/tratamiento farmacológico , VIH-1/efectos de los fármacos , Piridinas/administración & dosificación , Pironas/administración & dosificación , Ritonavir/administración & dosificación , Adulto , Anciano , Fármacos Anti-VIH/efectos adversos , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Quimioterapia Combinada , Femenino , Humanos , Masculino , Piridinas/efectos adversos , Pironas/efectos adversos , Ritonavir/efectos adversos , Sulfonamidas , Resultado del TratamientoRESUMEN
BACKGROUND: Tipranavir, a novel protease inhibitor, has demonstrated antiviral activity against protease inhibitor-resistant human immunodeficiency virus type 1 (HIV-1) isolates. The Randomized Evaluation of Strategic Intervention in multi-drug reSistant patients with Tipranavir (RESIST-2) trial is an ongoing, open-label, phase III trial comparing ritonavir-boosted tipranavir (TPV/r) plus an optimized background regimen with an individually optimized, ritonavir-boosted protease inhibitor in treatment-experienced, HIV-1-infected patients. METHODS: Patients at 171 sites in Europe and Latin America who had received > or = 2 previous protease inhibitor regimens, had triple-antiretroviral class experience, had an HIV-1 RNA level > or = 1000 copies/mL, and had genotypically demonstrated primary protease inhibitor resistance were eligible. After genotypic resistance tests were performed, a protease inhibitor and optimized background regimen were selected before randomization. Patients were randomized to receive either TPV/r or comparator protease inhibitor-ritonavir (CPI/r) and were stratified on the basis of preselected protease inhibitor and enfuvirtide use. Treatment response was defined as a confirmed HIV-1 load reduction > or = 1 log10 less than the baseline value without a treatment change at week 24. RESULTS: A total of 863 patients were randomized and treated. At baseline, the mean HIV-1 load was 4.73 log10 copies/mL, and the mean CD4+ cell count was 218 cells/mm3. The preplanned 24-week efficacy analyses of 539 patients demonstrated treatment response rates of 41% in the TPV/r arm and 14.9% in the CPI/r arm (intent-to-treat analysis; P<.0001). The mean CD4+ cell count increased by 51 cells/mm3 in the TPV/r arm and by 18 cells/mm3 in the CPI/r arm. The most common adverse events were mild-to-moderate diarrhea, nausea, and headache. Grade 3 or greater elevations in serum transaminase, cholesterol, and triglyceride levels were more frequent in the TPV/r arm. CONCLUSIONS: TPV/r had superior antiviral activity and increased immunologic benefits, compared with CPI/r, at week 24 among treatment-experienced patients infected with multidrug-resistant HIV-1.
Asunto(s)
Inhibidores de la Proteasa del VIH/farmacología , VIH-1/efectos de los fármacos , Piridinas/farmacología , Pironas/farmacología , Ritonavir/farmacología , Adolescente , Adulto , Anciano , Quimioterapia Combinada , Femenino , Infecciones por VIH/tratamiento farmacológico , Inhibidores de la Proteasa del VIH/uso terapéutico , VIH-1/fisiología , Humanos , Masculino , Persona de Mediana Edad , Piridinas/uso terapéutico , Pironas/uso terapéutico , Ritonavir/uso terapéutico , SulfonamidasRESUMEN
BACKGROUND: Improved treatment options are needed for patients infected with multidrug-resistant human immunodeficiency virus type 1 (HIV-1). The nonpeptidic protease inhibitor tipranavir has demonstrated antiviral activity against many protease inhibitor-resistant HIV-1 isolates. The Randomized Evaluation of Strategic Intervention in multi-drug reSistant patients with Tipranavir (RESIST-1) trial is an ongoing, open-label study comparing the efficacy and safety of ritonavir-boosted tipranavir (TPV/r) with an investigator-selected ritonavir-boosted comparator protease inhibitor (CPI/r) in treatment-experienced, HIV-1-infected patients. METHODS: Six hundred twenty antiretroviral-experienced patients were treated at 125 sites in North America and Australia. Before randomization, all patients underwent genotypic resistance testing, which investigators used to select a CPI/r and an optimized background regimen. Patients were randomized to receive TPV/r or CPI/r and were stratified on the basis of preselected protease inhibitor and enfuvirtide use. Treatment response was defined as a confirmed reduction in the HIV-1 load of > or = 1 log10 less than the baseline level without treatment change at week 24. RESULTS: Mean baseline HIV-1 loads and CD4+ cell counts were 4.74 log10 copies/mL and 164 cells/mm3, respectively. At week 24, a total of 41.5% of patients in the TPV/r arm and 22.3% in the CPI/r arm had a > or = 1-log10 reduction in the HIV-1 load (intent-to-treat population; P<.0001). Mean increases in the CD4+ cell count of 54 and 24 cells/mm3 occurred in the TPV/r and CPI/r groups, respectively. Adverse events were slightly more common in the TPV/r group and included diarrhea, nausea, and vomiting. Elevations in alanine and aspartate aminotransferase levels and in cholesterol/triglyceride levels were more frequent in the TPV/r group. CONCLUSIONS: TPV/r demonstrated superior antiviral activity, compared with investigator-selected, ritonavir-boosted protease inhibitors, at week 24 in treatment-experienced patients with multidrug-resistant HIV-1 infection.
Asunto(s)
Infecciones por VIH/tratamiento farmacológico , Inhibidores de la Proteasa del VIH/farmacología , VIH-1/efectos de los fármacos , Piridinas/farmacología , Pironas/farmacología , Ritonavir/farmacología , Adulto , Anciano , Anciano de 80 o más Años , Recuento de Linfocito CD4 , Quimioterapia Combinada , Femenino , Infecciones por VIH/inmunología , Inhibidores de la Proteasa del VIH/uso terapéutico , VIH-1/fisiología , Humanos , Masculino , Persona de Mediana Edad , Piridinas/uso terapéutico , Pironas/uso terapéutico , Ritonavir/uso terapéutico , Sulfonamidas , Carga ViralRESUMEN
BACKGROUND: To determine the impact of HIV-1 drug resistance at baseline and antiretroviral drug levels (DL) during follow-up on virologic response to the next antiretroviral regimen. METHODS: Baseline genotypic and phenotypic susceptibility was obtained for plasma virus from patients failing a protease inhibitor-containing regimen. Untimed plasma antiretroviral DL were performed and the distribution of DL after 12 weeks of follow-up was classified as above (DLHigh) or below (DLLow) the median. Inhibitory quotients [IQ = (DL at week 12)/(fold change in IC50 to wild-type)] were determined for each drug in the regimen. Primary outcome was change in log10 plasma HIV-1 RNA viral load (DeltaVL) from baseline to 12 weeks. RESULTS: There were 137 patients who had baseline resistance data available for the antiretroviral drugs used in the salvage regimen, and DL at week 12. Each drug with DLHigh was associated with DeltaVL = -0.40 (P = 0.0002) while each drug with DLLow had DeltaVL = -0.16 (P = 0.11). In multivariate models DeltaVL associated with each active drug (defined by genotype) with DLHigh was -0.48 log10 (P < 0.0001), and with each active drug with DLLow was -0.22 (P = 0.03). The DeltaVL was -0.18 if no drugs in the regimen had an IQ > median, compared to -0.58 for one drug, -1.06 for two drugs, -0.86 for three drugs, and -1.44 for four or five drugs with IQ > median (P < 0.0001 for trend). CONCLUSIONS: In salvage therapy, both the number of active drugs and the DL for each drug in the new regimen determine the antiviral response.