RESUMEN
Human immunodeficiency virus (HIV) continues to pose a serious threat to global health. Oral preexposure prophylaxis (PrEP), considered highly effective for HIV prevention, is the utilisation of antiretroviral (ARV) drugs before HIV exposure in high-risk uninfected individuals. However, ARV drugs are associated with poor patient compliance and pill fatigue due to their daily oral dosing. Therefore, an alternative strategy for drug delivery is required. In this work, two dissolving microneedle patches (MNs) containing either bictegravir (BIC) or tenofovir alafenamide (TAF) solid drug nanoparticles (SDNs) were developed for systemic delivery of a novel ARV regimen for potential HIV prevention. According to ex vivo skin deposition studies, approximately 11% and 50% of BIC and TAF was delivered using dissolving MNs, respectively. Pharmacokinetic studies in Sprague Dawley rats demonstrated that BIC MNs achieved a long-acting release profile, maintaining the relative plasma concentration above the 95% inhibitory concentration (IC95) for 3 weeks. For TAF MNs, a rapid release of drug and metabolism of TAF into TFV were obtained from the plasma samples. This work has shown that the proposed transdermal drug delivery platform could be potentially used as an alternative method to systemically deliver ARV drugs for HIV PrEP.
Asunto(s)
Administración Cutánea , Alanina , Fármacos Anti-VIH , Infecciones por VIH , Agujas , Profilaxis Pre-Exposición , Ratas Sprague-Dawley , Tenofovir , Animales , Tenofovir/administración & dosificación , Tenofovir/farmacocinética , Tenofovir/análogos & derivados , Alanina/farmacocinética , Alanina/administración & dosificación , Alanina/química , Fármacos Anti-VIH/administración & dosificación , Fármacos Anti-VIH/farmacocinética , Profilaxis Pre-Exposición/métodos , Infecciones por VIH/prevención & control , Masculino , Adenina/administración & dosificación , Adenina/farmacocinética , Adenina/análogos & derivados , Adenina/química , Ratas , Nanopartículas/administración & dosificación , Nanopartículas/química , Liberación de Fármacos , Compuestos Heterocíclicos de 4 o más Anillos/farmacocinética , Compuestos Heterocíclicos de 4 o más Anillos/administración & dosificación , Compuestos Heterocíclicos de 4 o más Anillos/química , Piridonas/administración & dosificación , Piridonas/farmacocinética , Sistemas de Liberación de Medicamentos , Piperazinas/farmacocinética , Piperazinas/administración & dosificación , Piperazinas/química , Ciclopropanos/administración & dosificación , Ciclopropanos/farmacocinética , Compuestos Heterocíclicos con 3 Anillos/farmacocinética , Compuestos Heterocíclicos con 3 Anillos/administración & dosificación , Amidas/administración & dosificación , Amidas/farmacocinética , Amidas/químicaRESUMEN
OBJECTIVE: There is limited information on favipiravir pharmacokinetics in critically ill patients and no studies on pharmacokinetics in patients with moderate and severe kidney dysfunction. The aim was to determine favipiravir pharmacokinetics (oral, 1,600 mg, q12h on day 1, then 600 mg, q12h for 4 days) in critically ill COVID-19 patients with kidney dysfunction and to compare those with observations reported in healthy adults. MATERIALS AND METHODS: In a descriptive study, blood samples taken from patients meeting the relevant criteria (estimated glomerular filtration rate < 60 mL/min) were collected and analyzed. Analysis of blood samples was done by high performance liquid chromatography (HPLC), and the maximal concentration (Cmax), the time of maximal concentration (tmax), half-life (T1/2) and area under the curve (AUC0-12h) of favipiravir were calculated (WinNonlin) and compared to reported data in healthy subjects after first administration. RESULTS: Based on analysis of samples collected in 7 patients, the Cmax (29.99 vs. 64.5 µg/mL) of favipiravir was decreased, T1/2 (5.8 vs. 4.8 hours) longer, tmax delayed, while total exposure was lower (AUC0-12: 192.53 vs. 446.09 µg/mL) compared to reported data in healthy subjects after first administration. Exposure remained lower up to day 5. CONCLUSION: In patients with kidney dysfunction related to COVID-19, favipiravir did not reach the expected exposure. This may be due to poorer and delayed absorption, and subsequent altered disposition. Population pharmacokinetic and mechanistic studies are needed to better explore the relevant covariates and to determine the optimal dose in these patients, as this drug is likely of relevance for other indications.
Asunto(s)
Amidas , Antivirales , Tratamiento Farmacológico de COVID-19 , Pirazinas , Humanos , Amidas/farmacocinética , Pirazinas/farmacocinética , Pirazinas/administración & dosificación , Masculino , Persona de Mediana Edad , Femenino , Anciano , Antivirales/farmacocinética , Antivirales/administración & dosificación , Enfermedad Crítica , Semivida , COVID-19/complicaciones , Área Bajo la Curva , Adulto , SARS-CoV-2 , Tasa de Filtración Glomerular , Insuficiencia Renal/metabolismo , Insuficiencia Renal/complicaciones , Índice de Severidad de la EnfermedadRESUMEN
BACKGROUND: Coformulated bictegravir, emtricitabine, and tenofovir alafenamide is a single-tablet regimen and was efficacious and well tolerated in children and adolescents with HIV (aged 6 years to <18 years) in a 48-week phase 2/3 trial. In this study, we report data from children aged at least 2 years and weighing 14 kg to less than 25 kg. METHODS: We conducted this open-label, multicentre, multicohort, single-arm study in South Africa, Thailand, Uganda, and the USA. Participants were virologically suppressed children with HIV, aged at least 2 years, weighing 14 kg to less than 25 kg. Participants received bictegravir (30 mg), emtricitabine (120 mg), and tenofovir alafenamide (15 mg) once daily, switching to bictegravir (50 mg), emtricitabine (200 mg), and tenofovir alafenamide (25 mg) upon attaining a bodyweight of at least 25 kg. The study included pharmacokinetic evaluation at week 2 to confirm the dose of coformulated bictegravir, emtricitabine, and tenofovir alafenamide for this weight band by comparing with previous adult data. Primary outcomes were bictegravir area under the curve over the dosing interval (AUCtau) and concentration at the end of the dosing interval (Ctau) at week 2, and incidence of treatment-emergent adverse events and laboratory abnormalities until the end of week 24 in all participants who received at least one dose of bictegravir, emtricitabine, and tenofovir alafenamide. This study is registered with ClinicalTrials.gov, NCT02881320. FINDINGS: Overall, 22 participants were screened (from Nov 14, 2018, to Jan 11, 2020), completed treatment with bictegravir, emtricitabine, and tenofovir alafenamide (until week 48), and entered an extension phase. The geometric least squares mean (GLSM) ratio for AUCtau for bictegravir was 7·6% higher than adults (GLSM ratio 107·6%, 90% CI 96·7-119·7); Ctau was 34·6% lower than adults (65·4%, 49·1-87·2). Both parameters were within the target exposure range previously found in adults, children, or both". Grade 3-4 laboratory abnormalities occurred in four (18%) participants by the end week 24 and six (27%) by the end of week 48. Drug-related adverse events occurred in three participants (14%) by the end of week 24 and week 48; none were severe. No Grade 3-4 adverse events, serious adverse events, or adverse events leading to discontinuation occurred by the end of week 24 and week 48. INTERPRETATION: Data support the use of single-tablet coformulated bictegravir (30 mg), emtricitabine (120 mg), and tenofovir alafenamide (15 mg) for treatment of HIV in children aged at least 2 years and weighing 14 kg to less than 25 kg. FUNDING: Gilead Sciences.
Asunto(s)
Adenina , Alanina , Amidas , Fármacos Anti-VIH , Emtricitabina , Infecciones por VIH , Compuestos Heterocíclicos con 3 Anillos , Compuestos Heterocíclicos de 4 o más Anillos , Piperazinas , Piridonas , Tenofovir , Tenofovir/análogos & derivados , Humanos , Emtricitabina/farmacocinética , Emtricitabina/administración & dosificación , Emtricitabina/uso terapéutico , Emtricitabina/efectos adversos , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , Tenofovir/farmacocinética , Tenofovir/administración & dosificación , Tenofovir/efectos adversos , Tenofovir/uso terapéutico , Niño , Masculino , Femenino , Fármacos Anti-VIH/farmacocinética , Fármacos Anti-VIH/efectos adversos , Fármacos Anti-VIH/administración & dosificación , Fármacos Anti-VIH/uso terapéutico , Preescolar , Alanina/farmacocinética , Alanina/efectos adversos , Compuestos Heterocíclicos de 4 o más Anillos/farmacocinética , Compuestos Heterocíclicos de 4 o más Anillos/efectos adversos , Compuestos Heterocíclicos de 4 o más Anillos/administración & dosificación , Amidas/farmacocinética , Adolescente , Piridonas/farmacocinética , Piridonas/efectos adversos , Compuestos Heterocíclicos con 3 Anillos/farmacocinética , Compuestos Heterocíclicos con 3 Anillos/efectos adversos , Compuestos Heterocíclicos con 3 Anillos/administración & dosificación , Piperazinas/efectos adversos , Piperazinas/farmacocinética , Adenina/análogos & derivados , Adenina/farmacocinética , Adenina/efectos adversos , Adenina/administración & dosificación , Adenina/uso terapéutico , Tailandia , Estados Unidos , Sudáfrica , Combinación de Medicamentos , Uganda , Carga Viral/efectos de los fármacosRESUMEN
OBJECTIVES: Pecto-intercostal fascial block (PIFB) and rectus sheath block (RSB) have been combined to offer better analgesia for cardiac surgery patients, but safety of the analgesic protocol with a large volume of ropivacaine is uncertain. METHODS: This is a prospective observational study at Peking University People's Hospital to investigate the pharmacokinetic profile of ropivacaine after combined regional blocks. Patients undergoing elective cardiac surgery by a median sternotomy were enrolled to receive bilateral PIFB and RSB with 70 mL 0.3% ropivacaine (total dose 210 mg). Blood was sampled at 5, 10, 15, 30, 60, 90 and 120 mins after blocks. Total blood concentration of ropivacaine for patients were measured. RESULTS: Ten patients were enrolled and analyzed. The peak total ropivacaine concentration varied from 0.67 to 2.42 µg/mL. Time to reach the peak values mainly located between 10 and 30 mins after the performance. No patients had ropivacaine concentration values above toxic threshold (4.3 µg/mL), and there were no systemic toxicity symptoms during the perioperative period. CONCLUSIONS: PIFB combined with RSB in a general injection of 70 mL 0.3% ropivacaine does not give rise to toxic levels, and it is an effective and safe analgesic protocol for cardiac surgery patients.
Asunto(s)
Procedimientos Quirúrgicos Cardíacos , Bloqueo Nervioso , Humanos , Amidas/farmacocinética , Analgésicos , Anestésicos Locales/farmacocinética , Bloqueo Nervioso/métodos , Dolor Postoperatorio/diagnóstico , Dolor Postoperatorio/prevención & control , Ropivacaína , Estudios ProspectivosRESUMEN
BACKGROUND AND OBJECTIVES: The pathophysiology of chronic fatigue syndrome (CFS) and Q fever fatigue syndrome (QFS) remains elusive. Recent data suggest a role for neuroinflammation as defined by increased expression of translocator protein (TSPO). In the present study, we investigated whether there are signs of neuroinflammation in female patients with CFS and QFS compared with healthy women, using PET with the TSPO ligand 11C-(R)-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinoline-carbox-amide ([11C]-PK11195). METHODS: The study population consisted of patients with CFS (n = 9), patients with QFS (n = 10), and healthy subjects (HSs) (n = 9). All subjects were women, matched for age (±5 years) and neighborhood, aged between 18 and 59 years, who did not use any medication other than paracetamol or oral contraceptives, and were not vaccinated in the last 6 months. None of the subjects reported substance abuse in the past 3 months or reported signs of underlying psychiatric disease on the Mini-International Neuropsychiatric Interview. All subjects underwent a [11C]-PK11195 PET scan, and the [11C]-PK11195 binding potential (BPND) was calculated. RESULTS: No statistically significant differences in BPND were found for patients with CFS or patients with QFS compared with HSs. BPND of [11C]-PK11195 correlated with symptom severity scores in patients with QFS, but a negative correlation was found in patients with CFS. DISCUSSION: In contrast to what was previously reported for CFS, we found no significant difference in BPND of [11C]-PK11195 when comparing patients with CFS or QFS with healthy neighborhood controls. In this small series, we were unable to find signs of neuroinflammation in patients with CFS and QFS. TRIAL REGISTRATION INFORMATION: EudraCT number 2014-004448-37.
Asunto(s)
Encéfalo/diagnóstico por imagen , Síndrome de Fatiga Crónica/diagnóstico por imagen , Fatiga/diagnóstico por imagen , Enfermedades Neuroinflamatorias/diagnóstico por imagen , Fiebre Q/diagnóstico por imagen , Adolescente , Adulto , Amidas/farmacocinética , Fatiga/etiología , Femenino , Humanos , Isoquinolinas/farmacocinética , Persona de Mediana Edad , Tomografía de Emisión de Positrones , Fiebre Q/complicaciones , Receptores de GABA , Adulto JovenRESUMEN
BACKGROUND: Bictegravir coformulated with emtricitabine and tenofovir alafenamide as a fixed-dose combination (BIC/FTC/TAF 50/200/25 mg) is recommended as an initial regimen in patients who are antiretroviral (ARV)-naïve or virologically suppressed on a stable ARV regimen. However, no real-world pharmacokinetic (PK) data are available in treatment-experienced patients with antiretroviral resistance receiving BIC/FTC/TAF plus a boosted protease inhibitor. SETTING/METHODS: This prospective, single-center, nonrandomized pharmacokinetic study enrolled adult treatment-experienced persons with HIV and creatinine clearance >30 mL/min receiving BIC/FTC/TAF + DRV/c as part of routine clinical care. Steady-state PK profiles of BIC, TAF, tenofovir (TFV), and DRV after daily dosing of BIC/FTC/TAF + darunavir/cobicistat (DRV/c) were obtained with samples at predose and 0.5, 1, 2, and 4 hours postdose. The AUC0-24 at steady state was extrapolated by imputing C0 for C24 for each participant (AUC0-tau,exp). RESULTS: Nine participants were enrolled with a median age of 59 years (range 54-67) and median number of years on ART of 19 (range 5.8-30). The median (interquartile range [IQR]) BIC AUC0-tau,exp and Cmax values were 128.9 µg*h/mL (78.1-159.5) and 6.9 µg/mL (5.1-9.8), respectively. The median (IQR) TAF AUC0-tau,exp and Cmax values were 0.376 µg*h/mL (0.199-0.430) and 0.276 µg/mL (0.149-0.543), respectively. Predose concentrations of TFV and DRV were comparable with historical data. CONCLUSION: Treatment-experienced persons with HIV receiving BIC/FTC/TAF + darunavir/cobicistat (DRV/c) had BIC exposures (AUC0-tau) that were increased by approximately 26% compared with historical PK data. Although TAF exposures were substantially increased, plasma TFV was only modestly higher. These results suggest that BIC/TAF/FTC + DRV/c is a viable antiviral regimen option for treatment-experienced persons.
Asunto(s)
Amidas/farmacocinética , Fármacos Anti-VIH/farmacocinética , Cobicistat/farmacocinética , Darunavir/farmacocinética , Infecciones por VIH/tratamiento farmacológico , Compuestos Heterocíclicos con 3 Anillos/farmacocinética , Piperazinas/farmacocinética , Piridonas/farmacocinética , Tenofovir/farmacocinética , Anciano , Amidas/sangre , Fármacos Anti-VIH/sangre , Terapia Antirretroviral Altamente Activa/métodos , Cromatografía Liquida , Cobicistat/sangre , Darunavir/sangre , Femenino , Compuestos Heterocíclicos con 3 Anillos/sangre , Humanos , Masculino , Persona de Mediana Edad , Piperazinas/sangre , Estudios Prospectivos , Piridonas/sangre , Espectrometría de Masas en Tándem , Tenofovir/sangreRESUMEN
Coronavirus disease 2019 (COVID-19) has spread across the world, and no specific antiviral drugs have yet been approved to combat this disease. Favipiravir (FAV) is an antiviral drug that is currently in clinical trials for use against COVID-19. However, the delivery of FAV is challenging because of its limited solubility, and its formulation is difficult with common organic solvents and water. To address these issues, four FAV ionic liquids (FAV-ILs) were synthesized as potent antiviral prodrugs and were fully characterized by nuclear magnetic resonance (NMR) spectroscopy, Fourier-transform infrared (FT-IR) spectrometry, powder X-ray diffraction (PXRD), thermogravimetric analysis (TGA), derivative thermogravimetry (DTG), and differential scanning calorimetry (DSC). The aqueous solubility and in vivo pharmacokinetic properties of the FAV-ILs were also evaluated. The FAV-ILs exhibited improved aqueous solubility by 78 to 125 orders of magnitude when compared with that of free FAV. Upon oral dosing in mice, the absolute bioavailability of the ß-alanine ethyl ester FAV formulation was increased 1.9-fold compared with that of the control FAV formulation. The peak blood concentration, elimination half-life, and mean absorption time of FAV were also increased by 1.5-, 2.0-, and 1.5-fold, respectively, compared with the control. Furthermore, the FAV in the FAV-ILs exhibited significantly different biodistribution compared with the control FAV formulation. Interestingly, drug accumulation in the lungs and liver was improved 1.5-fold and 1.3-fold, respectively, compared with the control FAV formulation. These results indicate that the use of ILs exhibits potential as a simple, scalable strategy to improve the solubility and oral absorption of hydrophobic drugs, such as FAV.
Asunto(s)
Amidas/administración & dosificación , Antivirales/administración & dosificación , Líquidos Iónicos/química , Pirazinas/administración & dosificación , Administración Oral , Amidas/síntesis química , Amidas/química , Amidas/farmacocinética , Animales , Femenino , Ratones , Ratones Endogámicos BALB C , Pirazinas/síntesis química , Pirazinas/química , Pirazinas/farmacocinética , Solubilidad , Distribución Tisular , Tratamiento Farmacológico de COVID-19RESUMEN
The antiretroviral drug favipiravir (FPV) inhibits RNA-dependent RNA polymerase. It has been developed for the treatment of the novel coronavirus (severe acute respiratory syndrome coronavirus 2) infection disease, coronavirus disease 2019 (COVID-19). However, its pharmacokinetics in patients with COVID-19 is poorly understood. In this study, we measured FPV serum concentration by liquid chromatography-tandem mass spectrometry and conducted population pharmacokinetic analysis. A total of 39 patients were enrolled in the study: 33 were administered FPV 1600 mg twice daily (b.i.d.) on the first day followed by 600 mg b.i.d., and 6 were administered FPV 1800 mg b.i.d. on the first day followed by 800 mg or 600 mg b.i.d. The median age was 68 years (range, 27-89 years), 31 (79.5%) patients were men, median body surface area (BSA) was 1.72 m2 (range, 1.11-2.2 m2 ), and 10 (25.6%) patients required invasive mechanical ventilation (IMV) at the start of FPV. A total of 204 serum concentrations were available for pharmacokinetic analysis. A one-compartment model with first-order elimination was used to describe the pharmacokinetics. The estimated mean clearance/bioavailability (CL/F) and distribution volume/bioavailability (V/F) were 5.11 L/h and 41.6 L, respectively. Covariate analysis revealed that CL/F was significantly related to dosage, IMV use, and BSA. A simulation study showed that the 1600 mg/600 mg b.i.d. regimen was insufficient for the treatment of COVID-19 targeting the 50% effective concentration (9.7 µg/mL), especially in patients with larger BSA and/or IMV. A higher FPV dosage is required for COVID-19, but dose-dependent nonlinear pharmacokinetics may cause an unexpected significant pharmacokinetic change and drug toxicity. Further studies are warranted to explore the optimal FPV regimen.
Asunto(s)
Amidas/administración & dosificación , Antivirales/administración & dosificación , Tratamiento Farmacológico de COVID-19 , Pirazinas/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Amidas/farmacocinética , Antivirales/farmacocinética , COVID-19/sangre , Cromatografía Liquida , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Humanos , Masculino , Persona de Mediana Edad , Modelos Teóricos , Pirazinas/farmacocinética , Estudios Retrospectivos , Espectrometría de Masas en Tándem , Resultado del TratamientoRESUMEN
BACKGROUND: Bictegravir is a potent integrase strand-transfer inhibitor (INSTI) with a high genetic barrier to resistance. Bictegravir, coformulated with emtricitabine and tenofovir alafenamide, is recommended by key European and US HIV treatment guidelines as the preferred single-tablet regimen for adults and adolescents. The aim of this study was to assess the pharmacokinetics, safety, and efficacy of switching to this regimen in virologically suppressed children and adolescents with HIV. METHODS: In this single-arm, open-label trial, we enrolled virologically suppressed children and adolescents (aged 6 to <18 years) with HIV at 22 hospital clinics in South Africa, Thailand, Uganda, and the USA. Eligible participants had a bodyweight of at least 25 kg, were virologically suppressed (HIV-1 RNA <50 copies per mL) on a stable ART regimen for at least 6 months before screening, had a CD4 count of at least 200 cells per µL, and an estimated glomerular filtration rate of at least 90 mL/min per 1·73 m2 by the Schwartz formula at screening. All participants received the fixed-dose regimen of coformulated bictegravir 50 mg, emtricitabine 200 mg, and tenofovir alafenamide 25 mg once daily. Pharmacokinetic analysis was used for dosing confirmation, and results compared with adult values. The primary outcomes were area under the curve at the end of the dosing interval (AUCtau) and concentration at the end of the dosing interval (Ctau) of bictegravir, and incidence of treatment-emergent adverse events and laboratory abnormalities at week 24. Efficacy and safety analyses included all participants who received at least one dose of study drug. We report the 48-week results. This study is registered with ClinicalTrials.gov, NCT02881320. FINDINGS: Between Sept 29, 2016 and Feb 16, 2018, we enrolled 102 participants. 100 participants received bictegravir, emtricitabine, and tenofovir alafenamide (cohort 1 [adolescents aged 12 to <18 years], n=50; cohort 2 [children aged 6 to <12 years], n=50). The mean bictegravir AUCtau was 89 100 ng × h/mL (coefficient of variation 31·0%) in adolescents (cohort 1) and 128 000 ng × h/mL (27·8%) in children (cohort 2). Compared with adults, bictegravir Ctau was 35% lower in adolescents and 11% lower in children. The 90% CIs of both parameters were within the predefined pharmacokinetic equivalence boundary and within overall range of exposures observed in adults and deemed to be safe and efficacious (geometric least-squares mean ratio [GLSM] 86·3% [90% CI 80·0-93·0] for AUCtau and 65·4% [58·3-73·3] for Ctau in adolescents; GLSM 125% [90% CI 117-134] for AUCtau and 88·9% [80·6-98·0] for Ctau for children). Bictegravir, emtricitabine, and tenofovir alafenamide was well tolerated; most adverse events were grade 2 or less in severity and no study drug-related serious adverse events were reported. One participant discontinued study drug due to adverse events (grade 2 insomnia and anxiety). Virological suppression (HIV-1 RNA <50 copies per mL) was maintained by all 100 participants at week 24 and by 98 (98%) of 100 at week 48; no participants had treatment-emergent resistance. INTERPRETATION: In adolescents and children with HIV, the bictegravir, emtricitabine, and tenofovir alafenamide single-tablet regimen was well tolerated and maintained virological suppression. Our data support the treatment of HIV in adolescents and children with this single-tablet regimen. At present, the single-tablet regimen is recommended as first-line treatment in the USA for adolescents and as an alternative regimen in children and has the potential to represent an important regimen in the paediatric population. FUNDING: Gilead Sciences.
Asunto(s)
Alanina , Antirretrovirales , Monitoreo de Drogas/métodos , Emtricitabina , Infecciones por VIH , Tenofovir/análogos & derivados , Adolescente , Alanina/administración & dosificación , Alanina/efectos adversos , Alanina/farmacocinética , Amidas/administración & dosificación , Amidas/efectos adversos , Amidas/farmacocinética , Antirretrovirales/administración & dosificación , Antirretrovirales/efectos adversos , Antirretrovirales/farmacocinética , Recuento de Linfocito CD4/métodos , Niño , Cálculo de Dosificación de Drogas , Quimioterapia Combinada/métodos , Emtricitabina/administración & dosificación , Emtricitabina/efectos adversos , Emtricitabina/farmacocinética , Femenino , Infecciones por VIH/sangre , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , Compuestos Heterocíclicos con 3 Anillos/administración & dosificación , Compuestos Heterocíclicos con 3 Anillos/efectos adversos , Compuestos Heterocíclicos con 3 Anillos/farmacocinética , Humanos , Masculino , Piperazinas/administración & dosificación , Piperazinas/efectos adversos , Piperazinas/farmacocinética , Piridonas/administración & dosificación , Piridonas/efectos adversos , Piridonas/farmacocinética , Tenofovir/administración & dosificación , Tenofovir/efectos adversos , Tenofovir/farmacocinética , Resultado del Tratamiento , Carga Viral/métodosRESUMEN
BACKGROUND: The rising number of infections due to Severe Acute Respiratory Syndrome Coronavirus-2 (popularly known as COVID-19) has brought to the fore new antiviral drugs as possible treatments, including favipiravir. However, there is currently no data regarding the safety of this drug in patients with kidney impairment. The aim of this paper, therefore, is to share our experience of the use of favipiravir in pediatric patients affected by COVID-19 with any degree of kidney impairment. METHODS: The study enrolled pediatric patients aged under 18 years and confirmed as suffering from COVID-19 and multisystem inflammatory syndrome in children (MIS-C) with any degree of kidney injury, who were treated with favipiravir at the time of admission. RESULTS: Out of a total of 11 patients, 7 were diagnosed with MIS-C and 4 with severe COVID-19. The median age of the cases was 15.45 (9-17.8) years and the male/female ratio was 7/4. At the time of admission, the median serum creatinine level was 1.1 mg/dl. Nine patients were treated with favipiravir for 5 days, and 2 patients for 5 days followed by remdesivir for 5-10 days despite kidney injury at the time of admission. Seven patients underwent plasma exchange for MIS-C while 2 severely affected cases underwent continuous kidney replacement therapy (CKRT) as well. One severe COVID-19 patient received plasma exchange as well as CKRT. Serum creatinine values returned to normal in mean 3.07 days. CONCLUSIONS: Favipiravir seems a suitable therapeutic option in patients affected by COVID-19 with kidney injury without a need for dose adjustment.
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Lesión Renal Aguda/fisiopatología , Amidas/administración & dosificación , Tratamiento Farmacológico de COVID-19 , COVID-19/complicaciones , Pirazinas/administración & dosificación , Eliminación Renal , Síndrome de Respuesta Inflamatoria Sistémica/tratamiento farmacológico , Lesión Renal Aguda/tratamiento farmacológico , Lesión Renal Aguda/inmunología , Lesión Renal Aguda/virología , Adenosina Monofosfato/administración & dosificación , Adenosina Monofosfato/análogos & derivados , Adenosina Monofosfato/farmacocinética , Adolescente , Alanina/administración & dosificación , Alanina/análogos & derivados , Alanina/farmacocinética , Amidas/farmacocinética , COVID-19/inmunología , COVID-19/virología , Niño , Creatinina/sangre , Relación Dosis-Respuesta a Droga , Quimioterapia Combinada , Femenino , Tasa de Filtración Glomerular , Humanos , Masculino , Pirazinas/farmacocinética , SARS-CoV-2/aislamiento & purificación , Síndrome de Respuesta Inflamatoria Sistémica/complicaciones , Síndrome de Respuesta Inflamatoria Sistémica/inmunología , Síndrome de Respuesta Inflamatoria Sistémica/virología , Resultado del TratamientoRESUMEN
There is an urgent need for antivirals targeting the SARS-CoV-2 virus to fight the current COVID-19 pandemic. The SARS-CoV-2 main protease (3CLpro) represents a promising target for antiviral therapy. The lack of selectivity for some of the reported 3CLpro inhibitors, specifically versus cathepsin L, raises potential safety and efficacy concerns. ALG-097111 potently inhibited SARS-CoV-2 3CLpro (IC50 = 7 nM) without affecting the activity of human cathepsin L (IC50 > 10 µM). When ALG-097111 was dosed in hamsters challenged with SARS-CoV-2, a robust and significant 3.5 log10 (RNA copies/mg) reduction of the viral RNA copies and 3.7 log10 (TCID50/mg) reduction in the infectious virus titers in the lungs was observed. These results provide the first in vivo validation for the SARS-CoV-2 3CLpro as a promising therapeutic target for selective small molecule inhibitors.
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Amidas/farmacología , Tratamiento Farmacológico de COVID-19 , Proteasas 3C de Coronavirus/antagonistas & inhibidores , Inhibidores de Cisteína Proteinasa/farmacología , Modelos Animales de Enfermedad , SARS-CoV-2/efectos de los fármacos , SARS-CoV-2/enzimología , Amidas/farmacocinética , Animales , COVID-19/virología , Catepsina L/antagonistas & inhibidores , Línea Celular , Cricetinae , Inhibidores de Cisteína Proteinasa/farmacocinética , Femenino , Humanos , Concentración 50 Inhibidora , Masculino , Mesocricetus/virología , Reproducibilidad de los Resultados , SARS-CoV-2/crecimiento & desarrollo , Serina Endopeptidasas , Especificidad por Sustrato , Replicación Viral/efectos de los fármacosRESUMEN
SAR efforts directed at identifying RORγt inverse agonists structurally different from our clinical compound 1 (BMS-986251) led to tricyclic-carbocyclic analogues represented by 3-7 and culminated in the identification of 3d (BMS-986313), with structural differences distinct from 1. The X-ray co-crystal structure of 3d with the ligand binding domain of RORγt revealed several key interactions, which are different from 1. The in vitro and in vivo PK profiles of 3d are described. In addition, we demonstrate robust efficacy of 3d in two preclinical models of psoriasis-the IMQ-induced skin lesion model and the IL-23-induced acanthosis model. The efficacy seen with 3d in these models is comparable to the results observed with 1.
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Amidas/uso terapéutico , Hidrocarburos Cíclicos/uso terapéutico , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/antagonistas & inhibidores , Psoriasis/tratamiento farmacológico , Amidas/química , Amidas/farmacocinética , Animales , Agonismo Inverso de Drogas , Femenino , Humanos , Hidrocarburos Cíclicos/química , Hidrocarburos Cíclicos/farmacocinética , Interleucina-23 , Ratones Endogámicos C57BL , Microsomas Hepáticos/metabolismo , Estructura Molecular , Psoriasis/inducido químicamente , Ratas , Relación Estructura-ActividadRESUMEN
Clinical studies in aging people living with HIV (PLWH) are sparse for the novel integrase inhibitor bictegravir, leading to some uncertainty about dosing recommendations for elderly PLWH. The objective of this study was to investigate the continuous impact of aging on bictegravir pharmacokinetics by combining clinically observed data with modeling to support a safe and efficient anti-HIV therapy with advanced age. A physiologically-based pharmacokinetic (PBPK) model was developed for bictegravir with clinically observed data from phase I studies. The predictive model performance was verified using bictegravir plasma concentrations sampled as part of the general therapeutic drug monitoring (TDM) program of the Swiss HIV Cohort Study in young (20-55 years) and elderly PLWH (55-85 years). The verified PBPK model subsequently predicted the continuous impact of aging on bictegravir pharmacokinetics across adulthood (20-99 years). Bictegravir exposure was unchanged in elderly compared with young PLWH when analyzing the TDM data of the Swiss HIV Cohort Study. PBPK simulations predicted clinically observed data from 60 young and 32 elderly PLWH mostly within the 95% confidence interval, demonstrating the predictive power of the used modeling approach. Simulations predicted drug exposure to increase up to 40% during adulthood, which was not statistically significantly different from the age-related pharmacokinetic changes of other HIV and non-HIV drugs. Sex had no impact on the age-related changes of bictegravir pharmacokinetics. Considering the safety margin of bictegravir, a dose adjustment for the novel integrase inhibitor is a priori not necessary in elderly PLWH in the absence of severe comorbidities.
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Envejecimiento/fisiología , Amidas/farmacocinética , Antirretrovirales/farmacocinética , Infecciones por VIH/tratamiento farmacológico , Inhibidores de Integrasa VIH/farmacocinética , Compuestos Heterocíclicos con 3 Anillos/farmacocinética , Piperazinas/farmacocinética , Piridonas/farmacocinética , Adulto , Anciano , Anciano de 80 o más Años , Amidas/uso terapéutico , Antirretrovirales/uso terapéutico , Área Bajo la Curva , Monitoreo de Drogas , Femenino , Inhibidores de Integrasa VIH/uso terapéutico , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Humanos , Masculino , Tasa de Depuración Metabólica , Persona de Mediana Edad , Modelos Biológicos , Piperazinas/uso terapéutico , Piridonas/uso terapéutico , Suiza , Adulto JovenRESUMEN
A novel, simple and rapid UPLC-MS/MS method was developed and validated for determination of favipiravir (FAV) in human plasma. Lamivudine was used as an internal standard (IS). The Xevo TQD LC-MS/MS was operated under the multiple-reaction monitoring mode using electrospray ionization. Precipitation with acetonitrile was used in sample preparation as it gives relatively cleaner plasma samples. The prepared samples were chromatographed using an Acquity UPLC® HSS C18 (100 × 2.1 mm, 1.8 µm) column. The mobile phase was composed of ammonium formate and methanol in a gradient mode that was pumped at a flow rate of 0.35 ml/min. The developed method was validated as per the FDA guidelines and linearity was in the range of 0.25-16 µg/ml for FAV. The intra- and inter-day precision and accuracy results were within the acceptable limits. A run time of 4.5 min and a low quantification limit of FAV allowed the application of the developed method for the determination of FAV in a bioequivalence study in healthy human volunteers.
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Amidas/sangre , Cromatografía Líquida de Alta Presión/métodos , Pirazinas/sangre , Espectrometría de Masas en Tándem/métodos , Adulto , Amidas/química , Amidas/farmacocinética , Femenino , Humanos , Límite de Detección , Masculino , Persona de Mediana Edad , Pirazinas/química , Pirazinas/farmacocinética , Reproducibilidad de los Resultados , Equivalencia Terapéutica , Adulto JovenRESUMEN
Malaria control programs continue to be threatened by drug resistance. To identify new antimalarials, we conducted a phenotypic screen and identified a novel tetrazole-based series that shows fast-kill kinetics and a relatively low propensity to develop high-level resistance. Preliminary structure-activity relationships were established including identification of a subseries of related amides with antiplasmodial activity. Assaying parasites with resistance to antimalarials led us to test whether the series had a similar mechanism of action to chloroquine (CQ). Treatment of synchronized Plasmodium falciparum parasites with active analogues revealed a pattern of intracellular inhibition of hemozoin (Hz) formation reminiscent of CQ's action. Drug selections yielded only modest resistance that was associated with amplification of the multidrug resistance gene 1 (pfmdr1). Thus, we have identified a novel chemical series that targets the historically druggable heme polymerization pathway and that can form the basis of future optimization efforts to develop a new malaria treatment.
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Amidas/farmacología , Antimaláricos/farmacología , Hemoglobinas/metabolismo , Plasmodium falciparum/efectos de los fármacos , Tetrazoles/farmacología , Amidas/síntesis química , Amidas/farmacocinética , Antimaláricos/síntesis química , Antimaláricos/farmacocinética , Farmacorresistencia Microbiana/efectos de los fármacos , Hemoproteínas/antagonistas & inhibidores , Células Hep G2 , Humanos , Estructura Molecular , Pruebas de Sensibilidad Parasitaria , Plasmodium falciparum/metabolismo , Bibliotecas de Moléculas Pequeñas/síntesis química , Bibliotecas de Moléculas Pequeñas/farmacocinética , Bibliotecas de Moléculas Pequeñas/farmacología , Relación Estructura-Actividad , Tetrazoles/síntesis química , Tetrazoles/farmacocinéticaRESUMEN
Bictegravir is equally metabolized by cytochrome P450 (CYP)3A and uridine diphosphate-glucuronosyltransferase (UGT)1A1. Drug-drug interaction (DDI) studies were only conducted for strong inhibitors and inducers, leading to some uncertainty whether moderate perpetrators or multiple drug associations can be safely coadministered with bictegravir. We used physiologically-based pharmacokinetic (PBPK) modeling to simulate DDI magnitudes of various scenarios to guide the clinical DDI management of bictegravir. Clinically observed DDI data for bictegravir coadministered with voriconazole, darunavir/cobicistat, atazanavir/cobicistat, and rifampicin were predicted within the 95% confidence interval of the PBPK model simulations. The area under the curve (AUC) ratio of the DDI divided by the control scenario was always predicted within 1.25-fold of the clinically observed data, demonstrating the predictive capability of the used modeling approach. After the successful verification, various DDI scenarios with drug pairs and multiple concomitant drugs were simulated to analyze their effect on bictegravir exposure. Generally, our simulation results suggest that bictegravir should not be coadministered with strong CYP3A and UGT1A1 inhibitors and inducers (e.g., atazanavir, nilotinib, and rifampicin), but based on the present modeling results, bictegravir could be administered with moderate dual perpetrators (e.g., efavirenz). Importantly, the inducing effect of rifampicin on bictegravir was predicted to be reversed with the concomitant administration of a strong inhibitor such as ritonavir, resulting in a DDI magnitude within the efficacy and safety margin for bictegravir (0.5-2.4-fold). In conclusion, the PBPK modeling strategy can effectively be used to guide the clinical management of DDIs for novel drugs with limited clinical experience, such as bictegravir.
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Amidas/farmacocinética , Inductores del Citocromo P-450 CYP3A/farmacocinética , Inhibidores del Citocromo P-450 CYP3A/farmacocinética , Interacciones Farmacológicas/fisiología , Glucuronosiltransferasa/antagonistas & inhibidores , Compuestos Heterocíclicos con 3 Anillos/farmacocinética , Modelos Biológicos , Piperazinas/farmacocinética , Piridonas/farmacocinética , Adulto , Cobicistat/farmacocinética , Femenino , Humanos , Masculino , Persona de Mediana Edad , Ritonavir/farmacocinética , Voriconazol/farmacocinética , Adulto JovenRESUMEN
BACKGROUND: Many people infected with hepatitis C virus have comorbidities, including hypercholesterolemia, that are treated with statins. In this study, we evaluated the drug-drug interaction potential of the hepatitis C virus inhibitors elbasvir (EBR) and grazoprevir (GZR) with statins. Pitavastatin, rosuvastatin, pravastatin, and atorvastatin are substrates of organic anion-transporting polypeptide 1B, whereas rosuvastatin and atorvastatin are also breast cancer resistance protein substrates. METHODS: Three open-label, phase I clinical trials in healthy adults were conducted with multiple daily doses of oral GZR or EBR/GZR and single oral doses of statins. Trial 1: GZR 200 mg plus pitavastatin 10 mg. Trial 2: Part 1, GZR 200 mg plus rosuvastatin 10 mg, then EBR 50 mg/GZR 200 mg plus rosuvastatin 10 mg; Part 2, EBR 50 mg/GZR 200 mg plus pravastatin 40 mg. Trial 3: EBR 50 mg/GZR 200 mg plus atorvastatin 10 mg. RESULTS: Neither GZR nor EBR pharmacokinetics were meaningfully affected by statins. Coadministration of EBR/GZR did not result in clinically relevant changes in the exposure of pitavastatin or pravastatin. However, EBR/GZR increased exposure to rosuvastatin (126%) and atorvastatin (94%). Coadministration of statins plus GZR or EBR/GZR was generally well tolerated. CONCLUSIONS: Although statins do not appreciably affect EBR or GZR pharmacokinetics, EBR/GZR can impact the pharmacokinetics of certain statins, likely via inhibition of breast cancer resistance protein but not organic anion-transporting polypeptide 1B. Coadministration of EBR/GZR with pitavastatin or pravastatin does not require adjustment of either dose of statin, whereas the dose of rosuvastatin and atorvastatin should be decreased when coadministered with EBR/GZR.
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Amidas/farmacocinética , Antivirales/farmacocinética , Benzofuranos/farmacocinética , Carbamatos/farmacocinética , Ciclopropanos/farmacocinética , Imidazoles/farmacocinética , Quinoxalinas/farmacocinética , Sulfonamidas/farmacocinética , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/metabolismo , Adolescente , Adulto , Atorvastatina/farmacocinética , Interacciones Farmacológicas , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proteínas de Neoplasias/metabolismo , Pravastatina/farmacocinética , Quinolinas/farmacocinética , Rosuvastatina Cálcica/farmacocinética , Adulto JovenRESUMEN
Lassa fever is an haemorrhagic fever caused by Lassa virus (LASV). There is no vaccine approved against LASV and the only recommended antiviral treatment relies on ribavirin, despite limited evidence of efficacy. Recently, the nucleotide analogue favipiravir showed a high antiviral efficacy, with 100% survival obtained in an otherwise fully lethal non-human primate (NHP) model of Lassa fever. However the mechanism of action of the drug is not known and the absence of pharmacokinetic data limits the translation of these results to the human setting. Here we aimed to better understand the antiviral effect of favipiravir by developping the first mathematical model recapitulating Lassa viral dynamics and treatment. We analyzed the viral dynamics in 24 NHPs left untreated or treated with ribavirin or favipiravir, and we put the results in perspective with those obtained with the same drugs in the context of Ebola infection. Our model estimates favipiravir EC50 in vivo to 2.89 µg.mL-1, which is much lower than what was found against Ebola virus. The main mechanism of action of favipiravir was to decrease virus infectivity, with an efficacy of 91% at the highest dose. Based on our knowledge acquired on the drug pharmacokinetics in humans, our model predicts that favipiravir doses larger than 1200 mg twice a day should have the capability to strongly reduce the production infectious virus and provide a milestone towards a future use in humans.
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Amidas , Antivirales , Fiebre de Lassa/virología , Virus Lassa , Pirazinas , Ribavirina , Amidas/farmacocinética , Amidas/farmacología , Amidas/uso terapéutico , Animales , Antivirales/farmacocinética , Antivirales/farmacología , Antivirales/uso terapéutico , Femenino , Interacciones Huésped-Patógeno/efectos de los fármacos , Fiebre de Lassa/tratamiento farmacológico , Virus Lassa/efectos de los fármacos , Virus Lassa/patogenicidad , Virus Lassa/fisiología , Macaca fascicularis , Modelos Biológicos , Pirazinas/farmacocinética , Pirazinas/farmacología , Pirazinas/uso terapéutico , Ribavirina/farmacocinética , Ribavirina/farmacología , Ribavirina/uso terapéutico , Carga Viral/efectos de los fármacosRESUMEN
BACKGROUND: Effective antiviral drugs for COVID-19 are still lacking. This study aims to evaluate the clinical outcomes and plasma concentrations of baloxavir acid and favipiravir in COVID-19 patients. METHODS: Favipiravir and baloxavir acid were evaluated for their antiviral activity against SARS-CoV-2 in vitro before the trial initiation. We conducted an exploratory trial with 3 arms involving hospitalized adult patients with COVID-19. Patients were randomized assigned in a 1:1:1 ratio into baloxavir marboxil group, favipiravir group, and control group. The primary outcome was the percentage of subjects with viral negative by Day 14 and the time from randomization to clinical improvement. Virus load reduction, blood drug concentration and clinical presentation were also observed. The trial was registered with Chinese Clinical Trial Registry (ChiCTR 2000029544). RESULTS: Baloxavir acid showed antiviral activity in vitro with the half-maximal effective concentration (EC50) of 5.48 µM comparable to arbidol and lopinavir, but favipiravir didn't demonstrate significant antiviral activity up to 100 µM. Thirty patients were enrolled. The percentage of patients who turned viral negative after 14-day treatment was 70%, 77%, and 100% in the baloxavir marboxil, favipiravir, and control group respectively, with the medians of time from randomization to clinical improvement was 14, 14 and 15 days, respectively. One reason for the lack of virological effect and clinical benefits may be due to insufficient concentrations of these drugs relative to their antiviral activities. One of the limitations of this study is the time from symptom onset to randomization, especially in the baloxavir marboxil and control groups, which is higher than the favipiravir group. CONCLUSIONS: Our findings could not prove a benefit of addition of either baloxavir marboxil or favipiravir under the trial dosages to the existing standard treatment.
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Amidas , Tratamiento Farmacológico de COVID-19 , COVID-19 , Dibenzotiepinas , Morfolinas , Pirazinas , Piridonas , Triazinas , Amidas/administración & dosificación , Amidas/sangre , Amidas/farmacocinética , Antivirales/administración & dosificación , Antivirales/sangre , Antivirales/farmacocinética , COVID-19/sangre , COVID-19/diagnóstico , COVID-19/fisiopatología , Dibenzotiepinas/administración & dosificación , Dibenzotiepinas/sangre , Dibenzotiepinas/farmacocinética , Monitoreo de Drogas/métodos , Femenino , Humanos , Concentración 50 Inhibidora , Masculino , Persona de Mediana Edad , Morfolinas/administración & dosificación , Morfolinas/sangre , Morfolinas/farmacocinética , Pirazinas/administración & dosificación , Pirazinas/sangre , Pirazinas/farmacocinética , Piridonas/administración & dosificación , Piridonas/sangre , Piridonas/farmacocinética , SARS-CoV-2/efectos de los fármacos , SARS-CoV-2/aislamiento & purificación , SARS-CoV-2/fisiología , Evaluación de Síntomas , Resultado del Tratamiento , Triazinas/administración & dosificación , Triazinas/sangre , Triazinas/farmacocinética , Carga Viral/efectos de los fármacosRESUMEN
BACKGROUND: The pharmacokinetics and appropriate dose regimens of favipiravir are unknown in hospitalized influenza patients; such data are also needed to determine dosage selection for favipiravir trials in COVID-19. METHODS: In this dose-escalating study, favipiravir pharmacokinetics and tolerability were assessed in critically ill influenza patients. Participants received one of two dosing regimens; Japan licensed dose (1600 mg BID on day 1 and 600 mg BID on the following days) and the higher dose (1800 mg/800 mg BID) trialed in uncomplicated influenza. The primary pharmacokinetic endpoint was the proportion of patients with a minimum observed plasma trough concentration (Ctrough) ≥20 mg/L at all measured time points after the second dose. RESULTS: Sixteen patients were enrolled into the low dose group and 19 patients into the high dose group of the study. Favipiravir Ctrough decreased significantly over time in both groups (p <0.01). Relative to day 2 (48 hrs), concentrations were 91.7% and 90.3% lower in the 1600/600 mg group and 79.3% and 89.5% lower in the 1800/800 mg group at day 7 and 10, respectively. In contrast, oseltamivir concentrations did not change significantly over time. A 2-compartment disposition model with first-order absorption and elimination described the observed favipiravir concentration-time data well. Modeling demonstrated that less than 50% of patients achieved Ctrough ≥20 mg/L for >80% of the duration of treatment of the two dose regimens evaluated (18.8% and 42.1% of patients for low and high dose regimen, respectively). Increasing the favipravir dosage predicted a higher proportion of patients reaching this threshold of 20 mg/L, suggesting that dosing regimens of ≥3600/2600 mg might be required for adequate concentrations. The two dosing regimens were well-tolerated in critical ill patients with influenza. CONCLUSION: The two dosing regimens proposed for uncomplicated influenza did not achieve our pre-defined treatment threshold.