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Identifying and understanding potential drug-drug interactions (DDIs) are vital for the treatment of human immunodeficiency virus type 1 (HIV-1) infection. This article discusses DDIs between doravirine, a nonnucleoside reverse transcriptase inhibitor (NNRTI), and cytochrome P450 3A (CYP3A) substrates and drugs that modulate CYP3A activity. Consistent with previously published in vitro data and DDI trials with the CYP3A substrates midazolam and atorvastatin, doravirine did not have any meaningful impact on the pharmacokinetics of the CYP3A substrates ethinyl estradiol and levonorgestrel. Coadministration of doravirine with CYP3A inhibitors (ritonavir or ketoconazole) increased doravirine exposure approximately 3-fold. However, these increases were not considered clinically meaningful. Conversely, previously published trials showed that coadministered CYP3A inducers (rifampin and rifabutin) decreased doravirine exposure by 88% and 50%, respectively (K. L. Yee, S. G. Khalilieh, R. I. Sanchez, R. Liu, et al., Clin Drug Investig 37:659-667, 2017 [https://doi.org/10.1007/s40261-017-0513-4]; S. G. Khalilieh, K. L. Yee, R. I. Sanchez, R. Liu, et al., J Clin Pharmacol 58:1044-1052, 2018 [https://doi.org/10.1002/jcph.1103]), while doravirine exposure following prior efavirenz administration led to an initial reduction in doravirine exposure of 62%, but the reduction became less pronounced with time (K. L. Yee, R. I. Sanchez, P. Auger, R. Liu, et al., Antimicrob Agents Chemother 61:e01757-16, 2017 [https://doi.org/10.1128/AAC.01757-16]). Overall, the coadministration of doravirine with CYP3A inhibitors and substrates is, therefore, supported by these data together with efficacy and safety data from clinical trials, while coadministration with strong CYP3A inducers, such as rifampin, cannot be recommended. Concomitant dosing with rifabutin (a CYP3A inducer less potent than rifampin) is acceptable if doravirine dosing is adjusted from once to twice daily; however, the effect of other moderate inducers on doravirine pharmacokinetics is unknown.
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Inhibidores del Citocromo P-450 CYP3A/farmacocinética , Citocromo P-450 CYP3A/metabolismo , Piridonas/farmacocinética , Triazoles/farmacocinética , Adolescente , Adulto , Anciano , Alquinos , Benzoxazinas/farmacocinética , Ciclopropanos , Interacciones Farmacológicas , Femenino , Humanos , Cetoconazol/farmacocinética , Masculino , Persona de Mediana Edad , Ritonavir/farmacocinética , Adulto JovenRESUMEN
AIMS: Rosuvastatin and pitavastatin have been proposed as probe substrates for the organic anion-transporting polypeptide (OATP) 1B, but clinical data on their relative sensitivity and selectivity to OATP1B inhibitors are lacking. A clinical study was therefore conducted to determine their relative suitability as OATP1B probes using single oral (PO) and intravenous (IV) doses of the OATP1B inhibitor rifampicin, accompanied by a comprehensive in vitro assessment of rifampicin inhibitory potential on statin transporters. METHODS: The clinical study comprised of two separate panels of eight healthy subjects. In each panel, subjects were randomized to receive a single oral dose of rosuvastatin (5 mg) or pitavastatin (1 mg) administered alone, concomitantly with rifampicin (600 mg) PO or IV. The in vitro transporter studies were performed using hepatocytes and recombinant expression systems. RESULTS: Rifampicin markedly increased exposures of both statins, with greater differential increases after POâ vs.â IV rifampicin only for rosuvastatin. The magnitudes of the increases in area under the plasma concentration-time curve were 5.7- and 7.6-fold for pitavastatin and 4.4- and 3.3-fold for rosuvastatin, after PO and IV rifampicin, respectively. In vitro studies showed that rifampicin was an inhibitor of OATP1B1 and OATP1B3, breast cancer resistance protein and multidrug resistance protein 2, but not of organic anion transporter 3. CONCLUSIONS: The results indicate that pitavastatin is a more sensitive and selective and thus preferred clinical OATP1B probe substrate than rosuvastatin, and that a single IV dose of rifampicin is a more selective OATP1B inhibitor than a PO dose.
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Fluorobencenos/farmacocinética , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacocinética , Pirimidinas/farmacocinética , Quinolinas/farmacocinética , Rifampin/farmacología , Sulfonamidas/farmacocinética , Administración Intravenosa , Administración Oral , Adulto , Área Bajo la Curva , Estudios Cruzados , Interacciones Farmacológicas , Femenino , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Humanos , Transportador 1 de Anión Orgánico Específico del Hígado , Masculino , Persona de Mediana Edad , Transportadores de Anión Orgánico/antagonistas & inhibidores , Transportadores de Anión Orgánico/metabolismo , Transportadores de Anión Orgánico Sodio-Independiente/antagonistas & inhibidores , Transportadores de Anión Orgánico Sodio-Independiente/metabolismo , Rifampin/administración & dosificación , Rosuvastatina Cálcica , Miembro 1B3 de la Familia de los Transportadores de Solutos de Aniones Orgánicos , Adulto JovenRESUMEN
Purpose: To evaluate the preclinical effects, and preclinical and clinical ocular and systemic pharmacokinetics of a new topical, non-preserved ocular anesthetic, AG-920 (articaine ophthalmic solution). Methods: Five studies: one in vitro melanin binding study; three studies in rabbits receiving an ocular dose of AG-920 evaluating corneal sensitivity, ocular tolerability, and systemic exposure to articaine and its inactive metabolite, articainic acid; and one clinical study in 14 healthy adult volunteers receiving an ocular dose of AG-920, with blood samples over 24 h. A liquid chromatography with tandem mass spectrometry (LC-MS-MS) method was used to detect both parent and metabolite with a lower limit of quantitation (LLOQ) of 0.1 and 0.2 ng/mL, respectively. Results: Melanin binding of articaine was up to 7.4%. A decrease in corneal sensitivity was noted for 20 min post-treatment in all active groups, and returned to baseline by 60 min post-dose. No dose-response relationship was observed. Concentrations of articaine in ocular matrices generally peaked early and then decreased over time. Both parent and metabolite were observed in blood at early time points. There were no ocular safety issues with AG-920. Conclusions: These early stage development studies showed that AG-920 was well tolerated in the standard preclinical models and did not cause any toxicity. AG-920 ophthalmic solution elicited a rapid onset and potentially clinically useful duration of corneal anesthesia. The studies supported the clinical evaluation of the 8% strength. Registered with clinicaltrials.gov as NCT04759339.
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Carticaína , Melaninas , Adulto , Anestésicos Locales/farmacología , Animales , Carticaína/química , Carticaína/farmacocinética , Cromatografía Liquida , Estudios Clínicos como Asunto , Humanos , Soluciones Oftálmicas/farmacología , ConejosRESUMEN
Heightened recognition of impacts to coastal salt marshes from sea-level rise has led to expanding interest in using thin-layer sediment placement (TLP) as an adaptation tool to enhance future marsh resilience. Building on successes and lessons learned from the Gulf and southeast U.S. coasts, projects are now underway in other regions, including New England where the effects of TLP on marsh ecosystems and processes are less clear. In this study, we report on early responses of a drowning, microtidal Rhode Island marsh (Ninigret Marsh, Charlestown, RI) to the application of a thick (10-48 cm) application of sandy dredged material and complimentary extensive adaptive management to quickly build elevation capital and enhance declining high marsh plant species. Physical changes occurred quickly. Elevation capital, rates of marsh elevation gain, and soil drainage all increased, while surface inundation, die-off areas, and surface ponding were greatly reduced. Much of the marsh revegetated within a few years, exhibiting aspects of classic successional processes leading to new expansive areas of high marsh species, although low marsh Spartina alterniflora recovered more slowly. Faunal communities, including nekton and birds, were largely unaffected by sediment placement. Overall, sediment placement provided Ninigret Marsh with an estimated 67-320 years of ambient elevation gain, increasing its resilience and likely long-term persistence. Project stakeholders intentionally aimed for the upper end of high marsh plant elevation growth ranges to build elevation capital and minimize maintenance costs, which also resulted in new migration corridors, providing pathways for future marsh expansion.
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OBJECTIVES: A phase 1, double-blind, placebo-controlled trial was conducted to evaluate the safety, tolerability, and exploratory efficacy of repeat monthly doses of subcutaneous (SC) casirivimab and imdevimab (CAS+IMD) in uninfected adult volunteers. METHODS: Participants were randomized (3:1) to SC CAS+IMD 1200 mg or placebo every 4 weeks for up to six doses. Primary and secondary end points evaluated safety, pharmacokinetics, and immunogenicity. Exploratory efficacy was evaluated by the incidence of COVID-19 or SARS-CoV-2 seroconversion. RESULTS: In total, 969 participants received CAS+IMD. Repeat monthly dosing of SC CAS+IMD led to a 92.4% relative risk reduction in clinically defined COVID-19 compared with placebo (3/729 [0.4%] vs 13/240 [5.4%]; odds ratio 0.07 [95% CI 0.01-0.27]), and a 100% reduction in laboratory-confirmed COVID-19 (0/729 vs 10/240 [4.2%]; odds ratio 0.00). Development of anti-drug antibodies occurred in a small proportion of participants (<5%). No grade ≥3 injection-site reactions (ISRs) or hypersensitivity reactions were reported. Slightly more participants reported treatment-emergent adverse events with CAS+IMD (54.9%) than with placebo (48.3%), a finding that was due to grade 1-2 ISRs. Serious adverse events were rare. No deaths were reported in the 6-month treatment period. CONCLUSION: Repeat monthly administration of 1200 mg SC CAS+IMD was well-tolerated, demonstrated low immunogenicity, and showed a substantial risk reduction in COVID-19 occurrence.
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Tratamiento Farmacológico de COVID-19 , COVID-19 , Adulto , Anticuerpos Monoclonales Humanizados , COVID-19/prevención & control , Método Doble Ciego , Humanos , SARS-CoV-2RESUMEN
Sarcoma is a rare cancer that can be found anywhere in the body. Approximately 1% of all adult cancers are sarcoma, and angiosarcomas account for approximately 1% to 2% of all sarcomas. Although rare, when clinical and radiographic changes suggestive of neoplasm are seen in the lower extremities, and if metastasis is suspected, angiosarcoma should be among the differential diagnosis. In this report, we describe the case of an elderly woman who presented with epithelioid angiosarcoma of the talus. Although the patient became aware of the sarcoma only after pain developed after minor trauma to her foot, evaluation of the injury revealed the presence of metastatic disease, and the patient succumbed to the cancer shortly after the diagnosis was made.
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Neoplasias Óseas/patología , Hemangiosarcoma/patología , Invasividad Neoplásica/patología , Astrágalo/patología , Anciano , Biopsia con Aguja , Neoplasias Óseas/diagnóstico , Neoplasias Óseas/cirugía , Resultado Fatal , Femenino , Hemangiosarcoma/diagnóstico , Hemangiosarcoma/cirugía , Humanos , Inmunohistoquímica , Imagen por Resonancia Magnética , Estadificación de Neoplasias , Cuidados Posoperatorios/métodos , Negativa del Paciente al TratamientoRESUMEN
INTRODUCTION: Tafenoquine has been recently registered for the prevention of relapse in Plasmodium vivax malaria. OBJECTIVE: This study assessed the pharmacodynamic effects of 300-mg single-dose tafenoquine on the retina. METHODS: This phase I, prospective, multicenter, randomized, single-masked, placebo-controlled, parallel-group study was conducted between 2 February 2016 and 14 September 2017 at three US study centers. Adult healthy volunteers were randomized (2:1) to receive either a single 300-mg oral dose of tafenoquine or matched placebo on day 1. Ophthalmic assessments, including spectral domain optical coherence tomography (SD-OCT) and fundus autofluorescence (FAF), were conducted at baseline and day 90 and evaluated for pre-determined endpoints by an independent, masked reading center. RESULTS: One subject in each group met the composite primary endpoint for retinal changes identified with SD-OCT or FAF, i.e., one out of 306 (0.3%) with tafenoquine, one out of 161 (0.6%) with placebo. Both cases had unilateral focal ellipsoid zone disruption at day 90 with no effect on best-corrected visual acuity. The tafenoquine-treated subject had this abnormality at baseline, and was enrolled in error. There was no difference in ophthalmic safety between tafenoquine and placebo. CONCLUSION: There was no evidence of any pharmacodynamic effect of 300-mg single-dose tafenoquine on the retina or any short-term clinically relevant effects on ophthalmic safety. This clinical trial is registered with ClinicalTrials.gov (identifier: NCT02658435).
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Aminoquinolinas/administración & dosificación , Antimaláricos/administración & dosificación , Retina/efectos de los fármacos , Agudeza Visual/efectos de los fármacos , Administración Oral , Adolescente , Adulto , Aminoquinolinas/efectos adversos , Antimaláricos/efectos adversos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Imagen Óptica , Estudios Prospectivos , Método Simple Ciego , Tomografía de Coherencia Óptica , Adulto JovenRESUMEN
Smoking continues to be a major preventable cause of early mortality worldwide, and nicotine replacement therapy has been demonstrated to increase rates of abstinence among smokers attempting to quit. Nicotine transdermal systems (also known as nicotine patches) attach to the skin via an adhesive layer composed of a mixture of different-molecular-weight polyisobutylenes (PIBs) in a specific ratio. This randomized, single-dose, 2-treatment, crossover pharmacokinetic (PK) trial assessed the bioequivalence of nicotine patches including a replacement PIB adhesive (test) compared with the PIB adhesive historically used on marketed patches (reference). The test and reference patches were bioequivalent, as determined by the PK parameters of Cmax and AUC0-t . In addition, the parameters Tmax and t1/2 did not significantly differ between the 2 patches, supporting the bioequivalence finding from the primary analysis. The tolerability profiles of the patches containing the replacement and previously used PIB adhesives were similar; application-site adverse events did not significantly differ between test and reference patches. Overall, these data establish the bioequivalence of the nicotine patch with the replacement PIB adhesive formulation and the previously utilized PIB adhesive formulation.
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Adhesivos/química , Polienos/química , Polímeros/química , Agentes para el Cese del Hábito de Fumar/farmacocinética , Dispositivos para Dejar de Fumar Tabaco , Administración Cutánea , Adulto , Estudios Cruzados , Femenino , Humanos , Masculino , Persona de Mediana Edad , Peso Molecular , Agentes para el Cese del Hábito de Fumar/administración & dosificación , Agentes para el Cese del Hábito de Fumar/química , Equivalencia Terapéutica , Adulto JovenRESUMEN
Diverse nicotine replacement therapy options may improve consumer usage. This study was conducted to establish the bioequivalence of a new cherry-flavored mini lozenge with that of a currently marketed mint-flavored mini lozenge. The rate (Cmax ) and extent (AUC0-t ) of plasma nicotine absorption were compared after administration of 2- and 4-mg doses of each lozenge in healthy adult smokers (n = 43). The bioequivalence of each respective dose was established based on the 90% confidence interval for the ratio of geometric means for both Cmax and AUC0-t lying within the range of 0.80 to 1.25. Adverse-event profiles were similar between formulations.
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Aromatizantes/química , Agentes para el Cese del Hábito de Fumar/administración & dosificación , Agentes para el Cese del Hábito de Fumar/farmacocinética , Adulto , Área Bajo la Curva , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Composición de Medicamentos , Femenino , Voluntarios Sanos , Humanos , Masculino , Persona de Mediana Edad , Agentes para el Cese del Hábito de Fumar/química , Equivalencia Terapéutica , Dispositivos para Dejar de Fumar Tabaco/efectos adversos , Adulto JovenRESUMEN
BACKGROUND: Patients experiencing disuse atrophy report acute loss of skeletal muscle mass which subsequently leads to loss of strength and physical capacity. In such patients, especially the elderly, complete recovery remains a challenge even with improved nutrition and resistance exercise. This study aimed to explore the clinical potential of bimagrumab, a human monoclonal antibody targeting the activin type II receptor, for the recovery of skeletal muscle volume from disuse atrophy using an experimental model of lower extremity immobilization. METHODS: In this double-blind, placebo-controlled trial, healthy young men (n = 24; mean age, 24.1 years) were placed in a full-length cast of one of the lower extremities for 2 weeks to induce disuse atrophy. After cast removal, subjects were randomized to receive a single intravenous (i.v.) dose of either bimagrumab 30 mg/kg (n = 15) or placebo (n = 9) and were followed for 12 weeks. Changes in thigh muscle volume (TMV) and inter-muscular adipose tissue (IMAT) and subcutaneous adipose tissue (SCAT) of the thigh, maximum voluntary knee extension strength, and safety were assessed throughout the 12 week study. RESULTS: Casting resulted in an average TMV loss of -4.8% and comparable increases in IMAT and SCAT volumes. Bimagrumab 30 mg/kg i.v. resulted in a rapid increase in TMV at 2 weeks following cast removal and a +5.1% increase above pre-cast levels at 12 weeks. In comparison, TMV returned to pre-cast level at 12 weeks (-0.1%) in the placebo group. The increased adiposity of the casted leg was sustained in the placebo group and decreased substantially in the bimagrumab group at Week 12 (IMAT: -6.6%, SCAT: -3.5%). Knee extension strength decreased by ~25% in the casted leg for all subjects and returned to pre-cast levels within 6 weeks after cast removal in both treatment arms. Bimagrumab was well tolerated with no serious or severe adverse events reported during the study. CONCLUSIONS: A single dose of bimagrumab 30 mg/kg i.v. safely accelerated the recovery of TMV and reversal of accumulated IMAT following 2 weeks in a joint-immobilizing cast.
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Anticuerpos Bloqueadores/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Composición Corporal/efectos de los fármacos , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/patología , Atrofia Muscular/tratamiento farmacológico , Atrofia Muscular/patología , Muslo , Adolescente , Adulto , Anticuerpos Bloqueadores/farmacología , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales Humanizados , Moldes Quirúrgicos/efectos adversos , Femenino , Humanos , Imagen por Resonancia Magnética/métodos , Masculino , Fuerza Muscular/efectos de los fármacos , Músculo Esquelético/diagnóstico por imagen , Atrofia Muscular/etiología , Tamaño de los Órganos , Resultado del Tratamiento , Adulto JovenRESUMEN
PURPOSE: Selumetinib (AZD6244, ARRY-142886) is an oral, potent, and selective allosteric mitogen-activated protein kinase 1/2 inhibitor with a short t1/2. The purpose of this study was to characterize the effect of selumetinib on cardiac repolarization and a potential exposure-QT effect relationship. METHODS: A double-blind (selumetinib), randomized, 3-period crossover study was conducted to assess the effects of a single oral dose of selumetinib (75 mg) on the QTc interval compared with placebo, using moxifloxacin as an open-label positive control, in healthy male subjects aged 18 to 45 years. QT intervals were evaluated by using the Fridericia formula (QTcF) and the Bazett formula. Further analysis was conducted by using nonlinear mixed effects modeling to characterize any relationship between selumetinib exposure and QTc and was used to predict the effect if selumetinib 150 mg was administered. All adverse events were characterized and recorded. FINDINGS: A total of 54 healthy male subjects were enrolled, and 48 completed all treatments. Mean age was 27 years; four subjects were of Hispanic or Latino ethnicity, and 53.7% were White and 46.3% were Black. The BMI of subjects ranged from 19.4 to 29.6 kg/m2. After a single oral dose of selumetinib 75 mg, the highest upper bound of the 2-sided 90% CI for placebo-corrected, baseline-adjusted QTcF (ΔΔQTcF) over the 24-hour postdose measurement interval was 2.5 milliseconds, which was well below the 10-millisecond upper bound for concluding no effect. The relationship between ΔΔQTcF and selumetinib concentrations was adequately described by using a nonlinear mixed effect model. The mean estimated ∆∆QTcF interval prolongation based on the geometric mean Cmax of 75 mg selumetinib was 2.38 milliseconds (90% CI, 1.25 to 3.52), which was in good agreement with the statistical analysis results. The model also predicted mean ∆∆QTcF interval prolongations of 4.70 milliseconds (90% CI, 2.46 to 6.95) after a single supratherapeutic dose of selumetinib 150 mg, indicating the upper bound of 2-sided 90% CIs for ΔΔQTcF are predicted to be <10 milliseconds. Selumetinib, administered as a single 75 mg oral dose, was generally safe and well tolerated. IMPLICATIONS: Selumetinib 75 mg did not cause any QT/QTc interval prolongation in these healthy subjects, and selumetinib is not expected to have a clinically relevant effect on cardiac repolarization in patients at the anticipated therapeutic dose of 75 mg. The model also demonstrated the low potential for any QTc effects of selumetinib at doses higher than the standard therapeutic dose.
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Antineoplásicos/farmacología , Bencimidazoles/farmacología , Corazón/efectos de los fármacos , Proteínas Quinasas Activadas por Mitógenos/antagonistas & inhibidores , Adolescente , Adulto , Antineoplásicos/sangre , Bencimidazoles/sangre , Estudios Cruzados , Método Doble Ciego , Electrocardiografía , Femenino , Fluoroquinolonas/farmacología , Corazón/fisiología , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Masculino , Moxifloxacino , Adulto JovenRESUMEN
PURPOSE: This study assessed the effect of mirabegron on ocular safety in healthy volunteers. METHODS: This was an 8-week, randomized, double-masked, placebo-controlled study. PARTICIPANTS: Consenting adults aged ≥18 years with a normal intraocular pressure (IOP, ≥10 to ≤21 mmHg) were eligible to enter the study. Of the 321 randomized subjects, 305 completed the study. Subjects were randomized 1:1 to a supratherapeutic dose of oral mirabegron 100 mg or placebo once daily for 56 days. The IOP was measured at screening, baseline, day 10, and day 56/end of treatment using Goldmann applanation tonometry. Visual acuity and biomicroscopy were also evaluated. The primary endpoint was the mean change from baseline in the IOP at 56 days or end of treatment with mirabegron versus placebo. Secondary outcome variables included change from baseline to day 10 in the IOP, and increases in the IOP of ≥6 mmHg and ≥10 mmHg in either eye from baseline to day 10 and day 56. RESULTS: The mean (standard error, SE) IOP at baseline was 15.3 (0.16) mmHg for mirabegron and 15.4 (0.16) mmHg for placebo; values at day 56 were 15.0 (0.16) mmHg and 15.2 (0.17) mmHg, respectively. The adjusted mean IOP change from baseline to day 56 was -0.3 mmHg for mirabegron and -0.2 mmHg for placebo (-0.1 mmHg difference [95% confidence interval, CI, -0.4 to 0.3]). For the primary endpoint, mirabegron was noninferior to placebo, based on the prespecified limit of 1.5 mmHg. No statistically significant treatment effects on the IOP were seen at day 10. No subject discontinued due to increased IOP. Clinically significant increases from baseline in the IOP occurred rarely and only with placebo treatment. Changes in the visual acuity and biomicroscopy were not suggestive of a mirabegron effect. No treatment-emergent adverse event (AE) of glaucoma was reported. CONCLUSIONS: Mirabegron 100 mg orally once daily for 8 weeks of treatment does not increase the IOP, and was generally safe and well tolerated.
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Acetanilidas/administración & dosificación , Ojo/efectos de los fármacos , Presión Intraocular/efectos de los fármacos , Tiazoles/administración & dosificación , Agudeza Visual/efectos de los fármacos , Acetanilidas/farmacocinética , Adolescente , Adulto , Anciano , Método Doble Ciego , Femenino , Voluntarios Sanos , Humanos , Masculino , Persona de Mediana Edad , Tiazoles/farmacocinética , Distribución Tisular , Resultado del Tratamiento , Adulto JovenRESUMEN
Anacetrapib is a novel cholesteryl ester transfer protein (CETP) inhibitor in development for treatment of dyslipidemia. This open-label, fixed-sequence, 3-period study was intended to evaluate the potential of anacetrapib to be a victim of OATP1B1/3 inhibition and strong CYP3A induction using acute and chronic dosing of rifampin, respectively, as a probe. In this study, 16 healthy subjects received 100 mg anacetrapib administered without rifampin (Day 1, Period 1), with single-dose (SD) 600 mg rifampin (Day 1, Period 2), and with multiple-dose (MD) 600 mg rifampin for 20 days (Day 14, Period 3). Log-transformed anacetrapib AUC0-∞ and Cmax were analyzed by a linear mixed effects model. The GMRs and 90% CIs for anacetrapib AUC0-∞ and Cmax were 1.25 (1.04, 1.51) and 1.43 (1.13, 1.82) for SD rifampin (Period 2/Period 1) and 0.35 (0.29, 0.42) and 0.26 (0.21, 0.32) for MD rifampin (Period 3/Period 1), respectively. Anacetrapib was generally well tolerated in both the absence/presence of SD and MD rifampin. In conclusion, treatment with SD rifampin, which inhibits the OATP1B1/3 transporter system, did not substantially influence the SD pharmacokinetics of anacetrapib, while chronic (20 days) administration of rifampin, which strongly induces CYP3A isozymes, reduced mean systemic exposure to SD anacetrapib by 65%.
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Transportadores de Anión Orgánico Sodio-Independiente/antagonistas & inhibidores , Transportadores de Anión Orgánico/antagonistas & inhibidores , Oxazolidinonas/administración & dosificación , Oxazolidinonas/farmacocinética , Rifampin/farmacología , Adulto , Área Bajo la Curva , Citocromo P-450 CYP3A/metabolismo , Interacciones Farmacológicas , Femenino , Humanos , Inactivación Metabólica , Transportador 1 de Anión Orgánico Específico del Hígado , Masculino , Persona de Mediana Edad , Transportadores de Anión Orgánico/metabolismo , Transportadores de Anión Orgánico Sodio-Independiente/metabolismo , Rifampin/efectos adversos , Miembro 1B3 de la Familia de los Transportadores de Solutos de Aniones Orgánicos , Adulto JovenRESUMEN
PURPOSE: Amuvatinib is a multi-targeted tyrosine kinase inhibitor with activity that also disrupts DNA damage repair through suppression of homologous recombination protein Rad51. Amuvatinib dry-powder capsules (DPC) showed evidence of activity in early Phase 1 cancer studies but low systemic exposure. The purposes of the studies were to investigate the cause of low exposure, develop, and test an alternative formulation with improved exposure, and establish the dose to be tested in future studies in cancer patients. METHODS: Three studies were conducted in a total of 58 healthy subjects: a food-effect study using amuvatinib DPC, a single-dose pharmacokinetic study comparing amuvatinib DPC to a new lipid-suspension capsules (LSC), and a multiple-dose pharmacokinetic study using amuvatinib LSC. RESULTS: A high-fat meal administered with amuvatinib DPC increased the rate and extent of absorption compared to the Fasted state, a 183 and 118% increase in the mean C(max) and AUC(0-∞) of amuvatinib, respectively. The single-dose pharmacokinetics of amuvatinib LSC resulted in an approximately two-third-fold increased exposure (AUC) compared with amuvatinib DPC. The multiple-dose pharmacokinetics of the amuvatinib LSC 300 mg administered every 8 h exhibited improved accumulation compared with the 12-h regimens and achieved presumed therapeutic level safely with no serious or severe adverse events reported. No subject discontinued treatment due to an adverse event. CONCLUSION: Amuvatinib LSC, 300 mg every 8 h, is being studied in cancer patients based on the improved exposure and similar safety profile to amuvatinib DPC. A lipid-based formulation approach may be a useful tool for other low aqueous soluble compounds.