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Abrocitinib is a selective Janus kinase 1 inhibitor approved for the treatment of atopic dermatitis. It is metabolized primarily by cytochrome P450 (CYP) 2C19 (approximately 53%) and CYP2C9 (approximately 30%), which form 2 active metabolites. The pharmacologic activity of abrocitinib is attributable to the unbound exposures of abrocitinib and those metabolites with active moiety area under the plasma concentration-time curve (AUC) considered the best measure of the total pharmacological effect. The effect of CYP2C19 and/or CYP2C9 genotypes on abrocitinib and active moiety exposures were evaluated using a meta-analysis of the noncompartmental estimates of exposure pooled from 10 clinical studies. A linear mixed-effects model was developed on the basis of the power model to evaluate the effect of CYP2C19 and/or CYP2C9 genotypes on exposure (i.e., abrocitinib AUC and peak plasma concentration, active moiety AUC and peak plasma concentration). The genotypes were evaluated individually and as a combined phenotype effect. When evaluating the poor metabolizers of CYP2C19 or CYP2C9 individually, the estimated increases were 44.9% and 42.0% in active moiety AUC, respectively. The combined phenotype models showed a 0.6% decrease, and 25.1% and 10.5% increases in the active moiety AUC for "elevated," "mixed," and "reduced" metabolizers, respectively. Overall, the active moiety exposures did not appear to be affected to a clinically meaningful extent by different genotypes of CYP2C19 and/or CYP2C9.
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INTRODUCTION: The objective of this study was to utilize the data generated by the City of Toronto, Street Needs Assessment conducted in 2021 to explore the prevalence, causes, experiences, and characteristics of 2-spirit, lesbian, gay, bisexual, transgender, queer, and questioning (2SLGBTQ+) individuals experiencing homelessness in Toronto, Ontario, Canada. METHODS: Data was collected by the City of Toronto during its Street Needs Assessment in April 2021. The Street Needs Assessment is a needs assessment survey and Point-in-Time count of people experiencing homelessness across the city of Toronto. Homelessness included any individual who was sleeping outdoors or staying in City-administered emergency/transitional shelters and shelter motels/hotels on the night of data collection. The Street Needs Assessment survey was administered to clients by trained shelter and outreach staff using a computer or mobile device. To ensure that survey questions were 2SLGBTQ+ inclusive, questions on sexual orientation, gender identity, and 2SLGBTQ+ identity were included in the survey. RESULTS: Two hundred and eighty-eight 2SLGBTQ+ individuals completed the survey. Compared to non-2SLGBTQ+ individuals experiencing homelessness, 2SLGBTQ+ respondents were younger at the time of survey completion and when they first experienced homelessness, were more likely to have been in foster care or a group home, reported higher rates of conflict with and/or abuse by a parent/guardian as their main pathway into homelessness, and were more likely to experience chronic homelessness. CONCLUSION: Our study results demonstrate that Street Needs Assessments and Point-in-Time counts can be used to examine homelessness in marginalized populations, including 2SLGBTQ+ individuals and that sexual orientation and gender identity questions need to be included on future government surveys. The consistency of findings from this study and previous research suggests that 2SLGBTQ+ individuals experience a significant need for population-based housing and social support services aimed at meeting the needs of 2SLGBTQ+ populations.
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Identidad de Género , Personas con Mala Vivienda , Humanos , Masculino , Femenino , Evaluación de Necesidades , Encuestas y Cuestionarios , Ontario/epidemiologíaRESUMEN
BACKGROUND AND OBJECTIVES: Encorafenib is a kinase inhibitor indicated for the treatment of patients with unresectable or metastatic melanoma or metastatic colorectal cancer, respectively, with selected BRAF V600 mutations. A clinical drug-drug interaction (DDI) study was designed to evaluate the effect of encorafenib on rosuvastatin, a sensitive substrate of OATP1B1/3 and breast cancer resistance protein (BCRP), and bupropion, a sensitive CYP2B6 substrate. Coproporphyrin I (CP-I), an endogenous substrate for OATP1B1, was measured in a separate study to deconvolute the mechanism of transporter DDI. METHODS: DDI study participants received a single oral dose of rosuvastatin (10 mg) and bupropion (75 mg) on days - 7, 1, and 14 and continuous doses of encorafenib (450 mg QD) and binimetinib (45 mg BID) starting on day 1. The CP-I data were collected from participants in a phase 3 study who received encorafenib (300 mg QD) and cetuximab (400 mg/m2 initial dose, then 250 mg/m2 QW). Pharmacokinetic and pharmacodynamic analysis was performed using noncompartmental and compartmental methods. RESULTS: Bupropion exposure was not increased, whereas rosuvastatin Cmax and area under the receiver operating characteristic curve (AUC) increased approximately 2.7 and 1.6-fold, respectively, following repeated doses of encorafenib and binimetinib. Increase in CP-I was minimal, suggesting that the primary effect of encorafenib on rosuvastatin is through BCRP. Categorization of statins on the basis of their metabolic and transporter profile suggests pravastatin would have the least potential for interaction when coadministered with encorafenib. CONCLUSION: The results from these clinical studies suggest that encorafenib does not cause clinically relevant CYP2B6 induction or inhibition but is an inhibitor of BCRP and may also inhibit OATP1B1/3 to a lesser extent. Based on these results, it may be necessary to consider switching statins or reducing statin dosage accordingly for coadministration with encorafenib. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT03864042, registered 6 March 2019.
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Bupropión , Carbamatos , Coproporfirinas , Interacciones Farmacológicas , Inhibidores de Hidroximetilglutaril-CoA Reductasas , Rosuvastatina Cálcica , Sulfonamidas , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/metabolismo , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/genética , Bupropión/administración & dosificación , Bupropión/farmacocinética , Carbamatos/administración & dosificación , Carbamatos/farmacocinética , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacocinética , Inhibidores de Hidroximetilglutaril-CoA Reductasas/administración & dosificación , Transportador 1 de Anión Orgánico Específico del Hígado/antagonistas & inhibidores , Transportador 1 de Anión Orgánico Específico del Hígado/genética , Transportador 1 de Anión Orgánico Específico del Hígado/metabolismo , Rosuvastatina Cálcica/farmacocinética , Rosuvastatina Cálcica/administración & dosificación , Sulfonamidas/administración & dosificación , Sulfonamidas/farmacocinética , Sulfonamidas/farmacología , Anciano de 80 o más AñosRESUMEN
OBJECTIVE: To evaluate pathological lesions suggesting the presence of rickets and to place the diagnosis into bioarchaeological and historical context. MATERIALS: The remains of a 3-year ± 12-month-old child discovered during a rescue excavation in Heuvelton, New York. METHODS: We examined the individual macroscopically and conducted a differential diagnosis following established protocols in the palaeopathological literature. RESULTS: Bony change on the orbits, mandible, ribs, clavicles, left scapula, humerii, radii, ulnae, femora, tibiae, fibulae (e.g., porosity, diaphyseal thickening, flaring, bowing), and dental lesions were recorded. CONCLUSIONS: We demonstrate that the child likely presented with vitamin D deficiency rickets during crawling and as they learned to walk. SIGNIFICANCE: This example offers an important contribution to the bioarchaeological literature, as few cases of rickets have been recorded in rural North America using updated diagnostic criteria and little is known of the health and lifeways of early settlers in 19th-century upstate New York. LIMITATIONS: It is not possible to ascertain the precise aetiology of this child's rachitic state and to compare this individual with others in the population. SUGGESTIONS FOR FURTHER RESEARCH: Examination (and re-assessment) of other North and South American skeletal assemblages for signs of vitamin D deficiency rickets following current bioarchaeological standards.
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Raquitismo , Deficiencia de Vitamina D , Niño , Humanos , Vitamina D , New York , Raquitismo/diagnóstico , Deficiencia de Vitamina D/patología , Diagnóstico DiferencialRESUMEN
OBJECTIVE: The medication administration process is complex and consequently prone to errors. Closed Loop Medication Administration solutions aim to improve patient safety. We assessed the impact of a novel medication scanning device (MedEye) on the rate of medication administration errors in a large UK Hospital. METHODS: We performed a feasibility before and after study on one ward at a tertiary-care teaching hospital that used a commercial electronic prescribing and medication administration system. We conducted direct observations of nursing drug administration rounds before and after the MedEye implementation. We calculated the rate and type ('timing', 'omission' or 'other' error) of medication administration errors (MAEs) before and after the MedEye implementation. RESULTS: We observed a total of 1069 administrations before and 432 after the MedEye intervention was implemented. Data suggested that MedEye could support a reduction in MAEs. After adjusting for heterogeneity, we detected a decreasing effect of MedEye on overall errors (p = 0.0753). Non-timing errors ('omission' and 'other' errors) reduced from 51 (4.77%) to 11 (2.55%), a reduction of 46.5%, which had borderline significance at the 5% level, although this was lost after adjusting for confounders. CONCLUSIONS: This pilot study detected a decreasing effect of MedEye on overall errors and a reduction in non-timing error rates that was clinically important as such errors are more likely to be associated with harm. Further research is needed to investigate the impact on a larger sample of medications.
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Hospitales , Errores de Medicación , Estudios de Factibilidad , Humanos , Errores de Medicación/prevención & control , Preparaciones Farmacéuticas , Proyectos PilotoRESUMEN
Preparations of plasma-derived small extracellular vesicles (sEVs) were deployed as liquid biopsy to study cytochrome P450 (CYP) 3A4 (CYP3A4) induction following modafinil 400 mg once daily × 14 days (young healthy volunteers, N = 10 subjects). Induction was confirmed using the 4ß-hydroxycholesterol-to-cholesterol (4ßHC/C) ratio, a plasma CYP3A4/5 biomarker, with a mean 2.1-fold increase (Day 15 vs. Day 1; 90% confidence interval (CI) = 1.8-2.3; P value = 0.0004). Proteomic analysis revealed the induction (mean Day 15 vs. Day 1 fold-increase (90% CI)) of both liver (1.3 (1.1-1.5), P value = 0.014) and nonliver (1.9 (1.6-2.2), P value = 0.04) sEV CYP3A4 protein expression. In CYP3A5 nonexpresser subjects, the baseline (pre-dose) 4ßHC/C plasma ratio was more highly correlated with liver sEVs (r = 0.937, P value = 0.001) than nonliver sEVs (r = 0.619, P value = 0.101) CYP3A4 protein expression. When CYP3A5 expressers (CYP3A5*1/*3) were included, the correlation with liver sEVs (r = 0.761, P value = 0.011) and nonliver sEVs (r = 0.391, P value = 0.264) CYP3A4 protein was weaker. Although modafinil-induced changes in plasma 4ßHC/C ratio did not correlate with sEVs CYP3A4 protein expression, the individual subject sEVs proteomic data were used successfully to predict victim drug (midazolam, triazolam, dextromethorphan, 17α-ethinylestradiol, and abemaciclib) area under the plasma concentration-time curve (AUC) ratios (AUCRs) following modafinil. Based on the AUCR values, modafinil was classified as a weak to moderate CYP3A4 inducer (vs. rifampicin). For the first time, it was possible to deploy plasma-derived sEVs to study CYP3A4 induction beyond rifampicin, a more potent CYP3A4 inducer.
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Inductores del Citocromo P-450 CYP3A/administración & dosificación , Citocromo P-450 CYP3A/biosíntesis , Modafinilo/administración & dosificación , Biomarcadores/sangre , Citocromo P-450 CYP3A/sangre , Citocromo P-450 CYP3A/genética , Inductores del Citocromo P-450 CYP3A/efectos adversos , Esquema de Medicación , Interacciones Farmacológicas , Inducción Enzimática , Vesículas Extracelulares/efectos de los fármacos , Vesículas Extracelulares/enzimología , Voluntarios Sanos , Humanos , Hidroxicolesteroles/sangre , Biopsia Líquida , Hígado/enzimología , Modafinilo/efectos adversos , Modelos Biológicos , Plasma/enzimología , Proteómica , Rifampin/administración & dosificación , Rifampin/efectos adversos , Factores de TiempoRESUMEN
BACKGROUND: The most frequently reported treatment-related adverse event in clinical trials with the cyclin-dependent kinase 4/6 (CDK4/6) inhibitor palbociclib is neutropenia. Allelic variants in ABCB1 and ERCC1 might be associated with early occurrence (i.e., end of week 2 treatment) of grade 3/4 neutropenia. Pharmacogenetic analyses were performed to uncover associations between single nucleotide polymorphisms (SNPs) in these genes, patient baseline characteristics, and early occurrence of grade 3/4 neutropenia. MATERIALS AND METHODS: ABCB1 (rs1045642, rs1128503) and ERCC1 (rs3212986, rs11615) were analyzed in germline DNA from palbociclib-treated patients from PALOMA-2 (n = 584) and PALOMA-3 (n = 442). SNP, race, and cycle 1 day 15 (C1D15) absolute neutrophil count (ANC) data were available for 652 patients. Univariate and multivariable analyses evaluated associations between SNPs, patient baseline characteristics, and early occurrence of grade 3/4 neutropenia. Analyses were stratified by Asian (n = 122) and non-Asian (n = 530) ethnicity. Median progression-free survival (mPFS) was estimated using the Kaplan-Meier method. The effect of genetic variants on palbociclib pharmacokinetics was analyzed. RESULTS: ABCB1 and ERCC1_rs11615 SNP frequencies differed between Asian and non-Asian patients. Multivariable analysis showed that low baseline ANC was a strong independent risk factor for C1D15 grade 3/4 neutropenia regardless of race (Asians: odds ratio [OR], 6.033, 95% confidence interval [CI], 2.615-13.922, p < .0001; Non-Asians: OR, 6.884, 95% CI, 4.138-11.451, p < .0001). ABCB1_rs1128503 (C/C vs. T/T: OR, 0.57, 95% CI, 0.311-1.047, p = .070) and ERCC1_rs11615 (A/A vs. G/G: OR, 1.75, 95% CI, 0.901-3.397, p = .098) were potential independent risk factors for C1D15 grade 3/4 neutropenia in non-Asian patients. Palbociclib mPFS was consistent across genetic variants; exposure was not associated with ABCB1 genotype. CONCLUSION: This is the first comprehensive assessment of pharmacogenetic data in relationship to exposure to a CDK4/6 inhibitor. Pharmacogenetic testing may inform about potentially increased likelihood of patients developing severe neutropenia (NCT01740427, NCT01942135). IMPLICATIONS FOR PRACTICE: Palbociclib plus endocrine therapy improves hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer outcomes, but is commonly associated with neutropenia. Genetic variants in ABCB1 may influence palbociclib exposure, and in ERCC1 are associated with chemotherapy-induced severe neutropenia. Here, the associations of single nucleotide polymorphisms in these genes and baseline characteristics with neutropenia were assessed. Low baseline absolute neutrophil count was a strong risk factor (p < .0001) for grade 3/4 neutropenia. There was a trend indicating that ABCB1_rs1128503 and ERCC1_rs11615 were potential risk factors (p < .10) for grade 3/4 neutropenia in non-Asian patients. Pharmacogenetic testing could inform clinicians about the likelihood of severe neutropenia with palbociclib.
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Neoplasias de la Mama , Neutropenia , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias de la Mama/tratamiento farmacológico , Femenino , Humanos , Neutropenia/inducido químicamente , Neutropenia/genética , Pruebas de Farmacogenómica , Piperazinas , Piridinas , Receptor ErbB-2/uso terapéuticoRESUMEN
Ertugliflozin, a sodium-glucose cotransporter 2 inhibitor, is primarily metabolized via glucuronidation by the uridine 5'-diphospho-glucuronosyltransferase (UGT) isoform UGT1A9. This noncompartmental meta-analysis of ertugliflozin pharmacokinetics evaluated the relationship between ertugliflozin exposure and dose, and the effect of UGT1A9 genotype on ertugliflozin exposure. Pharmacokinetic data from 25 phase 1 studies were pooled. Structural models for dose proportionality described the relationship between ertugliflozin area under the plasma concentration-time curve (AUC) or maximum observed plasma concentration (Cmax ) and dose. A structural model for the UGT1A9 genotype described the relationship between ertugliflozin AUC and dose, with genotype information on 3 UGT1A9 polymorphisms (UGT1A9-2152, UGT1A9*3, UGT1A9*1b) evaluated as covariates from the full model. Ertugliflozin AUC and Cmax increased in a dose-proportional manner over the dose range of 0.5-300 mg, and population-predicted AUC and Cmax values for the 5- and 15-mg ertugliflozin tablets administered in the fasted state demonstrated good agreement with the observed data. The largest change in ertugliflozin AUC was in subjects carrying the UGT1A9*3 heterozygous variant, with population-predicted AUC (90% confidence interval) values of 485 ng·h/mL (458 to 510 ng·h/mL) and 1560 ng·h/mL (1480 to 1630 ng·h/mL) for ertugliflozin 5 and 15 mg, respectively, compared with 436 ng·h/mL (418 to 455 ng·h/mL) and 1410 ng·h/mL (1350 to 1480 ng·h/mL), respectively, in wild-type subjects. Overall, the mean effects of the selected UGT1A9 variants on ertugliflozin AUC were within ±10% of the wild type. UGT1A9 genotype did not have any clinically meaningful effects on ertugliflozin exposure in healthy subjects. No ertugliflozin dose adjustment would be required in patients with the UGT1A9 variants assessed in this study.
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Compuestos Bicíclicos Heterocíclicos con Puentes/farmacocinética , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacocinética , UDP Glucuronosiltransferasa 1A9/genética , Área Bajo la Curva , Compuestos Bicíclicos Heterocíclicos con Puentes/administración & dosificación , Ensayos Clínicos Fase I como Asunto , Relación Dosis-Respuesta a Droga , Genotipo , Glucuronosiltransferasa/genética , Humanos , Tasa de Depuración Metabólica , Modelos Biológicos , Polimorfismo Genético , Inhibidores del Cotransportador de Sodio-Glucosa 2/administración & dosificaciónRESUMEN
Liver-derived small extracellular vesicles (sEVs), prepared from small sets of banked serum samples using a novel two-step protocol, were deployed as liquid biopsy to study the induction of cytochromes P450 (CYP3A4, CYP3A5, and CYP2D6) and organic anion transporting polypeptides (OATP1B1 and OATP1B3) during pregnancy (nonpregnant (T0), first, second, and third (T3) trimester women; N = 3 each) and after administration of rifampicin (RIF) to healthy male subjects. Proteomic analysis revealed induction (mean fold-increase, 90% confidence interval) of sEV CYP3A4 after RIF 300 mg × 7 days (3.5, 95% CI = 2.5-4.5, N = 4, P = 0.029) and 600 mg × 14 days (3.7, 95% CI = 2.1-6.0, N = 5, P = 0.018) consistent with the mean oral midazolam area under the plasma concentration time curve (AUC) ratio in the same subjects (0.28, 95% CI = 0.22-0.34, P < 0.0001; and 0.17, 95% CI = 0.13-0.22, P < 0.0001). Compared with CYP3A4, liver sEV CYP3A5 protein (subjects genotyped CYP3A5*1/*3) was weakly induced (≤ 1.5-fold). It was also possible to measure liver sEV-catalyzed dextromethorphan (DEX) O-demethylation to dextrorphan (DXO), correlated with sEV CYP2D6 expression (r = 0.917, P = 0.0001; N = 10) and 3-hour plasma DXO-to-DEX concentration ratio (r = 0.843, P = 0.002, N = 10), and show that CYP2D6 was not induced by RIF. Nonparametric analysis of liver sEV revealed significantly higher CYP3A4 (3.2-fold, P = 0.003) and CYP2D6 (3.7-fold, P = 0.03) protein expression in T3 vs. T0 women. In contrast, expression of both OATPs in liver sEV was unaltered by RIF administration and pregnancy.
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Sistema Enzimático del Citocromo P-450/metabolismo , Vesículas Extracelulares/metabolismo , Hígado/metabolismo , Transportadores de Anión Orgánico/metabolismo , Adulto , Área Bajo la Curva , Sistema Enzimático del Citocromo P-450/genética , Dextrometorfano/farmacocinética , Inducción Enzimática/efectos de los fármacos , Inducción Enzimática/genética , Femenino , Genotipo , Humanos , Biopsia Líquida , Hígado/enzimología , Masculino , Midazolam/farmacocinética , Embarazo , Proteómica , Rifampin/farmacología , Adulto JovenRESUMEN
Endogenous biomarkers are emerging to advance clinical drug-drug interaction (DDI) risk assessment in drug development. Twelve healthy subjects received a multidrug and toxin exclusion protein (MATE) inhibitor (pyrimethamine, 10, 25, and 75 mg) in a crossover fashion to identify an appropriate endogenous biomarker to assess MATE1/2-K-mediated DDI in the kidneys. Metformin (500 mg) was also given as reference probe drug for MATE1/2-K. In addition to the previously reported endogenous biomarker candidates (creatinine and N1 -methylnicotinamide (1-NMN)), N1 -methyladenosine (m1 A) was included as novel biomarkers. 1-NMN and m1 A presented as superior MATE1/2-K biomarkers since changes in their renal clearance (CLr ) along with pyrimethamine dose were well-correlated with metformin CLr changes. The CLr of creatinine was reduced by pyrimethamine, however, its changes poorly correlated with metformin CLr changes. Nonlinear regression analysis (CLr vs. mean total concentration of pyrimethamine in plasma) yielded an estimate of the inhibition constant (Ki ) of pyrimethamine and the fraction of the clearance pathway sensitive to pyrimethamine. The in vivo Ki value thus obtained was further converted to unbound Ki using plasma unbound fraction of pyrimethamine, which was comparable to the in vitro Ki for MATE1 (1-NMN) and MATE2-K (1-NMN and m1 A). It is concluded that 1-NMN and m1 A CLr can be leveraged as quantitative MATE1/2-K biomarkers for DDI risk assessment in healthy volunteers.
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Biomarcadores/metabolismo , Interacciones Farmacológicas/fisiología , Proteínas de Transporte de Catión Orgánico/metabolismo , Adulto , Pueblo Asiatico , Línea Celular , Creatinina/metabolismo , Estudios Cruzados , Células HEK293 , Voluntarios Sanos , Humanos , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/sangre , Hipoglucemiantes/metabolismo , Riñón/metabolismo , Masculino , Metformina/uso terapéutico , Pirimetamina/administración & dosificación , Pirimetamina/sangre , Pirimetamina/metabolismo , Medición de Riesgo , Adulto JovenRESUMEN
To address the most appropriate endogenous biomarker for drug-drug interaction risk assessment, eight healthy subjects received an organic anion transporting polypeptide 1B (OATP1B) inhibitor (rifampicin, 150, 300, and 600 mg), and a probe drug cocktail (atorvastatin, pitavastatin, rosuvastatin, and valsartan). In addition to coproporphyrin I, a widely studied OATP1B biomarker, we identified at least 4 out of 28 compounds (direct bilirubin, glycochenodeoxycholate-3-glucuronide, glycochenodeoxycholate-3-sulfate, and hexadecanedioate) that presented good sensitivity and dynamic range in terms of the rifampicin dose-dependent change in area under the plasma concentration-time curve ratio (AUCR). Their suitability as OATP1B biomarkers was also supported by the good correlation of AUC0-24h between the endogenous compounds and the probe drugs, and by nonlinear regression analysis (AUCR-1 vs. rifampicin plasma Cmax (maximum total concentration in plasma)) to yield an estimate of the inhibition constant of rifampicin. These endogenous substrates can complement existing OATP1B-mediated drug-drug interaction risk assessment approaches based on agency guidelines in early clinical trials.
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Interacciones Farmacológicas/fisiología , Transportador 1 de Anión Orgánico Específico del Hígado/sangre , Rifampin/administración & dosificación , Rifampin/sangre , Adulto , Antibióticos Antituberculosos/administración & dosificación , Antibióticos Antituberculosos/sangre , Biomarcadores/sangre , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Evaluación de Medicamentos , Voluntarios Sanos , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/administración & dosificación , Inhibidores de Hidroximetilglutaril-CoA Reductasas/sangre , MasculinoRESUMEN
PURPOSE: Cytochrome P450 (CYP) 3A plays an important role in the metabolism of many clinically used drugs and exhibits substantial between-subject variability (BSV) in activity. Current methods to assess variability in CYP3A activity have limitations and there remains a need for a minimally invasive clinically translatable strategy to define CYP3A activity. The purpose of this study was to evaluate the potential for a caffeine metabolic ratio to describe variability in CYP3A activity. METHODS: The metabolic ratio 1,3,7-trimethyluric acid (TMU) to caffeine was evaluated as a biomarker to describe variability in CYP3A activity in a cohort (n = 28) of healthy 21 to 35-year-old males. Midazolam, caffeine, and TMU concentrations were assessed at baseline and following dosing of rifampicin (300 mg daily) for 7 days. RESULTS: At baseline, correlation coefficients for the relationship between apparent oral midazolam clearance (CL/F) with caffeine/TMU ratio measured at 3, 4, and 6 h post dose were 0.82, 0.79, and 0.65, respectively. The strength of correlations was retained post rifampicin dosing; 0.72, 0.87, and 0.82 for the ratios at 3, 4, and 6 h, respectively. Weaker correlations were observed between the change in midazolam CL/F and change in caffeine/TMU ratio post/pre-rifampicin dosing. CONCLUSION: BSV in CYP3A activity was well described by caffeine/TMU ratios pre- and post-induction. The caffeine/TMU ratio may be a convenient tool to assess BSV in CYP3A activity, but assessment of caffeine/TMU ratio alone is unlikely to account for all sources of variability in CYP3A activity.
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Cafeína/sangre , Citocromo P-450 CYP3A/metabolismo , Ácido Úrico/análogos & derivados , Adulto , Biomarcadores/sangre , Cafeína/farmacocinética , Citocromo P-450 CYP3A/genética , Inductores del Citocromo P-450 CYP3A/sangre , Inductores del Citocromo P-450 CYP3A/farmacocinética , Dieta , Genotipo , Humanos , Masculino , Midazolam/sangre , Midazolam/farmacocinética , Fenotipo , Grupos Raciales/genética , Rifampin/sangre , Rifampin/farmacocinética , Ácido Úrico/sangre , Adulto JovenRESUMEN
Maraviroc is a C-C chemokine receptor type-5 antagonist approved for the treatment of HIV-1. Previous studies show that cytochrome P450 3A5 (CYP3A5) plays a role in maraviroc metabolism. CYP3A5 is subject to a genetic polymorphism. The presence of 2 functional alleles (CYP3A5*1/*1) confers the extensive metabolism phenotype, which is rare in whites but common in blacks. The effect of CYP3A5 genotype on maraviroc and/or metabolite pharmacokinetics was evaluated in 2 clinical studies: a post hoc analysis from a phase 2b/3 study (NCT00098293) conducted in 494 HIV-1-infected subjects (study 1) in which the impact on maraviroc efficacy in 303 subjects was also assessed, and a study conducted in 47 healthy volunteers (study 2). In study 2 (NCT02625207), extensive metabolizers had 26% to 37% lower mean area under the concentration-time curve compared with poor metabolizers (no CYP3A5*1 alleles). This effect diminished to 17% in the presence of potent CYP3A inhibition. The effect of CYP3A5 genotype was greatest in the formation of the metabolite (1S,2S)-2-hydroxymaraviroc. In study 1, the CYP3A5*1/*1 genotype unexpectedly had higher maraviroc area under the curve predictions (20%) compared with those with no CYP3A5*1 alleles. The reason for this disparity remains unclear. The proportions of subjects with viral loads <50 and <400 copies/mL for maraviroc were comparable among all 3 CYP3A5 genotypes. In both studies maraviroc exposures were in the range of near-maximal viral inhibition in the majority of subjects. These results demonstrate that although CYP3A5 contributes to the metabolism of maraviroc, CYP3A5 genotype does not affect the clinical response to maraviroc in combination treatment of HIV-1 infection at approved doses.
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Citocromo P-450 CYP3A/genética , Inhibidores de Fusión de VIH/farmacocinética , Inhibidores de Fusión de VIH/uso terapéutico , Infecciones por VIH , VIH-1 , Maraviroc/farmacocinética , Maraviroc/uso terapéutico , Adulto , Método Doble Ciego , Femenino , Genotipo , Inhibidores de Fusión de VIH/sangre , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/genética , Infecciones por VIH/metabolismo , Voluntarios Sanos , Humanos , Masculino , Maraviroc/sangre , Persona de Mediana Edad , Polimorfismo Genético , Resultado del Tratamiento , Adulto JovenRESUMEN
AIMS: Demonstrate the presence of cytochrome P450 (CYP) and UDP-glucuronosyltransferase (UGT) proteins and mRNAs in isolated human plasma exosomes and evaluate the capacity for exosome-derived biomarkers to characterize variability in CYP3A4 activity. METHODS: The presence of CYP and UGT protein and mRNA in exosomes isolated from human plasma and HepaRG cell culture medium was determined by mass spectrometry and reverse transcription-polymerase chain reaction, respectively. The concordance between exosome-derived CYP3A4 biomarkers and midazolam apparent oral clearance (CL/F) was evaluated in a small proof-of-concept study involving six genotyped (CYP3A4 *1/*1 and CYP3A5 *3/*3) Caucasian males. RESULTS: Exosomes isolated from human plasma contained peptides and mRNA originating from CYP 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 2 J2, 3A4 and 3A5, UGT 1A1, 1A3, 1A4, 1A6, 1A9, 2B4, 2B7, 2B10 and 2B15, and NADPH-cytochrome P450 reductase. Mean (95% confidence interval) exosome-derived CYP3A4 protein expression pre- and post-rifampicin dosing was 0.24 (0.2-0.28) and 0.42 (0.21-0.65) ng ml-1 exosome concentrate. Mean (95% confidence interval) exosome CYP3A4 mRNA expression pre- and post-rifampicin dosing was 6.0 (1.1-32.7) and 48.3 (11.3-104) × 10-11 2-ΔΔCt , respectively. R2 values for correlations of exosome-derived CYP3A4 protein expression, CYP3A4 mRNA expression, and ex vivo CYP3A4 activity with midazolam CL/F were 0.905, 0.787 and 0.832, respectively. CONCLUSIONS: Consistent strong concordance was observed between exosome-derived CYP3A4 biomarkers and midazolam CL/F. The significance of these results is that CYP3A4 is the drug-metabolizing enzyme of greatest clinical importance and variability in CYP3A4 activity is poorly described by existing precision dosing strategies.
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Variación Biológica Poblacional , Citocromo P-450 CYP3A/metabolismo , Monitoreo de Drogas/métodos , Exosomas/química , Administración Oral , Adulto , Biomarcadores/análisis , Línea Celular , Estudios de Cohortes , Citocromo P-450 CYP3A/análisis , Citocromo P-450 CYP3A/genética , Técnicas de Genotipaje , Glucuronosiltransferasa/análisis , Glucuronosiltransferasa/genética , Voluntarios Sanos , Humanos , Masculino , Espectrometría de Masas , Tasa de Depuración Metabólica , Midazolam/administración & dosificación , Midazolam/farmacocinética , Prueba de Estudio Conceptual , ARN Mensajero/análisis , Adulto JovenRESUMEN
BACKGROUND: Patients heterozygous for an abnormal α-1 antitrypsin (A1AT) mutation may have an increased risk of liver disease in the setting of a secondary contributing factor. METHODS: This single-center retrospective cohort study compared donor and recipient outcomes of A1AT heterozygous versus normal phenotype adult living-donor liver transplants (LDLTs). RESULTS: Between 2010 and 2016, 11 A1AT heterozygous donors and 10 recipients were compared to 57 normal donors and 41 recipients. There were no significant differences in sex, age, or race/ethnicity by A1AT phenotype. Heterozygous donors had significantly lower serum A1AT (median 100 mg/dL versus 131 mg/dL; P < 0.001). Median liver volume at 3 months post-LDLT was not different among donors or their recipients (1164 mm in heterozygous versus 1257 mm in normal [P = 0.449] for donors; 1563 mm versus 1606 mm [P = 0.387], respectively, for recipients). Recipient serum alkaline phosphatase at 1 month and 1 year post-LDLT was significantly higher in recipients of A1AT heterozygous grafts (160 U/L versus 99.5 U/L; P = 0.025 at 1 mo) but did not persist at 2 years. In addition, there was no association between A1AT level and liver volume at 3 months posttransplant in donors or recipients. CONCLUSIONS: Patients with a heterozygous A1AT mutation should be considered for living-liver donation.
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Selección de Donante , Heterocigoto , Trasplante de Hígado , Donadores Vivos , Mutación , Deficiencia de alfa 1-Antitripsina/genética , alfa 1-Antitripsina/genética , Adulto , Toma de Decisiones Clínicas , Femenino , Humanos , Trasplante de Hígado/efectos adversos , Masculino , Fenotipo , Complicaciones Posoperatorias/etiología , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo , Factores de Tiempo , Resultado del Tratamiento , Deficiencia de alfa 1-Antitripsina/sangre , Deficiencia de alfa 1-Antitripsina/diagnósticoRESUMEN
BACKGROUND: Individuals with an extremely rare inherited condition, termed Congenital Insensitivity to Pain (CIP), do not feel pain in response to noxious stimuli. Variants in SCN9A, encoding the transmembrane voltage-gated sodium channel Nav1.7, have previously been reported in subjects with CIP accompanied by anosmia, which are typically transmitted in a recessive pattern. Functional characterisations of some of these SCN9A mutations show that they result in complete loss-of-function of Nav1.7. METHODS: In a consanguineous family we performed whole exome sequencing of three members who have a diagnosis of CIP and one unaffected family member. The functional effects of the segregating variant in SCN9A were determined using patch clamp electrophysiology in human embryonic kidney (HEK) 293 cells transfected with the variant. RESULTS: We found that each CIP subject was homozygous for a putatively nonsense variant, R1488*, in SCN9A. This variant was reported elsewhere in a subject with CIP, though the functional effect was not determined. Using electrophysiology, we confirm that this variant results in a complete loss-of-function of Nav1.7. CONCLUSIONS: We confirm through electrophysiological analysis that this R1488* variant in SCN9A results in complete loss-of-function of Nav1.7, which is consistent with reports on other variants in this gene in subjects with CIP.
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Canal de Sodio Activado por Voltaje NAV1.7/genética , Línea Celular , Codón sin Sentido/genética , Fenómenos Electrofisiológicos/genética , Femenino , Células HEK293 , Humanos , Masculino , Mutación/genética , Linaje , Secuenciación del Exoma/métodosRESUMEN
This article provides Section 1 of the 2017 Edition 2 Medical Writing Competency Model that describes the core work functions and associated tasks and activities related to professional medical writing within the life sciences industry. The functions in the Model are scientific communication strategy; document preparation, development, and finalization; document project management; document template, standard, format, and style development and maintenance; outsourcing, alliance partner, and client management; knowledge, skill, ability, and behavior development and sharing; and process improvement. The full Model also includes Section 2, which covers the knowledge, skills, abilities, and behaviors needed for medical writers to be effective in their roles; Section 2 is presented in a companion article. Regulatory, publication, and other scientific writing as well as management of writing activities are covered. The Model was developed to aid medical writers and managers within the life sciences industry regarding medical writing hiring, training, expectation and goal setting, performance evaluation, career development, retention, and role value sharing to cross-functional partners.
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Escritura Médica/normas , Disciplinas de las Ciencias Biológicas , Guías como Asunto , Humanos , Competencia ProfesionalRESUMEN
This article provides Section 2 of the 2017 Edition 2 Medical Writing Competency Model that describes the knowledge, skills, abilities, and behaviors that professional medical writers need in order to perform effectively within the life sciences industry. What a medical writer should know, what they should be able to do, and how they should use this knowledge and these skills to facilitate their primary work function is a focus. Regulatory, publication, and other scientific writing as well as management of writing activities are covered. The full Model also includes Section 1, which covers the core work functions and associated tasks and activities related to professional medical writing within the life sciences industry; Section 1 is included in a companion article. The Model was developed to aid medical writers and managers within the life sciences industry regarding medical writing hiring, training, expectation and goal setting, performance evaluation, career development, retention, and role value sharing to cross-functional partners.
Asunto(s)
Escritura Médica/normas , Conducta , Disciplinas de las Ciencias Biológicas , Guías como Asunto , Humanos , Competencia ProfesionalRESUMEN
PURPOSE: Cytochrome P450 (CYP) 3A4 is responsible for the metabolism of more than 30% of clinically used drugs. Inherent between subject variability in clearance of CYP3A4 substrates is substantial; by way of example, midazolam clearance varies by > 10-fold between individuals before considering the impact of extrinsic factors. Relatively little is known about inter-racial variability in the activity of this enzyme. METHODS: This study assessed inter-racial variability in midazolam exposure in a cohort (n = 30) of CYP3A genotyped, age-matched healthy males of Caucasian and South Asian ancestries. Midazolam exposure was assessed at baseline, following 7 days of rifampicin and following 3 days of clarithromycin. RESULTS: The geometric mean baseline midazolam area under the plasma concentration curve (AUC0-6) in Caucasians (1057 µg/L/min) was 27% greater than South Asians (768 µg/L/min). Similarly, the post-induction midazolam AUC0-6 in Caucasians (308 µg/L/min) was 50% greater than South Asians (154 µg/L/min), while the post-inhibition midazolam AUC0-6 in Caucasians (1834 µg/L/min) was 41% greater than South Asians (1079 µg/L/min). The difference in baseline AUC0-6 between Caucasians and South Asians was statistically significant (p ≤ 0.05), and a trend toward significance (p = 0.067) was observed for the post-induction AUC0-6 ratio, in both unadjusted and genotype adjusted analyses. CONCLUSIONS: Significantly higher midazolam clearance was observed in healthy age-matched males of South Asian compared to Caucasian ancestry that was not explained by differences in the frequency of CYP3A genotypes.
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Pueblo Asiatico , Citocromo P-450 CYP3A/metabolismo , Midazolam/farmacocinética , Población Blanca , Adulto , Área Bajo la Curva , Pueblo Asiatico/genética , Claritromicina/sangre , Claritromicina/farmacocinética , Claritromicina/farmacología , Citocromo P-450 CYP3A/genética , Inductores del Citocromo P-450 CYP3A/sangre , Inductores del Citocromo P-450 CYP3A/farmacocinética , Inductores del Citocromo P-450 CYP3A/farmacología , Inhibidores del Citocromo P-450 CYP3A/sangre , Inhibidores del Citocromo P-450 CYP3A/farmacocinética , Inhibidores del Citocromo P-450 CYP3A/farmacología , Inducción Enzimática , Genotipo , Humanos , Masculino , Midazolam/sangre , Grupos Raciales , Rifampin/sangre , Rifampin/farmacocinética , Rifampin/farmacología , Población Blanca/genética , Adulto JovenRESUMEN
Living donor liver transplantation (LDLT) is a comparable alternative to deceased donor liver transplantation and can mitigate the risk of dying while waiting for transplant. Although evidence exists of decreased utilization of living donor kidney transplants among racial minorities, little is known about access to LDLT among racial/ethnic minorities. We used Organ Procurement and Transplantation Network/United Network for Organ Sharing data from February 27, 2002 to June 4, 2014 from all adult liver transplant recipients at LDLT-capable transplant centers to evaluate differential utilization of LDLTs based on race/ethnicity. We then used data from 2 major urban transplant centers to analyze donor inquiries and donor rule-outs based on racial/ethnic determination. Nationally, of 35,401 total liver transplant recipients performed at a LDLT-performing transplant center, 2171 (6.1%) received a LDLT. In multivariate generalized estimating equation models, racial/ethnic minorities were significantly less likely to receive LDLTs when compared to white patients. For cholestatic liver disease, the odds ratios of receiving LDLT based on racial/ethnic group for African American, Hispanic, and Asian patients compared to white patients were 0.35 (95% CI, 0.20-0.60), 0.58 (95% CI, 0.34-0.99), and 0.11 (95% CI, 0.02-0.55), respectively. For noncholestatic liver disease, the odds ratios by racial/ethnic group were 0.53 (95% CI, 0.40-0.71), 0.78 (95% CI, 0.64-0.94), and 0.45 (95% CI, 0.33-0.60) respectively. Transplant center-specific data demonstrated that African American patients received fewer per-patient donation inquiries than white patients, whereas fewer African American potential donors were ruled out for obesity. In conclusion, racial/ethnic minorities receive a disproportionately low percentage of LDLTs, due in part to fewer initial inquiries by potential donors. This represents a major inequality in access to a vital health care resource and demands outreach to both patients and potential donors.