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Mobocertinib (formerly known as TAK-788) is a targeted covalent tyrosine kinase inhibitor of epidermal growth factor receptor with exon 20 insertion mutations. This article describes the metabolism and excretion of mobocertinib in healthy male subjects after a single oral administration of [14C]mobocertinib. Mobocertinib related materials were highly covalently bound to plasma proteins such as human serum albumin. The mean extraction recovery of total radioactivity was only 3.9% for 6 individual Hamilton pooled plasma samples. After extraction, mobocertinib was the most abundant component accounting for 7.7% of total extracted circulating radioactivity (TECRA) in the supernatant. Each of identified metabolites accounted for <10% of TECRA. Mobocertinib underwent extensive first-pass metabolism with the fraction of the dose absorbed estimated to be approximately 91.7%. Fecal excretion of mobocertinib metabolites was the major elimination route. Mobocertinib was mainly eliminated via oxidative metabolism with a fraction of approximately 88% metabolized by CYP3A4/5. The other minor elimination pathways included cysteine conjugation, metabolism by other CYPs, and renal excretion of unchanged mobocertinib. Significance Statement This manuscript describes the metabolism and excretion of a targeted covalent inhibitor mobocertinib in humans after a single oral administration of [14C]mobocertinib. Mobocertinib was highly covalently bound to human plasma proteins. No metabolite accounted for >10% of total extracted circulating radioactivity in human plasma. Mobocertinib was mainly eliminated via CYP3A4/5 mediated oxidative metabolism followed by fecal excretion after approximately 91.7% of the dose was absorbed.
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Mobocertinib (TAK-788) is a first-in-class oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that received accelerated approval for the treatment of patients with non-small cell lung cancer with EGFR exon 20 insertion mutations previously treated with platinum-based chemotherapy. This phase 1, 2-period, study was conducted to assess the absolute bioavailability of mobocertinib (Period 1), as well as mass balance, pharmacokinetics, metabolism, and excretion of [14C]-mobocertinib (Period 2) in healthy adult males. In Period 1, participants received a single oral capsule dose of 160 mg mobocertinib, followed by a 15-minute intravenous infusion of 50 µg (~ 2 µCi) [14C]-mobocertinib administered from 3.75 to 4 h after the capsule dose. In Period 2, a single oral dose of 160 mg (~ 100 µCi) [14C]-mobocertinib was administered as an oral solution. The geometric mean absolute bioavailability of mobocertinib was determined to be 36.7%. After oral administration of [14C]-mobocertinib, mobocertinib and its active metabolites, AP32960 and AP32914, were minor components in plasma, accounting for only 0.275% of total plasma radioactivity as the majority of mobocertinib-related material was covalently bound to plasma proteins. The geometric mean percentage of the administered radioactive dose recovered in the urine and feces was 3.57% and 76.0%, respectively. Only 0.39% of the oral dose of [14C]-mobocertinib was recovered in the urine as mobocertinib; thus, indicating that renal excretion of unchanged drug was a very minor pathway of elimination. In both treatment periods, mobocertinib was generally safe and well-tolerated as all adverse events were Grade 1 in severity. (Trial registration number ClinicalTrials.gov NCT03811834. Registration date January 22, 2019).
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Disponibilidade Biológica , Receptores ErbB , Inibidores de Proteínas Quinases , Humanos , Masculino , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Adulto , Administração Oral , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/administração & dosagem , Voluntários Saudáveis , Adulto Jovem , Éxons , Mutagênese Insercional , Radioisótopos de Carbono , Compostos de Anilina , Indóis , PirimidinasRESUMO
AIMS: Our aim was to determine the absolute bioavailability, mass balance, metabolism and excretion of soticlestat (TAK-935). METHODS: An open-label, two-period, single-site, phase 1 study was conducted in six healthy men. In Period 1, a single 300 mg dose of soticlestat was administered orally, followed by a 15-min intravenous infusion of [14 C]soticlestat 50 µg (~1 µCi) 10 min later. In Period 2, a single 300 mg dose (~100 µCi) of [14 C]soticlestat in solution was administered orally. Samples were collected, analysed for radioactivity or unchanged soticlestat, and profiled for metabolites. RESULTS: In Period 1, soticlestat had an absolute bioavailability of 12.6% (90% confidence interval, 7.81-20.23%). In Period 2, there was near-complete recovery of total radioactivity (TRA) following a 300 mg dose of [14 C]soticlestat: urine, 94.8% (standard deviation [SD], 1.35%); faeces, 2.7% (SD, 1.67%). Of TRA, 0.1% (SD, 0.09%) and 0.6% (SD, 0.21%) were recovered as soticlestat and metabolite M-I in urine, respectively. In plasma, soticlestat and M-I reached geometric mean maximum observed concentrations of 1352 ng/mL (geometric percent coefficient of variation [gCV%], 61.3) and 253.2 ng/mL (gCV%, 44.1) after 25 min and declined with mean terminal half-lives (SD) of 5.7 (2.90) and 2.0 (0.15) h, respectively. Soticlestat represented 4.9% of TRA in plasma. Soticlestat was rapidly eliminated primarily via O-glucuronidation to metabolite M3, which was the dominant species in plasma (92.6%) and urine (86%). CONCLUSIONS: This study indicates that soticlestat and its metabolites are rapidly cleared and eliminated, lowering the risk of dose accumulation from repeated dosing and supporting further investigation of soticlestat.
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Piperidinas , Piridinas , Humanos , Masculino , Administração Oral , Disponibilidade Biológica , Colesterol 24-Hidroxilase , Voluntários SaudáveisRESUMO
Therapeutic peptides (TPeps) have expanded from the initial endogenous peptides to complex modified peptides through medicinal chemistry efforts for almost a century. Different from small molecules and large proteins, the diverse submodalities of TPeps have distinct structures and carry different absorption, distribution, metabolism, and excretion (ADME) properties. There is no distinct regulatory guidance for the industry on conducting ADME studies (what, how, and when) for TPeps. Therefore, the Peptide ADME Working Group sponsored by the Translational and ADME Sciences Leadership Group of the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) was formed with the goal to develop a white paper focusing on metabolism and excretion studies to support discovery and development of TPeps. In this paper, the key learnings from an IQ industry survey and U.S. Food and Drug Administration/European Medicines Agency submission documents of TPeps approved between 2011 and 2022 are outlined in detail. In addition, a comprehensive assessment of in vitro and in vivo metabolism and excretion studies, mitigation strategies for TPep metabolism, analytical tools to conduct studies, regulatory status, and Metabolites in Safety Testing considerations are provided. Finally, an industry recommendation on conducting metabolism and excretion studies is proposed for regulatory filing of TPeps. SIGNIFICANCE STATEMENT: This white paper presents current industry practices for metabolism and excretion studies of therapeutic peptides based on an industry survey, regulatory submission documents, and expert opinions from the participants in the Peptide Absorption, Distribution, Metabolism, and Excretion Working Group of the International Consortium for Innovation and Quality in Pharmaceutical Development. The group also provides recommendations on the Metabolites in Safety Testing considerations and metabolism and excretion studies for regulatory filing of therapeutic peptides.
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Desenvolvimento de Medicamentos , Indústria Farmacêutica , Humanos , PeptídeosRESUMO
Pregnancy rates in ß-thalassemia are increasing but the risk of complications is higher; thus, better understanding of maternal and fetal iron homeostasis in this disorder is needed. HbbTh3/+ (Th3/+) mice model human ß-thalassemia. Both the murine and human diseases are characterized by low hepcidin, high iron absorption, and tissue iron overload, with concurrent anemia. We hypothesized that disordered iron metabolism in pregnant Th3/+ mice would negatively affect their unborn offspring. The experimental design included these groups: wild-type (WT) dams carrying WT fetuses (WT1); WT dams carrying WT and Th3/+ fetuses (WT2); Th3/+ dams carrying WT and Th3/+ fetuses (Th3/+); and age-matched, nonpregnant adult females. Serum hepcidin was low, and mobilization of splenic and hepatic storage iron was enhanced in all 3 groups of experimental dams. Intestinal 59Fe absorption was lower in Th3/+ dams (as compared with WT1/2 dams) but splenic 59Fe uptake was higher. Th3/+ dams had hyperferremia, which led to fetal and placenta iron loading, fetal growth restriction, and placentomegaly. Notably, Th3/+ dams loaded Th3/+ and WT fetuses, with the latter situation more closely mirroring human circumstances when mothers with thalassemia have relatively unaffected (thalassemia trait) offspring. Iron-related oxidative stress likely contributed to fetal growth impairment; enhanced placental erythropoiesis is a probable cause of placental enlargement. Moreover, high fetal liver iron transactivated Hamp; fetal hepcidin downregulated placental ferroportin expression, limiting placental iron flux and thus mitigating fetal iron loading. Whether gestational iron loading occurs in human thalassemic pregnancy, when blood transfusion can further elevate serum iron, is worth consideration.
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Hepcidinas , Talassemia beta , Camundongos , Feminino , Humanos , Gravidez , Animais , Talassemia beta/metabolismo , Placenta/metabolismo , Ferro/metabolismo , Feto/metabolismo , HomeostaseRESUMO
Iron-deficiency anemia is common worldwide and typically treated by oral iron supplementation. Excess enteral iron, however, may cause pathological outcomes. Developing new repletion approaches is thus warranted. Previous experimentation revealed that select amino acids (AAs) induce trafficking of transporters onto the enterocyte brush-border membrane (BBM) and enhance electrolyte absorption/secretion. Here, we hypothesized that certain AAs would increase the abundance of the main intestinal iron importer, divalent metal-ion transporter 1 (DMT1), on the BBM of duodenal enterocytes, thus stimulating iron absorption. Accordingly, all 20 AAs were screened using an ex vivo duodenal loop/DMT1 western blotting approach. Four AAs (Asp, Gln, Glu, and Gly) were selected for further experimentation and combined into a new formulation. The 4 AAs stimulated 59Fe transport in mouse duodenal epithelial sheets in Ussing chambers (â¼4-fold; P < .05). In iron-deprived mice, oral intragastric administration of the 4 AA formulation increased DMT1 protein abundance on the enterocyte BBM by â¼1.5-fold (P < .05). The 4 AAs also enhanced in vivo 59Fe absorption by â¼2-fold (P < .05), even when â¼26 µg of cold iron was included in the transport solution (equal to a human dose of â¼73 mg). Further experimentation using DMT1int/int mice showed that intestinal DMT1 was required for induction of iron transport by the 4 AAs. Select AAs thus enhance iron absorption by inducing DMT1 trafficking onto the apical membrane of duodenal enterocytes. We speculate that further refinement of this new 4 AA formulation will ultimately allow iron repletion at lower effective doses (thus mitigating negative side effects of excess enteral iron).
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Sobrecarga de Ferro , Ferro , Aminoácidos/metabolismo , Animais , Duodeno/metabolismo , Ferro/metabolismo , CamundongosRESUMO
INTRODUCTION: Deep dyspareunia is a common symptom in women, including in half of women with endometriosis, but little is known about its response to treatment and predictors of persistent deep dyspareunia over time. AIM: To follow up deep dyspareunia severity over a 1-year prospective cohort at an interdisciplinary center, and to identify baseline predictors of more persistent deep dyspareunia at 1 year. METHODS: Prospective 1-year cohort study at a tertiary referral center for pelvic pain and endometriosis, where a range of interdisciplinary treatments are provided at a single center (surgical, hormonal, physical, and psychological therapies). Exclusion criteria were menopause, age >50 years, and never previously sexually active. Primary outcome (deep dyspareunia severity) and secondary outcome (sexual quality of life) were followed up over 1 year. Ordinal logistic regression was performed, controlling for baseline severity of deep dyspareunia, to identify baseline predictors of deep dyspareunia severity at 1 year. MAIN OUTCOME MEASURE: Primary outcome was severity of deep dyspareunia on an 11-point numeric rating scale (0-10), categorized into absent-mild (0-3), moderate (4-6), and severe (7-10); secondary outcome was sexual quality of life measured by the Endometriosis Health Profile-30. RESULTS: 1-year follow-up was obtained for 278 subjects (56% response rate at 1 year; 278/497). Severity of deep dyspareunia improved over the 1 year (McNemar test, P < .0001): the proportion of patients in the severe category decreased from 55.0% to 30.4%, the moderate category remained similar from 17.7% to 25.0%, and the absent-mild category increased from 27.3% to 44.6%. Sexual quality of life also improved (56% to 43% on the sex subscale of the Endometriosis Health Profile-30) (Welch t test, P < .001). On ordinal regression, severity of deep dyspareunia at 1 year was independently associated with younger age (OR = 0.94, 95% CI = 0.91-0.97, P = .008), and with a higher baseline depression score on the Patient Health Questionnaire-9 (OR = 1.07, 95% CI = 1.03-1.11, P = .01). CLINICAL IMPLICATIONS: Clinicians should consider employing an interdisciplinary approach for deep dyspareunia, and screening for and treating depression symptoms in these women. STRENGTH & LIMITATIONS: Strengths of the study include its prospective nature, and assessment of deep dyspareunia specifically (as opposed to superficial dyspareunia). Limitations include non-randomized design, and the patients lost to follow-up over the 1 year. CONCLUSION: Over 1 year in an interdisciplinary setting, improvements were observed in deep dyspareunia and sexual quality of life, but younger women and those with more severe depression at baseline had more persistent deep dyspareunia at 1 year. Yong PJ, Williams C, Bodmer-Roy S, et al. Prospective Cohort of Deep Dyspareunia in an Interdisciplinary Setting. J Sex Med 2018;15:1765-1775.
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Depressão/psicologia , Dispareunia/psicologia , Dor Pélvica/psicologia , Qualidade de Vida/psicologia , Comportamento Sexual/psicologia , Adulto , Estudos de Coortes , Depressão/complicações , Dispareunia/complicações , Endometriose/complicações , Feminino , Humanos , Comunicação Interdisciplinar , Dor Pélvica/complicações , Estudos Prospectivos , Adulto JovemRESUMO
BACKGROUND: Chronic pelvic pain affects â¼15% of women, and presents a challenging problem for gynecologists due to its complex etiology involving multiple comorbidities. Thus, an interdisciplinary approach has been proposed for chronic pelvic pain, where these multifactorial comorbidities can be addressed by different interventions at a single integrated center. Moreover, while cross-sectional studies can provide some insight into the association between these comorbidities and chronic pelvic pain severity, prospective longitudinal cohorts can identify comorbidities associated with changes in chronic pelvic pain severity over time. OBJECTIVE: We sought to describe trends and factors associated with chronic pelvic pain severity over a 1-year prospective cohort at an interdisciplinary center, with a focus on the role of comorbidities and controlling for baseline pain, demographic factors, and treatment effects. STUDY DESIGN: This was a prospective 1-year cohort study at an interdisciplinary tertiary referral center for pelvic pain and endometriosis, which provides minimally invasive surgery, medical management, pain education, physiotherapy, and psychological therapies. Exclusion criteria included menopause or age >50 years. Sample size was 296 (57% response rate at 1 year; 296/525). Primary outcome was chronic pelvic pain severity at 1 year on an 11-point numeric rating scale (0-10), which was categorized for ordinal regression (none-mild 0-3, moderate 4-6, severe 7-10). Secondary outcomes included functional quality of life and health utilization. Baseline comorbidities were endometriosis, irritable bowel syndrome, painful bladder syndrome, abdominal wall pain, pelvic floor myalgia, and validated questionnaires for depression, anxiety, and catastrophizing. Multivariable ordinal regression was used to identify baseline comorbidities associated with the primary outcome at 1 year. RESULTS: Chronic pelvic pain severity decreased by a median 2 points from baseline to 1 year (6/10-4/10, P < .001). There was also an improvement in functional quality of life (42-29% on the pain subscale of the Endometriosis Health Profile-30, P < .001), and a reduction in subjects requiring a physician visit (73-36%, P < .001) or emergency visit (24-11%, P < .001) in the last 3 months. On multivariable ordinal regression for the primary outcome, chronic pelvic pain severity at 1 year was independently associated with a higher score on the Pain Catastrophizing Scale at baseline (odds ratio, 1.10; 95% confidence interval, 1.00-1.21, P = .04), controlling for baseline pain, treatment effects (surgery), age, and referral status. CONCLUSION: Improvements in chronic pelvic pain severity, quality of life, and health care utilization were observed in a 1-year cohort in an interdisciplinary setting. Higher pain catastrophizing at baseline was associated with greater chronic pelvic pain severity at 1 year. Consideration should be given to stratifying pelvic pain patients by catastrophizing level (rumination, magnification, helplessness) in research studies and in clinical practice.