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Pharmacokinetics of capmatinib in participants with hepatic impairment: A phase 1, open-label, single-dose, parallel-group study
No full textAims: Capmatinib, a mesenchymal–epithelial transition factor tyrosine kinase inhibitor, is metabolized by cytochrome P450 (CYP) 3A4 and aldehyde oxidase. In individuals with hepatic impairment, alterations in hepatobiliary excretion and metabolism could lead to higher capmatinib exposure. We compared the pharmacokinetics of a single oral dose of capmatinib 200 mg administered to participants with varying degrees of hepatic impairment vs. matched controls with normal hepatic function. Methods: This phase 1, multicentre, open-label, parallel-group study enrolled adult participants with normal hepatic function and mild, moderate and severe hepatic impairments. Eligible participants received a single oral dose of 200 mg capmatinib. The pharmacokinetic parameters of capmatinib were analysed and compared across participants with impaired and normal hepatic function. Results: Of 31 enrolled participants, 29 had an evaluable pharmacokinetic profile: normal (n = 9); mild (n = 6); moderate (n = 8); severe (n = 6). Compared with the normal group, geometric mean (GM) maximum (peak) observed plasma drug concentration after single-dose administration decreased by 27.6% in the mild group (GM ratio [GMR] = 0.724; 90% confidence interval [CI]: 0.476–1.10), by 17.2% in the moderate group (GMR = 0.828; 90% CI: 0.563–1.22) and remained unchanged in the severe group (GMR = 1.02; 90% CI: 0.669–1.55). Compared with the normal group, GM area under the plasma concentration–time curve from time zero to infinity decreased by 23.3% in the mild group (GMR = 0.767; 90% CI: 0.532–1.11), by 8.6% in the moderate group (GMR = 0.914; 90% CI: 0.652–1.28) and increased by 24% in the severe group (GMR = 1.24; 90% CI: 0.858–1.78). Conclusion: Mild, moderate and severe hepatic impairment did not have a clinically relevant impact on capmatinib pharmacokinetics. No new safety findings are reported in this study
Population Pharmacokinetic Analysis of Indacaterol/Glycopyrronium/Mometasone Furoate After Administration of Combination Therapies Using the Breezhaler® Device in Patients with Asthma
No full textBackground and Objective: Clinical evidence suggests no clinically relevant pharmacokinetic interactions between indacaterol (IND), glycopyrronium (GLY) and mometasone furoate (MF). A population pharmacokinetic (popPK) analysis was conducted to identify structural models describing systemic pharmacokinetic profiles of IND, GLY and MF, and estimate the effect of covariates on their pharmacokinetics following inhalation as IND/GLY/MF. Methods: Pharmacokinetic data from 698 patients with asthma were pooled from two Phase III studies that evaluated IND/MF medium- (150/160 µg) and high-dose (150/320 µg), IND/GLY/MF medium- (150/50/80 μg) and high-dose (150/50/160 μg), and a device bridging Phase II study with MF. One popPK model was developed each for IND, GLY and MF using a nonlinear mixed-effect modelling approach. Maximal and trough plasma concentrations were compared across formulations and studies, including data for IND/GLY from chronic obstructive pulmonary disease (COPD) patients. The effect of predefined covariates on the pharmacokinetics of components was evaluated using a full covariate modelling approach. Results: The final pharmacokinetic models were two-compartment disposition models with first-order elimination and sequential zero-order/first-order absorption (IND), with bolus administration and first-order elimination (GLY), and with mixed zero-order/first-order absorption and first-order elimination (MF). All model parameters were estimated with good precision (% relative standard error: IND and MF ≤25%; GLY <10%). No clinically relevant covariate effect was observed on the pharmacokinetics of IND, GLY and MF. IND and GLY pharmacokinetic profiles were similar across different formulations. Conclusion: Two-compartment popPK models adequately described the pharmacokinetics of IND, GLY and MF. The effect of covariates was not clinically relevant. The pharmacokinetic profiles of MF were comparable for combination products at corresponding medium- or high-dose inhaled corticosteroids. On a population level, the pharmacokinetics of IND and GLY were comparable between patients with asthma and COPD
Predicting Oral Absorption for Compounds Outside the Rule of Five Property Space
No full textThe estimation of the extent of absorption of drug candidates intended for oral drug delivery is an
important selection criteria in drug discovery. The use of cell-based transwell assays examining flux
across cell-monolayers (e.g., Caco-2 or MDCK cells) usually provide satisfactory predictions of the extent
of absorption in vivo. These predictions often fall short of expection for molecules outside the traditional
low molecular weight property space. In this manuscript the transwell permeability assay was modified
to circumvent potential issues that can be encountered when evaluating the aforementioned drug
molecules. Particularly, the addition of albumin in the acceptor compartment to reduce potential binding
to cells and the acceptor compartment, improved the predictive power of the assay. Cellular binding and
lysosomal trapping effects are significantly reduced for larger molecules, particularly lipophilic bases
under these more physiological conditions, resulting in higher recovery values and a better prediction
power. The data indicate that lysosomal trapping does not impact the rate of absorption of lipophilic
bases in general but is rather an exception. Finally, compounds believed to permeate by passive mechanisms
were used in a calibration curve for the effective prediction of the fraction absorbed of molecules
of interest in current medicinal chemistry efforts
The tumor suppressor WT1 drives progenitor cell progression and epithelialization to prevent Wilms tumorigenesis in human kidney organoids
No full textWilms tumor is the most widespread kidney cancer in children and frequently associated with homozygous loss of the tumor suppressor WT1. Pediatric tumorigenesis is largely inaccessible in humans. Here, we develop a human kidney organoid model for Wilms tumor formation and show that deletion of WT1 during organoid development induces overgrowth of kidney progenitor cells at the expense of differentiating glomeruli and tubules. Functional and gene expression analyses demonstrate that absence of WT1 halts progenitor cell progression at a pre-epithelialized cell state and recapitulates the transcriptional changes detected in a subgroup of Wilms tumor patients with ectopic myogenesis. By "transplanting" WT1 mutant cells into wild-type kidney organoids, we find that their propagation requires an untransformed microenvironment. This work defines the role of WT1 in kidney progenitor cell progression and tumor suppression, and establishes human kidney organoids as a phenotypic model for pediatric tumorigenesis
Drug-induced phospholipidosis confounds drug repurposing for SARS-CoV-2
No full textRepurposing drugs as treatments for COVID-19 has drawn much attention. Beginning with sigma receptor ligands, and expanding to other drugs from screening in the field, we became concerned that phospholipidosis was a shared mechanism underlying the antiviral activity of many repurposed drugs. For all of the 23 cationic amphiphilic drugs tested, including hydroxychloroquine, azithromycin, amiodarone, and four others already in clinical trials, phospholipidosis was monotonically correlated with antiviral efficacy. Conversely, drugs active against the same targets that did not induce phospholipidosis were not antiviral. Phospholipidosis depends on the physicochemical properties of drugs, and does not reflect specific target-based activities, rather it may be considered a toxic confound in early drug discovery. Early detection of phospholipidosis could eliminate these artifacts, enabling a focus on molecules with therapeutic potential
Interlaboratory study of a Supercritical Fluid Chromatography method for the determination of pharmaceutical impurities: evaluation of multi-systems reproducibility
No full textModern Supercritical Fluid Chromatography (SFC) is now a well-established technique, especially in the field of pharmaceutical analysis. We recently demonstrated the transferability and the reproducibility of a SFC method for pharmaceutical impurities by means of an inter-laboratory study. However, as this study involved only one brand of SFC instrumentation, the present study extends the purpose to multi-instrumentations evaluation. In this context, three instrument types, namely Agilent®, Shimadzu®, Waters®, were included through 21 laboratories (n = 7 for each instrument). Firstly, method transfer was performed to assess the separation quality using these instruments and to set up the specific instrument parameters of Agilent® and Shimadzu® instruments. Secondly, the inter-laboratory study was performed following the protocol defined by the sending lab. Analytical results were deeply examined regarding consistencies within- and between-laboratories criteria. Afterwards, the method reproducibility was estimated taking into account variances in replicates, between-days and between-laboratories. Obviously, reproducibility variance was larger than that observed during the first study involving only one single type of instrumentation. Indeed, we clearly observed an ‘instrument type’ effect. Moreover, general speaking, the reproducibility variance was larger when considering all instruments than each type separately. The configuration of each modern SFC instrument easily explained the variability induced by the instrument. Nevertheless, repeatability and reproducibility variances were found to be similar than those described for LC methods (i.e. reproducibility RSD around 15%). These results highlighted the robustness and the interest of SFC to provide accurate results for pharmaceutical quality control analysis
Compounds from plantar foot sweat, nesting material, and urine show strain patterns associated with agonistic and affiliative behaviors in group housed male mice, Mus musculus.
No full textExcessive home cage aggression often results in severe injury and subsequent premature euthanasia of male laboratory mice. Aggression can be reduced by transferring used nesting material during cage cleaning, which is thought to contain aggression appeasing odors from the plantar sweat glands. However, neither the composition of plantar sweat nor the deposits on used nesting material have been evaluated. The aims of this study were to (1) identify and quantify volatile compounds deposited in the nest site and (2) determine if nest and sweat compounds correlate with social behavior. Home cage aggression and affiliative behavior were evaluated in 3 strains: SJL, C57BL/6N, and A/J. Individual social rank was assessed via the tube test, because ranking may influence compound levels. Sweat and urine from the dominant and subordinate mouse in each cage, plus cage level nest samples were analyzed for volatile compound content using gas chromatography-mass spectrometry. Behavior data and odors from the nest, sweat, and urine were statistically analyzed with separate principal component analyses (PCA). Significant components, from each sample analysis, and strain were run in mixed models to test if odors were associated with behavior. Aggressive and affiliative behaviors were primarily impacted by strain. However, compound PCs were also impacted by strain, showing that strain accounts for any relationship between odors and behavior. C57BL/6N cages displayed the most allo-grooming behavior and had high scores on sweat PC1. SJL cages displayed the most aggression, with high scores on urine PC2 and low scores on nest PC1. These data show that certain compounds in nesting material, urine, and sweat display strain specific patterns which match strain specific behavior patterns. These results provide preliminary information about the connection between home cage compounds and behavior. Salient compounds will be candidates for future controlled studies to determine their direct effect on mouse social behavior
Education Pathway to Diversify STEM Workforce: A Call to Action for a Collaborative Ecosystem
No full textA session was held during the 2020 AAPS meeting that highlighted the benefits of a diverse and inclusive (D&I) workforce in the pharmaceutical industry and the need for improved recruiting of D&I candidates (Coker, 2020). In this article, we describe a successful ecosystem involving academia, biotech/pharma, and students that promotes degree attainment, job placement (internships, co-op, and fulltime employment), and career advancement. The Associate’s to Master's (A2M) degree pathway involves close collaboration between Middlesex Community College (MCC), Northeastern University, and over 30 advisory board members from the biotechnology and pharmaceutical industries. The objective of the pathway is to increase degree attainment rates of low-income students who are disproportionately underrepresented minorities by eliminating barriers to education. As part of this National Science Foundation (NSF) funded program, students receive full scholarships as they earn their Associate (AS) , Bachelor of Science (BS), and/or Master of Science (MS) degree in Biotechnology, and are provided additional support, including mentoring, tutoring, seminars, lab tours and more. Importantly, the education pathway has been built in partnership with industry leaders to meet the demands of local employers, focusing on both technical and soft skill development. The A2M Scholars are all low-income, full-time, domestic students per NSF requirements, and over 53% identify as underrepresented minorities in STEM. Nationally, the retention rate for BS degree STEM students is 53.7% (What is the S&E retention rate in U.S. 4-year institutions?). In contrast to the national retention rates, the A2M degree pathway has retention rates that exceed 90% at all three degree levels. By sharing this program and its outcomes, we hope to promote future development of similar pathways within all industries, and encourage continued support of industry partners
A phase 1 study of a CDH6-Targeting antibody-drug conjugate in patients with advanced solid tumors with evaluation of inflammatory and neurological adverse events
No full textPurpose: This first-in-human study (NCT02947152) evaluated the safety, tolerability, pharmacokinetics, and preliminary efficacy of HKT288, a first-in-class CDH6-targeting antibody-drug conjugate (ADC). Experimental Design: HKT288 was administered intravenously (IV) every 3 weeks until patients experienced unacceptable toxicity or progressive disease (PD). The starting dose of 0.3 mg/kg was determined based on the highest nonseverely toxic dose in monkeys, which was 2 mg/kg IV weekly. Based on preclinical toxicology, skin, eyes, bone marrow, and liver were expected targets of toxicity. Results: Nine patients were enrolled: 5 with renal cell carcinoma and 4 with epithelial ovarian cancer. The best overall response on the 0.3 mg/kg cohort in patients with measurable disease was RECIST v1.1 stable disease in 3 patients and PD in 2 patients. The most frequent adverse events (AEs) regardless of causality were pyrexia (44.4%), constipation (44.4%), fatigue (33.3%), and vomiting (33.3%). Three suspected-related neurologic AEs (Grade 2) were reported on the 0.75 mg/kg cohort: seizure in 1 patient and another patient with aphasia and encephalopathy. Further studies were unable to identify the underlying mechanism of the neurologic AEs, and the study was terminated early. Conclusions: Preclinical toxicology did not predict the neurotoxicity observed with HKT288, and a comprehensive assessment performed post hoc did not identify the mechanism of toxicity. The development of further CDH6-targeting ADCs should be pursued with caution
LLF580, an FGF21 Analog, Reduces Triglycerides and Hepatic Fat in obese persons with modestly elevated triglycerides: A 12 Week Randomized Double Blind Placebo Controlled Study
No full textPurpose: To evaluate the safety and potential efficacy of LLF580, a genetically engineered variant of human fibroblast growth factor-21, for triglyceride lowering, weight loss, and hepatic fat reduction.
Methods: A multicenter, double-blind, parallel design trial in obese, mildly hypertriglyceridemic and otherwise apparently healthy adults randomized (1:1) to LLF580 300 mg or placebo subcutaneously every four weeks for three doses.
Results: Of 64 randomized study participants, 61 (mean±SD: age 45±11 years, 49% male, 80/15/5% Caucasian/African American/Other, BMI 36.1±3.8 kg/m2) received LLF580 (n=30) or placebo (n=31) at 7 research sites in the USA. LLF580 lowered serum triglycerides by 54% (least square mean placebo adjusted change from baseline), total cholesterol 7%, LDL-cholesterol 12%, and increased HDL-cholesterol 36% compared to placebo (all P<0.001) over 12 weeks. Substantial reduction of liver fat of 52% over placebo (P<0.001) was also demonstrated, in the setting of improved liver function tests including alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase, the composite enhanced liver fibrosis score, and N-terminal type III collagen propeptide (all P<0.05). Insulin and C-peptide levels and insulin resistance by HOMA-IR were all lower, and adiponectin higher with LLF580 treatment compared to placebo, while fasting glucose and HbA1c were unchanged. Reductions in biomarkers of bone formation without differences in markers of bone resorption were observed. LLF580 was generally safe and well tolerated, except for higher incidence of generally mild to moderate gastrointestinal adverse effects.
Conclusions: In obese, mildly hypertriglyceridemic adults, LLF580 was generally safe and demonstrated beneficial effects on serum lipids, liver fat and biomarkers of liver injury, suggesting it may be effective for treatment of select metabolic disorders including hypertriglyceridemia and non-alcoholic fatty liver disease. Assessments of longer-term safety and efficacy are warranted