COVID-19 caused by the SARS-CoV-2 virus has become a global pandemic. 3CL protease is a virally encoded protein that is essential across a broad spectrum of coronaviruses with no close human analogs. ...PF-00835231, a 3CL protease inhibitor, has exhibited potent in vitro antiviral activity against SARS-CoV-2 as a single agent. Here we report, the design and characterization of a phosphate prodrug PF-07304814 to enable the delivery and projected sustained systemic exposure in human of PF-00835231 to inhibit coronavirus family 3CL protease activity with selectivity over human host protease targets. Furthermore, we show that PF-00835231 has additive/synergistic activity in combination with remdesivir. We present the ADME, safety, in vitro, and in vivo antiviral activity data that supports the clinical evaluation of PF-07304814 as a potential COVID-19 treatment.
Drug metabolism by the human gut microbiome Eng, Heather; Scott Obach, R.; Moen, Mark
Drug metabolism and pharmacokinetics,
April 2024, 2024-04-00, Letnik:
55
Journal Article
Adenosine monophosphate-activated protein kinase (AMPK) is a protein kinase involved in maintaining energy homeostasis within cells. On the basis of human genetic association data, AMPK activators ...were pursued for the treatment of diabetic nephropathy. Identification of an indazole amide high throughput screening (HTS) hit followed by truncation to its minimal pharmacophore provided an indazole acid lead compound. Optimization of the core and aryl appendage improved oral absorption and culminated in the identification of indole acid, PF-06409577 (7). Compound 7 was advanced to first-in-human trials for the treatment of diabetic nephropathy.
Prospective predictions of human hepatic clearance for anionic/zwitterionic compounds, which are oftentimes subjected to transporter-mediated uptake, are challenging in drug discovery. We evaluated ...the utility of preclinical species, rats and cynomolgus monkeys nonhuman primates (NHPs), to predict the human hepatic clearance using a diverse set of acidic/zwitterionic drugs. Preclinical clearance data were generated following intravenous dosing in rats/NHPs and compared to the human clearance data (n = 18/27). Single-species scaling of NHP clearance with an allometric exponent of 0.50 allowed for good prediction of human clearance (fold error ∼2.1, bias ∼1.0), with ∼86% predictions within 3-fold. In comparison, rats underpredicted the clearance of lipophilic acids, while overprediction was noted for hydrophilic acids. Finally, an in vitro clearance assay based on human hepatocytes, which is routinely used in discovery setting, markedly underpredicted human clearance (bias ∼0.12). Collectively, this study provides insights into the usefulness of the preclinical models in enabling pharmacokinetic optimization for acid/zwitterionic drug candidates.
Respiratory syncytial virus (RSV) is becoming increasingly recognized as a serious threat to vulnerable population subgroups. This study describes the statistical analysis plan for a retrospective ...cohort study of adults hospitalized for acute respiratory infection (ARI) to estimate the population burden of RSV especially for groups such as the elderly, pregnant women and solid organ transplant patients. Disease burden estimates are essential for setting vaccine policy, e.g., should RSV vaccine become available, burden estimates may inform recommendations to prioritize certain high-risk groups. The study population is residents of Allegheny County, Pennsylvania ≥18 years of age who were hospitalized in Pennsylvania during the period September 1, 2015-August 31, 2018. Data sources will include U.S. Census, Pennsylvania Health Care Cost Containment Council (PHC4) and the electronic medical record for the health system to which the hospitals belong. The algorithm involves: 1) ARI-associated hospitalizations in PHC4 data; 2) adjustment for ARI hospitalizations among county residents but admitted to hospitals outside the county; and 3) RSV detections from respiratory viral panels. Key sensitivity analyses will adjust for undertesting for viruses in the fall and spring quarters. The results will be population-based estimates, stratified by age and risk groups. Adjusting hospitalization data using a multiplier method is a simple means to estimate the impact of RSV in a given area. This algorithm can be applied to other health systems and localities to estimate RSV and other respiratory pathogen burden in adults, to estimate burden following introduction of RSV vaccine and to make cost-effectiveness estimates.
Abstract
Background
Influenza causes significant morbidity and mortality and stresses hospital resources during periods of increased circulation. We evaluated the effectiveness of the 2019–2020 ...influenza vaccine against influenza-associated hospitalization in the United States.
Methods
We included adults hospitalized with acute respiratory illness at 14 hospitals and tested for influenza viruses by reserve-transcription polymerase chain reaction. Vaccine effectiveness (VE) was estimated by comparing the odds of current-season influenza vaccination in test-positive influenza cases vs test-negative controls, adjusting for confounders. VE was stratified by age and major circulating influenza types along with A(H1N1)pdm09 genetic subgroups.
Results
A total of 3116 participants were included, including 18% (n = 553) influenza-positive cases. Median age was 63 years. Sixty-seven percent (n = 2079) received vaccination. Overall adjusted VE against influenza viruses was 41% (95% confidence interval CI, 27%–52%). VE against A(H1N1)pdm09 viruses was 40% (95% CI, 24%–53%) and 33% against B viruses (95% CI, 0–56%). Of the 2 major A(H1N1)pdm09 subgroups (representing 90% of sequenced H1N1 viruses), VE against one group (5A + 187A,189E) was 59% (95% CI, 34%–75%) whereas no VE was observed against the other group (5A + 156K) (–1% 95% CI, –61% to 37%).
Conclusions
In a primarily older population, influenza vaccination was associated with a 41% reduction in risk of hospitalized influenza illness.
During the 2019-2020 United States influenza season, genetically diverse influenza A(H1N1)pdm09 and influenza B viruses of the Victoria lineage co-circulated. Overall vaccine effectiveness against influenza-associated hospitalization was 41% despite circulation of multiple antigenically drifted viruses.
Abstract Background Postpartum depression incurs significant burden and suffering. Methods We investigated the latent structure of the most commonly used screening measure, the Edinburgh Postnatal ...Depression Scale (EPDS) in women ( N = 15,172) and tested its predictive validity for the diagnosis of depression as determined with a structured clinical interview. Exploratory and confirmatory factor analyses, Receiver Operating Characteristic curves, and logistic regression analyses were conducted. Results A seven-item one factor scale (items 1, 2, 6, 7, 8, 9, 10) emerged with a Goodness of Index Fit Index (GFI) = 0.96, relative to the ten-item two factor version of the EPDS (GFI =0.94). The seven-item EPDS achieved good sensitivity and specificity in predicting the 10-item EPDS, with a cut point score of 4 on the seven item EPDS to predict a 10-item EPDS score of 10 or more (sensitivity = 95%, specificity = 91%). The seven and 10-item EPDS showed a similar ability to predict a diagnoses of depression (area under the ROC curve=0.795 for the 10-item, 0.770 for the seven-item EPDS). Logistic regression analyses showed similar predictive ability between the seven- and 10-item scales in predicting scores higher than 18 on the clinical interview Limitations The sample represents women from one Midwest medical center and the EPDS was measured via phone. Conclusion The seven-item one factor version of the EPDS is an efficient and effective measure of depression severity on par with the two factor 10-item version of the EPDS.
The aim of the present study was to quantitatively evaluate the drug-drug interactions (DDIs) of maraviroc (MVC) with various perpetrator drugs, including telaprevir (TVR), using an in vitro ...data-informed physiologically based pharmacokinetic (PBPK) model. MVC showed significant active uptake and biliary excretion in sandwich-cultured human hepatocytes, and biphasic organic anion transporting polypeptide (OATP)1B1-mediated uptake kinetics in transfected cells (high-affinity
∼5
M). No measureable active uptake was noted in OATP1B3- and OATP2B1-transfceted cells. TVR inhibited OATP1B1-mediated MVC transport in vitro, and also exhibited CYP3A time-dependent inhibition in human hepatocytes (inactivation constant,
= 2.24
M, and maximum inactivation rate constant,
= 0.0112 minute
). The inactivation efficiency (
/
) was approximately 34-fold lower in human hepatocytes compared with liver microsomes. A PBPK model accounting for interactions involving CYP3A, P-glycoprotein (P-gp), and OATP1B1 was developed based on in vitro mechanistic data. MVC DDIs with ketoconazole (inhibition of CYP3A and P-gp), ritonavir (inhibition of CYP3A and P-gp), efavirenz (induction of CYP3A), rifampicin (induction of CYP3A and P-gp; inhibition of OATP1B1), and TVR (inhibition of CYP3A, P-gp, and OATP1B1) were well described by the PBPK model with optimized transporter
values implying that OATP1B1-mediated uptake along with CYP3A metabolism determines the hepatic clearance of MVC, and P-gp-mediated efflux limits its intestinal absorption. In summary, MVC disposition involves intestinal P-gp/CYP3A and hepatic OATP1B1/CYP3A interplay, and TVR simultaneously inhibits these multiple mechanisms leading to a strong DDI-about 9.5-fold increase in MVC oral exposure.
Abstract
Background
The 2016–2017 and 2017–2018 influenza seasons were notable for the high number of hospitalizations for influenza A(H3N2) despite vaccine and circulating strain match.
Methods
We ...evaluated vaccine effectiveness (VE) against hospitalization in the test-negative HAIVEN study. Nasal-throat swabs were tested by quantitative reverse transcription polymerase chain reaction (RT-PCR) for influenza and VE was determined based on odds of vaccination by generalized estimating equations. Vaccine-specific antibody was measured in a subset of enrollees.
Results
A total of 6129 adults were enrolled from 10 hospitals. Adjusted VE against A(H3N2) was 22.8% (95% confidence interval CI, 8.3% to 35.0%), pooled across both years and 49.4% (95% CI, 34.3% to 61.1%) against B/Yamagata. In 2017–2018, the A(H3N2) VE point estimate for the cell-based vaccine was 43.0% (95% CI, −36.3% to 76.1%; 56 vaccine recipients) compared to 24.0% (95% CI, 3.9% to 39.9%) for egg-based vaccines. Among 643 with serology data, hemagglutinin antibodies against the egg-based A(H3N2) vaccine strain were increased in influenza-negative individuals.
Conclusions
Low VE for the A/Hong Kong/4801/2014 vaccine virus in both A(H3N2) seasons emphasizes concerns for continued changes in H3N2 antigenic epitopes, including changes that may impact glycosylation and ultimately reduce VE.
Across 2 years of a prospective, multicenter, test-negative study of influenza vaccine effectiveness in prevention of hospitalization, we found VE of 33.5% against any influenza-associated hospitalization and a low VE of 22.8% for the A/Hong Kong/4801/2014 vaccine strain.
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