pharmacodynamic profile
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2022 ◽  
Vol 8 ◽  
Author(s):  
Ana Sánchez-Fuentes ◽  
José Miguel Rivera-Caravaca ◽  
Raquel López-Gálvez ◽  
Francisco Marín ◽  
Vanessa Roldán

Non-vitamin K antagonist oral anticoagulants (NOACs) are a therapeutic option to prevent stroke in patients with atrial fibrillation (AF). In fact, NOACs have become the recommended choice by international clinical practice guidelines over vitamin K antagonists (VKA), because of their efficacy and safety profile, especially in newly initiated patients. The more predictable pharmacokinetic and pharmacodynamic profile of this family of drugs allows preventing anticoagulation drug monitoring. Furthermore, NOACs have significantly fewer drug and food interactions in comparison with VKAs. Despite this, there are no studies that compare the effects on the quality of anticoagulation of NOACs with the intake of potential interactions drugs of P-glycoprotein and cytochrome P450 (CYP). This review brings an overview of NOACs pharmacokinetics profile and their potential drug-food interactions. We also briefly discuss the potential role of prebiotics and probiotics in patients under therapy with NOACs.


2022 ◽  
pp. 1-15
Author(s):  
Brian A. Willis ◽  
Stephen L. Lowe ◽  
Scott A. Monk ◽  
Patrick J. Cocke ◽  
Christopher D. Aluise ◽  
...  

Background: The development of beta-site amyloid-beta precursor protein cleaving enzyme (BACE) 1 inhibitors for the treatment of Alzheimer’s disease requires optimization of inhibitor potency, selectivity, and brain penetration. Moreover, there is a need for low-dose compounds since liver toxicity was found with some BACE inhibitors. Objective: To determine whether the high in vitro potency and robust pharmacodynamic effect of the BACE inhibitor LY3202626 observed in nonclinical species translated to humans. Methods: The effect of LY3202626 versus vehicle on amyloid-β (Aβ) levels was evaluated in a series of in vitro assays, as well as in in vivo and multi-part clinical pharmacology studies. Aβ levels were measured using analytical biochemistry assays in brain, plasma, and cerebrospinal fluid (CSF) of mice, dogs and humans. Nonclinical data were analyzed using an ANOVA followed by Tukey’s post hoc test and clinical data used summary statistics. Results: LY3202626 exhibited significant human BACE1 inhibition, with an IC50 of 0.615±0.101 nM in a fluorescence resonance energy transfer assay and an EC50 of 0.275±0.176 nM for lowering Aβ 1–40 and 0.228±0.244 nM for Aβ 1–42 in PDAPP neuronal cultures. In dogs, CSF Aβ 1hboxx concentrations were significantly reduced by ∼80% at 9 hours following a 1.5 mg/kg dose. In humans, CSF Aβ 1–42 was reduced by 73.1±7.96 % following administration of 6 mg QD. LY3202626 was found to freely cross the blood-brain barrier in dogs and humans. Conclusion: LY3202626 is a potent BACE1 inhibitor with high blood-brain barrier permeability. The favorable safety and pharmacokinetic/pharmacodynamic profile of LY3202626 supports further clinical development.


2021 ◽  
Vol 12 ◽  
Author(s):  
Marco Dionisi ◽  
Sara Cairoli ◽  
Raffaele Simeoli ◽  
Francesca De Gennaro ◽  
Valeria Paganelli ◽  
...  

Background: Eltrombopag (EPAG) is an oral thrombopoietin receptor agonist, approved for refractory primary immune thrombocytopenia (ITP) in pediatric patients. In two pediatric RCTs, EPAG led to an improvement of platelet counts and a reduction in bleeding severity. However, a significant number of pediatric patients did not achieve the primary endpoints. We performed a pharmacokinetic evaluation of EPAG in pediatric patients with refractory ITP.Methods: Outpatients aged from 1 to 17 y, affected by refractory ITP to first-line treatment, were enrolled for a pharmacokinetic assessment. The analysis of drug plasma concentration was performed by the LC-MS/MS platform. Non-compartmental and statistical subgroup analyses were carried out using the R package ncappc.Results: Among 36 patients eligible for PK analysis, the median dose of EPAG given once daily was 50 mg. The EPAG peak occurs between 2 and 4 h with a population Cmax and AUC 0–24 geo-mean of 23, 38 μg/ml, and 275, 4 µg*h/mL, respectively. The pharmacokinetic profile of EPAG did not show a dose proportionality. Female patients showed a statistically significant increase of dose-normalized exposure parameters, increasing by 110 and 123% for Cmax and AUC 0–24, respectively, when compared to male patients. Patients aged 1–5 y showed values increased by more than 100% considering both exposure parameters, compared to older children. Furthermore, patients presenting complete response (83%), showed augmented EPAG exposure parameters compared to subjects with partial or no response.Conclusion: These data highlight the need to further explore the variability of EPAG exposure and its pharmacokinetic/pharmacodynamic profile in pediatric patients also in a real-life setting.


Molecules ◽  
2021 ◽  
Vol 26 (22) ◽  
pp. 7025
Author(s):  
Katarzyna Kucwaj-Brysz ◽  
Anna Dela ◽  
Sabina Podlewska ◽  
Marek Bednarski ◽  
Agata Siwek ◽  
...  

Several studies confirmed the reciprocal interactions between adrenergic and serotoninergic systems and the influence of these phenomena on the pathogenesis of anxiety. Hence, searching for chemical agents with a multifunctional pharmacodynamic profile may bring highly effective therapy for CNS disorders. This study presents a deep structural insight into the hydantoin-arylpiperazine group and their serotonin/α-adrenergic activity. The newly synthesized compounds were tested in the radioligand binding assay and the intrinsic activity was evaluated for the selected derivatives. The computer-aided SAR analysis enabled us to answer questions about the influence of particular structural fragments on selective vs. multifunctional activity. As a result of the performed investigations, there were two leading structures: (a) compound 12 with multifunctional adrenergic-serotonin activity, which is a promising candidate to be an effective anxiolytic agent; (b) compound 14 with high α1A/α1D affinity and selectivity towards α1B, which is recommended due to the elimination of probable cardiotoxic effect. The structural conclusions of this work provide significant support for future lead optimization in order to achieve the desired pharmacodynamic profile in searching for new CNS-modulating agents.


Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2303-2303
Author(s):  
Pilar Martínez Sánchez ◽  
Paul Gordon ◽  
Stefan Schwartz ◽  
Giuseppe Rossi ◽  
Francoise Huguet ◽  
...  

Abstract Background Blinatumomab is a BiTE ® (bispecific T cell engager) molecule that engages patients' T cells to the CD19 antigen on lymphoid tumor cells. Blinatumomab administered as a 28-day continuous intravenous infusion (cIV) is approved in multiple regions for the treatment of R/R B-ALL in adults and children. Subcutaneous delivery may improve the convenience and satisfaction of patients with R/R B-ALL who are candidates for blinatumomab therapy. Here we report the results from the first cohort of adults with R/R B-ALL receiving SC blinatumomab. Methods In this ongoing multicenter, single arm, open-label, phase 1b dose-finding study (NCT04521231), patients received multiple cycles of SC blinatumomab. Each cycle included a treatment period and a treatment-free interval. In cohort 1, cycle 1, patients received a lower first dose of SC blinatumomab for several days followed by a higher dose multiple times weekly; in subsequent cycles, patients received the higher dose several times weekly during the treatment period. Bone marrow (BM) evaluation was performed on day 27 of each cycle. Results Six patients from cohort 1 were included in this June 22, 2021 data cutoff. Median age was 64 (range 38-83) years. The number of prior therapies ranged from 2-4. Two patients had disease refractory to primary therapy or salvage therapy, 2 patients relapsed after chemotherapy, and 2 patients relapsed after prior allogeneic hematopoietic stem cell transplant. Median BM blast count at study start was 85% (range 28%-95%). Only 1 patient had <50% BM blasts (BM blasts=28%). At enrollment, all patients had an ECOG score of 0-1. The median number of SC blinatumomab cycles initiated was 1 (range 1-3). Preliminary pharmacokinetic results support the SC dosing intervals used in this study and potentially longer intervals. Exposures for SC doses were similar to the efficacious exposures of the approved cIV regimen: mean average concentrations at steady state of 215 and 853 pg/mL for the lower and higher SC dosing regimens of cohort 1, respectively, vs mean steady state concentrations of 228 and 616 pg/mL for 9 and 28 µg/day cIV dosing, respectively. The pharmacodynamic profile following SC blinatumomab of peripheral immune cell redistribution (circulating CD3+ and CD8+ CD69+ T cells), transient cytokine elevation (IL-6, IL-10, IFN-γ) and CD19+ B cell counts declining below the detection limit was consistent with the historical pharmacodynamic profile following cIV blinatumomab. No grade ≥3 cytokine release syndrome events were reported (Table). One patient developed herpes encephalitis and experienced a grade 5 neurological event unrelated to blinatumomab; no other neurological events were reported. Two patients discontinued treatment because of adverse events (injection site reaction in patient with no response, hyperleukocytosis due to disease progression). Three patients had complete hematological response (CR) with no measurable residual disease (MRD) (<10 -4) within 2 cycles and 1 patient had a morphological partial response (95% BM blasts at start of cycle 1 to 22% blasts on day 15). This patient discontinued on day 15 of cycle 1 after progression of extramedullary disease. At the time of the data cutoff, 2 patients remained on study. These patients had CR with no MRD. Conclusions In this phase 1b dose-finding study, SC blinatumomab has demonstrated encouraging anti-leukemia activity in heavily pretreated patients with R/R B-ALL. Pharmacokinetic and pharmacodynamic results support the use of SC dosing in this population. The safety profile was manageable and consistent with that reported for cIV blinatumomab. Figure 1 Figure 1. Disclosures Gordon: Amgen: Current Employment, Current equity holder in publicly-traded company. Schwartz: Morphosys: Research Funding; Pfizer: Honoraria, Speakers Bureau; Gilead: Other: Travel grants, Speakers Bureau; Jazz Pharmaceuticals: Other: Travel grants, Speakers Bureau; Novartis: Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: Travel grants, Speakers Bureau; BTG International Inc: Membership on an entity's Board of Directors or advisory committees; MSD Sharp & Dohme: Membership on an entity's Board of Directors or advisory committees; Basilea: Other: Travel grants. Rossi: Celgene: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Honoraria; Abbvie: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria; Alexion: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Huguet: Novartis: Other: Advisor; Jazz Pharmaceuticals: Other: Advisor; Celgene: Other: Advisor; BMS: Other: Advisor; Amgen: Other: Advisor; Pfizer: Other: Advisor. Hernández-Rivas: Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene/BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Wong: Amgen: Current equity holder in publicly-traded company; Amgen: Current Employment. Markovic: Amgen: Current Employment, Current equity holder in publicly-traded company. Katlinskaya: Amgen: Current Employment, Current equity holder in publicly-traded company. Panwar: Amgen: Current Employment, Current equity holder in publicly-traded company. Zugmaier: Micromet/Amgen: Patents & Royalties: Patents 20190300609 and 20130323247 licensed; receives royalties of family members of international applications published as WO2010/052014; WO2010/052013; WO2011/051307; WO2012/055961; WO 2012/062596; WO2014/122251; and WO2015/181683; Amgen: Current Employment; Amgen: Current equity holder in publicly-traded company.


2021 ◽  
Vol 8 (Supplement_1) ◽  
pp. S710-S710
Author(s):  
Abigail K Kois ◽  
Tomefa E Asempa ◽  
David P Nicolau

Abstract Background Prior investigations evaluating the predictive value of zinc-depleted media for MBL-susceptibility testing have focused on Enterobacterales. Therein, bacterial killing observed with meropenem (MEM) in vivo was concordant with its pharmacodynamic profile using MIC values determined in zinc-depleted media compared with conventional cation-adjusted Mueller-Hinton broth (CAMHB). This study aims to evaluate the exposure-response relationship of MEM against VIM- and NDM-harboring P. aeruginosa (PSA) using the murine thigh infection model and zinc-depleted MICs. Methods MBL-harboring PSA isolates (VIM n=11; NDM n=10) were tested both in vivo (neutropenic murine thigh infection model) and in vitro (broth microdilution). The 24h murine thigh study was conducted with treatment groups receiving a humanized MEM 2g q8h (3h infusion) dose. Six different zinc-limited media were prepared by the addition of EDTA at concentrations ranging from 3 to 300 mg/L to CAMHB. MEM MICs were determined in triplicate in conventional CAMHB and zinc-limited media. Time > MIC values (generated in each zinc-depleted media) were then plotted against the change in 24h bacterial density count in an Emax model. Results Average 0 h bacterial densities were 5.21 ± 0.40 and 5.13 ± 0.81 log10 CFU/thigh for NDM and VIM isolates, respectively. MEM resulted in -0.09 CFU reduction to +3.69 CFU growth against NDM isolates. MEM resulted in -2.59 CFU reduction to +4.81 CFU growth against VIM isolates. All MEM MICs in conventional CAMHB were >64 µg/mL for NDM and ranged from 8 to >64 µg/mL for VIM isolates. Increasing EDTA concentrations resulted in several-fold MIC reductions and on average, a larger magnitude of reduction was observed among VIM- (6-fold) compared with NDM-harboring PSA (4-fold) in CAMHB-EDTA 300 mg/L relative to CAMHB. For both NDM- and VIM-harboring PSA, an Emax model with MICs generated in CAMHB+EDTA 30 mg/L (r2 = 0.88) provided the highest correlation with MEM in vivo activity compared with CAMHB (r2 = 0.55). Conclusion Results indicate that MIC values generated in conventional CAMHB do not appropriately characterize the in vivo efficacy of meropenem against MBL-harboring PSA, and addition of EDTA (30 mg/L) to CAMHB appears to be a viable option for in vitro testing of these organisms. Disclosures David P. Nicolau, PharmD, Abbvie, Cepheid, Merck, Paratek, Pfizer, Wockhardt, Shionogi, Tetraphase (Other Financial or Material Support, I have been a consultant, speakers bureau member, or have received research funding from the above listed companies.)


2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A549-A549
Author(s):  
John Powderly ◽  
Teleen Norman ◽  
Meghan Duncan ◽  
Martin Huber ◽  
Jennifer O’Neil ◽  
...  

BackgroundAnti-CTLA-4 agents have demonstrated clinical benefit in a range of tumors; however, the safety risks limit the dose and their use in certain settings.1-4 XTX101 is a fully humanized mAb with an engineered Fc region for enhanced FcγR binding and with covalently linked peptides that mask each CTLA-4 antigen-binding region of the antibody. The masking peptides are designed to be selectively cleaved and released by proteases that are more active in the tumor microenvironment compared to healthy tissue. XTX101 is intended to have minimal peripheral CTLA-4 binding and inhibition. Upon proteolytic cleavage of the masking peptides within the tumor microenvironment, the cleaved and active form of XTX101 is intended to bind to CTLA-4, inhibit its function, and induce antibody-dependent cellular cytotoxicity (ADCC). Here we describe the first-in-human study that is currently enrolling subjects with locally advanced or metastatic disease who have failed standard therapy, or standard therapy is not curative or available.MethodsThe objectives of this study are to determine a dose or doses of XTX101 administered every 21 days that are well-tolerated, biologically active, and suitable for advancing into further studies. The initial portion of the study consists of three parts. Part 1A will evaluate ascending fixed doses of XTX101 monotherapy using an accelerated, single-subject, dose-level design for the first three dose cohorts followed by a standard 3+3 design. Part 1B will examine XTX101 monotherapy in patients with any histologically or cytologically confirmed solid tumor malignancy for which anti–PD-1 or anti–PD-L1 treatment is approved and has progressed on or after prior anti–PD-1 or anti–PD-L1 therapy. Currently approved tumor types for anti–PD-1 or anti–PD-L1 treatment include melanoma, squamous cell skin cancer, non-small cell lung cancer, head and neck carcinoma, esophageal carcinoma, renal cell cancer, urothelial carcinoma, or microsatellite instability-high/mismatch deficient colorectal cancer. Part 1B will require mandatory fresh tumor biopsies pre-dose and post-dose to fully characterize the pharmacodynamic profile of XTX101. Part1C will examine escalating doses of XTX101 in combination with pembrolizumab. Subjects may receive XTX101 for up to 24 months in the absence of disease progression, toxicity, a complete response, or termination of the study. Disease responses will be determined by iRECIST methods every third treatment cycle for the first year and then every four treatment cycles thereafter until progressive disease.Trial RegistrationNCT04896697ReferencesHamid O, Schmidt H, Nissan A, et al. A prospective phase II trial exploring the association between tumor microenvironment biomarkers and clinical activity of ipilimumab in advanced melanoma. J Transl Med 2011;9:204–19.Lebbé C, Meyer N, Mortier L, et al. Evaluation of two dosing regimens for nivolumab in combination with ipilimumab in patients with advanced melanoma: results from the phase IIIb/IV CheckMate 511 trial. J Clin Oncol 2019;37:867–875.Wolchok JD, Hodi FS, Weber JS, et al. Development of ipilimumab: a novel immunotherapeutic approach for the treatment of advanced melanoma. Ann N Y Acad Sci 2013; 1291:1-13.Wolchok JD, Neyns B, Linette G, et al. Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study. Lancet Oncol 2010;11:155–64.Ethics ApprovalThis study was approved by an Institutional Review Board for each participating site.


Author(s):  
M. Farouk Chughlay ◽  
Karen I. Barnes ◽  
Myriam El Gaaloul ◽  
Nada Abla ◽  
Jörg J Möhrle ◽  
...  

Despite repeated malaria infection, individuals living in malaria endemic areas remain vulnerable to re-infection. The Janus kinase (JAK1/2) inhibitor ruxolitinib could potentially disrupt the parasite-induced dysfunctional immune response when administered with anti-malarial therapy. This randomized, single-blind, placebo-controlled, single center phase 1 trial investigated the safety, tolerability, pharmacokinetic and pharmacodynamic profile of ruxolitinib and the approved antimalarial artemether-lumefantrine in combination. Ruxolitinib pharmacodynamics were assessed by inhibition of phosphorylation of signal transducer and activator of transcription 3 (pSTAT3). Eight healthy male and female participants aged 18–55 years were randomized to either ruxolitinib (20 mg) ( n = 6) or placebo ( n = 2) administered 2 h after artemether-lumefantrine (80/480 mg) twice daily for three days. Mild adverse events occurred in six participants (four ruxolitinib; two placebo). The combination of artemether-lumefantrine and ruxolitinib was well tolerated, with adverse events and pharmacokinetics consistent with the known profiles of both drugs. The incidence of adverse events and artemether, dihydroartemisinin (the major active metabolite of artemether) and lumefantrine exposure were not affected by ruxolitinib co-administration. Ruxolitinib co-administration resulted in a 3-fold greater pSTAT3 inhibition compared to placebo (geometric mean ratio: 3.01 [90%CI 2.14, 4.24]), with a direct and predictable relationship between ruxolitinib plasma concentrations and %pSTAT3 inhibition. This study supports the investigation of the combination of artemether-lumefantrine and ruxolitinib in healthy volunteers infected with Plasmodium falciparum malaria. (This study has been registered at ClinicalTrials.gov under registration no. NCT04456634).


Author(s):  
Vallabh D. Suryavanshi ◽  
Sanjay Sharma ◽  
Jagdish K Sahu

: Hyperglycemia and its associated disorders like Diabetes mellitus are engulfing the world’s population at a faster pace. New-age medications like the SGLT 2 inhibitors have found their place in the run to combat DM. Drugs with these properties have proven to be effective in treating hyperglycemia, Obesity, and major Cardiac disorders. The interesting fact about these drugs is that they act independently of insulin levels in the patient’s body. The fact that they even bypass the side effects shown by currently used anti-diabetic medications has attracted the world’s hope to neutralize diabetes mellitus. The invention of Remogliflozin etabonate (RGE), an SGLT 2 inhibitor, has therefore added a silver lining to the gliflozin-family of drugs in the fight against DM. This is due to its least side effects as well as its effective mechanisms to treat hyperglycemia. It can be administered not only as a single entity but also can be co-administered in combination with other anti-hyperglycemic agents. RGE is already sold in the Indian market as REMO-ZEN, by Glenmark Pharmaceuticals. It has been studied thoroughly for its pharmacokinetic & pharmacodynamic profile. It is a benzylpyrazole glucoside. Various analytical methods have been formulated for its detection, quantification, and routine quality control activities. RGE can be studied with the help of UV-visible spectrophotometry, High-Performance Liquid Chromatography (HPLC) & Hyphenated techniques like Liquid Chromatography-Mass Spectroscopy (LC-MS/MS). This review briefs about overall chemical, pharmacological, pharmacokinetic & pharmacodynamics properties of RGE. It mainly discusses about various analytical techniques used for determining & estimating RGE.


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