Pharmacodynamic Comparison Research Articles

Pharmacodynamic Comparison of Two Aspirin Formulations in the Caribbean: The ARC Study.

This prospective, single-arm, crossover pharmacodynamic study assessed the effect of Bayer® low-dose enteric-coated aspirin 81mg tablets (LD EC-ASA) (Bayer AG, Leverkusen, North Rhine-Westphalia, Germany) compared to Vazalore® low-dose phospholipid-aspirin liquid-filled 81mg capsules (LD PL-ASA) (PLx Pharma Inc., Sparta, NJ, USA) on platelet reactivity with respect to aspirin reaction units (ARU). Forty-seven healthy volunteers were recruited. Platelet function was evaluated with the VerifyNow™ ARU assay (Werfen, Bedford, MA, USA) and assessed post-initiation of Bayer® LD EC-ASA daily for 14days, with a washout period of 28days, followed by Vazalore® LD PL-ASA daily for 14days, again followed by ARU testing. Participants on LD EC-ASA had a mean ARU score of 426, with 19.1% of participants having an ARU > 550; patients on LD PL-ASA derived a mean ARU score of 435, with 14.9% achieving an ARU > 550. There were no significant differences in aspirin resistance (ARU > 550) according to the formulation (Bayer® LD EC-ASA vs. Vazalore® LD PL-ASA) used. Aspirin resistance was independent of ethnicity regardless of the formulation used. In addition, there were no significant associations between body surface area (BSA) and Bayer® LD EC-ASA ARU value (p value 0.788) or Vazalore® LD PL-ASA ARU value (p value 0.477). No patients experienced any serious adverse events or treatment-emergent adverse events. There were no significant differences in aspirin resistance between Bayer® LD EC-ASA and Vazalore® LD PL-ASA. This dedicated pharmacodynamic study could potentially be informative and applicable for Trinidadian patients on dual antiplatelet therapy (DAPT). Further studies are required to confirm these exploratory findings. ClinicalTrials.gov identifier, NCT06228820, prospectively registered 1/18/2024.

In Vivo Bioluminescence Imaging Reveals Differences in Leishmania infantum Parasite Killing Kinetics by Antileishmanial Reference Drugs.

The bioluminescent Leishmania infantum BALB/c mouse model was used to evaluate the parasiticidal drug action kinetics of the reference drugs miltefosine, paromomycin, sodium stibogluconate, and liposomal amphotericin B. Infected mice were treated for 5 days starting from 7 days post-infection, and parasite burdens were monitored over time via bioluminescence imaging (BLI). Using nonlinear regression analyses of the BLI signal, the parasite elimination half-life (t1/2) in the liver, bone marrow, and whole body was determined and compared for the different treatment regimens. Significant differences in parasiticidal kinetics were recorded. A single intravenous dose of 0.5 mg/kg liposomal amphotericin B was the fastest acting with a t1/2 of less than 1 day. Intraperitoneal injection of paromomycin at 320 mg/kg for 5 days proved to be the slowest with a t1/2 of about 5 days in the liver and 16 days in the bone marrow. To conclude, evaluation of the cidal kinetics of the different antileishmanial reference drugs revealed striking differences in their parasite elimination half-lives. This BLI approach also enables an in-depth pharmacodynamic comparison between novel drug leads and may constitute an essential tool for the design of potential drug combinations.

Assessment for the influence of processing methods on chemical compositions and pharmacodynamics of Epimedii Folium and revealing the component transformation mechanism

Epimedii Folium is a traditional medicinal plant commonly used in Northeast Asia. The nonuniform drying methods during processing is an important factor leading to the uneven quality of commercial Epimedii Folium, which further results in low resource utilization. Our previous studies have proved that the content of icariin and baohuoside I, the quality control markers in Epimedii Folium, was significantly increased during thermal-processing of Epimedium koreanum Nakai, but the quality and component transformation mechanisms remained unclear. Therefore, in this study, chemical composition analysis, combined with pharmacodynamics were carried out for the first time to comprehensively evaluate the influence of three processing methods, including traditional shade-drying, oven-drying and classical suet stir-frying, on Epimedii Folium, and reveal the component transformation mechanism. A total of 50 components were identified using UHPLC-ESI-Q/TOF-MS, of which 3′′′-carbonyl-2′′-β-L-quinovosyl baohuoside I was identified to be a new prenylflavonoid diglycoside. To clarify the types of components that can convert into icariin and baohuoside I, their content in different elution fractions of E. koreanum aqueous extract before and after baking were compared by HPLC-DAD for the first time. The source of increased icariin and baohuoside I was determined to be prenylflavonoid triglycosides and diglycosides, respectively. In order to explore the component transformation mechanism, the content of 15 main components, including five major prenylflavonoid triglycosides and three diglycosides in shade-drying, oven-drying and suet stir-frying E. koreanum were analyzed using UPLC-PDA. The result was demonstrated for the first time that icariin and baohuoside I were possibly mainly derived from the heat-labile prenylflavonoid glycosides, such as 3′′′-carbonyl-2′′-β-L-quinovosyl icariin and 3′′′-carbonyl-2′′-β-L-quinovosyl baohuoside I, rather than the previously reported common prenylflavonoid glycosides with stable structures. The pharmacodynamic comparison results indicated for the first time that both shade-drying and oven-drying E. koreanum were less potent than suet stir-frying E. koreanum in ameliorating renal function. However, based on the comprehensive evaluation of the content and efficacy in this study, oven-drying was still considered to have advantages over the traditional drying methods such as shade-drying, in elevating drying efficiency, content of bioactive components and the resource utilization rate of Epimedii Folium and worth popularizing.

Discovery and verification of Q-markers for promoting blood circulation and removing stasis of raw and wine-steamed Vaccaria segetalis based on pharmacological evaluation combined with chemometrics

Ethnopharmacological relevanceDried and mature seeds of Vaccaria segetalis (Neck.) Garcke ex Asch. (VS) are known for their therapeutic effects, as they stimulate blood circulation, promote menstruation and diuresis and eliminate gonorrhoea. However, due to its hard shell, the dissolution of its active ingredients is often improved by steaming and frying in clinical applications. Among the processed products, wine-steamed Vaccaria segetalis (WVS) is one of the commonly used ones. Numerous historical records have shown that wine steaming can enhance the efficacy of drugs to promote blood circulation and remove blood stasis. However, the differences in the efficacy of VS and WVS in promoting blood circulation and removing blood stasis have not been thoroughly studied, and the possible reasons for these differences have not been reported. Aim of the studyThe objective of this study was to identify quality markers (Q-markers) that could differentiate the efficacy of promoting blood circulation and removing blood stasis of VS and WVS, which could serve as a basis for the rational application of VS and WVS in clinical settings. Materials and methodsA pharmacodynamic comparison between the water extracts of VS and WVS was carried out based on a mouse acute blood stasis model (ABS) and thrombus zebrafish model. The potential bioactive substances of WVS were screened by investigating the correlation between common peaks identified for 10 batches of WVS by ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS/MS) and their rate of thrombosis inhibition in zebrafish. Furthermore, multivariate statistical analysis of chemical components between VS and WVS was conducted to speculate the Q-markers combined with the results of the bioactive components. Based on the efficacy verification of Q-markers, the content of Q-markers in 10 batches of WVS was evaluated. ResultsThe results of efficacy comparison assays demonstrated that the efficacy of WVS was more prominent than VS at the same dose. Five components were screened as effective components of WVS for promoting blood circulation and removing blood stasis by correlation analysis. Furthermore, a total of 24 common ingredients were identified in VS and WVS extracts, and 9 of them showed increased dissolution rate after wine steaming, including 4 active ingredients, Hypaphorine, Vaccarin, Saponarin, and Isovitexin-2″-O-arabinoside, which were screened out by correlation analysis. The monomer test suggested that these 4 components could activate blood circulation and remove blood stasis in a dose-dependent manner. Consequently, Hypaphorine, Vaccarin, Saponarin, and Isovitexin-2″-O-arabinoside were selected as Q-markers to distinguish between VS and WVS. The content determination showed that the total contents of 4 Q-markers of WVS from 10 batches with different origins ranged from 0.478% to 0.716%. ConclusionsThis study compared the efficacy of VS and WVS in promoting blood circulation and resolving stasis and revealed Q-markers that reflected the difference in efficacy between them for the first time, which laid the foundation for establishing quality standards for WVS.

Pharmacokinetic and Pharmacodynamic Comparison of Fluticasone Propionate/Formoterol Fumarate Administered via a Pressurized Metered-Dose Inhaler and a Novel Breath-Actuated Inhaler in Healthy Volunteers.

Introduction: Fluticasone propionate/formoterol fumarate (fluticasone/formoterol) exposures, following administration of Flutiform® K-haler®, a breath-actuated inhaler (BAI), were compared with the Flutiform pressurized metered-dose inhaler (pMDI) with/without spacer in two healthy volunteer studies. In addition, formoterol-induced systemic pharmacodynamic (PD) effects were examined in the second study. Methods: Study 1: single-dose, three-period, crossover pharmacokinetic (PK) study with oral charcoal administration. Fluticasone/formoterol 250/10 μg was administered via BAI, pMDI, or pMDI with spacer (pMDI+S). Pulmonary exposure for BAI was deemed no less than for pMDI (primary comparator) if the lower limit of 94.12% confidence intervals (CIs) for BAI:pMDI maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUCt) ratios was ≥80%. Study 2: two-stage adaptive design, both stages being single-dose, crossover without charcoal administration. The PK stage compared fluticasone/formoterol 250/10 μg via BAI, pMDI, or pMDI+S. The primary comparisons were as follows: BAI versus pMDI+S for fluticasone and BAI versus pMDI for formoterol. Systemic safety with BAI was deemed no worse than primary comparator if the upper limit of 94.12% CIs for Cmax and AUCt ratios was ≤125%. PD assessment was to be conducted if BAI safety was not confirmed in the PK stage. Based on PK results, only formoterol PD effects were evaluated. The PD stage compared fluticasone/formoterol 1500/60 μg via BAI, pMDI, or pMDI+S; fluticasone/formoterol 500/20 μg pMDI; and formoterol 60 μg pMDI. The primary endpoint was maximum reduction in serum potassium within 4 hours postdose. Equivalence was defined as 95% CIs for BAI versus pMDI+S and pMDI ratios within 0.5-2.0. Results: Study 1: lower limit of 94.12% CIs for BAI:pMDI ratios >80%. Study 2, PK stage: upper limit of 94.12% CIs for fluticasone (BAI:pMDI+S) ratios <125%; upper limit of 94.12% CIs for formoterol (BAI:pMDI) ratios >125% (for Cmax, not AUCt). Study 2, PD stage: 95% CIs for serum potassium ratios 0.7-1.3 (BAI:pMDI+S) and 0.4-1.5 (BAI:pMDI). Conclusions: Fluticasone/formoterol BAI performance was within the range observed for the pMDI with/without a spacer. Sponsor: Mundipharma Research Ltd. EudraCT 2012-003728-19 (Study 1) and 2013-000045-39 (Study 2).

Pharmacokinetic and pharmacodynamic comparison of epinephrine, administered intranasally and intramuscularly: An integrated analysis

BackgroundManual intramuscular epinephrine injection is the standard of care for treating severe allergic reactions and anaphylaxis. Epinephrine autoinjectors were approved on the basis of the assumption that their pharmacokinetic and pharmacodynamic profiles are equivalent to manual intramuscular injection; however, although there is emerging evidence for product-related differences in pharmacokinetic profiles, very little is known about the comparative pharmacodynamic profiles. ObjectiveTo compare pharmacokinetic and pharmacodynamic profiles of epinephrine delivered through manual intramuscular injection, autoinjectors, and intranasal spray. MethodsThis integrated analysis was based on data from 4 randomized cross-over phase 1 trials that compared the pharmacokinetics and pharmacodynamics of epinephrine using manual intramuscular epinephrine 0.3 mg injection, epinephrine 0.3 mg autoinjectors (Symjepi and EpiPen), and epinephrine 1 mg intranasal spray (neffy). ResultsData from 175 participants showed that although neffy (1.0 mg intranasal spray) resulted in a maximum concentration (258 pg/mL) that was lower than or comparable with manual epinephrine intramuscular injection (254 pg/mL), Symjepi (438 pg/mL) and EpiPen (503 pg/mL), it led to comparable increases in systolic blood pressure (maximum effect [Emax], 16.9, 10.9, 14.9, and 18.1 mm Hg, respectively). The effect of neffy on diastolic blood pressure was also markedly more pronounced than that of other products (Emax, 9.32, 5.51, 5.78, and 5.93 mm Hg, respectively). ConclusionIntranasal delivery of epinephrine using neffy increases systolic blood pressure more efficiently than do manual intramuscular injection and epinephrine autoinjectors, despite lower maximum plasma concentrations.

Comparison of pharmacokinetics, pharmacodynamics, safety, and immunogenicity of teriparatide biosimilar with EU- and US-approved teriparatide reference products in healthy men and postmenopausal women

SummaryBiosimilar teriparatide (INTG-8) was tested in a healthy population of males and postmenopausal females to assess pharmacokinetic bioequivalence to originator teriparatide comparator products. Primary pharmacokinetic comparison confirmed bioequivalence. Pharmacodynamics, safety, and tolerability were comparable to the originator products. INTG-8 was therefore confirmed to be biosimilar to originator products.IntroductionThe purpose of this present study was to demonstrate pharmacokinetic (PK) equivalence of a biosimilar teriparatide (INTG8) to EU- and US-approved teriparatide reference products in healthy men and postmenopausal women. Secondary objectives included comparison of the pharmacodynamics (PD), safety, and tolerability.MethodsOne hundred and five subjects randomly (1:1:1) received single subcutaneous 20 μg injection of teriparatide biosimilar, EU- and US-teriparatide on 3 consecutive days in this assessor-blind, three-period, single-dose, crossover study. Maximum serum concentration (Cmax), area under the curve (AUC) from time zero to t (AUC0-t), and AUC from time zero extrapolated to infinity (AUC0-∞) were primary PK parameters, analyzed by non-compartmental methods. The secondary PD endpoints were maximum observed effect (Emax), area under the effect curve (AUE) from time zero to the last measurable concentration (AUE0–t), and time to maximum observed effect (Tmax) for total serum calcium levels. Safety, tolerability, and immunogenicity were also evaluated. This study was registered with ctri.nic.in/ (CTRI/2020/10/028627) on 26 October 2020.ResultsBaseline demographics were similar across the three-treatment sequence groups. The 90% confidence intervals (CI) for the geometric mean ratios (test:reference) of Cmax, AUC0-t, and AUC0-∞ were within the predefined bioequivalence criterion of 80.00% to 125.00%, which demonstrated PK equivalence of teriparatide biosimilar to EU- and US-teriparatide for all primary endpoints. The PD comparability was demonstrated by similar serum calcium levels. Study treatments were generally well tolerated and showed no meaningful differences in safety or immunogenicity profiles. There were no deaths, or serious AEs were reported during this study.ConclusionThe study demonstrated PK bioequivalence of teriparatide biosimilar to the EU- and US-teriparatide reference products with comparable PD, safety, and immunogenicity profiles.

Combination therapy with antipsychotics and antidepressants (pharmacological approach)

Objective. To perform a pharmacological analysis of treatment received by patients with schizophrenia spectrum disorders and to elaborate the principles of combination therapy with antipsychotics and antidepressants based on pharmacodynamics and pharmacokinetics.Materials and methods. The study included 311 inpatients with schizophrenia spectrum disorders admitted to the V.M. Bekhterev National Medical Research Centre for Psychiatry and Neurology for the management of treatment resistance. A comprehensive pharmacological analysis was performed including a retrospective evaluation of the quality of patients’ treatment (based on their medical records) and a comparison of the neurochemical activity of the drugs in order to determine the rationality of combined use of antipsychotics and antidepressants. Statistical analysis included descriptive statistics and frequency analysis.Results. An analysis of treatment data for 311 patients has demonstrated that given the significant frequency of combined administration of antipsychotics and antidepressants (29.3%), the choice of drugs was based on clinical judgment, without considering the pharmacological effects of the drugs being used. A comparison of pharmacodynamics has allowed to arrange antipsychotics and antidepressants according to their binding affinities to neurochemical targets. A methodological approach to evaluating the compatibility of combined drugs based on their neurochemical activity and affinity to specific receptors has been argued. The principles of combination therapy with antipsychotics antidepressants have been elaborated.Conclusion. Combined use of an antipsychotic and an antidepressant without considering their ‘neurochemical compatibility’ regarding postsynaptic targets may decrease efficacy and potentiate adverse effects. In combination therapy with an antipsychotic and an antidepressant, drugs should be started one at a time taking into account their pharmacokinetics in order to avoid the possibility of competitive neurochemical effects prior to establishing a specific drug homeostasis. The development of rational strategies for combination therapy should be based on the assessment of pharmacodynamics and pharmacokinetics of the drugs.

Tissue biodistribution of intravenous iron-carbohydrate nanomedicines differs between preparations with varying physicochemical characteristics in an anemic rat model

Intravenously administered iron-carbohydrate preparations are a structurally heterogenous class of nanomedicines. Iron biodistribution to target tissues is greatly affected by the physicochemical characteristics of these nanoparticles. Some regulatory agencies have recommended performing studies in animal models for biodistribution characterization and bioequivalence evaluation. In the present work, a systematic comparison of iron exposure, tissue biodistribution and pharmacodynamics of four intravenous iron-carbohydrates in anemic CD rats was conducted. A pilot study was performed to establish the anemic rat model, followed by a control study to evaluate the pharmacokinetics (serum iron, biodistribution) and pharmacodynamics (hematological parameters) in healthy and anemic controls and anemic rats receiving ferric carboxymaltose (FCM). The same parameters were then evaluated in a comparative study in anemic rats receiving FCM, iron sucrose (IS), iron isomaltoside 1000 (IIM), and iron dextran (ID). Despite similar serum iron profiles observed across the investigated nanomedicines, tissue iron biodistribution varied markedly between the individual intravenous iron-carbohydrate complexes. Tissue iron repletion differences were also confirmed by histopathology. These results suggest that employing serum iron profiles as a surrogate for tissue biodistribution may be erroneous. The variability observed in tissue biodistribution may indicate different pharmacodynamic profiles and warrants further study.

Comparison of Pharmacodynamics and Celiac Effects of Olmesartan Medoxomil Formulations by using Olmesartan-induced Celiac-rat-model.

Olmesartan Medoxomil (OM) is an angiotensin receptor blocker and has the adverse effect of celiac like enteropathy which was accepted by the FDA in 2013. This disease is characterized by severe diarrhea, weight loss and enteropathy. Although there are many case reports associated with olmesartan-related enteropathy in humans, it has not been described in a long-term animal model study so far. We developed a self-microemulsifying drug delivery system (OM-SMEDDS) in our previous study to reduce this side effect of the drug and to enhance bioavailability. In this study, an artificial hypertension model was established with a dose of 185 μmol /kg L-NAME (N ω-nitro-L-arginine methyl ester) twice in a day intraperitoneally in Wistar albino rats. To determine and compare side effects, the OM-Suspension and OM-SMEDDS were administered at 1.3 mg/kg therapeutic dose during one-month period to the rats. Tension of rats was recorded by measuring from their tails with non invasive blood pressure system. We observed celiac like enteropathy findings like villous atrophy and intraepithelial lymphocytosis and clinical changes like weight loss and severe diarrhea after the treatment with OM-Suspension during one-month experiment. It was also observed that the antihypertensive efficacy of the OM-SMEDDS formulation was higher than the suspension during the experiment, which did not cause enteropathy, diarrhea and weight loss by reducing intestinal exposure. Hereby, we evaluated the side effects of two different pharmaceutical forms by designing a sustainable and reproducible celiac rat model that can be induced with olmesartan medoxomil.

Comparison of Pharmacokinetics and Pharmacodynamics of Inhaled Technosphere Insulin and Subcutaneous Insulin Lispro in the Treatment of Type 1 Diabetes Mellitus.

BackgroundThis study was performed to satisfy a US Food and Drug Administration post-marketing requirement to compare the dose responses for Technosphere® Insulin (TI; MannKind Corporation, Westlake Village, CA, USA) and subcutaneous insulin lispro (LIS) across a wide range of doses.ObjectivesThis single-center, open-label, randomized, cross-over study defined the pharmacokinetic/pharmacodynamic curves for inhaled TI vs subcutaneous LIS in persons with type 1 diabetes mellitus.MethodsEach volunteer received six treatments while undergoing euglycemic clamps: three doses of TI (10, 30 and 120 U) and LIS (8, 30, and 90 U). Primary endpoint was area under the glucose infusion rate vs time curve from start of treatment administration to end of clamp. Key secondary endpoints included readouts of insulin exposure and timing of pharmacokinetic/pharmacodynamic profiles.ResultsInsulin exposure was more than dose proportional, increasing with dose1.08 for LIS and dose1.35 for TI. Time to reach 10% of the maximum glucose infusion rate was 7 to 15 min for TI vs 21 to 38 min for LIS. End of effect was dose dependent for both treatments, ranging from 2 to 6 h (TI) and 5 to 10 h (LIS). Glucose infusion rate exhibited saturation for both treatments. Technosphere Insulin produced a lesser total effect per unit insulin than LIS due to its faster absorption and correspondingly shorter duration of exposure. The difference was large enough to require significantly different doses to achieve the same total effect.ConclusionsTechnosphere Insulin has a considerably faster onset and shorter duration of action than LIS. Consequently, the overall effect of TI is smaller than that of LIS and unit-for-unit dose conversion is not appropriate.Clinical Trial RegistrationClinicalTrials.gov, NCT02470637; 12 June, 2015Supplementary InformationThe online version contains supplementary material available at 10.1007/s40262-021-01084-0.

Pharmacodynamic comparison of acarbose tablets in Chinese healthy volunteers under chewing and swallowing conditions.

Acarbose can efficiently block glucose absorption in the intestine as an alpha-glucosidase inhibitor. It is currently manufactured in several oral dosage forms, with the most common types being tablets and chewable tablets. The acarbose tablet (Glucobay® , 50mg, Bayer) package insert gives instructions for either directly swallowing or chewing then swallowing. This study compared the pharmacodynamic effects of a single formulation of acarbose tablets under these two different administration routes. This randomized, crossover study enrolled 24 healthy subjects who were instructed to chew (C group) or swallow (S group) the acarbose tablet. Glucose levels were monitored in subjects for up to 4h following administration of 75g of sucrose to establish a baseline firstly, after which subjects in the C and S groups were administered 50- or 100-mg of acarbose along with 75g of sucrose. Then, subjects entered a 1-week washout period before being crossed over to the alternate dosing route. Compared with the S group, the C group had a lower maximum concentration of serum glucose (Cmax ) and areas under the concentration-time curve (AUC0-2 , AUC0-1.5 ). In addition, the maximum reduction in serum glucose (ΔCmax ) and the reduction in the AUC (AUEC0-1.5 ) were both increased in the S group. This occurred at both the 50mg and 100mg dosages. These results indicate that fluctuations in blood glucose were lower following chewing of the acarbose tablet. Both administration routes exhibited similar safety and tolerance profiles. In summary, chewing acarbose tablets appears to induce a superior glycaemic-controlling effect compared with swallowing them directly, at least with a single dose. It will be important to inform both clinicians and patients about these differences between the two administrations so that informed clinical decisions can be made, as numerous patients with diabetes are inclined to directly swallow acarbose tablets for convenience.

Comparison of pharmacodynamics between insulin glargine 100 U/mL and insulin glargine 300 U/mL in healthy cats

Insulin glargine (IGla) is a synthetic human-recombinant insulin analog that is used routinely in people as a q24h basal insulin. The 300 U/mL (U300) formulation of IGla is associated with longer duration of action and less within-day variability, making it a better basal insulin compared with the 100 U/mL (U100) formulation. We hypothesized that in healthy cats, IGlaU300 has a flatter time-action profile and longer duration of action compared with IGlaU100. Seven healthy neutered male, purpose-bred cats were studied in a randomized, crossover design. Pharmacodynamics of IGlaU100 and IGlaU300 (0.8 U/kg, subcutaneous) were determined by the isoglycemic clamp method. The time-action profile of IGlaU300 was flatter compared with IGlaU100 as demonstrated by lower peak (5.6 ± 1.1 mg/kg/min vs 8.3 ± 1.9 mg/kg/min, respectively; P = 0.04) with no difference in total metabolic effect (ME; P = 0.7) or duration of action (16.8 h ± 4.7 h vs 13.4 h ± 2.6 h; P = 0.2). The greater fraction of ME in the 12- to 24-h period postinjection (35 ± 23% vs 7 ± 8% respectively; P = 0.048) and lower intraday GIR% variability (7.8 ± 3.7% vs 17.4 ± 8.2% respectively; P = 0.03) supports a flatter time-action profile of IGlaU300. There were no differences in onset and end of the action. In summary, although both formulations have a similar duration of action that is well below 24 h, the ME of IGlaU300 is more evenly distributed over a 24 h period in healthy cats, making it a better candidate for once-daily injection in diabetics compared with IGlaU100.

Pharmacodynamic comparison of optimal platelet reactivity by multiple platelet function tests in Korean acute coronary syndrome patients with half-dose ticagrelor or prasugrel treatment

Abstract Background East Asians treated with potent P2Y12 inhibitors, prasugrel or ticagrelor exhibit more potent platelet inhibition than clopidogrel. Whether half-dose de-escalation strategy would improve optimal platelet reactivity at maintenance in East Asian patients with acute coronary syndrome (ACS) remains uncertain. Method In de-escalation strategy single center study, eligible Korean ACS patients (n=96) were assigned to receive standard-dose ticagrelor (n=33), prasugrel (n=28), followed by half-dose reduction at 1 month for maintenance, and clopidogrel (n=35) as control. Platelet reactivity was measured by VerifyNow, light transmittance aggregometry (LTA) and multiple electrode aggregometry (MEA). The investigators aim to compare optimal platelet reactivity status (OPR, defined as 85–208 P2Y12 reaction unit [PRU] for VerifyNow (VN), 16%–47% for LTA and 19–46 U for MEA) among 3 different platelet function tests at 3 months post PCI. Results At 3 months, ticagrelor achieved significantly lower PRU (17 [6–51] vs. 95 [61–151] vs. 172 [111–204]) than prasugrel and clopidogrel, resulting OPR rate 10% vs. 57.7% vs. 60.0%, respectively. Similar results were observed at LTA method (2% [0–12] in ticagrelor vs. 18% [13–22] in prasugrel vs. 18% [11–30] in clopidogrel), with OPR rate 11.8% vs. 69.2% vs. 50.0%, respectively. However, platelet reactivity was similar by MEA method (16 [13–20] in ticagrelor vs. 17 [13–22] in prasugrel vs. 19 [14–28] in clopidogrel), with OPR rate 33.3% vs. 40.0% vs. 42.0%, respectively (all p&amp;gt;0.005). Among the three tests, resulting higher correlation between VN and LTA (r=0.745), MEA and LTA vs. MEA and VN showed lower correlations (r=0.412 and r=0.303). (Fig.) Conclusion In Korean ACS patients with half-dose de-escalation strategy after 1 month, OPR rate in ticagrelor is still rare during 3-month treatment by VN and LTA methods, however, prasugrel appears comparable to clopidogrel. VN/LTA might overestimate platelet function than MEA or MEA underestimate OPR rate than VN/LTA. Funding Acknowledgement Type of funding source: Private grant(s) and/or Sponsorship. Main funding source(s): National Research Foundation of Korea

Pharmacodynamic comparison of different antimicrobial regimens against Staphylococcus aureus bloodstream infections with elevated vancomycin minimum inhibitory concentration

BackgroundStaphylococcus aureus is one of the major causes of bloodstream infections (BSI) worldwide, representing a major challenge for public health due to its resistance profile. Higher vancomycin minimum inhibitory concentrations (MIC) in S. aureus are associated with treatment failure and defining optimal empiric options for BSIs in settings where these isolates are prevalent is rather challenging. In silico pharmacodynamic models based on stochastic simulations (Monte Carlo) are important tools to estimate best antimicrobial regimens in different scenarios. We aimed to compare the pharmacodynamic profiles of different antimicrobials regimens for the treatment of S. aureus BSI in an environment with high vancomycin MIC.MethodsSteady-state drug area under the curve ratio to MIC (AUC/MIC) or the percent time above MIC (fT > MIC) were modeled using a 5000-patient Monte Carlo simulation to achieve pharmacodynamic exposures against 110 consecutive S. aureus isolates associated with BSI.ResultsCumulative fractions of response (CFRs) against all S. aureus isolates were 98% for ceftaroline; 79% and 92% for daptomycin 6 mg/kg q24h and for the high dose of 10 mg/kg q24h, respectively; 77% for linezolid 600 mg q12h when MIC was read according to CLSI M100-S26 instructions, and 64% when MIC was considered at the total growth inhibition; 65% and 86% for teicoplanin, three loading doses of 400 mg q12 h followed by 400 mg q24 h and for teicoplanin 400 mg q12 h, respectively; 61% and 76% for vancomycin 1000 mg q12 h and q8 h, respectively.ConclusionsBased on this model, ceftaroline and high-dose daptomycin regimens delivered best pharmacodynamic exposures against S. aureus BSIs. Teicoplanin higher dose regimen achieved the best CFR (86%) among glycopeptides, although optimal threshold was not achieved, and vancomycin performance was critically affected by the S. aureus vancomycin MIC ≥2 mg/L. Linezolid effectiveness (CFR of 73%) is also affected by high prevalence of isolates with linezolid MIC ≥2 mg/L. These data show the need to continually evaluate the pharmacodynamic profiles of antimicrobials for empiric treatment of these infections.

P2551A randomized, pharmacodynamic comparison of low dose ticagrelor (60mg bid) to low dose prasugrel (5mg od) in patients with prior myocardial infarction: the ALTIC-2 study

Abstract Background In patients with prior myocardial infarction (MI) and features of high ischemic and low bleeding risk, extending dual antiplatelet therapy beyond 1 year or reinitiating treatment is reasonable. A lower than the standard dose, namely ticagrelor 60mg bid instead of 90mg bid and prasugrel 5mg od instead of 10mg od, may be associated with reduced bleeding risk. In the Patients with Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin–Thrombolysis in Myocardial Infarction 54 (PEGASUS-TIMI 54) trial, ticagrelor 60mg bid reduced the ischemic events, at the cost of increased bleeding events. There is no data on the pharmacodynamic efficacy of ticagrelor 60mg bid over low dose prasugrel (5mg od). Purpose To compare platelet reactivity (PR) between prasugrel 5mg od and ticagrelor 60 mg bid in the chronic phase of stable post-MI patients. Methods The ALTIC-2 was a prospective, single-center, randomized, crossover study involving patients on aspirin 100mg od and PEGASUS-TIMI 54 characteristics: &gt;50 years old with MI 1–3 years earlier and at least one high risk feature (age &gt;65 years, diabetes mellitus, a second MI, multivessel disease, or renal dysfunction). After a 14-day washout period–if on P2Y12 receptor antagonist therapy-, patients were randomized to either ticagrelor 60mg bid or prasugrel 5mg od for 14 days, with a crossover directly to the alternate treatment for another 14 days. PR was assessed by the VerifyNow P2Y12 reaction assay in PRU at baseline, pre and post-crossover, 2 hours post last study-drug dose. Statistical analysis was performed with STATA13.0. Results We recruited 20 eligible patients (80% men, 40% diabetics, 65% smokers, 70% multivessel disease, with a mean age of 64.8±6.3 years) for participation in the study (10 in each treatment sequence). During pre-crossover period, in the group allocated first in prasugrel PR levels (mean ± standard deviation) decreased from 238.4±50 to 128±47 (p&lt;0.0001), while in the group allocated first in ticagrelor levels of PR decreased from 259.6±36 to 30.8±29 (p&lt;0.0001). At the end of the 2 treatments, PR levels decreased to 33±26 in the group allocated first in prasugrel (p=0.0001), while in the group allocated first in ticagrelor levels of PR increased to 136±61 (p=0.0001). Analysis of combined data of PR levels (pre- and post-crossover, primary endpoint) adjusted for baseline values and age showed a difference of PR levels (β: −103, 95% CI: −120 to −85) in favor of ticagrelor. A non-significant period effect was observed and no carry effect was found. The secondary endpoint of high PR (&gt;208 PRU) rate was 0% for ticagrelor and 5.0% for prasugrel. No patient exhibited a major bleeding event at either treatment group. Conclusions In patients with previous MI and at least one other high-risk feature, low dose of ticagrelor results in a significantly lower PR compared to prasugrel 5mg od. Acknowledgement/Funding National and Kapodistrian University of Athens

Comparison of pharmacodynamics and pharmacokinetics of insulin degludec and insulin glargine 300 U/mL in healthy cats

Insulin glargine 300 U/mL (IGla-U300) and insulin degludec (IDeg) are synthetic insulin analogs designed as basal insulin formulations. In people, IGla-U300 is more predictable and longer acting compared with glargine 100 U/mL. The duration of action of IDeg in people is > 42 h, allowing flexibility in daily administration. We hypothesized that IDeg would have longer duration of action compared with IGla-U300 in healthy purpose-bred cats. Seven cats received 0.4 U/kg (subcutaneous) of IDeg and IGla-U300 on two different days, >1 wk apart. Exogenous insulin was measured and pharmacodynamic parameters were derived from glucose infusion rates during isoglycemic clamps and suppression of endogenous insulin. The Shapiro-Wilk test was used to assess normality, and normally distributed parameters were compared using paired t-tests. There was no difference between IDeg and IGla-U300 in onset, peak action, or total metabolic effect. On average, time to peak action (TPEAK) of IGla-U300 was 145 ± 114 min (95% confidence interval [CI] = 25–264) longer than TPEAK of IDeg (P = 0.03) and duration of action (TDUR) of IGla-U300 was 250 ± 173 min (95% CI = 68–432) longer than TDUR of IDeg (P = 0.02). The “flatness” of the time-action profile (as represented by the quotient of peak action/TDUR) was significantly greater for IGla-U300 compared with IDeg (P = 0.04). Overall, insulin concentration measurements concurred with findings from isoglycemic clamps. Based on these data, IDeg is not suitable for once-daily administration in cats. The efficacy of once-daily IGla-U300 in diabetic cats should be further investigated.

Pharmacokinetic and pharmacodynamic comparison between Glucophage? and a generic metformin in a rat model

Pharmacokinetic and pharmacodynamic comparison between Glucophage? and a generic metformin in a rat model

Comparison of pharmacodynamics between different batches of recombinant decoy receptor innovative drug RC28-E1 and RC28-E2 in retinal angiogenesis and neovascularization and its mechanism

Objective To compare the pharmacodynamics between different batches of recombinant decoy receptor innovative drug RC28-E1 and RC28-E2 in retinal angiogenesis and neovascularization, and analyze its mechanism. Methods Sixty postnatal Day 4 (P4) C57BL/6J mice were randomly divided into normal control group, vascular endothelial growth factor (VEGF)+ fibroblast growth factor 2 (FGF2) group, VEGF+ FGF2+ RC28-E1 group, VEGF+ FGF2+ RC28-E2 group, VEGF+ FGF2+ conbercept group and VEGF+ FGF2+ FGF trap group by using a random number table, with 10 mice in each group.The mouse retinal explant culture system was established, and stimulated with the corresponding factors and drugs prepared in the starving culture media.The normal controls were treated with the starving media.Then the retinal explants were stained with Isolectin B4 and imaged.The number of filopodia per vascular length was quantified.In addition, ninety-six P7 C57BL/6J mice were randomly divided into normal control group, oxygen-induced retinopathy (OIR) model control group, OIR+ RC28-E1 group, OIR+ RC28-E2 group, OIR+ conbercept group and OIR+ FGF trap group by using a random number table, with 16 mice in each group.The normal controls were raised under normoxia for 10 days, and the rest of the groups were raised under hyperoxia for 5 days, then returned to normoxia for another 5 days.On P17, the retinas were isolated and stained with Isolectin B4.The stained retinas were mounted on the slides and photographed.The relative vessel obliteration and neovascularization in retina were analyzed with computer software.Then the protein levels of VEGF and FGF2 were examined by Western blot in the retinas of each group in the OIR experiment.Finally, in the RF/6A cells stimulated with VEGF and FGF2, the activities of the signaling pathways, including MEK-extracellular regulated protein kinases (Erk), protein kinase C (PKC) and protein kinase B (Akt) pathways, were examined by Western blot.All experimental procedures were evaluated and approved by the Institutional Animal Care and Use Committee of Tianjin Medical University (SYXK 2009-0001), and were in accordance with the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research. Results The results of retinal explant cultures showed that the numbers of filopodia per vascular length in VEGF+ FGF2+ RC28-E1, VEGF+ FGF2+ RC28-E2, VEGF+ FGF2+ conbercept, and VEGF+ FGF2+ FGF trap groups were all significantly less than that in the VEGF+ FGF2 group (all at P < 0.001). The filopodia number in retinal vascular front in RC28-E1 group was similar to that in the RC28-E2 group (P=0.15), whereas the filopodia numbers in both groups were significantly decreased as compared to those in VEGF+ FGF2+ conbercept group and VEGF+ FGF2+ FGF trap group (all at P<0.001). The results from the OIR mouse model showed that the relative vessel obliteration area in OIR model control group was dramatically higher than those in the drug intervention groups (all at P<0.05). There was no statistical significance in the relative vessel obliteration area between OIR+ RC28-E1 group and OIR+ RC28-E2 group (P=0.17), while the obliteration areas in both RC28-E-intervened groups were significantly lower than those in the OIR+ conbercept group and OIR+ FGF trap group (all at P<0.05). The relative neovascular pixels in the intervention groups were significantly lower than those in the OIR model control group (all at P<0.001). The neovascular pixels in OIR+ RC28-E1 group were significantly lower than those in VEGF+ FGF2+ conbercept group and VEGF+ FGF2+ FGF trap group (both at P<0.05), but comparable to those in OIR+ RC28-E2 group (P =0.39). Western blot result showed that, the protein expression of VEGF and FGF2 in the OIR mouse retinas were significantly upregulated compared to those in the normal ones (both at P<0.001). The upregulation of both genes were normalized by both RC28-E1 and RC28-E2.In addition, the stimulation of VEGF and FGF2 induced an enhanced activity in MEK-Erk pathway in RF/6A cells, whereas RC28-E1 inhibited the overactivation. Conclusions RC28-E1 and RC28-E2 both can inhibit angiogenesis in the retinal explants isolated from neonatal mice; they also reduce vessel obliteration and mitigate neovascularization in the OIR mouse model.Therefore, the pharmacology batch and pilot test batch of RC28-E have similar efficacies and reliable stability, and are superior in the anti-angiogenic and anti-neovascular efficacy to the currently clinically available drugs conbercept and FGF trap.RC28-E1 may suppress pathological neovascularization through inhibiting the overactivation of MEK-Erk pathway in retinal vascular endothelial cells. Key words: Retinal neovascularization; Decoy receptor; Basic fibroblast growth factor; Vascular endothelial growth factor; Recombinant protein drugs

Design, optimization and pharmacodynamic comparison of dorzolamide hydrochloride soluble ocular drug insert prepared by using 32 factorial design

The bioavailability of therapeutic agents from eye drops is usually limited due to corneal barrier functions and effective eye protective mechanisms. The current study aimed to enhance ocular bioavailability of dorzolamide hydrochloride, a potent antiglaucoma drug by preparing novel ophthalmic drug delivery system like soluble ophthalmic drug inserts (SODI).Various batches of dorzolamide hydrochloride Soluble Ocular Drug Insert were prepared using Polyvinyl Alcohol, Poloxamer 407 as polymer with Propylene Glycol as plasticizer by solvent casting method. The drug inserts were prepared by using 32 factorial designs (version 10). Solvent casting method was used to prepare drug inserts which were further evaluated for various parameters like drug interaction studies, physicochemical characteristics, in vitro release studies, transcorneal permeation study by using excised goat cornea. The optimized batch F2 showed 98.50 ± 0.05% drug release at the end of 6 h and has desired physicochemical properties. The gamma radiation sterilized batch F2 was subjected to sterility test as per Indian Pharmacopeia 2014 and accelerated stability studies as per International Conference on Harmonization stability testing of new drug substances and products guideline, ex vivo and Pharmacodynamic studies. The comparative pharmacokinetic result shows that Dorzolamide Hydrochloride SODI is more effective than the marketed formulation. The promising pharmacokinetic results and possibility of commercial applicability justifies the need of product in market.