A Population Pharmacokinetic Model for Concizumab Based on Phase 1 and Phase 2 Trial Data

Introduction Concizumab is a high-affinity anti-tissue factor pathway inhibitor (TFPI) monoclonal antibody in clinical investigation for the subcutaneous (SC) treatment of patients with hemophilia. The data generated from phase 1 and 2 concizumab trials have been used to develop a population pharmacokinetic (PK) model with the aim of supporting dose selection for phase 3 trials. WMethods The objective of this study was to develop a model to describe the PK of concizumab across administration routes in various groups of patients with hemophilia to generate a generally applicable population PK model of concizumab. The model was developed based on available PK data from four phase 1 trials (for both intravenous [IV] and SC concizumab administration) and two phase 2 trials (for SC concizumab administration). Trial populations in the phase 1 trials included both healthy subjects and patients with hemophilia, whilst the phase 2 trials enrolled patients with hemophilia A or B with inhibitors and patients with hemophilia A without inhibitors. A structural population PK model was first developed based on phase 1 data and the final population PK model was then estimated using data from both phase 1 and phase 2 trials. Simulations were performed for phase 3 concizumab exposure using a full parametric simulation (n=10,000), including both inter-individual and intra-individual variability for the selected population. Randomly sampled body weights from a normal distribution with mean and variance corresponding to body weight distribution from phase 2 trials were used to simulate patient profiles. WResults The population PK dataset used for the model comprised 1,504 observations from 119 subjects (89 patients and 30 healthy individuals), with a mean age of 35 years (range: 18-65 years) and mean body weight of 74.4 kg (range: 47.1-130 kg). The PK model parameters were first estimated based on phase 1 data alone, and after fixing the majority in order to ensure robustness of the model only a few parameters were re-estimated based on phase 1 and 2 data combined. The PK model (Figure 1) was evaluated by standard goodness-of-fit plots and qualification assessments. Using visual predictive checks, it was shown that the model was able to reproduce the median and the 5th and 95th percentiles of the observed concizumab concentrations from phase 1 and 2 trials, and so it was deemed suitable for simulation purposes. The PK model suggested a target-mediated drug disposition following concizumab binding to TFPI at the endothelium, and subsequent elimination of the complex to account for the non-linear elimination. WConclusions The developed model accurately described the PK of concizumab delivered at a wide dose range by either SC or IV administration to both healthy subjects and patients with hemophilia A or B with and without inhibitors. The model was used for simulations to select the dosing regimen for subsequent phase 3 studies. Figure 1. Concizumab pharmacokinetic model. Structure of the final concizumab PK model for SC and IV dosing with target-mediated drug disposition via the endothelial TFPI. CL, clearance; doseiv, intravenous dose; dosesc, subcutaneous dose; IV, intravenous; ka, absorption rate constant; kcom, elimination rate constant of the concizumab-TFPI complex; kon and koff, rate constants for binding of concizumab to the endothelial TFPI; ktr, rate constant from the transit compartment; Q, inter-compartmental clearance; Rtot, amount of endothelial TFPI available for concizumab binding; SC, subcutaneous; TFPI, tissue factor pathway inhibitor; V, volume. Figure Disclosures Høyer Rose: Novo Nordisk A/S: Current Employment, Divested equity in a private or publicly-traded company in the past 24 months. Hollensen:Novo Nordisk: Current Employment, Current equity holder in private company, Current equity holder in publicly-traded company. Agersø:Novo Nordisk A/S: Current Employment. Viig Overgaard:Novo Nordisk A/S: Current Employment, Current equity holder in publicly-traded company.

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Fitusiran Treatment Impacts on Health-Related Quality of Life in Subjects with Hemophilia A and B with Inhibitors Assessed with the Haemophilia Quality of Life Questionnaire for Adults (Haem-A-QoL)

Blood ◽

10.1182/blood-2020-142266 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 23-24

Author(s):

Sylvia Von Mackensen ◽

Pratima Chowdary ◽

Sarah Mangles ◽

Qifeng Yu ◽

Baisong Mei ◽

...

Keyword(s):

Quality Of Life ◽

Hemophilia A ◽

Phase 1 ◽

Phase 2 ◽

Publicly Traded ◽

Advisory Committees ◽

Related Quality ◽

Health Related ◽

Dose Dependent

Background: Fitusiran, an investigational RNA interference treatment for people with hemophilia A or B (PwH), with or without inhibitors, has shown dose-dependent lowering of antithrombin, increase in thrombin generation, and decrease in bleeding frequency in clinical trials. The novel mechanism of action and long pharmacodynamic effect enables once-monthly subcutaneous administration. This sustained hemostatic protection and less burdensome administration may improve patient-reported outcomes (PRO). Objective: To evaluate changes in PRO in terms of patient-relevant improvements in health-related quality of life (HRQoL) in PwH with inhibitors (PwHI) on prophylactic fitusiran treatment. Methods: Fitusiran was evaluated in a phase 1 dose-escalation study (NCT02035605) followed by a phase 2 open-label extension (OLE) study (NCT02554773) with monthly subcutaneous fixed doses of 50 mg or 80 mg. HRQoL was assessed using the Haem-A-QoL and the EuroQol 5 Dimensions (EQ-5D) questionnaires at baseline and at end of study in a cohort of 17 PwHI (Hemophilia A, n=15; Hemophilia B, n=2) from the phase 1 study. Results: Subjects previously treated on-demand or prophylactically had a mean (standard deviation [SD]) age of 34.6 (10.3) years and a mean (SD) number of bleeding episodes in the 6 months before baseline of 16.6 (10.7). Mean (SD) changes from baseline to end of study (day 84 or later) in Haem-A-QoL total (-9.2 [11.2]) and physical health (−12.3 [15.1]) domain scores suggest clinically meaningful improvement (lower scores indicate better HRQoL). Numeric reduction (i.e., improvement) in all other domains appeared to be dose-dependent (greater improvement in the 80 mg group) (Table 1). Changes in EQ-5D utility and EQ-VAS scores were not clinically meaningful. Further analyses in PwH with and without inhibitors from the phase 2 OLE will be presented. Conclusions: Fitusiran prophylaxis may improve HRQoL - particularly the Haem-A-QoL 'Physical health' domain (painful swelling, joint pain, pain with movement, difficulty walking, and time to get ready) as shown in a cohort of 17 PwHI . Additional analyses from ongoing OLE and phase 3 studies are planned to quantify the patient-relevant changes with fitusiran treatment in all hemophilia patients over time. Disclosures Von Mackensen: Sanofi, Bayer, Sobi, Chugai, Kedrion, Spark: Consultancy; Biotest, Sobi, CSL Behring: Honoraria; Novo Nordisk, Sobi: Research Funding. Chowdary:BioMarin: Honoraria; Bayer, CSL Behring, Freeline, Novo Nordisk, Pfizer and Sobi: Research Funding; Chugai, CSL Behring, Novo Nordisk, Pfizer, Roche, Sobi: Speakers Bureau; Bayer, Chugai, CSL Behring, Freeline, Novo Nordisk, Pfizer, Roche, Sanofi, Shire (Baxalta), Sobi, Spark: Membership on an entity's Board of Directors or advisory committees. Mangles:Roche, Takeda, Novo Nordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sobi, Octapharma, Novo Nordisk, Shire and Roche/Chugai: Other: travel funding. Yu:Sanofi: Other: was an employee and stockholder of Sanofi, at the time of study; Albireo Pharmaceuticals, Inc: Current Employment. Mei:Sanofi: Current Employment, Current equity holder in publicly-traded company. Andersson:Sanofi: Current Employment, Current equity holder in publicly-traded company. Dasmahapatra:Sanofi: Current Employment, Current equity holder in publicly-traded company.

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Population Pharmacokinetic Analyses for Omadacycline Using Phase 1 and 3 Data

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02263-19 ◽

2020 ◽

Vol 64 (7) ◽

Cited By ~ 2

Author(s):

Elizabeth A. Lakota ◽

Scott A. Van Wart ◽

Michael Trang ◽

Evan Tzanis ◽

Sujata M. Bhavnani ◽

...

Keyword(s):

Goodness Of Fit ◽

Phase 1 ◽

Peripheral Compartment ◽

Population Pharmacokinetic ◽

Uncomplicated Urinary Tract Infection ◽

Phase 3 ◽

Data Set ◽

First Order ◽

Final Population ◽

Population Pk

ABSTRACT Omadacycline, a novel aminomethylcycline antibiotic with activity against Gram-positive and -negative organisms, including tetracycline-resistant pathogens, received FDA approval in October 2018 for the treatment of patients with acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP). A previously developed population pharmacokinetic (PK) model based on phase 1 intravenous and oral PK data was refined using data from infected patients. Data from 10 phase 1 studies used to develop the previous model were pooled with data from three additional phase 1 studies, a phase 1b uncomplicated urinary tract infection study, one phase 3 CABP study, and two phase 3 ABSSSI studies. The final population PK model was a three-compartment model with first-order absorption using transit compartments to account for absorption delay following oral dosing and first-order elimination. Epithelial lining fluid (ELF) concentrations were modeled as a subcompartment of the first peripheral compartment. A food effect on oral bioavailability was included in the model. Sex was the only significant covariate identified, with 15.6% lower clearance for females than males. Goodness-of-fit diagnostics indicated a precise and unbiased fit to the data. The final model, which was robust in its ability to predict plasma and ELF exposures following omadacycline administration, was also able to predict the central tendency and variability in concentration-time profiles using an external phase 3 ABSSSI data set. A population PK model, which described omadacycline PK in healthy subjects and infected patients, was developed and subsequently used to support pharmacokinetic-pharmacodynamic (PK-PD) and PK-PD target attainment assessments.

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Population Pharmacokinetic Analyses for BC-3781 Using Phase 2 Data from Patients with Acute Bacterial Skin and Skin Structure Infections

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02033-13 ◽

2014 ◽

Vol 59 (1) ◽

pp. 282-288 ◽

Cited By ~ 19

Author(s):

C. M. Rubino ◽

B. Xue ◽

S. M. Bhavnani ◽

W. T. Prince ◽

Z. Ivezic-Schoenfeld ◽

...

Keyword(s):

Renal Function ◽

Body Size ◽

Phase 1 ◽

Compartment Model ◽

Volume Of Distribution ◽

Population Pharmacokinetic ◽

Phase 2 ◽

Data Set ◽

Skin Structure ◽

Population Pk

ABSTRACTBC-3781, a pleuromutilin antimicrobial agent, is being developed for the treatment of patients with acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia. Data from a phase 2 study of patients with ABSSSI were used to refine a previous population pharmacokinetic (PK) model and explore potential predictors of PK variability. The previously derived population PK model based on data from three phase 1 studies was applied to sparse sampling data from a phase 2 ABSSSI study and modified as necessary. Covariate analyses were conducted to identify descriptors (e.g., body size, renal function, age) associated with interindividual variability in PK. All population PK analyses were conducted by using Monte Carlo parametric expectation maximization implemented in S-ADAPT 1.5.6. The population PK data set contained 1,167 concentrations from 129 patients; 95% of the patients had 5 or more PK samples (median, 11). The previous population PK model (three-compartment model with first-order elimination and nonlinear protein binding) provided an acceptable and unbiased fit to the data from the 129 patients. Population PK parameters were estimated with acceptable precision; individual clearance values were particularly well estimated (median individual precision of 9.15%). Graphical covariate evaluations showed no relationships between PK and age or renal function but modest relationships between body size and clearance and volume of distribution, which were not statistically significant when included in the population PK model. This population PK model will be useful for subsequent PK-pharmacodynamic analyses and simulations conducted to support phase 3 dose selection. (This study has been registered at ClinicalTrials.gov under registration no. NCT01119105.)

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A Population Pharmacokinetic and Pharmacodynamic Evaluation of Pralatrexate in Patients with Hematologic Malignancies.

Blood ◽

10.1182/blood.v110.11.1370.1370 ◽

2007 ◽

Vol 110 (11) ◽

pp. 1370-1370 ◽

Cited By ~ 1

Author(s):

Diane R. Mould ◽

Kevin Sweeney ◽

Stephen Duffull ◽

Ellen Neylon ◽

Owen A. O’Connor

Keyword(s):

Adverse Event ◽

T Cell ◽

Vitamin B12 ◽

Cell Lymphoma ◽

Phase 1 ◽

T Cell Lymphoma ◽

Population Pharmacokinetic ◽

Phase 2 ◽

Peripheral T Cell Lymphoma ◽

Population Pk

Abstract Pralatrexate is a novel antifol designed to have high affinity for the reduced folate carrier, exhibiting improved internalization over other analogues. Phase 2 and subsequent Phase 1 studies revealed that patients with lymphoma exhibited a higher incidence of mucositis, compared to that reported in patients with solid tumors. The initial Phase 2 experiences employed dose escalation on an every other week schedule (135 to 240 mg/m2 QOW) while the follow-on Phase 1 and 2 studies employed a weekly dosing schedule (30 to 45 mg/m2 weekly for 6 of 7 weeks). The maximum tolerated dose (MTD) was 30 mg/m2 weekly for 6 of 7 weeks in lymphoma patients. Preliminary population pharmacokinetic (PK) and adverse event (AE) evaluations suggested that pralatrexate exposure could be controlled with weight or body size based dosing, and that pretreatment with folic acid and vitamin B12 could abrogate the mucositis. PK and AE data from 47 patients were evaluated using NONMEM Version V level 1.1. Model building followed standard approaches. The best PK model was a three compartment linear model, fitted to the natural log-transformed concentration versus time data. Patient weight and methylmalonic acid (MMA) were found to be predictive of inter-patient PK variability, supporting weight or body surface area (BSA) based dosing. There are observations of an apparent association between MMA concentrations and PDX PK which need to be further explored. The PK model was evaluated using bootstrapping and a visual predictive check. An ordered categorical logistic regression was conducted to evaluate the relationship between pralatrexate exposure and grade of mucositis. In this evaluation, pralatrexate area under the curve (AUC) and MMA were found to be predictive of toxicity, where patients with higher MMA or AUC had a higher probability of mucositis. Individualized dosing combined with vitamin pretreatment significantly improved the toxicity profile, allowing for a shift in the dose-limiting toxicity (DLT) from mucositis to thrombocytopenia. Although the data from the present study were limited, the covariates identified in the population PK and adverse event evaluations were comparable with those identified for other anti-folate agents. MMA is a sensitive indicator of vitamin B12 deficiency and its impact on toxicity is commonly reported for this class of agents. The rationale behind the influence of MMA on clearance is less clear and may be correlated with other aspects of patient health. Pralatrexate has exhibited promising activity in patients with chemotherapy refractory peripheral T-cell lymphoma, leading now to an international multi-center Phase 2 study in peripheral T-cell lymphoma. The application of a population PK model based analysis was a critical component in the development of this agent. Model-based evaluations allowed the identification of the safest schedules and supported the need for vitamin supplementation for the safe administration.

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Pharmacokinetic / Pharmacodynamic (PK/PD) Simulations Guide Selection of the Dose for Administration of Efgartigimod Subcutaneously in a Phase 3 Clinical Trial in Patients with Primary Immune Thrombocytopenia

Blood ◽

10.1182/blood-2021-153261 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3165-3165

Author(s):

Waleed Ghanima ◽

Vickie McDonald ◽

Shivi Jain ◽

Monica Carpenedo ◽

Esther N. Oliva ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Immune Thrombocytopenia ◽

Phase 1 ◽

Advisory Board ◽

Phase 2 ◽

Publicly Traded ◽

Phase 1 Study ◽

Phase 3 ◽

Advisory Committees

Abstract Introduction Efgartigimod (ARGX-113) is a human IgG1-derived Fc fragment that binds with high affinity to FcRn in a pH dependent way, resulting in a blockade of FcRn-mediated recycling of IgGs. This leads to rapid degradation of all IgGs, including disease associated autoantibodies. The efficacy, safety, tolerability, and pharmacokinetic (PK) and pharmacodynamic (PD) profile of intravenously (IV) administered efgartigimod have been assessed during a Phase 1 study in healthy subjects (Ulrichts P. JCI. 2018;128), Phase 2 studies in patients with Myasthenia gravis (MG) (Howard JF. Neurol. 2019;92) and Immune Thrombocytopenia (ITP) (Newland AC. Am J Hematol. 2020;95:178-187), and a Phase 3 study in MG (Howard JF. Lancet Neurol. 2021;20). These studies have demonstrated that a dose of 10 mg/kg efgartigimod, administered in four weekly (qw) IV infusions, achieves close to maximal immunoglobulin G (IgG) reduction and a significant reduction of pathogenic autoantibodies in patients with ITP and MG. Furthermore, this dose was well-tolerated in all populations. Based on the results of the Phase 2 study in Primary ITP, a Phase 3 study was designed for IV administration in patients with persistent or chronic primary ITP (ADVANCE NCT04188379). To allow for a convenient SC administration of efgartigimod at a dose that achieves a similar PD effect comparable to IV 10 mg/kg, a co-formulation with rHuPH20 SC was developed (recombinant human hyaluronidase PH20, an enzyme used to increase the dispersion and absorption of co-administered substances when administered subcutaneously). Here we describe the dose selection process for the SC dose to be used in a Phase 3 study of patients with persistent or chronic ITP. Methods PK and PD data from a Phase 1 study, including 32 healthy adult male subjects receiving 750 mg, 1250 mg, 1750 mg, or 10 mg/kg single SC injections of efgartigimod co-mixed with rHuPH20 (8 subjects/dose group), were used for a PK/PD analysis to predict the efgartigimod PH20 SC dose that would result in a similar PD effect compared to the benchmark dose from previous studies of 10 mg/kg IV (1 hour infusion and body weight of 70 kg). Results Weekly SC administration of 1000 mg efgartigimod co-mixed with 2000 U/mL rHuPH20 was predicted to result in comparable maximum total IgG reduction after the 4 th SC injection (days 22-29) as after the 4 th IV infusion of 10 mg/kg administered qw (Figure 1). Additionally, the area under the curve for total IgG concentration after the 4th dose (days 22-29) and trough IgG reduction (measured prior to dose on day 29) were predicted to be comparable between weekly 1000 mg SC and the weekly 10 mg/kg IV benchmark dose. No statistically significant effect of body weight on the PK and PD of efgartigimod PH20 SC was found. Discussion These results informed the weekly SC dose administration schedule in ADVANCE SC, a Phase 3, multicenter, randomized, double-blinded, placebo-controlled trial (NCT04687072) for evaluation of efficacy and safety of efgartigimod PH20 SC in adults with persistent or chronic primary ITP. Efgartigimod PH20 SC or placebo PH20 SC will be given weekly on visits 1-4 and then either weekly or every other week from visits 5 to 16, as determined by platelet counts. The frequency of administration will remain unchanged for the last 7 weeks (visits 17 to 24) to evaluate the sustainable platelet count improvement as the primary objective. Secondary objectives include extent of disease control (overall platelet count response, use of rescue treatment, and changes in concurrent ITP therapy), bleeding events, and quality of life assessments. ADVANCE SC recruitment is currently ongoing across approximately 70 sites in Asia-Pacific, Europe, Japan, Latin America, Middle East, Africa, and USA. Figure 1 Figure 1. Disclosures Ghanima: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Principia: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Bayer: Honoraria, Research Funding; Pfizer: Research Funding. McDonald: Bayer, Sobi, Novartis, Amgen, argenx: Honoraria; Grifols: Research Funding. Jain: GBT: Speakers Bureau; Novartis: Speakers Bureau; Argenx: Other: advisory board; Sanofi: Other: advisory board; DOVA: Other: advisory board. Oliva: Novartis, Celgene, Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Daiichi: Consultancy; Alexion, argenx, Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees. Hultberg: argenx: Current Employment, Patents & Royalties. Gandini: argenx: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Hofman: argenx: Current Employment. Van Bragt: Curare Consulting BV: Other: Partner; argenx: Consultancy. Parys: argenx: Current Employment. van Hoorick: argenx: Current Employment. Miyakawa: Sanofi: Consultancy; Zenyaku Kogyo: Consultancy; Sanofi: Research Funding; argenx: Consultancy, Research Funding. Broome: Alexion, argenx, Apellis, Sanofi: Honoraria.

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PENERAPAN MODEL QUANTUM LEARNING UNTUK MENINGKATKAN HASIL BELAJAR AUTOCAD SISWA KELAS X TEKNIK PEMESINAN SMK NEGERI 1 STABAT

Jurnal Teknologi Pendidikan (JTP) ◽

10.24114/jtp.v5i1.509 ◽

2013 ◽

Vol 5 (1) ◽

Author(s):

Abdul Hasan Saragih

Keyword(s):

Positive Response ◽

Phase 1 ◽

First Grade ◽

Learning Model ◽

Second Phase ◽

Phase 2 ◽

Phase 3 ◽

The Third ◽

Third Phase ◽

Quantum Learning

This classroom research was conducted on the autocad instructions to the first grade of mechinary class of SMK Negeri 1 Stabat aiming at : (1) improving the student’ archievementon autocad instructional to the student of mechinary architecture class of SMK Negeri 1 Stabat, (2) applying Quantum Learning Model to the students of mechinary class of SMK Negeri 1 Stabat, arising the positive response to autocad subject by applying Quantum Learning Model of the students of mechinary class of SMK Negeri 1 Stabat. The result shows that (1) by applying quantum learning model, the students’ achievement improves significantly. The improvement ofthe achievement of the 34 students is very satisfactory; on the first phase, 27 students passed (70.59%), 10 students failed (29.41%). On the second phase 27 students (79.41%) passed and 7 students (20.59%) failed. On the third phase 30 students (88.24%) passed and 4 students (11.76%) failed. The application of quantum learning model in SMK Negeri 1 Stabat proved satisfying. This was visible from the activeness of the students from phase 1 to 3. The activeness average of the students was 74.31% on phase 1,81.35% on phase 2, and 83.63% on phase 3. (3) The application of the quantum learning model on teaching autocad was very positively welcome by the students of mechinary class of SMK Negeri 1 Stabat. On phase 1 the improvement was 81.53% . It improved to 86.15% on phase 3. Therefore, The improvement ofstudent’ response can be categorized good.

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Clinical Drug Development for the Treatment of Pulmonary Arterial Hypertension: Collaboration With the Pharmaceutical Industry and Regulatory Agencies

Advances in Pulmonary Hypertension ◽

10.21693/1933-088x-9.4.214 ◽

2010 ◽

Vol 9 (4) ◽

pp. 214-219

Author(s):

Robyn J. Barst

Keyword(s):

Clinical Trials ◽

Pulmonary Arterial Hypertension ◽

Drug Development ◽

Phase 1 ◽

Preclinical Studies ◽

Phase 2 ◽

Phase 3 ◽

Preclinical Testing ◽

New Drug ◽

Pulmonary Arterial

Drug development is the entire process of introducing a new drug to the market. It involves drug discovery, screening, preclinical testing, an Investigational New Drug (IND) application in the US or a Clinical Trial Application (CTA) in the EU, phase 1–3 clinical trials, a New Drug Application (NDA), Food and Drug Administration (FDA) review and approval, and postapproval studies required for continuing safety evaluation. Preclinical testing assesses safety and biologic activity, phase 1 determines safety and dosage, phase 2 evaluates efficacy and side effects, and phase 3 confirms efficacy and monitors adverse effects in a larger number of patients. Postapproval studies provide additional postmarketing data. On average, it takes 15 years from preclinical studies to regulatory approval by the FDA: about 3.5–6.5 years for preclinical, 1–1.5 years for phase 1, 2 years for phase 2, 3–3.5 years for phase 3, and 1.5–2.5 years for filing the NDA and completing the FDA review process. Of approximately 5000 compounds evaluated in preclinical studies, about 5 compounds enter clinical trials, and 1 compound is approved (Tufts Center for the Study of Drug Development, 2011). Most drug development programs include approximately 35–40 phase 1 studies, 15 phase 2 studies, and 3–5 pivotal trials with more than 5000 patients enrolled. Thus, to produce safe and effective drugs in a regulated environment is a highly complex process. Against this backdrop, what is the best way to develop drugs for pulmonary arterial hypertension (PAH), an orphan disease often rapidly fatal within several years of diagnosis and in which spontaneous regression does not occur?

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PSVI-3 Dietary supplementation with coated omega-3 fatty acids has positive effects on growth performance and nutrients digestibility in weaned pigs

Journal of Animal Science ◽

10.1093/jas/skaa054.343 ◽

2020 ◽

Vol 98 (Supplement_3) ◽

pp. 196-197

Author(s):

Woo Jung Seok ◽

Je min Ahn ◽

Jing Hu ◽

Dexin Dang ◽

Yanjiao Li ◽

...

Keyword(s):

Fatty Acids ◽

Growth Performance ◽

Phase 1 ◽

Dietary Supplementation ◽

Basal Diet ◽

Phase 2 ◽

Omega 3 ◽

Phase 3 ◽

Linear Effect ◽

Weaning Pigs

Abstract The objective of this study was to evaluate the effects of dietary supplementation of coated omega-3 fatty acid (n-3 CFA) by corn cob power silica on performance of weaning pigs. A total of 200 weaned pigs [(Landrace x Yorkshire) x Duroc, average initial body weight at 6.97 ± 1.22 kg] were randomly assigned to four experimental treatments in a 6-week experiment in 3 phases as follows: CON, basal diet; 2) 0.3CFA, CON + phase 1(0.3% n-3CFA), phase 2(0.2% n-3CFA), phase 3(0.1% n-3CFA); 3) 0.6CFA, CON + phase 1(0.6% n-3CFA), phase 2(0.4% n-3CFA), phase 3(0.2% n-3CFA); 4) 0.9CFA, CON + phase 1(0.9% n-3CFA), phase 2(0.6% n-3CFA), phase 3 (0.3% n-3CFA). Each treatment had 10 replicates with 5 pigs (three gilts and two barrows) per replicate. The data were analyzed using the GLM procedure of SAS as a randomized complete block design. Pen served as the experimental unit. Linear, quadratic and cubic polynomial contrasts were used to examine effect of dietary treatment with coated n-3FA in the basal diet. Variability in the data was expressed as the standard error of means and P< 0.05 was considered to statistically significant. Increasing the level of n-3CFA in the diet linearly increased ADG and G/F of pigs (Table 1). Increasing the level of n-3CFA showed a linear increment in the digestibility of DM (83.59, 84.38, 85.13, 85.89 %) whereas nitrogen digestibility (81.79, 82.38, 82.96, 83.64 %) showed a trend (linear effect, p=0.0594) at the end of experiment. The fecal lactobacillus count was increased (7.22, 7.27, 7.33, 7.35 log10cfu/g) with the increase in the supplemental level of n-3CFA (linear effect; p< 0.05). However, there were no differences in the concentration of serum haptoglobin, or fecal E. coli, Clostridium and Salmonella counts despite the increase in n-3CFA levels in the diet. Supplementation of the diet with coated n-3 fatty acids positively affected growth performance and digestibility of dry matter and nitrogen, and enhanced the count of lactobacillus in weaning pigs.

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Dietary Inclusion of Blood Plasma with Yeast (Saccharomyces cerevisiae) Supplementation Enhanced the Growth Performance, Nutrient Digestibility, Lactobacillus Count, and Reduced Gas Emissions in Weaning Pigs

Animals ◽

10.3390/ani11030759 ◽

2021 ◽

Vol 11 (3) ◽

pp. 759

Author(s):

Vetriselvi Sampath ◽

Dong Heon Baek ◽

Sureshkumar Shanmugam ◽

In Ho Kim

Keyword(s):

Saccharomyces Cerevisiae ◽

Phase 1 ◽

Average Daily Gain ◽

Nutrient Digestibility ◽

Phase 2 ◽

Phase 3 ◽

Yeast Saccharomyces Cerevisiae ◽

Yeast Phase ◽

Weaning Pigs ◽

Daily Gain

This experiment was performed to examine the hypothesis that blood plasma (BP) with yeast (Saccharomyces cerevisiae) supplement in the diet of weaning pigs could provoke the growth performance, nutrient digestibility, fecal microbial, and reduce harmful gas excretion. A total of one hundred and eighty healthy piglets were taken and assigned (complete random blocks) to three dietary treatments as: Phase 1: Treatment (TRT) 1-6% BP; TRT 2-3% BP + 3% yeast; TRT 3-6% yeast. Phase 2: TRT 1-3%; BP., TRT 2-1.5% BP + 1.5% yeast; TRT 3- 3% yeast. Phase 3: TRT 1- Control (CON) (Basal diet); TRT 2- CON; TRT 3- CON for six- weeks. Each treatment had twelve replicates and five (three gilts and two barrows) pigs per pen. Dietary inclusion of BP with yeast supplementation significantly increased the body weight of piglets during phase 2 (p = 0.003) and phase 3 (p = 0.032). In addition, TRT2 group piglets had a significant improvement in average daily gain at the end of each phase and overall (p = 0.047, 0.025, 0.018 and 0.012, respectively). At phase 3, TRT2 group piglets showed a significant improvement on nutrient digestibility of dry matter (p = 0.012) and nitrogen (p = 0.040). The fecal microbiota of TRT2 group piglets showed a tendency to increase the number of Lactobacillus counts at phase 1 (p = 0.07) and phase 2 (p = 0.06) as well as, a significant improvement at phase 3 (p = 0.021). In addition, TRT2 group piglets had trend to decrease NH3 (p = 0.074) and H2S (p = 0.069) during phase 2, and significantly reduced NH3 (p = 0.038) and H2S (p = 0.046) at phase 3. However, the fecal score of piglets remains unaffected during the entire trial. At the end of phase 1 piglets’ IgG (p = 0.008) was significantly increased with the inclusion of BP with yeast supplementation. Based on the positive effects on body weight, average daily gain, nutrient digestibility, Lactobacillus count, and reduced gas emission, we suggest that dietary supplement with BP and yeast in the diet of weaned piglet could serve as an excellent alternative to antibiotics growth promoters.

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