Reduced Dosing Frequency Research Articles

Pharmacokinetic (PK)-pharamcodynamic (PD) analysis and receptor occupancy data to support every other week maintenance dosing of magrolimab in combination with azacitidine in MDS/AML patients.

e15098 Background: Magrolimab (Hu5F9-G4) is a monoclonal IgG4 antibody that binds to CD47 receptor and blocks its interaction with SIRPA, thereby enabling tumor cell phagocytosis and activation of an anti-tumor T-cell response. Magrolimab has shown encouraging efficacy and tolerable safety profiles in treatment-naïve myelodysplastic syndromes/acute myeloid leukemia (MDS/AML) patients on an every week (QW) maintenance dosing schedule. Reduced dosing frequency (e.g. every other week – Q2W) is desired to enhance patient convenience and quality of life. Methods: Interim pharmacokinetic (PK) and CD47 receptor occupancy (RO) data from study 5F9005 (Clinical Trial: NCT03248479) were used for this analysis. A previously developed population PK (PopPK) model of magrolimab was verified with observed PK data from study 5F9005. The PK model was linked to peripheral blood and bone marrow blast CD47 RO. The model-predicted RO was validated with observed RO data. Simulations of PK and RO were conducted to justify the proposed reduced dosing frequency of Q2W starting in Cycle 3 onward. Simulations were compared with preliminary observed RO data from the ongoing 5F9005 study after switching to Q2W dosing. Results: The results showed that observed magrolimab PK in study 5F9005 was consistent with model predictions. Model predicted RO was aligned with observed RO data. PK and RO simulations based on the model indicated > 99% RO in peripheral blood and ~90% RO in bone marrow are expected after switching to Q2W dosing regimen from Cycle 3 onward. Preliminary observed RO data confirmed these predictions. Conclusions: Magrolimab PK in AML/MDS is consistent with other patient populations including solid tumors and lymphomas. Model-based simulations and preliminary RO data support Q2W dosing of magrolimab from Cycle 3 onward as optimal RO is expected with the proposed dosing regimen. Clinical trial information: NCT03248479 .

Development of colon-specific mucoadhesive meloxicam microspheres for the treatment of CFA-induced arthritis in rats

To fulfill the multi-task functions like enhanced solubility and bioavailability of poorly soluble drug, reduce dosing frequency, avoid acidic degradation, etc., hence uncoated meloxicam (MLX)-loaded colon-specific mucoadhesive microspheres (MLX-Na-AGP) were prepared by ionotropic gelation method (crosslinking technique) using sodium alginate and aloe vera gel powder as a drug release modifiers to achieve controlled and prolonged release pattern with maximum bioavailability and Calcium chloride(CaCl2) as crosslinking agent. A fixed drug concentration and various ratios blend of polymeric matrix were used in the preparation of microspheres. The combinative therapeutic effect of MLX with well-known anti-inflammatory medicinal value of AGP, while AGP is used as a carrier to the colon-specific microspheres for the treatment of “complete Freund’s adjuvant” (CFA) induced rheumatoid arthritis (RA) in Wistar rats. Various parameters and drug release potential were evaluated for developed microspheres, which showed satisfactory results. In FTIR studies, no substantial drug–polymer interactions were found. In vitro drug release of MLX-Na-AGP microspheres of all batches was carried out at progressive pH using different buffer solutions (0.1 N HCl pH 1.2 and pH 4.5, pH 6.8, pH 7.4 PBS buffers) at different time intervals for 24 h, and it was found that drug release followed zero-order kinetics with super case II transport drug release mechanism. All microspheres exhibited much slow drug release at acidic pH and that was increased progressively with increased pH and maximum drug release was found for all batches at pH 7.4 PBS at the end of 24 h. The prepared microspheres exhibited satisfactory micromeritic flow attributes which evaluated in terms of angle of repose (24.87 ± 0.45–32.05 ± 0.19°), bulk density (0.528 ± 0.007–0.731 ± 0.032 g/cc) and tapped density (0.684 ± 0.009–0.949 ± 0.037 g/cc), Compressibility index (10.62 ± 0.42%–23.03 ± 0.423%) and Hausner’s ratio (1.118 ± 0.005–1.299 ± 0.007). Mean particle size of different batch of formulations (F1–F14) was found in a range of 109.16 ± 0.96–1,025.12 ± 0.29 µm, respectively. Drug entrapment efficiency of the formulations was found in the range of 51.02 ± 0.19%–91.44 ± 0.1%. In pharmacokinetic study optimized formulation (F12) showed 2.29 times higher bioavailability over the free drug, and also showed significant results in pharmacodynamic studies and AGP in CFA-induced RA in animal model of male albino Wistar rats.

Preparation and characterization of metformin hydrochloride controlled-release tablet using fatty acid coated granules

Metformin hydrochloride (MFM) is often used as a controlled-release (CR) tablet to reduce dosing frequency. However, the MFM CR tablet contains significant amounts of excipients and the tablet size is also large. Dosing convenience and patient compliance can be increased by reducing the size of the CR tablets. The aim of this study was to prepare and evaluate the MFM controlled-release tablet (MFM-CRT) using two types of release modulators, inner and outer. The MFM-CRT was prepared by coating the MFM granules using a binder solution containing aluminum stearate (ALS) as the inner release-modulator, and polyethylene oxide (PEO) as the outer release-modulator. The dispersion stability of the binder solution was optimized by the dispersion analyzer. The MFM-CRT was evaluated for dissolution rate and tablet volume. Additionally, dissolution behavior and dissolution kinetics of the MFM-CRT were analyzed using micro-computed tomography (micro-CT). Although the optimal MFM-CRT showed no difference in the release rate as compared to the commercially available product of Glucophage® XR 500 mg (f2 value: 72), the length of the long axis was reduced by 6 mm and the weight was reduced by about 27%. We expect patient compliance to improve because of effective sustained release and volume reduction of MFM-CRT.

In silico modeling of functionalized poly(methylvinyl ether/maleic acid) for controlled drug release in the ocular milieu.

Controlling structurally defined properties of drug-bound macromolecules such as surface adhesion and interaction with endogenous proteins in the surrounding environment using prior data from computer-assisted simulation can be of great use in designing controlled release macromolecular therapeutic systems. In this paper, we describe experimental correlation of real-time properties of a polymer with pendant drug molecules, with predicted values obtained from studying in silico molecular interactions of this polymer with ocular surface proteins (mucin) for formulating an ophthalmic in situ gel. Mucoretention of the drug (norfloxacin) within the eye sac is closely associated with binding interactions occurring on the ocular surface, and covalent association of the drug with the mucoadhesive polymer, poly(methylvinyl ether/maleic acid), can largely reduce dosing frequency eliciting prolonged antibacterial action much required in treating conjunctival infections. The physicochemical properties and 3D conformation of the drug-polymer conjugate were predicted by computational studies. Molecular docking of the drug-polymer conjugate with ocular surface mucin (MUC-1) suggested that amino acid residues Arg1095, Asn1091, and Gln1070 of mucin are involved in hydrogen bonding with carboxyl residues in the polymer structure. The orientation of the drug-polymer conjugate in solution profoundly depends on the properties of the drug. The studies further reveal that molecular interactions of MUC-1 with the drug in the drug-polymer conjugate influence the binding orientation of the drug-polymer to mucin. Computationally predicted solvation energies revealed a significant difference in energy values between drug molecule alone (- 113.04kcal/mol) and the drug-polymer (- 492.44kcal/mol) suggesting higher aqueous solvation of the drug-polymer conjugate compared with less-soluble drug, and that interactions between polymer chains and ocular aqueous environment dictate the drug-polymer conjugate's free energy. Our results demonstrate the fabrication of a macromolecular therapeutic gel using drug-polymer with controlled release properties and mucoadhesion guided by information predicted from computational software. Notably, in silico studies reveal that even small variations in molecular composition, in this case, an antibacterial drug that contributes less than half of the entire molecular weight can considerably change the drug's presentation to the ocular environment. Graphical abstract Table of contents graphic.

Development and Optimization of Nefopam Hydrochloride Push-Pull Osmotic Pumps by Design of Experiments

Nefopam hydrochloride (NFH) is one of the centrally acting NSAIDs drug used for pain management. The main objective of this research is to study the effect of ratio of Cellulose acetate: Polyethylene glycol (PEG) 3350, and %weight gain in extended release (ER) coating of push-pull osmotic pump (PPOP) tablets, optimized by the design of experiment (DoE) using response surface face center (α=1), the central composite design having two independent variables at three levels. PPOP tablets of NFH were administered once a day to reduce dosing frequency and improve patient compliance. PPOP tablets contain drug and push layers, compressed into bilayer tablets, coated with cellulose acetate (CA) as semipermeable membrane polymer, and PEG 3350 as a plasticizer or pore-forming agent. ER coated tablets mechanically drill ~0.50 mm on the drug layer part for the controlled release of the drug up to 24 hrs. Based on the results, the ratio of CA: PEG 3350 and % weight gain in ER coating of PPOP tablets shows a significant impact on % drug release. At lower % of PEG, burst release was observed due to cracking of ER coating layer, while at higher % of PEG, slightly rapid release of drug was observed. %Drug release is decreased with an increase in the %weight gain of tablets. PPOP Tablets with 10% PEG 3350 (Ratio of CA:PEG 3350, 90:10) and 8% weight gain exhibit zero-order kinetic drug release up to 24 hours.

Pharmacological Characterization of Apraglutide, a Novel Long-Acting Peptidic Glucagon-Like Peptide-2 Agonist, for the Treatment of Short Bowel Syndrome.

Glucagon-like peptide-2 (GLP-2) agonists have therapeutic potential in clinical indications in which the integrity or absorptive function of the intestinal mucosa is compromised, such as in short bowel syndrome (SBS). Native hGLP-2, a 33-amino acid peptide secreted from the small intestine, contributes to nutritional absorption but has a very short half-life because of enzymatic cleavage and renal clearance and thus is of limited therapeutic value. The GLP-2 analog teduglutide (Revestive/Gattex; Shire Inc.) has been approved for use in SBS since 2012 but has a once-daily injection regimen. Pharmacokinetic (PK) and pharmacodynamic studies confirm that apraglutide, a novel GLP-2 analog, has very low clearance, long elimination half-life, and high plasma protein binding compared with GLP-2 analogs teduglutide and glepaglutide. Apraglutide and teduglutide retain potency and selectivity at the GLP-2 receptor comparable to native hGLP-2, whereas glepaglutide was less potent and less selective. In rat intravenous PK studies, hGLP-2, teduglutide, glepaglutide, and apraglutide had clearances of 25, 9.9, 2.8, and 0.27 ml/kg per minute, respectively, and elimination half-lives of 6.4, 19, 16, and 159 minutes, respectively. The unique PK profile of apraglutide administered via intravenous and subcutaneous routes was confirmed in monkey and minipig and translated into significantly greater in vivo pharmacodynamic activity, measured as small intestinal growth in rats. Apraglutide showed greater intestinotrophic activity than the other peptides when administered at less-frequent dosing intervals because of its prolonged half-life. We postulate that apraglutide offers several advantages over existing GLP-2 analogs and is an excellent candidate for the treatment of gastrointestinal diseases, such as SBS. SIGNIFICANCE STATEMENT: Apraglutide is a potent and selective GLP-2 agonist with an extremely low clearance and prolonged elimination half-life, which differentiates it from teduglutide (the only approved GLP-2 agonist). The enhanced pharmacokinetics of apraglutide will benefit patients by enabling a reduced dosing frequency and removing the need for daily injections.

Reduced administration frequency for the treatment of fungal keratitis: a sustained natamycin release from a micellar solution

ABSTRACT Background Natamycin is the only topical ophthalmic antifungal drug approved by the Food and Drug Administration (FDA) of the United States, but has unsatisfactory factors such as high dosing frequency. Methods We report the synthesis and preparation of self-assembled poly(ethylene glycol)-block-poly(glycidyl methacrylate) (PEG-b-PGMA) micelles. These nanoparticles exhibit sustained delivery of a hydrophobic natamycin by topical administration on eye due to the hydrolysable properties of PGMA segments of micelle. Hydrolysis of glycidyl groups within a physiologically relevant environment provides an additional driving force for drug release by generation of hydrophilic hydroxyl groups to ‘push’ the encapsulated hydrophobic drug away from the resultant hydrophilic domains and into surrounding environment. Results In vitro and in vivo results revealed that the self-assembled micelles and the encapsulated natamycin were not cytotoxic and the released drug have strong antifungal ability to Candida albicans. Importantly, sustained natamycin release from micelles leads to the reduced administration frequency of natamycin from 8 times per day to 3 times per day in rabbits suffering from fungal keratitis (FK). Conclusion This study demonstrates a facile method that can greatly reduce dosing frequency of natamycin administration and thus improve long-term patient compliance.

Assessing prophylactic use and clinical outcomes in hemophilia A patients treated with rVIII-SingleChain and other common rFVIII products in Germany.

ObjectiveTo evaluate real‐world outcomes with rVIII‐SingleChain and other commonly used recombinant FVIII (rFVIII) products.MethodsHemophilia treatment centers in Germany (n = 21) contributed patient chart data. Inclusion criteria were prophylactic treatment with one of five rFVIII products for ≥8 weeks.ResultsMale patients (n = 225) were included: rVIII‐SingleChain (n = 40), rFVIIIFc (n = 47), octocog alfa (rFVIII; n = 58), octocog alfa (BAY 81‐8973; n = 40), or moroctocog alfa (n = 40). In patients with severe disease (n = 76), 66.6%, 70.0%, 20.0%, 7.7%, and 27.3% were dosed ≤2×/week, respectively. Irrespective of dosing frequency, mean annualized bleed rates (ABRs)/annualized spontaneous bleed rates (AsBRs) were 0.3/0.1, 0.8/0.4, 1.1/0.5, 1.5/0.8, and 1.4/0.6, and mean FVIII consumption (IU/kg/week) was 83.2, 97.2, 92.5, 104.0, and 102.1, respectively. Results for all patients were similar. Of the patients on prophylaxis with prior therapy and after switching to rVIII‐SingleChain (n = 21), mean ABR/AsBRs were 0.7/0.3 and 0.2/0.0, respectively. After switching to rVIII‐SingleChain, mean FVIII consumption reduced (109.4 vs 74.5 IU/kg/week), and percentage of patients dosed ≤2×/week increased (0% to 71.4%).ConclusionsrVIII‐SingleChain prophylaxis provides excellent bleeding protection, with potentially lowest factor consumption among the products assessed. Patients who switched to rVIII‐SingleChain prophylaxis reduced dosing frequency and consumption compared with prior treatment, with similar or potentially lower bleeding rates.

Developement and Characterization of Floating Tablets of Nizatidine for Peptic Ulcer

The objective of the present research work is to develop an ideal floating drug delivery system of nizatidine to increase the gastric residence time in stomach. To overcome the short half life and lower bioavailability of drug in tablet form we developed the drug in the form of effervescent floating tablet containing HPMC K100 and sodium bicarbonate by direct compression methodology. The prepared effervescent floating tablets were characterized by thickness, weight variation, hardness, friability, drug content uniformity, in vitro buoyancy time, swelling test, in vitro study and stability study and found that all formulations showed satisfactory results with enhanced half life and bioavailability that is among all formulations F1 formulation exhibited good drug release of 95.03% & has shown floating lag time 55 sec. Finally, it was concluded that formulations of nizatidine floating tablet were successfully prepared and found prolonged drug release for 12 hours thereby getting enhanced bioavailability, patient compliance by reducing dose frequency and gastric residence time.

DOP60 Vedolizumab treatment persistence and safety in an extended access program (XAP)

Abstract Background Vedolizumab, a gut-selective, α 4β 7 integrin antagonist, has been established as an effective and safe treatment for patients with UC or CD in the GEMINI phase 3 program and long-term safety (LTS) study. An extended access program (XAP) was initiated to provide continued access to patients who were benefiting from vedolizumab in GEMINI LTS and to monitor safety. We now report persistence and safety results from a 2-year data analysis. Methods Vedolizumab XAP (NCT02743806) is a phase 3b/4 prospective, open-label, multinational interventional study. A rollover from GEMINI LTS (NCT00790933) to the XAP, patients reduced dosing frequency from vedolizumab 300 mg IV every 4 weeks (Q4W) to every 8 weeks (Q8W) or remained on vedolizumab 300 mg IV Q4W if medically indicated. This 2-year data analysis assessed persistence on Q8W dosing after dosing frequency reduction, need for escalation to Q4W dosing, incidence of relapse (defined as dose escalation, study withdrawal due to adverse event, loss of adequate benefit from vedolizumab, or increased corticosteroid [CS] or immunomodulator dose), and safety 2 years after rollover from GEMINI LTS. Results A total of 311 patients (142 UC, 169 CD) from GEMINI LTS enrolled in the XAP. Median (range) duration of exposure to vedolizumab prior to the XAP was 8.0 years (5.2–10.0) for patients with UC and 7.5 years (5.4–9.9) for patients with CD. Of patients with UC and CD, 93.0% and 84.6%, respectively, reduced dosing frequency to Q8W at XAP start, and 87.3% and 77.5%, respectively, remained on Q8W after 2 years. At baseline, 93.0% of all patients with UC and 88.2% of all patients with CD were in CS-free remission; patients who maintained Q4W dosing at baseline had lower CS-free remission rates (62.5% in UC and 69.2% in CD). Of patients who initiated Q8W dosing at enrolment in the XAP, 95% had no relapse for ≥6 months (97.0% UC, 93.7% CD; Table 1). Only 7.3% of patients required dose escalation to Q4W, and 11.6% experienced relapse during the 2-year follow-up. Times to dose escalation and relapse were similar in patients with UC and CD (Figures 1 and 2). At 2 years, 4 of 8 patients with UC and 4 of 12 patients with CD who required dose escalation to Q4W discontinued vedolizumab early due to loss of benefit or adverse events. Adverse events related to vedolizumab were infrequent; no new or serious events attributed to vedolizumab were reported. Conclusion High patient persistence on Q8W vedolizumab was observed in the first 2 years after reduction of dosing frequency in the XAP. Overall, there were low rates of Q4W dose escalation and CD or UC disease relapse. The safety profile was consistent with previous reports with no new signals observed.

Sustained released Metformin microparticles for better management of type II diabetes mellitus: in-vitro studies

This work investigates Ethyl cellulose (EC) and polyethylene glycol (PEG) microparticles for prolonged delivery of Metformin HCl.The microparticles were synthesised by emulsion solvent evaporation technique; characterized for encapsulation efficiency, particle size, flow properties, surface morphology, FTIR, PXRD and drug release pattern; and investigated for the effect of formulation parameters like EC:PEG ratio, drug to polymers ratio and stirring speed on various properties of the microparticles. The drug entrapment efficiency, percent yield, particle size and drug release behaviour were found to be influenced by various formulation parameters.SEM images and size analysis confirmed formation of spherical shaped microparticles, with slightly rough surface and good flowability. FTIR revealed absence of any drug-polymer interaction and PXRD confirmed the molecular dispersion of drug with in microparticles. All the formulations showed sustained drug release pattern at pH 6.8, up to 91.34% ±1.68 metformin was released in 12 h with fickian diffusion mechanism. The designed microparticles could possibly be advantageous in terms of prolonged release, to achieve reduced dose frequency and improved patient compliance.

Retentive drug delivery systems based on shape memory materials

ABSTRACTRetentive drug delivery systems are intended for prolonged residence and release inside hollow organs of the body, in pursuit of either local or systemic therapeutic goals. Because of the relatively long‐lasting period of time they could cover during operation, a primary advantage arising from their use would lie in reduced dosing frequency, thereby improving the overall adherence of patients to prescribed medication regimens. The treatment of numerous pathologies that affect the urinary bladder and the stomach could especially benefit from viability of such delivery technologies. Moreover, by making use of effective gastroretentive dosage forms, the bioavailability of drugs that are preferably absorbed from the upper gastrointestinal tract could be increased. Expansion of devices following administration is often exploited for retention purposes, and several formulation strategies have been proposed in this respect. Innovative applications of shape memory materials have also been explored, highlighting the great inherent potential for facing the challenges involved. © 2019 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2020, 137, 48798.

Formulation and Evaluation of Tacrolimus Transdermal Gel

The present investigation is concerned with formulation and evaluation of Transdermal gels of Tacrolimus, anti-psoriasis drug, to circumvent the first pass effect and to improve its bioavailability with reduction in dosing frequency and dose related side effects. Twelve formulations were developed with varying concentrations of polymers like Carbopol 934P, HPMCK4M and Sodium CMC. The gels were tested for clarity, Homogeneity, Spreadability, Extrudability, Viscosity, surface pH, drug Content uniformity, in-vitro drug diffusion study and ex-vivo permeation study using rat abdominal skin. FTIR studies showed no evidence on interactions between drug, polymers and excipients. The best in-vitro drug release profile was achieved with the formulation F4 containing 0.5 mg of exhibited 6 hr drug release i.e. 98.68 % with desired therapeutic concentration which contains the drug and Carbopol 934p in the ratio of 1:2. The surface pH, drug content and viscosity of the formulation F4 was found to be 6.27, 101.3% and 3, 10,000cps respectively. The drug permeation from formulation F4 was slow and steady and 0.89gm of tacrolimus could permeate through the rat abdominal skin membrane with a flux of 0.071 gm hr-1 cm-2. The in-vitro release kinetics studies reveal that all formulations fit well with zero order kinetics followed by non-Fickian diffusion mechanism.
 Keywords: Transdermal gel, Viscosity, In-vitro drug release, In-vitro drug release kinetics study, Ex-vivo permeation study

An Optimized Surfactant-Based PEG-PLCL In Situ Gel Formulation For Enhanced Activity Of Rosuvastatin In Poloxamer-Induced Hyperlipidemic Rats.

BackgroundInjectable in situ gel (ISG) systems suffer from high initial drug release that may result in toxic effects.ObjectiveThis work aimed to develop an injectable sustained release rosuvastatin (RSV) ISG formulation with minimum initial drug burst and improved hyperlipidemic efficacy.MethodsSix formulation factors that affect RSV release after 0.5, 2 and 24 hrs have been screened and the significant ones were optimized utilizing an experimental design tool. The optimum ISG formulation components were physicochemically characterized. Kinetic treatment, dissolution efficiency and mean dissolution time were investigated for the developed ISG formulations. Pharmacodynamic effects of the optimized ISG formulation were studied and compared to ISG formulation loaded with free RSV and to a marketed oral drug product.ResultsThe concentration polylactide-co-ε-caprolactone (25: 75), the surfactant hydrophilic lipophilic balance (HLB) and the ratio of surfactant to polyethylene glycol 400 were significantly affecting the release of RSV during the first 24 h. Physicochemical characterization demonstrated complete dispersion of RSV in the polymeric matrix with slight changes in the drug crystalline structure. The optimized formulation demonstrated acceptable syringeability, good flow rate and was able to extend the in vitro drug release for 34 days. The ISG formulations complied with Weibull model. Pharmacodynamic study revealed a sustained reduction in the lipid profile that lasted for 21 days with a marked decrease in the lipid level during the first 24 hrs from the ISG system loaded with free RSV.ConclusionThe optimized RSV ISG formulation could be considered a promising strategy due to a reduction in dosing frequency and enhancement in hypolipidemic efficacy.

Three-dimensional (3D) printed tablets using ethyl cellulose and hydroxypropyl cellulose to achieve zero order sustained release profile

The main objective of this study was to investigate the potential of coupling hot-melt extrusion (HME) and 3D printing in order to design drug containing matrix tablets for the purpose of achieving zero order release. The effect of the blend ratio of ethyl cellulose (EC) and hydroxypropyl cellulose (HPC), carbamazepine (CBZ) as a model drug and triethyl citrate (TEC) on the mechanical and printability properties of extruded filaments was investigated. Filament formulation containing CBZ, EC and HPC (3, 64.7 and 32.3% w/w, respectively) and 20% w/w of TEC (by weight on the dry powder) showed optimum mechanical and printability properties and subsequently was printed into tablets (370 mg, 13 mm diameter, 3.5 mm thickness, cylinder-shaped) at 187 °C. The printed tablets showed good uniformity in drug content and appropriate mechanical properties. The optimum filament showed first order drug release pattern, while the 3D printed tablets showed zero-order drug release and slower drug release rate than the optimum filament. Overall, we have demonstrated that zero order release tablets can be prepared from a 2:1 ratio of EC to HPC, by combination of HME and 3D printing technologies with the capability of reducing dose frequency and adverse effects of drugs.

Formulation of sustained-release microspheres of cefixime with enhanced oral bioavailability and antibacterial potential.

Aim: The present work focused on the development of sustained-release microsphere formulation of cefixime to provide reduction in dosing frequency, improved antibacterial activity and patient compliance. Methodology & results: Microspheres were prepared by modified emulsion solvent evaporation method and evaluated by in vitro and in vivo studies. Optimized formulation (FK-07) was found to have entrapment efficiency of 81.12±0.93% and particle size of 166.82±0.86μm. FK-07 sustained release up to 24h as demonstrated by in vitro drug release and in vivo pharmacokinetic study in rats. FK-07 showed approximately twofold increase in bioavailability and twofold decrease in MIC90 value against Escherichia coli, Klebsiella pneumoniae and Salmonella typhi in comparison to marketed formulation. Conclusion: Sustaining the release of cefixime using microspheres enhanced its bioavailability, antibacterial efficacy and will help in reducing its dosing frequency.

Patients' and Caregivers' Preferences for Different Hemophilia a Treatment Attributes

Introduction: The treatment landscape for hemophilia A has evolved since the introduction of extended half-life (EHL) factor/non-factor VIII products, which allows for treatment personalization as per individual need, such as a less frequent infusion schedule and increased protection. Many different treatment attributes (e.g. safety, efficacy, and treatment burden) can influence patients' and caregivers' decisions in their choice of treatment. We used a discrete choice experiment (DCE) to elicit preferences from hemophilia A patients and caregivers for the treatment attributes of new EHL/non-factor products. Methods: Adult patients and caregivers providing care for a young patient (<18 years) were recruited via a hemophilia A patient panel to complete an online survey with 2 components: (1) sociodemographic and treatment experience; (2) DCE with 12 treatment choice questions. Each question required respondents to choose between 2 hypothetical treatment profiles varying in terms of 6 attributes (Figure): safety concerns with too much clotting, bleed protection, dosing frequency, length of time the product has been approved for use, product type, and joint health studies. These attributes were selected based on a targeted literature review, 10 in-depth interviews with patients and caregivers, and clinical expert input. The results from the qualitative work have been previously published. The DCE survey was pilot tested with patients (N=3) and caregivers (N=3) for comprehensibility and revised prior to data collection. We used random parameters logit models to estimate preference weights and relative attribute importance scores. Results: 113 patients (mean age: 35.5 years) and 96 caregivers (mean age of the child they cared for: 10.3 years) were included in the analysis. Among them, 88 patients (77.9%) self-reported having severe hemophilia while 81 (84.4%) caregivers reported that the child (<18 years) they cared for had severe hemophilia. Of these, 43 patients (38.1%) and 37 caregivers (38.5%) reported that their child with hemophilia used EHL/non-factor products. Among both patients and caregivers, the attributes from most to least important were as follows: (1) no safety concerns with too much clotting; (2) reducing annual bleeds from 5 to 0; (3) reducing weekly dosing from 4 to 1; (4) longer length of time the product has been approved for use (>6 years vs. <1 year); (5) factor product (vs. non-factor product), and (6) having studies demonstrating joint health improvement (vs. no studies) (Figure). The importance assigned to dosing frequency and bleed protection depended on the extent of improvement. For example, patients and caregivers valued having studies demonstrating joint health improvement more than they valued (a) a small improvement in bleed protection (i.e., 1/year to 0/year), or (b) a small improvement in dosing frequency (i.e., 2/week to 1/week). Lastly, further stratified analysis by patient and caregiver subgroups showed that patients viewed dosing frequency as the most important attribute influencing their treatment choices while caregivers valued safety the most. Among those who were not currently using EHL/non-factor products, the majority were willing to switch to EHL/non-factor products (81.4% of both cohorts). Bleed protection and dosing frequency were the most common reasons cited by respondents willing to switch treatments. Conclusions: Besides safety, other attributes of products such as bleed protection and reducing dosing frequency had an important influence on hemophilia A patients' and caregivers' treatment choices in the DCE survey. The importance that patients and caregivers placed on these attributes also depended on the extent of bleed protection improvement or dosing reduction. Adult patients and caregivers making treatment decisions for their young patients may value dosing and safety of treatments differently. With more treatment options becoming available for people with hemophilia, it is important that patients and caregivers are well-informed about the comprehensive benefit-risk profile of different products to make the most optimal decisions to improve their current treatment and outcomes. Figure Disclosures Joshi: Pharmerit International: Employment. Ng:Pharmerit International: Employment. Botteman:Alnylam Pharmaceuticals: Consultancy; Pharmerit International: Employment, Equity Ownership; Daiichi Sankyo: Consultancy, Research Funding. Li:Bioverativ, a Sanofi Company: Employment. Shah:Pharmerit International: Employment. Jain:Sanofi Genzyme: Employment, Equity Ownership. Lyn:Sanofi Genzyme: Employment. Su:Sanofi Genzyme: Employment, Equity Ownership.

<p>Population Pharmacokinetic Modeling Of On-Demand And Surgical Use Of Nonacog Beta Pegol (N9-GP) And rFIXFc Based Upon The paradigm 7 Comparative Pharmacokinetic Study</p>

Aim/objectiveUnderstanding pharmacokinetic (PK) differences between standard and extended half-life (EHL) products is important, particularly for factor IX (FIX), where differences are more significant than for factor VIII. Two single-dose PK trials showed N9-GP achieves higher FIX levels and greater area-under-the-curve than pdFIX, rFIX, and rFIXFc through higher recovery and longer terminal half-life. In paradigm 7, N9-GP demonstrated consistently favorable PK characteristics compared with rFIXFc. Collins et al explored population PK differences between N9-GP and pdFIX/rFIX based upon paradigm 1 data. This analysis uses population PK models based upon the paradigm 7 trial.Methods15 patients (21–65 years) with hemophilia B received single 50-IU/kg doses of N9-GP and rFIXFc ≥21 days apart. A population PK model developed from single-dose PK profiles simulated plasma FIX activity following dosing for surgery and on-demand treatment of bleeds. Simulations explored doses and frequencies required to sustain target World Federation of Hemophilia (WFH) factor activity levels.ResultsPK profiles of N9-GP and rFIXFc were described by one- and three-compartment models, respectively. Simulations predicted significantly reduced dosing frequency and consumption for N9-GP than rFIXFc. For severe bleeds, a single N9-GP dose (80 IU/kg) is sufficient to maintain WFH-recommended FIX levels, whereas multiple rFIXFc doses are required. For surgery, redosing in the first week with N9-GP is modeled at day 6 vs rFIXFc dosing at 6, 30, 54, 78, and 126 hrs. For life-threatening bleeds, N9-GP is required at days 0, 3, 6, 13, and 18 vs rFIXFc redosing after 6 hrs with 10 additional doses at 24-, 48-, and 72 hr intervals.ConclusionPK modeling approaches based upon direct comparative studies offer insights into PK differences between EHL FIX products. Model simulations show N9-GP may allow on-demand treatment and perioperative management with 55–75% fewer injections and 65–74% lower overall factor concentrate consumption than rFIXFc.

Preparation of an oil suspension containing ondansetron hydrochloride as a sustained release parenteral formulation.

Ondansetron hydrochloride (ODS) is a selective 5-hydroxytryptamine type 3 antagonist for nausea and emesis prevention in neoplastic patients. To reduce dosing frequency and side effects and improve patient compliance, a sustained release parenteral formulation of ODS was developed. Microparticles of methylcellulose (MC) and ODS were prepared using the spray-drying method and suspended in oils to form oil suspensions. The formulations were evaluated for residual moisture, drug content, size distribution, DSC, XRD, FTIR, SEM, drug release, and pharmacokinetic studies. The effects of polymers and oils on the drug release were evaluated. MC showed the most prominent sustained release effect among various polymers examined with the optimum MC/ODS ratio of 2:1 (w/w). The particle size of the produced microparticles was in the mean diameter of approximately 3 μm. Physicochemical characterization suggested that ODS existed in an amorphous matrix within the microparticles and interacted with MC via hydrogen bonds. Corn oil was selected as the appropriate oil for suspension due to the sustained release of ODS and the appropriate viscosity. The optimized sustained release formulation of ODS was the corn oil suspension of spray-dried microparticles containing MC and ODS (2:1, w/w). It showed an in vitro drug sustained release up to 120 h, while the oil suspension of ODS without any polymer released the drug within 2 h. Following subcutaneous administration in rats, the optimized formulation could prolong the drug release until 72 h with the enhanced bioavailability in comparison with the ODS solution. The oil suspension of spray-dried microparticles might be an efficient approach for prolongation of the drug effect in the management of nausea and emesis. Graphical abstract.

2499. Perceptions of and Preferences for Oral or Long-Acting Injectable Antiretroviral Treatment Regimens in the United States and Canada

BackgroundAntiretroviral treatment (ART) for patients living with HIV (PLHIV) has improved greatly, however, challenges with daily oral dosing remain. New ART options with reduced dosing frequency and innovative delivery methods may help address these challenges. This study assesses patient and physician satisfaction with current treatments and preferences for switching to a monthly or every other month long-acting injectable (LAI) ART.MethodsThis is a cross-sectional online survey of PLHIV and physicians treating PLHIV in United States and Canada. A literature review, clinical expert input, and qualitative and quantitative pilots informed survey design. Eligible PLHIV were on ART for ≥ 6 months and virally suppressed (self-reported). Survey questions for patients evaluate satisfaction and adherence to current ART. Treatment preferences are assessed using a discrete choice experiment (DCE), where respondents choose between staying on current ART, switching to another oral ART or switching to a LAI ART. DCE treatment attributes include dosing frequency, side effects, forgivability, food/mealtime restrictions, and mode of administration. Pilot data for US patients is included here; the main survey will include approximately 550 patients and 450 physicians.ResultsOf 51 PLHIV completing the pilot survey, 80% were male, mean age was 54 years, and 63% were on ART for ≥10 years. Switching ART was common, with 55% reporting changing their ART ≥ 3 times. Just under half of patients (47%) were not totally satisfied with their current ART. Most common reasons for dissatisfaction included daily reminder of having HIV (31%) and having to take medicine every day (28%). Just over a quarter of patients (28%) reported forgetting to take their ART in the prior month. Across all DCE choices, patients preferred to remain on their current treatment 47% of the time, while 45% of the time patients preferred switching to the LAI, and for the remaining 8%, patients chose switching to another oral ART regimen.ConclusionDespite advances in ART, treatment challenges remain. Among the treatment-experienced PLHIV in this pilot survey, over half of their choices resulted in switching to an alternative regimen, and when opting to switch, most patients preferred the long-acting injectable treatment regimen.Disclosures All authors: No reported disclosures.