Reference Product Research Articles

Real-world evaluation of oncolytic biosimilar adoption on medication adherence and out-of-pocket costs among members of a national payor.

e23092 Background: Biosimilars provide quality, safe, effective, and lower-cost alternative treatment options that have no difference from their reference product. CVS Health® recently launched a biosimilar adoption strategy to expand access to biosimilars and drive sustainable cost savings and options for consumers. The purpose of this study is to compare treatment duration, adherence, and out-of-pocket (OOP) costs between individuals receiving oncology biosimilars versus oncology reference branded products. Methods: This retrospective cohort study included adult commercial fully insured and Medicare members of a large national payor with ≥1 claim for a physician-administered oncology biosimilar or reference branded product between 12/01/2020 and 11/30/2022. To assess adherence, we compared claims per month, defined as the total claims during the study divided by the number of months patients received medication and time on therapy, defined as the number of months between first claim in period and last claim in period (inclusive). OOP costs, defined as the sum of deductible and applicable coinsurance at the time of visit, were examined as a secondary endpoint. Continuous variables were compared with Student’s t-test; categorical variables were compared with a Chi-squared test. P values < 0.05 were considered significant. Results: 2,597 individuals were included in the evaluation with between-group differences in age, gender, and agent received (all p < 0.001). 41,182 claims were evaluated; 59.2% were for reference branded products. 3,817 medication combinations were evaluated; 64.2% received a reference branded product. Individuals receiving biosimilar agents had more total claims (mean [standard deviation, SD]: 13.9 [6.3] vs. 13.1 [7.5]; p = 0.003) and claims per month (1.4 [0.5] vs. 1.3 [0.6]; p < 0.001). However, individuals receiving reference branded products had longer time on therapy (10.5 [4.1] vs. 10.0 [3.7] wk; p = 0.006). When examining oncology agents only (n = 1,992), individuals receiving biosimilar agents had more claims per month (1.4 [0.5] vs. 1.3 [0.6]; p < 0.001). In contrast, individuals receiving reference branded products had longer time on therapy (11.0 [4.1] vs. 10.1 [3.7] wk; p < 0.001). Individuals prescribed oncology support reference branded products and oncology treatment reference branded products experienced 475% and 350% higher OOP spend compared to individuals prescribed biosimilars (both p < 0.001), respectively. Conclusions: This real-world evaluation leveraging administrative claims revealed that individuals receiving oncology biosimilars appear to experience shorter observed time on therapy, higher adherence, and lower OOP spend than individuals receiving reference branded products. Despite superior member-centric outcomes, reference branded products were prescribed more often than biosimilars.

EE467 Estimation of Budget Impact With the Substitution of Biologic Reference Product for Biosimilars in Patients With Rheumatoid Arthritis From the Perspective of Medium Size Healthcare Insurance in Brazil

EE467 Estimation of Budget Impact With the Substitution of Biologic Reference Product for Biosimilars in Patients With Rheumatoid Arthritis From the Perspective of Medium Size Healthcare Insurance in Brazil

Enhancing solubility and oral bioavailability of rosuvastatin through interpenetrating polymer network (IPN) nanogels: Fabrication, characterization, and in-vivo efficacy assessment

Rosuvastatin (RST) exhibits low aqueous solubility, presenting a challenge for its effective oral administration. The objective of this study is to improve the solubility of RST through the creation and assessment of interpenetrating polymer network (IPN) nanogels. The nanogels were produced via a free radical polymerization method, where hydrophilic polymers β-cyclodextrin (β-CD) and Poloxamer-407 (P407) were combined with the monomer 2-acrylamido-2-methylpropane sulfonic acid (AMPS). Comprehensive characterization of the nanogels included drug loading efficiency, solubility studies, zeta sizer measurements, sol-gel analysis, Fourier-transform infrared (FTIR) spectroscopy, thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), scanning electron microscopy (SEM), swelling studies, and in-vitro release analysis. Oral toxicity experiments were performed to verify the safety of the β-CD/Poloxamer-407-co-poly (AMPS) IPN nanogels when taken by mouth. The scanning electron microscopy (SEM) investigation unveiled a network structure characterised by porosity and sponginess. The thermal stability and complex synthesis of the nanogel components were validated by the FTIR, TGA, and DSC spectra. X-ray diffraction (XRD) analysis indicated a reduction in the crystallinity of RST within the nanogel matrices. The optimized nanogels formulation demonstrated a particle size of 185.71 ± 1.03 nm. Comparative studies with a reference product highlighted significant enhancements in drug solubility and release characteristics attributed to the fabricated nanogels. Toxicity assessments confirmed the non-toxic nature of the nanogels, supporting their biocompatibility. In-vivo studies using hyperlipidemic animal models validated the anti-hyperlipidemic efficacy of the developed nanogels. The nanogels' biocompatibility, high solubilization capacity, improved dissolution profile, rapid production process, and superior physicochemical properties underscore their potential as an effective oral delivery system for lipophilic drugs.

Evaluation of Pharmacokinetics of a BCS Class III Drug with Two Different Study Designs: Tenofovir Alafenamide Monofumarate Film-coated Tablet.

Tenofovir alafenamide (TAF) is a BCS Class III compound and an oral pro-drug of Tenofovir (TFV) with limited oral bioavailability. The bioavailability of the oral intake increases with food as a result of the low stability of the active substance in the stomach. The reference drug is "Vemlidy® 25mg Film Tablet", which contains 25mg of TAF in "hemifumarate" form, is under patent protection until 15.08.2032 by Gilead, and so the "monofumarate" form was used in the present study. At first, a pilot study was conducted involving 12 subjects under fed conditions. The results of the pilot study revealed the test and reference products were not bioequivalent, as a result of insufficient statistical power and high inter-subject variability. Secondly, a physiologically based pharmacokinetic (PBPK) simulation was performed based on the pilot study results and literature data. Finally, the power of the design was increased and the pivotal study design was optimized into a four-period, full-replicated, cross-over study with 34 subjects under fed conditions and it was concluded that the test and reference products were bioequivalent. In conclusion, the present study proved the importance of a correct study design with higher statistical power for a BCS Class III compound with high variability, to present the pharmacokinetics.

Comparative evaluation of dissolution profiles of the generic drug lamivudine 150 mg tablet marketed in Peru vs. the innovative Epivir.

Lamivudine is one of the most prescribed drugs in the world, and is used to treat human immunodeficiency and hepatitis B. This study aimed to evaluate the quality attributes and compare the dissolution profiles of two batches (A and B) of generic lamivudine 150 mg tablets with the innovator drug Epivir 150 mg tablets. We conducted an analytical, experimental, cross-sectional study, and used a spectrophotometric method at a wavelength of maximum absorption (λ) corresponding to 270 nm, to measure the percentage of dissolved drug. The study evaluated identification, content, dissolution and mass uniformity. Apparatus 2 USP (Paddle) 75 rpm, 900 mL of dissolution medium (37 ± 0.5 °C) was used in three dissolution media: pH 1.2; 4.5 and 6.8. Samples of 5 mL were obtained at 5, 10, 15, 20 and 30 min. Both batches of generic lamivudine (A and B) were found to have the same dissolution kinetic profile as the innovator drug. Both formulations met the criteria of very fast dissolving (85% dissolved in 15 min), and fast dissolving (85% dissolved in 30 min) drugs. Therefore, it was not necessary to calculate the similarity factor. We concluded that generic drugs A and B are in vitro equivalents to the innovator drug Epivir. Motivation for the study. To evaluate the quality of antiretroviral drugs used in the treatment of HIV dispensed in the HAART Program of the Ministry of Health of Peru. Main findings. Two batches of generic lamivudine drugs were found to achieve a dissolution rate greater than 85% at 15 min, being equivalent in vitro to the reference product Epivir. Implications. There is a need to apply the current regulations regarding equivalence between drugs by the regulatory authority prior to their authorization and to include dissolution profile tests as a requirement in public drug purchases, especially in national strategies (HIV, TB, etc.), in order to ensure quality products for the population.

Locally acting dermatology drug products: Pharmaco-analytic considerations for bioequivalence

Bioequivalence determinations for locally acting dermatology drug products rely on assessing product sameness thru physicochemical composition and structure comparison, comparing the concentration of the active ingredient at the putative site of action, or comparing the clinical performance of the test (would-be generic) and reference products. Topical product action on cutaneous disease may be confounded by the action of excipients and are also subject to the inherent variability of how product may interact with the skin, including thermodynamic factors such as evaporation, spreadability, and interaction with the local environment such as heat and light and skin moisture.

Dual Functionalization of Hyaluronan Dermal Fillers with Vitamin B3: Efficient Combination of Bio-Stimulation Properties with Hydrogel System Resilience Enhancement.

Hyaluronic acid (HA) hydrogels are commonly used for facial dermal filling and for alternative medical aesthetic purposes. High diversity exists in commercial formulations, notably for the optimization of finished product stability, functionality, and performance. Polyvalent ingredients such as calcium hydroxylapatite (CaHA) or vitamin B3 (niacinamide) are notably used as bio-stimulants to improve skin quality attributes at the administration site. The aim of the present study was to perform multi-parametric characterization of two novel cross-linked dermal filler formulas (HAR-1 "Instant Refine" and HAR-3 "Maxi Lift") for elucidation of the various functional impacts of vitamin B3 incorporation. Therefore, the HAR products were firstly comparatively characterized in terms of in vitro rheology, cohesivity, injectability, and resistance to chemical or enzymatic degradation (exposition to H2O2, AAPH, hyaluronidases, or xanthine oxidase). Then, the HAR products were assessed for cytocompatibility and in vitro bio-stimulation attributes in a primary dermal fibroblast model. The results showed enhanced resilience of the cohesive HAR hydrogels as compared to JUVÉDERM® VOLBELLA® and VOLUMA® reference products in a controlled degradation assay panel. Furthermore, significant induction of total collagen synthesis in primary dermal fibroblast cultures was recorded for HAR-1 and HAR-3, denoting intrinsic bio-stimulatory effects comparable or superior to those of the Radiesse® and Sculptra™ reference products. Original results of high translational relevance were generated herein using robust and orthogonal experimental methodologies (hydrogel degradation, functional benchmarking) and study designs. Overall, the reported results confirmed the dual functionalization role of vitamin B3 in cross-linked HA dermal fillers, with a significant enhancement of hydrogel system stability attributes and the deployment of potent bio-stimulatory capacities.

Benefits of Biosimilars in the Management of Patients with Inflammatory Bowel Disease: An International Survey.

Background/Objectives: The development of biosimilar drugs has revolutionized the management of patients with inflammatory bowel diseases (IBD), significantly reducing healthcare costs. However, the impact of biosimilar availability on patient care is unknown. We conducted a survey to investigate the benefits of using biosimilars in patients with IBD. Methods: Physicians involved in the IBD care were invited to participate in an anonymous online survey. The questionnaire consisted of 42 questions addressing availability, cost, recommendations, and positioning regarding the use of biosimilars. Results: A total of 233 physicians (88.4% gastroenterologists) from 63 countries worldwide participated in the survey. Most respondents had >10 years of practice (202/233, 85.9%). Biosimilars were available in almost all cases (221, 94.8%), and over two-thirds of respondents had more than one biosimilar of adalimumab or infliximab on hospital formulary. In most cases, adalimumab and infliximab biosimilars had a reduced cost of at least 30% compared to the originators. The savings resulting from the use of biosimilars allowed physicians to improve patient care (3/233, 1.3%) or to improve research (2/233, 0.8%) in only a few cases. Interestingly, for about 50% of respondents, the cost of biologics was a limitation for patient access to therapy. For the majority of participants, the availability of biosimilars did not influence treatment decisions in Crohn's disease (70/165, 42.4%) and ulcerative colitis (83/165, 50.3%). Conclusions: The reduced cost of biosimilars compared to reference products is the main driver of choice in IBD. The impact of biosimilars of ustekinumab and vedolizumab in improving access to therapies and changing the treatment algorithm remains to be defined.

Drug dissolution and transit in a heterogenous gastric chyme after fed administration: Semi-mechanistic modeling and simulations for an immediate-release and orodispersible tablets containing a poorly soluble drug

Mathematical models that treat the fed stomach content as a uniform entity emptied with a constant rate may not suffice to explain pharmacokinetic profiles recorded in clinical trials. In reality, phenomena such as the Magenstrasse or chyme areas of different pH and viscosity, play an important role in the intragastric drug dissolution and its transfer to the intestine. In this study, we investigated the data gathered in the bioequivalence trial between an immediate-release tablet (Reference) and an orally dispersible tablet (Test) with a poorly soluble weak base drug administered with or without water after a high-fat high-calorie breakfast. Maximum concentrations (Cmax) were significantly greater after administering the Reference product than the Test tablets, despite similar in vitro dissolution profiles. To explain this difference, we constructed a novel semi-mechanistic IVIVP model including a heterogeneous gastric chyme. The drug dissolution in vivo was modeled from the in vitro experiments in biorelevant media simulating gastric and intestinal fluids in the fed state (FEDGAS and FeSSIF). The key novelty of the model was separating the stomach contents into two compartments: isolated chyme (the viscous food content) that carries the drug slowly, and aq_chyme open for rapid Magenstrasse-like routes of drug transit. Drug distribution between these two compartments was both formulation- and administration-dependent, and recognized the respective drug fractions from the clinical pharmacokinetic data. The model’s assumption about the nonuniform mixing of the API with the chyme, influencing differential drug dissolution and transit kinetics, led to simulating plasma concentration profiles that reflected well the variability observed in the clinical trial. The model indicated that, after administration, the Reference product mixes to a greater extent with aq_chyme, where the released drug dissolves better and transfers faster to the intestine. In conclusion, this novel approach underlines that diverse gastric emptying of different oral dosage forms may significantly impact pharmacokinetics and affect the outcomes of bioequivalence trials.

How monoterpene hydrocarbons could be an alternative insecticide for effective control of Lepidoptera defoliators?

In Tunisia, Orgyia trigotephras (Lepidoptera, Erebidae) is considered among the most harmful pests for forests that cause significant damage to kermes oak and its maquis. Thus, the aim of this study was to evaluate the insecticidal effect of essential oils of Eucalyptus camaldulensis, E. kirtoniana, Thymus algerienis and T. capitatus toward the 3rd instar larvae of O. trigotephras. The chemical composition of essential oils was studied using GC-MS. Different concentrations of essential oils were used for contact action and compared to synthetic insecticide deltamethrin as a reference product. The insecticidal effects of the essential oils were evaluated by measuring the lethal time of 50% of larvae (LT50) and the lethal time of 100% of larvae (LT100). Eucalyptus essential oils were found effective when compared with the essential oil of Thymus spp. and deltamethrin. Their high toxicity may be attributed to their richness in monoterpenes hydrocarbons. Compounds belonging to monoterpenes hydrocarbons may constitute an alternative insecticide for controlling Lepidoptera defoliators outbreaks.

Alcohol-Based Chlorhexidine and Potassium Sorbate Rub Strengthens the Effectiveness of Traditional Hand Scrubbing and Improves Long-Lasting Effectiveness-Evaluation of Hand Preparation Protocols According to EN 12791.

Despite the advantages of surgical handrub in terms of the ease of application and effectiveness, chlorhexidine (CHG)-based hand scrubbing remains the preferred method for surgical hand preparation. However, it does not systematically meet the non-inferiority requirement of the European norm (EN) 12791 with respect to n-propanol (the reference product) and does not provide the sustained efficacy expected for these long-lasting agents. Commercially available alcohol-based products have also failed to demonstrate sustained efficacy according to EN 12791. Multi-step protocols enhance the efficacy of hand scrubbing, yet their extended disinfection duration might diminish their allure for healthcare professionals. In this study, we show that hand scrubbing with CHG 4% followed by a 1 min rubbing with the novel formulation of ethanol (Et) 70%/CHG 3% plus 0.3% potassium sorbate food additive (PS) meets the non-inferiority requirement and demonstrates sustained efficacy when tested according to EN 12791. The immediate and 3 h effect of this protocol was significantly higher than that of n-propanol and the homologous disinfection protocol without PS (CHG 4% hand scrub plus Et 70%/CHG 3% rub), demonstrating that the inclusion of PS confers a notable residual effect. We speculate that this non-volatile ingredient acts synergistically with CHG. This promising combination represents an alternative method for the development of new disinfection strategies.

Formulation and evaluation of immediate-release capsules of pregabalin

The aim is to develop and evaluate capsules with various excipient compositions that satisfy the reference product's specifications to achieve an in-vitro correlation with the reference product after that. Pregabalin I.R. capsules were formulated using Corn starch, Dibasic calcium phosphate, Lactose anhydrous, and Avicel pH 102(Microcrystalline cellulose). After compatibility studies for the capsule blend were completed, the Drug was determined to be compatible with all excipients used in various formulations. After the blend was put into capsules, several metrics were examined, including average weight, disintegration, and assay. The formulation containing D.C.P. disintegrates at a faster rate than other formulations. It was discovered that the percentage of drug release in the F7 invitro dissolving profile was equal to that of the innovator product. Finally, it was concluded that the F7 formulation is better and similar to the innovator product.

Comparative Pharmacokinetic Study of Standard Astaxanthin and its Micellar Formulation in HealthyMale Volunteers.

Astaxanthin is a naturally occurring carotenoid with high anti-oxidant properties, but it is a very lipophilic compound with low oral bioavailability. This study was conducted to compare the pharmacokinetic parameters of a novel astaxanthin preparation based on micellar solubilization technology, NovaSOL® 400-mg capsules (Test product), and those of astaxanthin 400-mg capsules (reference product), after single oral dose administration to healthy male adults. A single oral dose (400 mg equivalent to 8 mg astaxanthin) of test and reference astaxanthin were administered with 240 mL of water to 12 volunteers according to crossover design, in two phases, with a washout period of 1week in between. Blood samples were collected at hourly intervals for the first 12 h, then at 24.0, 48.0, and 72.0 h after administration. Aliquots of plasma were centrifuged and the clear supernatant was injected into the high performance liquid chromatography-diode array detection (HPLC-DAD) system. Plasma concentration of astaxanthin versus time profiles were constructed, and the primary pharmacokinetic parameters, maximum concentration (Cmax), area under concentration time curve from time of administration (0) to time (t) [AUC0-t] or to infinity ∞, [AUC0-∞], half-life (T½) and time to reach Cmax (Tmax)were calculated. The test micellar astaxanthin reached a Cmax of 7.21 µg/ml after 3.67 h compared to only 3.86 µg/ml after 8.5 h for the reference native astaxanthin. Micellar formulation of astaxanthin is capable of producing a high concentration of astaxanthin in plasma in a shorter time, thereby expected to provide faster potential therapeutic efficacy.

Efficacy of Pirikool® 300 CS used for indoor residual spraying on three different substrates in semi-field experimental conditions

BackgroundVector control using insecticides is a key prevention strategy against malaria. Unfortunately, insecticide resistance in mosquitoes threatens all progress in malaria control. In the perspective of managing this resistance, new insecticide formulations are being tested to improve the effectiveness of vector control tools.MethodsThe efficacy and residual activity of Pirikool® 300 CS was evaluated in comparison with Actellic® 300 CS in experimental huts at the Tiassalé experimental station on three substrates including cement, wood and mud. The mortality, blood-feeding inhibition, exiting behaviour and deterrency of free-flying wild mosquitoes was evaluated. Cone bioassay tests with susceptible and resistant mosquito strains were conducted in the huts to determine residual efficacy.ResultsA total of 20,505 mosquitoes of which 10,979 (53%) wild female Anopheles gambiae were collected for 112 nights. Residual efficacy obtained from monthly cone bioassay was higher than 80% with the susceptible, laboratory-maintained An. gambiae Kisumu strain, from the first to the tenth study period on all three types of treated substrate for both Actellic® 300CS and Pirikool® 300CS. This residual efficacy on the wild Tiassalé strain was over 80% until the 4th month of study on Pirikool® 300CS S treated substrates. Overall 24-h mortalities of wild free-flying An. gambiae sensu lato which entered in the experimental huts over the 8-months trial on Pirikool® 300CS treatment was 50.5%, 75.9% and 52.7%, respectively, on cement wall, wood wall and mud wall. The positive reference product Actellic® 300CS treatment induced mortalities of 42.0%, 51.8% and 41.8% on cement wall, wood wall and mud wall.ConclusionPirikool® 300CS has performed really well against resistant strains of An. gambiae using indoor residual spraying method in experimental huts. It could be an alternative product for indoor residual spraying in response to the vectors' resistance to insecticides.

Cariprazine Orodispersible Tablet: A New Formulation for Cariprazine.

Cariprazine is an atypical dopamine receptor partial agonist antipsychotic available in the form of capsules. Although capsules are one of the most desirable routes of administration, there are certain situations (e. g., in an acute psychiatric setting, or when swallowing difficulties, or liquid shortages are present) when they cannot be administered. Therefore, alternative solutions like orodispersible tablets are needed. This study aimed to investigate the bioequivalence of a newly developed orodispersible tablet to the commercially available hard gelatine capsule of cariprazine 1.5 mg. This was a phase I, open-label, randomized, single-dose bioequivalence study. It had a 2-period, 2-sequence, cross-over design, where each subject received one test and one reference product in a randomized sequence, separated by a wash-out period of 55 days. Blood sampling was performed over 72 h after dosing. Cariprazine concentrations were analyzed by a validated HPLC-MS/MS method. Standard bioequivalence statistics was applied to PK parameters calculated by non-compartmental analysis. Safety measures were analyzed descriptively. Pharmacokinetic data of 43 healthy volunteers and safety data of 54 subjects was analyzed. Cariprazine AUC0-72h and Cmax geometric mean ratios were 117.76% and 100.88%, respectively. The 90% confidence intervals were within the pre-defined bioequivalence acceptance limits of 80.00% - 125.00%. Safety data was in line with the Summary of Product Characteristics of Cariprazine. The result of this clinical trial proved the bioequivalence of the new orodispersible tablet formulation when compared to hard gelatine capsules, enabling an alternative option for treatment of those suffering from schizophrenia.

Abstract PO3-17-04: HER2-directed biosimilar Ogivri in the treatment of breast cancer: real world reporting of symptoms and wellbeing using electronic patient reported outcome (ePRO)

Abstract Introduction: Trastuzumab has a major impact on the treatment of HER2 positive breast cancer (BC). Anti-HER2 biosimilars, such as OgivriTM, demonstrated safety and clinical equivalency to the reference product HerceptinTM in clinical trials. However, real-world reporting of side effects, quality of life (QoL) and outcome in patients treated with biosimilars has not yet been performed using electronic PROs. Here standardized and structured ePROs are dynamically recorded with the mediduxTM app during OgivriTM treatment and are applied to perform a comparative analysis with ePROs derived from 38 historical patients treated with HerceptinTM in two previous studies (NCT02004496, NCT03578731). Methodology: In this prospective observational study, patients with HER2-positive BC were treated with OgivriTM alone +/- Pertuzumab, +/- Chemotherapy and hormone therapy in neo-adjuvant, adjuvant and non-curative settings. Over an observational period of 6 weeks, patients used the mediduxTM app to dynamically record symptoms (according to CTCAE), well-being, EQ-5D-5L, cognitive capabilities, and vital parameters. Comparative analysis was performed with historical data from 38 patients that had reported 5217 ePROs and more than 1400 reports of well-being in similar therapeutic settings. Results: 52 females (age 37-86 yrs) were treated with OgivriTM. From 92 different symptoms available, 84 were entered (average > 2 symptoms/day) resulting in 10`532 individual patient entries. Among the most common symptoms reported in both groups were fatigue, taste disorder, nausea, diarrhea, dry mucosa, joint discomfort, tingling, sleep disorder, headache, appetite loss. As compared to HerceptinTM, overall, symptoms associated with OgivriTM were reported with a similar incidence and distribution among groups (p=0.68), although slightly but not significantly lower scores (p=0.24; CI: 0.08-0.31). Distribution of symptom grades in the OgivriTM cohort revealed that the vast majority of patients experienced mild and grade 1 toxicities, 13% grade 2, 2% grade 3 and 0.4% grade 4 toxicities, respectively. The latter finding could possibly also be attributed to a trend towards de-escalation in chemotherapeutic regimes during the past 5 years since data acquisition, affecting anthracyclines and taxanes, and that. Of note, when treatments were compared restricted to the trastuzumab antihormones and trastuzumab- paclitaxel therapies, this reported trend seamed weaker. Importantly, well-being of patients undergoing HER2 directed treatment did not differ (p=0.24; CI: 0.39-0.88) in both cohorts. Conclusion: No difference was reported for symptoms, adverse events, and well-being with respect to the Trastuzumab biosimilar OgivriTM in comparison with HerceptinTM. The integration of ePRO into research and clinical practice provides reliable information when investigating real world tolerability and outcomes of similar therapeutic compounds. Citation Format: Andreas Trojan, Sven Roth, Reinhard Zenhäusern, Yannick Kadvany, Christian Jackisch, Matti Aapro, Alexandru Eniu. HER2-directed biosimilar Ogivri in the treatment of breast cancer: real world reporting of symptoms and wellbeing using electronic patient reported outcome (ePRO) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-17-04.

Development of immediate-release formulation with reliable absorption of rivaroxaban in various meal regimes.

The bioavailability of rivaroxaban at the higher doses (15 and 20 mg) is considerably reduced when the drug is administered on an empty stomach. This can lead to inadequate anticoagulant effect, and therefore, it is recommended to use the higher doses at fed state. However, proper posology may represent a barrier for some patients. Therefore, the aim of this study was to evaluate innovative rivaroxaban-containing formulations designed to eliminate the food effect to ensure reliable absorption and thus to improve patient adherence with the treatment. Three prototypes (Cocrystal, HPMCP and Kollidon) with rivaroxaban were developed and their bioavailability and food effect in comparison to the reference product was tested in open label, randomized, single oral dose, crossover studies, where test products were administered under fasting and fed conditions and the reference product was administered under fed conditions. Comparable bioavailability for all tested prototypes both under fed and fasting conditions was demonstrated as the 90% confidence intervals of the geometric mean ratios for area under the concentration-time curve remained within the standard acceptance range of 80.00%-125.00%. An innovative immediate release form of rivaroxaban with no food effect on drug bioavailability has been developed, which may represent an important step toward increasing adherence, improving treatment outcome and reducing health care costs.

Association of baseline factors with 1-year outcomes in the SB11-ranibizumab equivalence trial: A post hoc analysis

PurposeTo identify baseline factors associated with 1-year outcomes when treating neovascular age-related macular degeneration (nAMD) with ranibizumab biosimilar SB11 or reference ranibizumab (rRBZ), and to compare efficacy of the two products within subgroups judged to be clinically relevant. DesignPost hoc analysis of a prospective, equivalence phase 3 randomized clinical trial (RCT) Methods705 patients with nAMD were randomized 1:1 to receive SB11 or rRBZ for 48 weeks. Pooled and randomized groups were used to identify baseline factors associated with clinical outcomes at Week 52 using multiple linear regression models. Significant factors identified in regression analyses were confirmed in analyses of variance. Subgroup analyses comparing best-corrected visual acuity (BCVA) changes between SB11 and rRBZ were conducted. Results634 (89.9%) participants completed the 52-week visit. Regression analyses showed that younger age, lower BCVA, and smaller total lesion area at baseline were associated with greater BCVA gain at Week 52, while older age, lower BCVA, and thicker central subfield thickness (CST) at baseline were predictors of greater CST reduction in the pooled group. Subgroup analyses demonstrated that BCVA outcomes appeared comparable for the SB11 and rRBZ groups. ConclusionPost hoc analyses of the SB11-rRBZ equivalence study showed that baseline age, BCVA, CST, and total lesion area were prognostic factors for visual or anatomical outcomes of nAMD, while subgroup analyses demonstrated comparable results for SB11 and rRBZ. Collectively, the results appear comparable to similar RCTs of anti-vascular endothelial growth factor reference products for nAMD and strengthen confidence in the biosimilarity of SB11.

Apixaban Pharmacokinetics and Bioequivalence of Two Tablet Formulations: A Randomized, Open-Label, Crossover Study, Fasting Condition in Healthy Indonesian Volunteers.

The present study aimed to assess the bioequivalence of a new apixaban generic with reference formulation. Twenty-six healthy volunteers were recruited for an open-label, balanced, randomized, 2-treatment, 2-sequence, 2-period, single oral dose study. Following overnight fasting, each volunteer received 5mg of apixaban test and reference formulations as single doses, separated by a 1-week washout period. Twenty blood samples were collected at predose and multiple time points between 0.5 and 72 hours after dosing. A validated ultra-performance liquid chromatography-tandem mass spectrometry detection method following a protein precipitation step was implemented to determine apixaban concentrations. Noncompartmental analysis was used to derive the pharmacokinetic parameters, which were then compared between the test and reference products using a multivariate analysis of variance. The pharmacokinetic parameters of the test product were not statistically different from the reference product, and the 90% confidence intervals of apixaban natural log-transformed area under the concentration-time curve from time 0 to infinity, area under the concentration-time curve from time 0 to the last measurable concentration, and maximum concentration were within 80%-125% based on the bioequivalence acceptance range criteria. The test and reference formulations of apixaban are bioequivalent in healthy subjects under fasting conditions.

Oil-Based Curcuminoid Phospholipid Formulation Mimicking Natural Digestion Enhances Oral Bioavailability of Curcuminoids in Healthy Subjects.

Curcumin, the fat-soluble active ingredient and major compound of curcuminoids contained in the curcuma root, is known for its physiological low absorption and bioavailability. Various formulations and galenic technologies are currently available on the market. In this study, the product tested was provided as a soft gelatin capsule containing curcuminoids in an oily matrix mixed with phospholipids (oil/phospholipids [PL]-based, no new technologies applied or artificial excipients added). This was intended to improve bioavailability of curcuminoids as well as to mimic the natural digestion process of fat-soluble substances. In particular, the oral bioavailability of curcuminoids in the oil/PL-based formulation was compared with the pure curcuminoids extract alone (reference product), in a randomized, cross-over, single oral dose study design. Twelve healthy subjects were administered 200 mg curcuminoids under fasting conditions. Pharmacokinetic parameters were analyzed from individual concentration-time curves of total curcuminoids, as well as the curcumin metabolite tetrahydrocurcumin (THC). Results showed significantly higher AUC0-8h levels after the intake of the oil/PL-based formulation for total curcuminoids (205.60 vs. 112.50 ng/mL*h, P = .0001) as well as for THC (347.30 vs. 118.90 ng/mL*h, P < .0001) in comparison to the pure curcuminoids extract. Cmax was also significantly higher for both parameters analyzed (total curcuminoids: 47.54 vs. 21.16 ng/mL, P = .0001; THC: 96.69 vs. 29.83 ng/mL, P < .0001). In addition, the uptake kinetic of total curcuminoids was significantly fastened with the oil/PL-based curcuminoids formulation compared with the pure curcuminoids extract (P = .0446). These data suggest an improved impact on curcuminoids uptake of the oil/PL-based formulation and confirms its good tolerability.