Film-coated Tablet Formulation Research Articles

(031) Bioequivalence Studies of Sildenafil Citrate Orodispersible Film Administered With and Without Water versus Viagra Film-Coated Tablets in Healthy Adult Male Volunteers

Abstract Introduction Orodispersible film (ODF) formulation offers ease of use, convenience of administration, and other advantages, especially for patients who have difficulty in swallowing or are on liquid restriction compared with conventional oral formulations for the treatment of erectile dysfunction. Objective These studies compared the bioequivalence of 50 mg sildenafil citrate ODF formulation (test drug) with the marketed 50 mg sildenafil citrate film-coated tablet (FCT) (Viagra; Pfizer, New York, NY) (reference drug), with and without water in 2 randomized cross-over studies. Methods Two randomized cross-over studies were conducted. The first study explored the bioequivalence of test drug administered with and without water compared with the reference drug with water. The second study investigated the bioequivalence of test drug, without water, compared with the reference drug with water. 42 healthy adult male volunteers started the first study and only 40 completed. While 80 subjects who were enrolled completed the second study. All the 120 subjects from both the studies were included for pharmacokinetic and bioequivalence analysis. All volunteers fasted for 10 hours pre-dose. A 1-day washout period between doses was observed. Blood samples were collected at regular intervals both before (up to 120 minutes before dosing) and after dosing (at different intervals up to 14 hours) dosing stages. Statistical analyses on pharmacokinetic parameters were performed. Safety and tolerability for both the formulations were evaluated. Results In the first study, bioequivalence was demonstrated for sildenafil citrate ODF administered with water when compared with the Viagra FCT. The ratios of adjusted geometric means (90% confidence interval (CI)) were maximum plasma concentration: 1.02 (94.91–108.78) and area under the plasma concentration-time curve: 1.09 (104.49–113.21) for sildenafil citrate ODF administered with water vs Viagra FCT. These ratios were within the bioequivalence acceptance range of 80% to 125%, indicating that the bioequivalence criteria were met. The pharmacokinetic parameters for the second study also demonstrated bioequivalence for sildenafil citrate ODF when administered without water compared with Viagra FCT. The ratios of adjusted geometric means (90% CI) were maximum plasma concentration: 1.02 (95.47–109.36) and area under the plasma concentration-time curve: 1.06 (103.42–108.40) for sildenafil citrate ODF administered without water vs Viagra FCT. Adverse events in both the studies occurred at similar rates for the 2 formulations and were mild in intensity and were expected from the known safety profile. Conclusions Sildenafil citrate ODF administered with and without water met bioequivalence criteria compared with Viagra FCT administered with water under fasted conditions in healthy adult male volunteers. These results suggest that the new ODF formulation can be used interchangeably with the marketed FCT formulation. Therefore, the new ODF formulation can be used as a suitable alternative to the conventional oral solid dosage form for the treatment of ED. Disclosure Yes, this is sponsored by industry/sponsor: Viatris Inc. Clarification: Industry initiated, executed and funded study. Any of the authors act as a consultant, employee or shareholder of an industry for: Viatris Inc.

Phase 1/2 Multicenter, Open-Label Study of CTX-712 in Patients with Relapsed/Refractory Acute Myeloid Leukemia and Higher Risk Myelodysplastic Syndromes

Background and Significance Dysregulation of alternative splicing, caused by abnormal expression or mutation of splicing factors, has been identified as an important contributor to the genesis and progression of cancer, and suggested as a novel target for anticancer treatment. CDC2-like kinases (CLK) represent a family of dual-specificity tyrosine and serine-threonine kinases that are involved in the regulation of splicing by phosphorylation of serine/arginine-rich splicing factors (SRSFs) which play a central role in exon recognition. CTX-712 is an orally available, potent, selective, and a first-in-class pan-CLK inhibitor (CLK 1-4), that inhibits phosphorylation of SRSFs resulting in significant antitumor activity in vitro and multiple xenograft models in vivo. CTX-712 formulated in capsules is currently being evaluated in an ongoing first-in-man study in Japan, evaluating tolerability and early efficacy in patients with solid tumors or hematologic malignancies (JapicCTI-184188). Preliminary data from the Japanese study were presented during ASCO 2022 and ASH 2022, and showed an acceptable safety profile (doses up to 175 mg (MTD 140 mg) twice a week in 28-day cycles, observed DLTs included dehydration, decreased platelets, hypokalemia, and pneumonia) with early signs of clinical antitumor activity (2 partial responses / 26 treated solid tumor patients, 5 complete remissions and complete remission with incomplete hematologic recovery/ 8 treated patients with AML or MDS), warranting further clinical investigations.. (J Clin Oncol (2022) 40(16_suppl):3080. Blood (2022) 140(Supplement 1):6211-2.). This abstract details a second study with CTX-712 that has just been initiated. Study Design and Methods A new film-coated tablet formulation will be evaluated in this phase 1/2 multicenter, open-label study of CTX-712 in patients with (mutated or wild type spliceosomes genes) relapsed/refractory AML, higher risk MDS (IPSS-R intermediate, high, or very high), or high marrow blast (≥5 %) MDS/MPN (including CMML). The phase 1 part of the study will be conducted at 4 US sites, and all sites are currently open for enrolment. The study allows patients with performance status 0, 1, or 2, adequate organ function, and up to four prior lines of therapy. Due to potential risk of interactions (in vitro studies suggest CYP3A4 as main metabolic pathway for CTX-712), concomitant use of strong CYP3A4 inhibitors is prohibited. Use of azole antifungals that are not strong CYP3A4 inhibitors (e.g., isavuconazole) is permitted. The phase 1 part of the study consists of dose-escalation (sequential standard 3 + 3 design), where cohorts of 3 (or 6) patients will receive ascending doses of CTX-712 once weekly in a 28-day cycle with continuous monitoring of emerging clinical PK, PD, safety, and efficacy data, to determine the recommended phase 2 dose (RP2D) based on the suggestion by the Safety Review Committee (SRC). The protocol defines five different dose levels (20-140 mg, once weekly) but also authorizes the SRC to suggest up to two interim dose levels or alternate schedules (e.g., dosing two times a week) if supported by emerging data. The suggested RP2D will be used in a confirmatory phase 1 expansion cohort where an additional 10 patients (total n = 16; 8 patients with AML and 8 patients with MDS) will be treated to gain further confidence in the selected dose level. The phase 2 part of the study will commence after the RP2D has been identified and confirmed and aims at evaluating therapeutic activity in R/R AML (Cohort 2a) or R/R HR-MDS (Cohort 2b), in addition to confirmation of the safety profile. Clinical trial registry number: NCT05732103

Patient preference for deferasirox film-coated versus dispersible tablet formulation: a sequential-design phase 2 study in patients with thalassemia.

Iron chelation therapy (ICT) is the mainstay of treatment in patients with thalassemia requiring blood transfusions. This phase 2 JUPITER study evaluated patient preference betweenfilm-coated tablet (FCT) and dispersible tablet (DT) in transfusion-dependent thalassemia (TDT) or non-TDT (NTDT) patients treated with both formulations in a sequential manner. The primary endpoint waspatient-reported preference for FCT over DT, while secondary outcomes included patient reported outcomes (PROs) evaluated by overall preference, and by age, thalassemia transfusion status, and previous ICT status. Out of183 patients screened, 140 and 136 patients completed the treatment periods 1 and 2 of the core study, respectively. At week48, themajority of patients preferred FCT over DT (90.3 vs. 7.5%; difference of percentage: 0.83 [95% confidence interval (CI), 0.75-0.89; P < 0.0001]). FCT scored better on secondary PROs and showed less severe gastrointestinal symptoms than DT, except in the change of modified Satisfaction with Iron Chelation Therapy (mSICT) preference scores, which were similar for both the formulations. Patients with TDT had stable ferritin levels, while it showed adownward trend up to week 48 in patients with NTDT on deferasirox treatment. Overall, 89.9% ofpatients reported ≥ 1 adverse event (AE), of which 20.3% experienced ≥ 1 serious AE. The most common treatment-emergent AEs were proteinuria, pyrexia, urine protein/creatinine ratio increase, diarrhea, upper respiratory tract infections, transaminase increase, and pharyngitis. Overall, this study reinforced the observations from theprevious study by showing a distinct patient preference for FCT over DT formulation and further supported the potential benefits oflife-long compliance with ICT.

The Bioequivalence Study of Two Dexketoprofen 25 mg Film-Coated Tablet Formulations in Healthy Males Under Fasting Conditions.

Dexketoprofen is a non-steroidal analgesic/anti-inflammatory drug and its trometamol salt is extensively preferred in mild or moderate pain due to its rapid onset of relief. A new formulation of 36.9 mg of dexketoprofen trometamol (equivalent to 25 mg dexketoprofen) tablet has been developed and its bioequivalence to the reference product was proven. An open-label, single-dose, randomized, two-period, and cross-over bioequivalence study was conducted with healthy males under fasting conditions for two different tablet formulations of 25 mg dexketoprofen. To prove the bioequivalence of the test product with the reference product, a comparison study has been performed in compliance with regulations in force under Good Clinical Practice principles. A single-center clinical study was run and blood samples of the participants were withdrawn at specified time points, before and after dosing, to measure the plasma concentrations of dexketoprofen trometamol. A validated analytical method has been developed using an liquid chromatography with tandem mass spectrometry. Instrument to assess the plasma concentrations of the test and reference products. Forty-seven volunteers completed clinical phase of the study. For the test and reference products, the mean ± standard deviations (SD) of Cmax were found 2543.82 ± 655.42 ng/mL and 2539.11 ± 662.57 ng/mL, and the mean ± SD of area under the curve (AUC) from time 0 to the last measurable concentration (AUC0-tlast) were found 3483.49 ± 574.42 h.ng/mL and 3560.75 ± 661.83 h.ng/mL, respectively. The primary target variables data demonstrate the bioequivalence of test and reference products with regard to 90% confidence interval for Cmax of 92.45-108.53% and for AUC0-tlast of 95.57-100.87%. The geometric mean ratios were found as 100.16% and 98.18% for Cmax and AUC0-tlast, respectively. There were no serious adverse events or adverse reactions reported throughout the study. After statistical evaluation of the analytical results, the test and reference products were considered bioequivalent. Both products were well tolerated and considered as safe.

Bioequivalence Study Comparing a Generic and Innovator Drug of Rosuvastatin 20 mg

The bioequivalence study was conducted to compare the bioavailability of two rosuvastatin 20 mg film-coated tablet formulations (test and reference formulation). This study was an open-label, randomized, single-dose, two-periods, twotreatments, and crossover study which included 32 healthy adult male and female subjects under fasting conditions. Each of the two study periods was separated by a 7 days washout period. A single oral dose of test or reference drug was administered to the subject in each period based on the randomization scheme. Plasma concentrations of the drug were determined by LC-MS/MS method. The pharmacokinetic parameters assessed in this study were the area under the plasma concentration-time curve from time zero to 72 h (AUC0-72h), area under the plasma concentration-time curve from time zero to infinity (AUC0-∞), the peak plasma concentration of the drug (Cmax), time needed to achieve the peak plasma concentration (Tmax), and the elimination half-life (T1/2). The geometric mean ratio (GMR) and 90% Confidence Interval (90% CI) for AUC0-72h and Cmax of test/reference drug for rosuvastatin were 97.05 % (89.07%– 105.74%) and 101.15% (89.53%– 114.26%). Since the 90% CI with α 0.05% for AUC0-72h and Cmax of rosuvastatin were within the standard bioequivalence range (80.00– 125.00%), it was concluded that the two rosuvastatin film-coated tablets (test and reference drug) were bioequivalence in terms of the rate and extent of absorption.

Bioequivalence Study of Two Etoricoxib 90 mg Film-Coated Tablet Formulations

The present study was conducted to compare the bioavailability of two etoricoxib 90 mg film-coated tablet formulations (test formulation and reference formulation). This study was an open-label, randomized, single-dose, two-periods, twotreatments, and crossover study which included 24 healthy adult male and female subjects under fasting conditions. Each of the two study periods was separated by a 7 days washout. A single dose of test or reference drug was administered to the subject in each period based on the randomization scheme. Plasma concentrations of the drug were determined by LC-MS/MS method. The pharmacokinetic parameters assessed in this study were the area under the plasma concentration-time curve from time zero to 96 h (AUC0-96h), area under the plasma concentration-time curve from time zero to infinity (AUC0-∞), the peak plasma concentration of the drug (Cmax), time needed to achieve the peak plasma concentration (Tmax), and the elimination half-life (T1/2). The geometric mean ratios (90% CI) of the test drug/reference drug for etoricoxib were 102.39% (97.63% – 107.38%) for AUC0-96h and 93.23% (86.54% – 100.43%) for Cmax. The 90% Confidence Intervals (CI) calculated for AUC0-96h and Cmax of etoricoxib were within the standard bioequivalence range (80.00– 125.00% for AUC0-t and Cmax). It was concluded that the two etoricoxib film-coated tablets (test and reference drug) were bioequivalent in terms of the rate and extent of absorption

Renal function in patients with thalassemia major receiving Exjade® dispersible tablets and a new film-coated tablet formulation of deferasirox (Nanojade®)

In patients with β-thalassemia major (TM), one of the long-term complications of regular blood transfusion is renal dysfunction. The purpose of the current study was to evaluate the renal function in TM patients receiving Exjade® dispersible tablets and a new film-coated tablet formulation of deferasirox (Nanojade®). In this descriptive cross-sectional study, a total of 80 TM patients aged 11-48-year-old entered the study. Patients received 20-30 mg/kg/d (single dose) Exjade® (Exjade group, n = 40) and Nanojade® (Nanojade group, n = 40) orally. To evaluated renal function, serum creatinine (SCr), estimated glomerular filtration rate (eGFR), blood urea nitrogen (BUN), 24-h urine protein (UPro), UCa/UCr, spot UPro/UCr ratio, and serum ferritin were calculated at baseline and every 3 months to 9 months. There was no significant difference in SCr, BUN, eGFR, 24-h UPro, UPro/UCr ratio, UCa/UCr ratio, and serum ferritin between groups at baseline and end of study (P baseline> 0.05, P end of study> 0.05). There was no significant difference in proteinuria between groups at baseline and end of study (P baseline> 0.05, P end of study> 0.05). The proportion of SCr, BUN, eGFR, 24-h UPro, UPro/UCr ratio, and UCa/UCr ratio was not significantly different in TM patients treated with Nanojade® compared to patients' received Exjade®. Nanojade® had similar effects to Exjade®, and therefore, the use of Nanojade® is safe in TM patients and does not seem to be associated with increased renal failure, proteinuria, and hypercalciuria.

Guidelines for the monitoring and management of iron overload in patients with haemoglobinopathies and rare anaemias.

Guidelines for the monitoring and management of iron overload in patients with haemoglobinopathies and rare anaemias.

One and Two-Step In Vitro-In Vivo Correlations Based on USP IV Dynamic Dissolution Applied to Four Sodium Montelukast Products.

Montelukast is a weak acid drug characterized by its low solubility in the range of pH 1.2 to 4.5, which may lead to dissolution-limited absorption. The aim of this paper is to develop an in vivo predictive dissolution method for montelukast and to check its performance by establishing a level-A in vitro-in vivo correlation (IVIVC). During the development of a generic film-coated tablet formulation, two clinical trials were done with three different experimental formulations to achieve a similar formulation to the reference one. A dissolution test procedure with a flow-through cell (USP IV) was used to predict the in vivo absorption behavior. The method proposed is based on a flow rate of 5 mL/min and changes of pH mediums from 1.2 to 4.5 and then to 6.8 with standard pharmacopoeia buffers. In order to improve the dissolution of montelukast, sodium dodecyl sulfate was added to the 4.5 and 6.8 pH mediums. Dissolution profiles in from the new method were used to develop a level-A IVIVC. One-step level-A IVIVC was developed from dissolution profiles and fractions absorbed obtained by the Loo–Riegelman method. Time scaling with Levy’s plot was necessary to achieve a linear IVIVC. One-step differential equation-based IVIVC was also developed with a time-scaling function. The developed method showed similar results to a previously proposed biopredictive method for montelukast, and the added value showed the ability to discriminate among different release rates in vitro, matching the in vivo clinical bioequivalence results.

Formulation of Coated Tablets Film of Jengkol Fruit Seeds (Pithecellobium lobatum Benth.) as A Selenium Herbal Supplement

The correlation between the high content of selenium (Se) in plasma and the low prevalence of cardiovascular disease has been published in previous epidemiological studies. The content of Se in the plasma is determined by daily intake. A preliminary surveillance of Se content of several plants showed that the seeds of jengkol (Pithecellobium lobatum Benth.) has the highest concentration of Se. This study aims to develop a pharmaceutical formulation of Se supplement for adjuvant therapy of cardiovascular disease. The jengkol seeds was made into film coated tablets with a wet granulation method. Optimization of the core tablet formula was carried out with variations of binder concentration and coating material. Evaluation was carried out on uniformity of size and weight, disintegration time, hardness and friability. The content evaluation was carried out including the levels of Se, water content, ash, fat, protein, carbohydrate and crude fiber. The results showed that the F3 had the lowest friability and highest hardness. The coating of tablets using PVA has covered the smell of jengkol seed. The evaluation results showed that film coated tablets contained the Se level content of 0.074 ± 0.004 µg/g, water content of 2.19%, ash content of 1.88%, fat content of 0.89%, protein content of 0.66%, carbohydrate content of 94.38% and crude fiber content 1.79%. The results showed that the jengkol seed film coated tablet formulation could be used as a supplement in additional therapy for cardiovascular disease.Keywords : Pithecellobium lobatum, film coated tablet, herbal supplement, selenium

Adherence to Iron Chelation Therapy with Deferasirox Formulations among Patients with Sickle Cell Disease and β-thalassemia

BackgroundIndividuals with hemoglobinopathies experience complications that often require management with multiple transfusions. These chronic transfusions can lead to iron overload, which places them at increased risk of organ damage, malignancy, and even death. Deferasirox is the most common iron chelator used to treat iron overload due to its safety, efficacy, and oral administration. The first formulation of deferasirox, a dispersible tablet for oral suspension (DT) called Exjade®, was associated with adherence challenges due to complaints from poor taste and side effects such as abdominal discomfort. A new film-coated tablet formulation (FCT) called Jadenu® was subsequently developed to overcome these challenges. ObjectiveThe objective of this study was to compare adherence rates between formulations of deferasirox (DT versus FCT) and describe associations between adherence to chelation therapy and changes in hematological parameters among patients with SCD and β-thalassemia. MethodsIn this retrospective study of 20 children and adults with sickle cell disease (SCD) and β-thalassemia with iron overload, we compared adherence rates for deferasirox DT versus deferasirox FCT. We reviewed data from the electronic medical record and pharmacy expense reports between 2014 and 2018. We calculated the mean medication possession ratio (MPR) and analyzed the mean paired difference in MPR and ferritin levels using paired sample t-test. ResultsThe overall mean MPR was 0.15 (0.25) for deferasirox DT and 0.44 (0.32) for deferasirox FCT. The mean paired difference in MPR when transitioning from deferasirox DT to deferasirox FCT was +0.29, p-value < 0.01 (95% CI: 0.19, 0.39). The mean paired difference in ferritin while on deferasirox DT compared to ferritin 6 months after transitioning to deferasirox FCT was −306 ng/mL p-value = 0.14 (95% CI: 719, 113). ConclusionThere was significant improvement in adherence to iron chelation therapy when patients transitioned from deferasirox DT to deferasirox FCT.

Real-World Experience of Switching from Deferasirox Dispersible to Film-Coated Tablets: Impact on Adherence to Chelation Therapy, Iron Overload and Renal Function

▪BackgroundChronic iron overload is an important complication of long-term blood transfusions for severe beta-thalassemias, sickle cell disease and other blood disorders.Iron chelation therapy (ICT) is required to bind and excrete excess iron, which would otherwise accumulate and lead to organ damage or failure.Deferasirox is a once-daily, orally administered ICT approved for the treatment of chronic iron overload due to frequent blood transfusions in patients with beta-thalassemia major and other anaemias. A film-coated tablet (FCT) formulation was launched in the UK in 2016 and replaced the dispersible tablet (DT) formulation.In the context of a randomised clinical trial, the FCT formulation showed greater adherence and patient satisfaction, better palatability and fewer tolerability concerns than the DT. Furthermore, treatment compliance by pill count was higher with FCT (92.9%) than with DT (85.3%) (Taher et al, 2017). Little information exists however about compliance, efficacy and tolerability outside of a clinical trial setting.ObjectivesWe wished to assess in a ‘real world’ situation, the effects of switching the deferasirox formulation from DT to FCT on patient adherence to ICT, iron overload and renal function.MethodsPatients receiving ICT with deferasirox who were switched from the DT to FCT formulations were followed over a 12-month period and results audited using hospital dispensing and biochemistry records. The date of the first FCT prescription was defined as baseline.The initial daily dose used for switching from DT to FCT was as per manufacturer's recommendations: 70% of the DT daily dose.The impact on iron overload was assessed by comparing serum ferritin levels at 3, 6, 9 and 12 months post-switch with baseline values. The impact on renal function was assessed by comparing serum creatinine levels at 3, 6, 9 and 12 months post-switch with baseline values as well as the number of serum creatinine increases of 30% or greater above baseline.The changes in serum ferritin and creatinine were subsequently analysed by paired t-test.The Proportion of Days Covered (PDC) was calculated as a measure of patient adherence to ICT in the 12 months before and after switching formulations.Results74 patients switched from deferasirox DT to FCT with the following diagnoses: beta-thalassemia (n = 45), sickle-cell disease (9), thalassemia-intermedia (6), HbE-thalassemia (5), other transfusion-dependent disorders (9). The median age was 36 (range: 1-78yo), mean baseline serum ferritin was 2767µg/L (range: 412-8742), mean baseline creatinine was 64.5 umol/L (range: 17-140) and the median prescribed daily dose of DT was 1250mg (range: 62.5 - 3500).The mean PDC in the 12 months prior to switching formulations was 0.80 (range: 0.31-1.00). This increased to 0.91 (range: 0.21-1.00) in the 12 months following the switch to FCT. The median prescribed daily dose of FCT was 900mg (range: 90 - 2520)The mean changes in ferritin and creatinine at 3, 6, 9 and 12 months post-switch are shown in the table.6 out of 74 patients (8%) had a creatinine increase of >30% from baseline whilst receiving the FCT, occurring after an average of 120 days (range: 30-260). All 6 patients were managed by dose adjustment of FCT and creatinine returned to the normal range in 5 out of 6 cases.ConclusionsThe switch from deferasirox DT to FCT resulted in improved patient adherence to chelation, a reduction in mean serum ferritin and a modest rise in mean serum creatinine. Some patients showed a reversible rise in creatinine from baseline.The median daily dose of FCT prescribed was 72% of the DT formulation, approximately equivalent according to the known bioavailability of the different preparations and suggesting that improvements in serum ferritin were due to the more consistent daily administration of the FCT rather than an increased daily deferasirox dose.We suggest that when the fall in ferritin is abrupt and/or to levels <1000µg/L, serum creatinine should be followed particularly carefully to avoid over-exposure to deferasirox from the FCT. We further speculate that patients who may have over-reported adherence to the DT prior to switching may be most susceptible to this effect.ReferenceTaher, A. T., et al. (2017). “New film-coated tablet formulation of deferasirox is well tolerated in patients with thalassemia or lower-risk MDS: Results of the randomized, phase II ECLIPSE study.” American journal of hematology 92(5): 420-428. [Display omitted] DisclosuresGarbowski:Vifor: Consultancy. Porter:Novartis: Consultancy; Cerus: Honoraria; Agios: Honoraria.

Retrospective Analysis of Compliance and Efficacy of a Novel Formulation of Deferasirox

Background: Transfusion-related iron overload is a complication of chronic transfusion therapy in patients with sickle cell disease. Iron overload can cause hepatic, cardiac and other end organ dysfunction, and greater iron burden has been associated with increased mortality in this population. Several medications are available to chelate iron, and adherence to chelation medication is critical to prevent the iron related damage. Jadenu®, a novel film-coated tablet formulation of deferasirox, was introduced in 2015. We assessed the impact of this formulation on adherence, iron control, and patient/parent reported preferences and quality of life in our chronically transfused patients with sickle cell disease.Methods: Patients with sickle cell disease receiving chronic transfusion therapy and chelation were invited to participate in this single-institution trial. Subjects and parents were administered a survey on medication preference and self-reported adherence. Subjects and parents completed the PedsQL™ Sickle Cell Disease Module 3.0 (acute and one month), as well as the PedsQL™ Quality of Life Short Form 4.0 (acute and one month). Retrospective measures of iron burden including laboratory values and imaging was abstracted from the electronic medical record. In subjects who transitioned to tablet deferasirox, iron measures were compared during the time period on their prior chelation and while they were taking tablet deferasirox. Unpaired and paired t-tests were used to compare continuous variables as appropriate. Fisher's exact testing was used to compare categorical data.Results: Twenty one subjects were enrolled in this study. Average age was 15yo (range 8-22yo). At the time of enrollment, 15 subjects were prescribed tablet deferasirox, and six were prescribed deferasirox for oral-suspension (dissolvable). Of those on tablet deferasirox, 92% reported missing more doses with the dissolvable formulation than with the tablet, with 50% reporting missing 3-4 doses per week of the dissolvable formulation. Participants reported barriers to taking the dissolvable formulation included: side effects, need to be taken on an empty stomach, taste, forgetfulness, and general dislike. The majority of subjects (64%) reported no side effects from either formulation. Cost did not appear to be a barrier to taking or obtaining either formulation. There were no statistically significant differences in quality of life measures between subjects taking the two formulations of deferasirox, except patient-reported psychosocial quality of life was higher in 8-13y cohort of subjects taking tablet deferasirox (70.0 vs 86.6, p=0.05). In general, parent-reports of quality of life measures were lower than patient-reports for both groups. For subjects who were on both formulations (n=10), average ferritin and liver iron concentration (LIC) were compared. Average ferritin was comparable during the time periods on dissolvable vs tablet (3358ng/dL vs 3395ng/dL, p>0.05), but there was a trend towards improved LIC on the tablet formulation (15.6mg/g dry weight vs 14.9mg/g dry weight, p>0.05).Discussion: Film-coated tablets were the patient preferred formulation of deferasirox and subjects reported improved adherence with this formulation. Though chelation had little impact on general and sickle cell specific measures of quality of life, there was a trend towards improved iron burden as measured by LIC. Long term evaluations of chelation adherence and impact of iron burden on mortality are needed in patients with sickle cell disease receiving chronic transfusion therapy. DisclosuresNo relevant conflicts of interest to declare.

Patient-reported outcomes from a randomized phase II study of the deferasirox film-coated tablet in patients with transfusion-dependent anemias

BackgroundAdherence to long-term chelation therapy in transfusion-dependent patients is critical to prevent iron overload-related complications. Once-daily deferasirox dispersible tablets (DT) have proven long-term efficacy and safety in patients ≥2 years old with chronic transfusional iron overload. However, barriers to optimal adherence remain, including palatability, preparation time, and requirements for fasting state. A new film-coated tablet (FCT) formulation was developed, swallowed once daily (whole/crushed) with/without a light meal.MethodsThe open-label, Phase II ECLIPSE study evaluated patient-reported outcomes (PROs) in transfusion-dependent thalassemia or lower-risk myelodysplastic syndromes patients randomized 1:1 to receive deferasirox DT or FCT over 24 weeks as a secondary outcome of the study. Three PRO questionnaires were developed to evaluate both deferasirox formulations: 1) Modified Satisfaction with Iron Chelation Therapy Questionnaire; 2) Palatability Questionnaire; 3) Gastrointestinal (GI) Symptom Diary.ResultsOne hundred seventy three patients were enrolled; 87 received the FCT and 86 the DT formulation. FCT recipients consistently reported better adherence (easier to take medication, less bothered by time to prepare medication and waiting time before eating), greater satisfaction/preference (general satisfaction and with administration of medicine), and fewer concerns (less worry about not swallowing enough medication, fewer limitations in daily activities, less concern about side effects). FCT recipients reported no taste or aftertaste and could swallow all their medicine with an acceptable amount of liquid. GI summary scores were low for both formulations.ConclusionsThese findings suggest a preference in favor of the deferasirox FCT formulation regardless of underlying disease or age group. Better patient satisfaction and adherence to chelation therapy may reduce iron overload-related complications.Trial registrationClinicalTrials.gov identifier: NCT02125877; registered April 26, 2014.

PSY56 - COST-UTILITY OF NEW FILM-COATED TABLET FORMULATION OF DEFERASIROX VERSUS DEFEROXAMINE AMONG MAJOR B-THALASSEMIA PATIENTS IN IRAN

Thalassemia is an important hereditary disease which caused economic burden in low and middle income countries. This study evaluated the cost utility of new film-coated tablet formulation of deferasirox versus deferoxamine (Desferal, Novartis) among major b-Thalassemia patients from payer perspective of Iran healthcare system. A model-based economic evaluation through Markov model was performed, including 3 states of A systematic review was conducted in order to evaluate the clinical effectiveness of comparators. Patients were assumed to be 2 years of age at initiation of chelation therapy and model was estimated lifetime costs and utilities. Costs were calculated to the Iran healthcare system through payer perspective and measured effectiveness using quality-adjusted life years (QALYs). The price of drugs was derived from Iran Food and Drug Administration official website. One-way sensitivity analysis and budget impact analysis was also employed. The 381 studies were found in the first phase of systematic searching through databases. After eliminating duplicate studies and studies incompatible with the inclusion and exclusion criteria of our study, 2 studies selected for evaluating the effectiveness of target medicines. FC Deferasirox (Jadenu, Novartis), was associated with an incremental cost-utility ratio of 82080907 versus deferoxamine (Desferal, Novartis) and it was lower than Iran health system threshold. Sensitivity analysis showed that different parameters except discount rate and indirect cost do not have impact on results. Also based on budget impact analysis, the increase in the cost of using FC deferasirox for one third of patients would be 0.08% of the total cost of using deferoxamin for all patients. Based on this analysis, d FC Deferasirox appeared to be cost-effective treatment available for managing chronic iron overload in b-thalassemia patients of Iran.

Comparative single-dose pharmacokinetics of sildenafil after oral and rectal administration in healthy beagle dogs

BackgroundSildenafil citrate, a highly selective phosphodiesterase type 5 inhibitor, is used to treat pulmonary hypertension (PH) in veterinary medicine. The objective of this study was to investigate pharmacokinetic profiles by oral administration of orally disintegrating film (ODF) and film coated tablet (FCT) formulations and rectal administration of ODF formulation in healthy dogs. Twelve healthy beagle dogs were administered four separate doses of sildenafil: FCT formulation 2 mg/kg orally, ODF formulation 2 mg/kg orally, ODF formulation 2 mg/kg rectally, and ODF formulation 10 mg/kg rectally. For 24 hours following administration, blood samples were collected and the plasma concentrations of sildenafil were assayed by liquid chromatography-tandem mass spectrometry.ResultsThere were no significant differences in all the pharmacokinetic parameters between FCT and ODF formulations when administrated orally. Cmax at the time of rectal administration was lower when the same dose was given as that orally administered. No serious systemic adverse events (AEs) were observed.ConclusionsThese findings suggest that sildenafil ODF formulation can be used as an alternative to FCT formulation in the treatment of canine PH patients; additionally, rectal administration of sildenafil ODF may be a beneficial treatment option for canine patients who are unable to receive medication orally.

Optimising management of deferasirox therapy for patients with transfusion-dependent thalassaemia and lower-risk myelodysplastic syndromes.

Effective iron chelation therapy is an important part of treatment in patients with transfusion-dependent thalassaemia and lower-risk myelodysplastic syndromes (MDS). Key strategies for optimising iron chelation therapy include ensuring good adherence and preventing and managing adverse events (AEs). Good adherence to iron chelation therapy with deferoxamine and deferasirox has been linked to improved survival and/or reductions in complications related to iron overload; however, maintaining good adherence to iron chelators can be challenging. Patients with transfusion-dependent thalassaemia or lower-risk MDS showed better adherence to the deferasirox film-coated tablet (FCT) formulation than to the deferasirox dispersible tablet formulation in the ECLIPSE trial, reflecting in part the improved palatability and convenience of deferasirox FCT. As well as affecting adherence, AEs may lead to dose reduction, interruption or discontinuation, resulting in suboptimal iron chelation therapy. Preventing and successfully managing AEs may help limit their impact on adherence, and following dosage and administration recommendations for iron chelators such as deferasirox may help minimise AEs and optimise treatment in patients with transfusion-dependent thalassaemia and lower-risk MDS.

Effectiveness and Safety of Oro-Dispersible Sildenafil in a New Film Formulation for the Treatment of Erectile Dysfunction: Comparison Between Sildenafil 100-mg Film-Coated Tablet and 75-mg Oro-Dispersible Film

BackgroundA new oro-dispersible film (ODF) formulation of sildenafil has been developed for the treatment of erectile dysfunction (ED) to overcome the drawbacks that some patients experience when taking the conventional film-coated tablet (FCT). AimTo assess the effectiveness and safety of sildenafil ODF formulation in patients with ED who were using the conventional FCT. MethodsFrom May 2017 through July 2017, 139 patients with ED were enrolled. Data from penile color-duplex ultrasound, medical history, hormonal evaluation, and patient self-administered questionnaires were collected. All patients were administered sildenafil 100-mg FCT for 4 weeks. Thereafter, they underwent a 2-week washout period and subsequently took sildenafil 75-mg ODF for 4 weeks. OutcomesThe International Index of Erectile Function (IIEF-15), Hospital Anxiety and Depression Scale (HADS), Patient Global Impressions of Improvement (PGI-I), and Clinician Global Impressions of Improvement (CGI-I) questionnaires were administered and severity of ED was classified as severe (IIEF-15 score ≤ 10), moderate (IIEF-15 score 11–16), or mild (IIEF-15 score = 17–25). ResultsAll patients completed the final protocol. Differences in mean IIEF scores for erectile function, orgasmic function, sexual desire, and intercourse satisfaction were significantly in favor of sildenafil 100-mg FCT, whereas the mean score for overall satisfaction was in favor of sildenafil 75-mg ODF. A significant difference in changes in HADS score was found from washout to final follow-up (mean difference = −0.19; P < .01). For the ODF formulation, the median CGI-I score was 3.5 (interquartile range [IQR] = 2.5–4.5) and the median PGI-I score was 3.0 (IQR = 2.0–4.0). The median action time was 20.0 minutes (IQR = 15.0–30.0) and the median mouth time was 60.0 seconds (IQR = 30.0–120.0). Clinical ImplicationsThe ODF formulation of a widely known drug, with the same safety and effectiveness of the FCT, was better appreciated by patients in overall satisfaction. Strengths and LimitationsThis is the first clinical trial to assess the efficacy of a new formulation of sildenafil in patients with ED. The limitations of the study are related to the methodology used: it was not a case-control study and the patients were not drug-naïve for ED treatment. Therefore, only the “additional” side effects of the ODF formulation compared with FCT are reported. ConclusionThe new ODF formulation is as efficient and safe as the FCT formulation and offers a new choice of treatment to specialists for more precisely tailored therapy.Cocci A, Capece M, Cito G, et al. Effectiveness and Safety of Oro-Dispersible Sildenafil in a New Film Formulation for the Treatment of Erectile Dysfunction: Comparison Between Sildenafil 100-mg Film-Coated Tablet and 75-mg Oro-Dispersible Film. J Sex Med 2017;14:1606–1611.

Comparative Bioavailability of Two Oral Perampanel Formulations in Healthy Subjects: A Randomized, Open Label, Single-Dose, 2-Way Crossover Study

Background: Perampanel is a glutamate non-competitive receptor antagonist that is effective as adjunctive treatment for epilepsy. No studies regarding comparative bioavailability between a generic perampanel formulation and the brand-name product have been published in the literature. Therefore, the goal of the present investigation was to compare the bioavailability and to evaluate the bioequivalence between a novel pharmaceutical equivalent 12 mg film-coated tablet formulation and the reference product. Methods: An open label, randomized-sequence, two-period, two-treatment, single-dose, crossover design study in healthy volunteers(n=24) was conducted. The treatment was split out by a 42 days wash-out period. The informed consent was signed by all volunteers. Healthy subjects of both genders, including non-pregnant and nonlactating females between 21-55 years with Quetelet index between 19-29 kg/m2 were enrolled. Blood samples were withdrawn in vacutainers with EDTA over 168 h and plasma levels of perampanel were measured by HPLC/ fluorescence method. Pharmacokinetic (PK) variables (Cmax, AUC0-last, and AUCinf) after a single oral administration dose of the test and reference treatments were analyzed by a non-compartmental PK model using natural logtransformed data and were compared by ANOVA for a two-treatment crossover design. Bioequivalence between the two formulations was evaluated using the 90% Confidence Interval (CI) comprised between 80-125% corresponding to the ratio of the geometric means for log-transformed PK parameters. Results: A similar bioavailability between products was determined. Test and reference formulations showed no statistically significant differences in relation to the fixed effect of period, sequence, treatment and volunteers within sequence as random effect for PK variables. The estimated point and 90% CI of the ratios of Cmax, AUC0-last and AUCinf were 0.92 (0.83-1.03), 1.04(0.98-1.10) and 0.98 (0.86-1.11), respectively. The formulations showed comparable safety and tolerability. Conclusion: The new pharmaceutical equivalent perampanel 12 mg film-coated tablet formulation was also bioequivalent to the reference product. Therefore, both drugs are interchangeable.

New Film-Coated Tablet Formulation of Deferasirox Is Well Tolerated in Patients with Thalassemia or MDS: Results of the Randomized, Phase II E.C.L.I.P.S.E. Study

▪Background: Patients (pts) compliant with iron chelation therapy (ICT) experience improved organ function and survival (Delea et al. Transfusion 2007;47:1919-29). Once-daily deferasirox (DFX) dispersible tablets (DT) have a well-defined safety and efficacy profile and, compared with parenteral deferoxamine, provide greater adherence, pt satisfaction, and quality of life (Cappellini et al. Clin Ther 2007;29:909-17). However, barriers exist to pt adherence to DFX DT, including GI tolerability and palatability, leading to development of a film-coated tablet (FCT) that can be taken with or without a light meal. The FCT contains the same active substance as DT but different excipients (lactose and sodium lauryl sulfate removed). Here we present results of the randomized, open-label, Phase II ECLIPSE study that evaluated safety of DFX FCT and DT formulations in pts with transfusion-dependent thalassemia (TDT) or IPSS-R very low-, low- or intermediate-risk MDS.Methods: ICT-naïve or pre-treatedpts aged ≥10 yrs, requiring ICT at DFX DT ≥30 mg/kg/day (TDT) or ≥20 mg/kg/day (MDS), with serum ferritin (SF) >1000 ng/mL, were enrolled. Exclusion criteria: creatinine clearance below contraindication limit per local label (<60 mL/min or <40 mL/min), serum creatinine >1.5xULN, alanine aminotransferase >5×ULN, urine protein/urine creatinine ratio (UPCR) >0.5 mg/mg, or impaired GI function. ICT-naïve pts received DFX DT 20 mg/kg/day or DFX FCT 14 mg/kg/day. ICT pre-treated pts received a DT or FCT dose equivalent to their pre-washout dose. FCT doses are 30% lower than DT doses due to improved bioavailability, conversion factor 1.43. Dose was adjusted based on SF and investigator’s judgment after wk 4 for ICT-naïve pts and after 3 months for ICT pre-treated pts (DT ±5-10 mg/kg/day, max 40 mg/kg/day; FCT ±3.5-7 mg/kg/day, max 28 mg/kg/day); dose adjustments for safety reasons were permitted at any time. Primary endpoint was overall safety, measured by frequency and severity of AEs and changes in laboratory values from baseline (BL) over 24 wks. A secondary endpoint was evaluation of selected GI AEs.Results: 173 pts were randomized 1:1 to DT or FCT (Table 1). Mean actual daily DFX dose ± SD over 24 wks was 27.5 ± 7.7 mg/kg/day (DT) and 20.8 ± 5.4 mg/kg/day (FCT). More FCT pts were started on a dose higher than the protocol-specified dose than DT pts (26.4% vs 9.3%). Mean/median duration of exposure was 155/168 days with DT and 163/169 days with FCT. 73 (84.9%; DT) and 77 (88.5%; FCT) pts completed 24 wks. Relative consumed tablet count was high, but lower with DT (85.3%) than FCT (92.9%). Absolute median (range) change in SF at end of treatment was -85.5 (-2146 to 8250) ng/mL (from 2485 [915-8250] ng/mL at BL) with DT, and -350 (-4440 to 3572) ng/mL (from 2983 [939-8250] ng/mL at BL) with FCT, corresponding to a median relative change of -4.1% (DT) and -14.0% (FCT) at end of treatment.AEs regardless of causality were reported in similar proportions of pts for each formulation (Table 2). Fewer severe AEs were observed in FCT pts. The most common AEs with either formulation were consistent with the known DFX safety profile. Notable laboratory evaluation frequencies were similar with both formulations (Table 3).61.6% (95% CI, 50.5-71.9%) of DT pts and 58.6% (95% CI, 47.6-69.1%) of FCT pts reported ≥1 GI AEs. Similar proportions of pts had diarrhea, nausea, and abdominal pain. Fewer FCT pts had constipation and vomiting than pts receiving DT. Fewer pts had severe GI AEs with FCT than with DT. In pts receiving DT prior to study entry, fewer FCT pts had GI AEs (53.5%, FCT; 60.3%, DT), particularly diarrhea, vomiting and constipation. Increased UPCR was reported in more FCT pts (12.8%, DT; 20.7%, FCT), which could be attributed to more FCT pts receiving a higher than recommended starting dose. Renal event frequency was similar when patients were started on a correct starting dose (30.9%, DT; 33.3%, FCT). 23 pts discontinued, 10 because of AEs (n=6, DT; n=4, FCT).Conclusions: These results in pts with TDT or very low-, low- or int-risk MDS demonstrate comparable FCT and DT safety profiles, consistent with the known DFX profile. In patients with prior DT exposure, fewer GI AEs were seen with FCT than DT. Pts receiving FCT had better compliance, continued longer on treatment and experienced greater SF reduction. DFX FCT may improve pt experience with ICT resulting in greater compliance and reduced frequency and severity of iron overload-related complications. [Display omitted] [Display omitted] [Display omitted] DisclosuresTaher:Novartis: Honoraria, Research Funding; Celgene: Research Funding. Origa:Novartis: Honoraria; Apopharma: Honoraria. Kouraklis:Gilead: Consultancy; Janssen: Honoraria; Novartis: Honoraria; Amgen: Honoraria; Roche: Consultancy; Celegene: Consultancy. Kattamis:Novartis: Honoraria, Research Funding; ApoPharma: Honoraria. Cortoos:Novartis: Employment. Huang:Novartis: Employment. Weill:Novartis: Employment. Herranz:Novartis: Employment. Porter:Novartis: Consultancy, Honoraria, Research Funding; Celegene: Consultancy; Agios Pharmaceuticals: Consultancy, Honoraria; Bluebird Bio: Consultancy.