10-mg Tablets Research Articles

Rationale and design for the peripartum cardiomyopathy in Nigeria (PEACE) registry

Background: Nigeria probably has the highest burden of peripartum cardiomyopathy (PPCM) in the world. The primary objective is to describe the burden, ventricular remodelling, and outcomes (rehospitalisation rate, cardioembolic events and survival) of PPCM in Nigeria. In the substudies, we aim to describe the relationship between selenium deficiency, oxidative stress and PPCM, the impact of sodium selenite supplementation on cardiac function in PPCM, and the prevalence of selenium deficiency and its relationship with cardiac function in apparently healthy pregnant women. Methods: The main registry and the first substudy are prospective longitudinal studies, while the second substudy is an openlabel randomised trial. 36 study centres across Nigeria have been registered and 10 of them are already recruiting subjects. Patients will be recruited from June to December 2017 and followed up till December 2018. Serum selenium and glutathione peroxidase will be assayed at recruitment for consecutive PPCM patients with left ventricular ejection fraction <45% at 6 months postpartum. 200 subjects with selenium deficiency will be randomised into treatment (selenium selenite 200 μg tablets daily for 3 months) and control arms. In the second substudy, 120 apparently healthy pregnant women will be recruited at 2838 weeks of gestation and reviewed at 68 weeks postpartum, and their serum selenium and glutathione peroxidas levels will be measured at recruitment. Conclusions: This will be the largest systematic evaluation of PPCM in Nigeria, and it is hoped that the information will assist in developing locally applicable treatment guidelines and policies for the disease.

Rationale and design for the peripartum cardiomyopathy in Nigeria (PEACE) registry

Background: Nigeria probably has the highest burden of peripartum cardiomyopathy (PPCM) in the world. The primary objective is to describe the burden, ventricular remodelling, and outcomes (rehospitalisation rate, cardioembolic events and survival) of PPCM in Nigeria. In the substudies, we aim to describe the relationship between selenium deficiency, oxidative stress and PPCM, the impact of sodium selenite supplementation on cardiac function in PPCM, and the prevalence of selenium deficiency and its relationship with cardiac function in apparently healthy pregnant women. Methods: The main registry and the first substudy are prospective longitudinal studies, while the second substudy is an openlabel randomised trial. 36 study centres across Nigeria have been registered and 10 of them are already recruiting subjects. Patients will be recruited from June to December 2017 and followed up till December 2018. Serum selenium and glutathione peroxidase will be assayed at recruitment for consecutive PPCM patients with left ventricular ejection fraction <45% at 6 months postpartum. 200 subjects with selenium deficiency will be randomised into treatment (selenium selenite 200 μg tablets daily for 3 months) and control arms. In the second substudy, 120 apparently healthy pregnant women will be recruited at 2838 weeks of gestation and reviewed at 68 weeks postpartum, and their serum selenium and glutathione peroxidas levels will be measured at recruitment. Conclusions: This will be the largest systematic evaluation of PPCM in Nigeria, and it is hoped that the information will assist in developing locally applicable treatment guidelines and policies for the disease.

Bioequivalence of 240mg Apalutamide Tablets and Preparation in Aqueous Food Vehicles for Alternative Administration.

A 240-mg single tablet has been developed with the focus of reducing the pill burden of the apalutamide daily dose of 240mg (4×60-mg tablets). An open-label, randomized, single-dose phase 1 study with a 2-sequence and 2-period crossover design in healthy men determined the bioequivalence of a 240-mg single tablet versus the currently available 4×60-mg tablets (Part 1, N = 74) and assessed effect of a high-fat meal (Part 2, N = 21) on apalutamide maximum plasma concentration (Cmax) and the area under the plasma concentration-time curve (AUC0-72h). The 90% confidence interval of geometric mean ratios for Cmax and AUC0-72h fell between 80% and 125% for both Part 1 and Part 2. No new safety concerns with the 240-mg single tablet were observed. To support the use of different food vehicles as well as nasogastric (NG) tubes for alternative administration, we conducted in vitro compatibility studies to evaluate the purity, dose, and stability of 240-mg tablets dispersed in applesauce/yogurt/orange juice/green tea as well as in NG tubes (polyurethane/silicone/polyvinyl chloride). The studies confirmed the alternative administrations do not affect the purity, dose-accuracy, or stability of apalutamide. The apalutamide 240-mg tablet is bioequivalent to 4×60-mg tablets and compatible with the tested food vehicles and NG tubes.

Assessing serum cytokine and immunoglobulin levels in patients with allergic rhinitis and allergic rhinoconjunctivitis before and after treatment supplemented with macromycetes

Background: In recent decades, the prevalence of allergic rhinitis (AR) has been increasing all over the world including Ukraine. Allergic rhinoconjunctivitis (ARC) is one of the most common clinical forms of AR. An imbalance between pro-inflammatory and anti-inflammatory cytokines is known to have a key role in allergic inflammation. Purpose: To compare cytokine and immunoglobulin levels among patients with AR and ARC treated with different therapeutic options. Material and Methods: Forty patients with AR and ARC (age range, 20 to 46 years) were included in the study. Disease duration ranged from 6 months to 2 years. Patients were divided into two subgroups of 20 patients each. Patients of subgroup 1 received the basic therapy (a 10-mg loratadin tablet daily and mometasone furoate nasal spray at a dosage of 200 μg once daily), whereas patients of subgroup 2, the basic therapy plus polypore macromycetes (Astmagan), one capsule twice daily. Treatment course duration was 90 days. The control group was composed of 25 healthy individuals. A comprehensive clinical immunological examination was conducted at baseline and on the completion of the treatment course. Enzyme-linked immunosorbent assay kits were used to determine serum levels of immunoglobulins A (IgA), IgM, IgG, and IgE, and cytokines (gamma interferon (IFN-γ) and IL4). Results: At baseline, serum levels of IgA, IgM and IgE were almost twice as high (р = 0.0008; 0.0005; and 0.0001, respectively); IgG, 1.2 times higher (р = 0.001); pro-inflammatory cytokine IL4, 3.5 times higher (р = 0.0001); and anti-inflammatory cytokine IFN-γ, 2.4 times lower (р = 0.0001) in patients with AR and ARC compared to controls, and these differences were significant. Astmagan, when used as an adjunct to the basic treatment of AR and ARC, contributed to 8%, 17%, 16.2%, 7.3% and 6.0% greater decreases in the serum levels of IgA, IgM, IgE, IgG and IL4, respectively, and a 16.6% greater increase in the serum level of IFN-γ compared to the basic treatment only, and these differences were significant, with an improvement in immune response to therapy.

To Assess the Association Between Decreased Uric Acid Level and Blood Pressure

Background: Asymptomatic hyperuricemia is commonly viewed as an entity that should not be treated. Treatment of asymptomatic hyperuricemia in patients with renal impairment is still in debate. There is no evidence to rationalize pharmacotherapy for patients with hyperuricemia with no complication and serum uric acid concentration is below 10 mg/dL. Objectives: To evaluate the association between decreased uric acid level and blood pressure. Methods: This was a single-center, single (patient blinded, placebo-controlled study conducted in chattogram medical college hospital over 1 year. Patients of both sexes aged above 18 years with eGFRs of 15 to 60 mL/ min/1.73 m2 (as calculated with the 4-variable MDRD) and serum uric acid levels ≥7 mg/dL were included. Patients were selected in purposive technique divided randomly by lottery into two groups. One group received febuxostat 40-mg tablet once daily and another group received placebo tablets at the same time. Both groups received antihypertensive and antidiabetic medication and diuretics as per needed. Drugs and placebo were continued throughout the study period. Patients were evaluated at baseline, 3rd and 6th months for history, physical examination, assessment of any adverse events or end points and relevant investigations. Results: 35 patients in each group were analyzed. Baseline characteristics were similar between the two groups. In febuxostat group the mean uric acid was decreased from 8.55 (±1.05) to 4.92 (±0.64) mg/dl, which was statistically significant (p <0.001) and in placebo group increased from 8.10 (±0.6) to 8.99 (±0.27) mg/dl which was statistically significant (P=0.001) after 6 months follow up. In case of mean eGFR in the febuxostat showed a nonsignificant increased from 25.28 (± 7.59) to 27.01 (±8.29) ml/min/1.73 m2, but in placebo group there was decreased mean eGFR from 26.81 (± 7.31) to 23.32(±7.72) ml/min/1.73 m2 which was statistically significant (p <0.001) and between group difference in eGFR was significant at 6 months (p = 0.048). Moreover after 6 months of treatment systolic and diastolic blood pressure were significantly lower in febuxostat group than placebo (p <0.05). Conclusion: Compared to placebo, febuxostat slowed the decline in eGFR in CKD stage 3 and 4

Prolonged release pirfenidone pharmacokinetics is modified in cirrhosis GENESIS study

BackgroundIn both clinical and experimental trials, pirfenidone (PFD) showed anti-inflammatory and antifibrogenic effects. Considering the wide variation in hepatic functional reserve in patients with cirrhosis, we decided to learn more about the pharmacokinetics of a new formulation of prolonged release PFD in this population (PR-PFD), focusing on assessing changes on AUC0–∞, AUC0–t, and Cmax. MethodsIn this study, 24 subjects with cirrhosis were included: eight subjects with mild liver impairment (Child–Pugh A) and eight with moderate liver impairment (Child–Pugh B), and a third group of eight age-matched subjects without fibrosis. All participants were under fasting conditions before receiving orally two 600-mg tablets of a prolonged-release formulation of pirfenidone (PR-PFD) and remained in the clinical unit for 36 h after PR-PFD administration. Serial blood samples were collected after dosing (0.5-36 h). A validated high-performance liquid chromatography–mass spectrometry method was used to determine PFD plasma concentrations. ResultsThe exposure to PR-PFD was 3.6- and 4.4-fold greater in subjects with Child–Pugh A and Child–Pugh B than in subjects without cirrhosis, and Cmax was 1.6- and 1.8-fold greater in subjects with Child–Pugh B and Child–Pugh-A than in patients without cirrhosis, without significant differences between the two cirrhotic groups. PFD was well tolerated. ConclusionThe pharmacokinetic parameters of PR-PFD are significantly modified in patients with cirrhosis compared with those in controls, indicating that liver impairment should be considered in clinical practice.

Effect of a High-Fat Diet on the Pharmacokinetics and Safety of Rivaroxaban in Healthy Chinese Subjects.

The effects of food on the pharmacokinetics (PKs) and safety of 10-mg rivaroxaban tablets in healthy Chinese subjects were investigated from 1 bioequivalence trial. The bioequivalence trial was designed as randomized, open-label, 2-sequence, 4-period crossover under both fasted and fed conditions. A total of 56 healthy subjects were enrolled, 62.5% were male. These subjects received a single oral 10-mg dose of rivaroxaban with a 7-day washout between 4 periods. Serial PK samples were collected and plasma concentrations were analyzed using validated high-performance liquid chromatography-mass spectrometry. Pharmacokinetic parameters were calculated by noncompartmental methods. The BE module of WinNonLin was used for statistical analysis of the maximum concentration (Cmax ), the area under the concentration-time curve from zero to the final measurable concentration (AUC0-t ), and the area under the concentration-time curve from time zero to infinity (AUC0-∞ ) of rivaroxaban in plasma. Compared with the fasted state, the Cmax , AUC0-t , and AUC0-∞ of rivaroxaban significantly increased by 47%, 28%, and 26%, respectively, with oral administration of rivaroxaban 10mg in the fed state. The incidence of adverse events (AEs) was similar between the fasted and fed states, and no serious AEs were observed. Food significantly increased the exposure to rivaroxaban 10mg in Chinese subjects.

Pharmacokinetic and Bioequivalence Evaluation of Two Cefprozil Dispersible Tablets in Healthy Chinese Volunteers.

This study aimed to assess the bioequivalence of 2 cefprozil dispersible tablet formulations (250mg) in healthy Chinese volunteers under fasting and fed conditions and to determine the pharmacokinetics of cefprozil. A randomized, single-dose, open-label, 2-formulation, 2-period study was conducted. The elimination period for this study was 7 days. Forty-eight healthy volunteers received 250-mg cefprozil dispersible tablets in each study period under both test and reference conditions. The test and the reference cefprozil were bioequivalent in healthy Chinese volunteers, and there was no significant food effect in individuals receiving either formulation. No serious adverse event was recorded, and no volunteers withdrew from the study.

Pharmacokinetics and Bioequivalence of Mirogabalin Orally Disintegrating Tablets and Conventional Tablets in Healthy Japanese Participants.

This single-center, randomized, open-label, single-dose, 2-group, 2-stage crossover trial evaluated the bioequivalence of 15mg of mirogabalin as orally disintegrating tablets (ODTs) with conventional mirogabalin tablets in healthy Japanese men. The trial involved two studies: in Study 1, the ODT formulation was taken without water, and in Study 2, the ODT formulation was taken with water. The conventional tablet was taken with water in both studies. We investigated the pharmacokinetic parameters and bioequivalence of the 2 formulations, including the maximum plasma concentration and the area under the plasma concentration-time curve up to the last quantifiable time. The plasma concentrations of mirogabalin were determined by a validated liquid chromatography with tandem mass spectrometry method. A total of 72 participants were enrolled and completed the trial. The geometric least-squares mean ratios of maximum plasma concentration of the ODT formulation to the conventional formulation were within the prespecified bioequivalence range of 0.80-1.25 (Study 1, 0.995; Study 2, 1.009), as was the area under the plasma concentration-time curve up to the last quantifiable time (Study 1, 1.023; Study 2, 1.035). No serious adverse events were observed. In conclusion, mirogabalin 15-mg ODTs, either with or without water, were bioequivalent to conventional 15-mg tablets.

Pharmacokinetics, Bioequivalence, and Safety Evaluation of 2 Formulations of 10-mg Rivaroxaban Tablets: A 4-Period Crossover Trial.

This study compared the safety, bioequivalence, and pharmacokinetic properties of 2 formulations of 10-mg rivaroxaban tablets in healthy Chinese participants in fasting and fed arms. The trial was an open, randomized, 4-period, replicated crossover scheme, and 36 volunteers were recruited separately for the fasting and fed arms. Volunteers were randomly administered a single dose of the test or reference formulation (10mg) orally, followed by a 5-day washout period. Rivaroxaban concentrations in the plasma were determined using liquid chromatography-tandem mass spectrometry, and pharmacokinetic parameters were obtained from the concentration-time profiles. The mean values of the test and the reference product for the area under the plasma concentration-time curve from time 0 to the last measurable concentration, area under the plasma concentration-time curve from time 0 to infinity, and maximum plasma concentration were 996 and 1014 ng • h/mL, 1024 and 1055 ng • h/mL, and 150 and 152ng/mL in the fasting arm, respectively; the values were 1155 and 1167 ng • h/mL, 1160 and 1172 ng • h/mL, and 202 and 193ng/mL in the fed arm, respectively. All the parameters were within acceptable limits in terms of bioequivalence. No serious adverse events were observed. This study demonstrated that the 2 rivaroxaban tablets were bioequivalent in healthy Chinese participants under fasting and fed conditions.

Pharmacokinetics comparison of vardenafil as administered by an intranasal spray formulation vs a 10-mg oral tablet.

Oral vardenafil (VDF) tablet is an effective treatment for erectile dysfunction (ED), but intranasal administration with a suitable formulation can lead to a faster onset of action and offer more convenient planning for ED treatment. The primary purpose of the present pilot clinical study was to determine whether intranasal VDF with an alcohol-based formulation can result in more "user-friendly pharmacokinetics" as compared with oral tablet administration. This single-dose randomized crossover study was conducted in 12 healthy young volunteers receiving VDF as a 10-mg oral tablet or 3.38-mg intranasal spray. Multiple blood concentrations were obtained, and VDF concentrations were determined with a liquid chromatography-tandem mass spectrometry assay. Pharmacokinetic parameters following each treatment were compared and adverse events assessed. Pharmacokinetic parameters were obtained: apparent elimination rate constant, elimination half-life, peak concentration, peak time, total area under the curve, and relative bioavailability. Although mean apparent elimination rate constant, elimination half-life, peak concentration, and total area under the curve were similar between intranasal and oral administration, the median peak time from intranasal was much shorter (10vs 58minutes, P < .001, Mann-Whitney U test). The variability of the pharmacokinetic parameters was also less with intranasal than oral administration. The relative bioavailability of intranasal to oral was 1.67. Intranasal VDF caused transient but tolerable local nasal reactions in 50% of subjects. Other adverse events (eg, headache) were similar between the treatments. The incidence of adverse events was, however, significantly less in the second treatment after initial exposure to VDF. No serious adverse events were noted. Intranasal VDF potentially offers a more timely and lower dose for the treatment of ED in patients who can tolerate the transient local adverse reactions. The strength of this study is its randomized crossover design. Because the study was conducted in 12 healthy young subjects, the results may not reflect those observed in elderly patients who may be likely taking VDF for ED. Nevertheless, the changes of pharmacokinetic parameters in the present study are likely a reflection of the differences between intranasal and oral administration of the formulations. Our study indicated that the present VDF formulation, when administered intranasally, can achieve a more rapid but similar plasma concentration with only about one-third dose when compared with the oral administration.

Relative bioavailability of delamanid 50 mg tablets dispersed in water in healthy adult volunteers.

Delamanid is a novel drug for the treatment of drug-resistant tuberculosis, manufactured as 50-mg solid and 25-mg dispersible tablets. We evaluated the effects of dispersing the 50-mg tablet, focusing on the relative bioavailability. Delamanid, 50-mg tablets administered dispersed vs swallowed whole, was investigated in a phase I, four-period, crossover study. Two of three dose strengths of delamanid (25, 50 or 100 mg) were given to healthy adult participants, in both whole and dispersed forms, with a 7-day washout period. Blood samples were collected over 168 h after each dose. Delamanid and its metabolite DM-6705 were analysed with a validated liquid chromatography tandem mass spectrometry assay. The pharmacokinetics of both analytes were analysed using nonlinear mixed-effect modelling. Palatability and acceptability were determined using a standardized questionnaire. Twenty-four participants completed the study. The bioavailability of dispersed tablets was estimated to be 107% of whole tablets, with a 90% confidence interval of 99.7-114%, fulfilling bioequivalence criteria. The two formulations were not significantly different regarding either bioavailability or its variability. Bioavailability increased at lower doses, by 34% (26-42%) at 50 mg and by 74% (64-86%) at 25 mg, relative to 100 mg. The majority of participants (93%) found the dispersed formulation acceptable in palatability across all delamanid doses. Dispersed 50-mg delamanid tablets have similar bioavailability to tablets swallowed whole in adult volunteers. This can be an option for children and other patients who cannot swallow whole tablets, improving access to treatment.

Evaluation of acceptability, safety, and continuation rates of centchroman as postabortion nonsteroidal contraceptive pill

ObjectivesTo evaluate acceptability, safety, and continuation rates of centchroman following abortion. Study designProspective, observational study. Following spontaneous/induced abortion, women were offered centchroman, 30-mg tablet twice weekly for first 3 months, then once weekly with 1 year of follow-up. ResultsOf 120 women who opted for centchroman, continuation rate was 91% at 12 months. There was one case of user failure and one method failure and 26% had infrequent cycles. ConclusionsCentchroman is safe, effective, has good acceptance, and continuation rate post abortion with infrequent menstrual cycles as the main limiting factor for its continuation. ImplicationsCentchroman, available in Government scheme for contraception, has good acceptance and continuation rate post abortion. Its inclusion in contraceptive choices offered for postabortion contraception can go a long way in spacing of pregnancies, decreasing repeated unintended pregnancies, unsafe abortions, maternal morbidity, and mortality.

Selective Inhibition of the MK2 Pathway: Data From a Phase IIa Randomized Clinical Trial in Rheumatoid Arthritis

The study objective was to evaluate the safety, tolerability, pharmacodynamics, and preliminary efficacy of ATI-450 with methotrexate in patients with rheumatoid arthritis (RA). A parallel-assignment, placebo-controlled, investigator-blinded/patient-blinded multicenter study evaluated patients with moderate-to-severe RA aged 18 to 70 years. Eligible patients were randomized (1:1) to ATI-450 50-mg oral tablets twice daily or placebo with a stable weekly dose of methotrexate for 12 weeks. The primary objective was to assess ATI-450 safety and tolerability. The secondary objectives were to assess the median percentage change from baseline high-sensitivity C-reactive protein (hs-CRP) levels, the mean change from baseline in Disease Activity Score in 28 joints based on CRP level (DAS28-CRP) and Rheumatoid Arthritis Magnetic Resonance Imaging Score hand-wrist assessments of synovitis or bone erosion at week 12, and the proportion of patients with American College of Rheumatology 20/50/70 (ACR 20/50/70) and with DAS28-CRP scores of less than 2.6. The exploratory outcomes were change from baseline in endogenous and ex vivo-stimulated cytokine levels. ATI-450 was well tolerated with no severe adverse events reported. ATI-450 reduced median hs-CRP levels by 42% or more at all posttreatment timepoints. In the ATI-450 group, a mean (median) decrease in DAS28-CRP score of 2.0 (2.1) was observed at week 12; proportions of patients with an ACR 20/50/70 response in the per-protocol population were 60%, 33%, and 20%, respectively, at week 12. Endogenous plasma levels of key inflammatory cytokines (tumor necrosis factor α, macrophage inflammatory protein 1β, interleukin 6, interleukin 8) were reduced across the 12 treatment weeks. This is the first clinical study demonstrating that selective mitogen-activated protein kinase (MAPK)-activated protein kinase 2 (MK2) pathway blockade leads to a sustained antiinflammatory effect. This suggests that targeting the MK2 pathway mitigates the tachyphylaxis observed with p38 MAPK inhibitors in RA and supports further exploration.

An Integrated Population Pharmacokinetic Analysis for Posaconazole Oral Suspension, Delayed-Release Tablet, and Intravenous Infusion in Healthy Volunteers.

Posaconazole is widely used for the prophylaxis and treatment of invasive fungal diseases. Because of the limited and variable absorption of the initially available oral suspension, a delayed-release tablet and intravenous formulation were developed. This study aimed to characterize the pharmacokinetics, including the absolute oral bioavailability, of all posaconazole formulations in healthy volunteers. Data from 182 healthy volunteers with 3898 densely sampled posaconazole concentrations were pooled from eight phase I clinical studies on the three formulations of various single and multiple dosage regimens between 50 and 400 mg. Analysis and simulations were performed using NONMEM 7.5.0. In the covariate analysis, the influence of food (fed vs fasted), nonlinearity, and for the delayed-release tablet, comedication (antacid, ranitidine, esomeprazole, and metoclopramide) were tested. A two-compartment model with respectively, four and eight absorption transit compartments, best described the profiles of the oral suspension and delayed-release tablet. For the suspension, both a food effect and a dose-dependent nonlinear bioavailability were quantified, resulting in lower bioavailability when fasted or at a higher dose. The typical bioavailability of the suspension at 100 mg and 400 mg was derived to be respectively, 17.1% and 10.1% under fasted conditions and 59.1% and 49.2% under fed conditions. The absolute bioavailability of the delayed-release tablet was 58.8% (95% confidence interval 33.2-80.4) under fasted conditions and approached complete absorption under fed conditions for dosages up to 300 mg. Food intake reduced the absorption rate constant of the suspension by 52.2% (confidence interval 45.2-59.2). The impact of comedication on the absorption of the delayed-release tablet was not statistically significant. Model-based simulations indicate that under fed conditions, the licensed dosages of the three formulations yield a steady-state trough concentration ≥0.7 mg/L in over 90% of healthy volunteers. About 35% of healthy volunteers who receive the licensed 300-mg delayed-release tablet under fasted conditions do not achieve this target, while for the suspension this percentage varies between 55 and 85%, depending on the dose. For both oral posaconazole formulations, we quantified bioavailability and absorption rate, including food effects, in healthy volunteers. The pharmacokinetic superiority of the delayed-release tablet was demonstrated under both fed and fasted conditions, compared with the oral suspension. The impact of food on the bioavailability of the delayed-release tablet was larger than anticipated, suggesting that administering the delayed-release tablet with food enhances absorption.

Effects of Tablet Formulation, Food, or Gastric pH on the Bioavailability of Asundexian.

Absolute bioavailability (F) and the impact of gastric pH, tablet formulation, and food on the pharmacokinetics and safety of asundexian, an oral factor XIa inhibitor, was assessed in healthy White men aged 18-45 years in 4 studies. For F, fasted participants received 50 μg of [13 C7 ,15 N]-labeled asundexian intravenously 2 hours after 25 mg of asundexian orally. Tablet formulation (50-mg immediate release [IR], and different amorphous solid dispersion [ASD] IR 25-mg and 50-mg ASD IR tablets) and food effects were explored in 2 studies. Formulation was compared using 50-mg IR versus 25-mg ASD IR and 25-mg ASD IR versus 50-mg ASD IR (fasted); food effect using 25-mg ASD IR and 50-mg ASD IR. Gastric pH modulation was assessed using omeprazole or antacid coadministration with asundexian in the fasted state. Pharmacokinetic parameters included area under the concentration-time curve (AUC; and AUC/dose [D]) and maximum observed concentration (Cmax and Cmax /D) data were evaluable for 59 participants. F was 103.9%. Relative bioavailability with 25-mg ASD IR and 50-mg ASD IR tablets, respectively, was marginally affected by formulation (AUC/D ratios, 94.3% and 95.1%; Cmax /D ratios, 95.5% and 88.7%), food (AUC[/D] ratios, 91.1% and 96.9%; Cmax [/D] ratios: 78.3% and 95.1%), and gastric pH (omeprazole, no effect; antacid, AUC ratio, 89.9% and Cmax ratio, 83.7%). No serious adverse events or deaths occurred; most adverse events were mild or moderate. In summary, oral asundexian was well tolerated and demonstrated complete bioavailability irrespective of tablet formulation, food, or gastric pH.

Development of an Immediate-Release Prototype Tablet Formulation of Hydroxychloroquine Sulfate with an Interwoven Taste-Masking System

Hydroxychloroquine sulfate (HCQS) was granted US-FDA approval in 1955 for the prevention and treatment of malaria. Since then, its uses have expanded to treat systemic lupus erythematosus and rheumatoid arthritis. For each indication, HCQS is a crucial option for the treatment of pediatric, juvenile, adult, and elderly populations. Existing currently on the market are only 200-mg strength tablets exclusively for adult administration. To facilitate weight-based administration for pediatric and juvenile patients, an HCQS suspension is made by compounding a 200-mg HCQS tablet and suspending the crushed granules into water and Ora-Plus®. The Ora-Plus® suspension does not alter the extreme bitterness of HCQS such that it facilitates oral administration. Additional research has been executed to affirm that a slightly buffered, ion-pairing system, reduces the bitterness of HCQS. The buffered, ion-pairing system can be interwoven into an immediate-release tablet formulation likely without compromising tablet performance. With the taste-masking system embedded, the tablet could be more easily be compounded and suspended in water to generate a palatable oral suspension. Such a novel HCQS 200-mg tablet would be tailored for adult usages wherein the interwoven task-masking system could be utilized to facilitate weight-based administration for pediatric and juvenile patients. The dual quality target product profile of the tablet and the tablet compounded for suspension in water would make the tablet formulation applicable to a wide patient population ranging from pediatric to elder adults to facilitate in improving compliance and overall health outcomes.

Pharmacokinetics, Bioavailability, and Swallowing Safety With Riluzole Oral Film.

Dysphagia is highly prevalent in patients with amyotrophic lateral sclerosis (ALS). Riluzole is a US Food and Drug Administration-approved treatment for ALS. Riluzole oral film (ROF; Exservan™) contains riluzole in a polymer-based film matrix. The ROF is administered by placing on the tongue, where it dissolves and the drug is ingested with the saliva. Two clinical trials assessed the safety and tolerability of the ROF. Bioavailability and pharmacokinetics (PK) were evaluated in an open-label, randomized, single-dose, replicate crossover study of 50mg of ROF and riluzole 50-mg tablets in 32 healthy volunteers. The second study was a videofluoroscopic swallowing examination conducted with nine patients with ALS before and after receiving a single dose of 50mg of ROF. The primary outcome was change on penetration-aspiration scale (PAS) scores from pre- to post-dose. Overall, the PK parameters for ROF and riluzole tablets were comparable between treatments and administrations when administered under fasting conditions. Administration of ROF with food resulted in a 15% reduction in area under the curve and a 45% reduction in maximum serum concentration. A total of 44 treatment-emergent adverse events (AEs) were reported in the study; all were mild in severity. No serious AEs were observed and no subjects discontinued due to AEs. In the swallowing study, very little numerical or categorical change was observed following the dose of ROF. No evidence of deterioration of swallowing function was observed post-dose. The ROF was bioequivalent to riluzole tablets, was well tolerated, and had no detrimental effect on swallowing.

Ibrexafungerp: A new triterpenoid antifungal.

The pharmacology, microbiology, pharmacokinetics, pharmacodynamics, efficacy, safety, and role of ibrexafungerp in the treatment of fungal infections are reviewed. Ibrexafungerp is the first triterpenoid antifungal. Similarly to echinocandins, it inhibits the synthesis of 1,3-β-d-glucan. However, it binds to a different site on the enzyme than echinocandins, resulting in limited cross-resistance. Ibrexafungerp exerts concentration-dependent fungicidal activity against Candida species and retains in vitro activity against most fluconazole-resistant strains. It is also active against Aspergillus species. Ibrexafungerp has been shown to be safe and effective in the treatment of vulvovaginal candidiasis caused by Candida albicans in phase 2 and phase 3 clinical trials. It is approved for vulvovaginal candidiasis in adult and postmenarchal pediatric females and is given as two 150-mg tablets orally, administered 12 hours apart. Ibrexafungerp is contraindicated in pregnancy. The most commonly reported adverse reactions were diarrhea, nausea, abdominal pain, dizziness, and vomiting. Ibrexafungerp should be avoided with strong or moderate CYP3A inducers, and the dose should be reduced with strong CYP3A inhibitors. Ibrexafungerp may be useful for patients who are not able to receive fluconazole or prefer oral therapy for the treatment of vulvovaginal candidiasis. However, it is more expensive than the 150-mg tablet of generic fluconazole, which is the current standard of care for vulvovaginal candidiasis. Clinical trials are ongoing for recurrent and complicated vulvovaginal candidiasis as well as invasive candidiasis and pulmonary aspergillosis. Ibrexafungerp is an alternative to fluconazole for the treatment of vulvovaginal candidiasis in nonpregnant females. It has the potential to be useful for recurrent and complicated vulvovaginal candidiasis as well as certain invasive fungal infections.

Pharmacokinetics and Bioequivalence of 2 Safinamide Tablets in Healthy Chinese Volunteers Under Fasting and Fed Conditions.

To assess the bioequivalence of a generic safinamide tablet (test) vs a brand-name safinamide tablet (reference) and effects of food on the pharmacokinetics of safinamide in healthy Chinese subjects, a single-center, single-dose, randomized, open-label, 2-preparation, 2-period study with a 15-day washout period was undertaken. A total of 56 healthy subjects were recruited in this study (fasting, n = 28; fed, n = 28). A single dose of a 100-mg test or reference safinamide tablet was administered to each subject in a randomized sequence. Blood samples were obtained at 5minutes before drug administration and during the 120hours after dosing. The safinamide concentration in plasma was determined by high-performance liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters were analyzed with noncompartmental methods. Safety was also monitored. The major pharmacokinetic parameters including maximum plasma drug concentration, area under plasma concentration-time curve (AUC) from zero to time t (AUC0-t ), and AUC from time 0 to infinity (AUC0-∞ ) were similar between the test and reference tablets under fasting and fed conditions. The 90% CIs of the test/reference ratios of log-transformed maximum plasma drug concentration, AUC from zero to time t, and AUC from time 0 to infinity all fell within the equivalence interval (80.0%-125%) whether under fasting condition or fed condition. In conclusion, the 2 formulations of safinamide tablets were bioequivalent and well tolerated under both fasting and fed conditions in healthy Chinese volunteers. High-fat food delayed the absorption of safinamide but did not affect the final bioavailability.