Once-daily Formulation Research Articles

Evaluation of Effective Half-Life and Its Impact on Time to Steady State for Oral MeltDose Tacrolimus (LCPT) in De Novo Kidney Transplant Recipients.

For extended-release drug formulations, effective half-life (t1/2eff) is a relevant pharmacokinetic parameter to inform dosing strategies and time to reach steady state. Tacrolimus, an immunosuppressant commonly used for the prophylaxis of organ rejection in transplant patients, is available as both immediate- and extended-release formulations. To the best of our knowledge, the t1/2eff of tacrolimus from these different formulations has not yet been assessed. The objective of this study was to characterize the t1/2eff and terminal half-life (t1/2z) of an extended-release once-daily tacrolimus formulation (LCPT) and twice-daily immediate-release tacrolimus (IR-Tac). A noncompartmental analysis of pharmacokinetic data obtained from a phase 2 study in de novo kidney transplant recipients receiving either LCPT or IR-Tac was conducted. Intensive blood sampling was performed on days 1, 7, and 14, and tacrolimus whole blood concentrations were measured using a validated liquid chromatography with tandem mass spectrometry method. T1/2eff was estimated using within-participant accumulation ratios. T1/2z was estimated by linear regression of the terminal phase of the concentration versus time profile. The median accumulation ratios of LCPT and IR-Tac on day 14 were 3.18 and 2.06, respectively.The median (interquartile range; IQR) t1/2eff for LCPT at day 14 of dosing was 48.4 (37.4-77.9) hours, whereas the t1/2z was 20.3 (17.6-22.9) hours. For IR-Tac, the median (IQR) t1/2eff and t1/2z on day 14 were 12.5 (8.8-23.0) hours and 12.2 (9.2-15.7) hours, respectively. Consistent with its prolonged release of tacrolimus, LCPT demonstrated a higher accumulation ratio and a longer t1/2eff compared with IR-Tac. These findings underscore the pharmacokinetic differences between different drug formulations of the same moiety and may help inform dose adjustments for LCPT in kidney transplantation.

12670 CHAMPAIN Study: Initial Results From A Phase II Study Of Efficacy, Safety And Tolerability Of Modified-release Hydrocortisones: Chronocort® (Efmody®) Versus Plenadren®, In Primary Adrenal Insufficiency

Abstract Disclosure: A. Prete: Research Investigator; Self; Diurnal. V. Theiler-Schwetz: Research Investigator; Self; Diurnal. W. Arlt: Research Investigator; Self; Diurnal. I.O. Chifu: Research Investigator; Self; Diurnal. B. Harbeck: Research Investigator; Self; Diurnal. C. Napier: Research Investigator; Self; Diurnal. J.D. Newell-Price: Research Investigator; Self; Diurnal. A. Rees: Research Investigator; Self; Diurnal. N. Reisch: Research Investigator; Self; Diurnal. G.K. Stalla: Research Investigator; Self; Diurnal. N. Aslam: Employee; Self; Diurnal. H. Coope: Employee; Self; Diurnal. K. Maltby: Employee; Self; Diurnal. J. Porter: Employee; Self; Diurnal. J. Quirke: Employee; Self; Diurnal. R.J. Ross: Consulting Fee; Self; Diurnal. Background: Current glucocorticoid replacement regimens for patients with primary adrenal insufficiency (PAI) mean patients wake with either low or undetectable cortisol levels[1], associated with fatigue and a reduced quality of life (QoL)2. Plenadren® (Takeda, UK) is a once-daily modified-release formulation of hydrocortisone that replaces daytime cortisol levels whereas Chronocort® (modified-release hydrocortisone hard capsules, Diurnal, UK) when taken twice-daily, has been shown to replicate the normal overnight rise in serum cortisol concentration and provide physiological levels throughout the day. We have undertaken a double-blind, double-dummy, two-way cross-over, randomised, phase II study of efficacy, safety and tolerability of modified-release hydrocortisones: Chronocort® Versus Plenadren®. Aim: To test the hypothesis that Chronocort® provides more physiological waking cortisol levels than Plenadren®. Methodology: The study was conducted across 8 sites in the UK and Germany. Male and female patients, aged ≥18 with confirmed PAI (defined as morning pre-dose cortisol <50 nMol/l) on stable therapy over the preceding three months and not currently treated with Chronocort®/Plenadren®. Participants with congenital adrenal hyperplasia (CAH), secondary or tertiary AI were excluded. Each participant was randomised on a 1:1 basis to either; treatment sequence I (Chronocort® first) or treatment sequence II (Plenadren® first) taking a 25mg total daily dose for 4 weeks; either Plenadren® 25mg in the morning or Chronocort® 10mg in the morning and 15mg at night with the associated dummy preparation followed immediately by the other treatment. The pre-dose morning serum cortisol level was assayed at baseline and after each treatment period. A physiological morning cortisol level was defined as a pre-dose level of >140nMol/L. Secondary measures included: morning fatigue measured using the Multidimensional Assessment of Fatigue (MAF) questionnaire and the PROMIS® 7b questionnaire; QoL was assessed using the EuroQol 5-level Standardised Health Questionnaire (EQ-5D-5L™); Health-related Quality of Life in Addison’s disease (AddiQoL) questionnaire and the 36-Item Short Form Health Survey (SF-36®) questionnaire. Results: Of 49 evaluable participants with PAI, 45 achieved a physiological morning cortisol after four weeks of Chronocort® compared with 2 after four weeks of Plenadren® (P<0.0001). The mean (standard deviation) waking cortisol was 422.85 (203.50) vs 36.98 (113.87), respectively. Conclusion: Chronocort® provides more physiological waking cortisol levels than Plenadren®. Further analysis will test the hypothesis that waking with physiological cortisol levels improves fatigue and QoL in patients with PAI. 1.Mah PM, et al. Clin Endocrinol (Oxf). 2004;61(3):367-75.2.Wichers M, et al. Clin Endocrinol (Oxf). 1999;50(6):759-65. Presentation: 6/3/2024

9341 CHAMPAIN Study: Initial Results From A Phase II Study Of Efficacy, Safety And Tolerability Of Modified-release Hydrocortisones: Chronocort® (Efmody®) Versus Plenadren®, In Primary Adrenal Insufficiency

Abstract Disclosure: A. Prete: Research Investigator; Self; Diurnal. V. Theiler-Schwetz: Research Investigator; Self; Diurnal. W. Arlt: Research Investigator; Self; Diurnal. I.O. Chifu: Research Investigator; Self; Diurnal. B. Harbeck: Research Investigator; Self; Diurnal. C. Napier: Research Investigator; Self; Diurnal. J.D. Newell-Price: Research Investigator; Self; Diurnal. A. Rees: Research Investigator; Self; Diurnal. N. Reisch: Research Investigator; Self; Diurnal. G.K. Stalla: Research Investigator; Self; Diurnal. N. Aslam: Employee; Self; Diurnal. H. Coope: Employee; Self; Diurnal. K. Maltby: Employee; Self; Diurnal. J. Porter: Employee; Self; Diurnal. J. Quirke: Employee; Self; Diurnal. R.J. Ross: Consulting Fee; Self; Diurnal. Background: Current glucocorticoid replacement regimens for patients with primary adrenal insufficiency (PAI) mean patients wake with either low or undetectable cortisol levels[1], associated with fatigue and a reduced quality of life (QoL)2. Plenadren® (Takeda, UK) is a once-daily modified-release formulation of hydrocortisone that replaces daytime cortisol levels whereas Chronocort® (modified-release hydrocortisone hard capsules, Diurnal, UK) when taken twice-daily, has been shown to replicate the normal overnight rise in serum cortisol concentration and provide physiological levels throughout the day. We have undertaken a double-blind, double-dummy, two-way cross-over, randomised, phase II study of efficacy, safety and tolerability of modified-release hydrocortisones: Chronocort® Versus Plenadren®. Aim: To test the hypothesis that Chronocort® provides more physiological waking cortisol levels than Plenadren®. Methodology: The study was conducted across 8 sites in the UK and Germany. Male and female patients, aged ≥18 with confirmed PAI (defined as morning pre-dose cortisol <50 nMol/l) on stable therapy over the preceding three months and not currently treated with Chronocort®/Plenadren®. Participants with congenital adrenal hyperplasia (CAH), secondary or tertiary AI were excluded. Each participant was randomised on a 1:1 basis to either; treatment sequence I (Chronocort® first) or treatment sequence II (Plenadren® first) taking a 25mg total daily dose for 4 weeks; either Plenadren® 25mg in the morning or Chronocort® 10mg in the morning and 15mg at night with the associated dummy preparation followed immediately by the other treatment. The pre-dose morning serum cortisol level was assayed at baseline and after each treatment period. A physiological morning cortisol level was defined as a pre-dose level of >140nMol/L. Secondary measures included: morning fatigue measured using the Multidimensional Assessment of Fatigue (MAF) questionnaire and the PROMIS® 7b questionnaire; QoL was assessed using the EuroQol 5-level Standardised Health Questionnaire (EQ-5D-5L™); Health-related Quality of Life in Addison’s disease (AddiQoL) questionnaire and the 36-Item Short Form Health Survey (SF-36®) questionnaire. Results: Of 49 evaluable participants with PAI, 45 achieved a physiological morning cortisol after four weeks of Chronocort® compared with 2 after four weeks of Plenadren® (P<0.0001). The mean (standard deviation) waking cortisol was 422.85 (203.50) vs 36.98 (113.87), respectively. Conclusion: Chronocort® provides more physiological waking cortisol levels than Plenadren®. Further analysis will test the hypothesis that waking with physiological cortisol levels improves fatigue and QoL in patients with PAI. 1.Mah PM, et al. Clin Endocrinol (Oxf). 2004;61(3):367-75.2.Wichers M, et al. Clin Endocrinol (Oxf). 1999;50(6):759-65. Presentation: 6/3/2024

Guiding the starting dose of the once-daily formulation of tacrolimus in "de novo" adult renal transplant patients: a population approach.

The once-daily extended-release tacrolimus formulation (ER-Tac) has demonstrated similar efficacy and safety to the twice-daily immediate-release formulation (IR-Tac), but few population-based pharmacokinetic models have been developed in de novo kidney transplant patients to optimize doses. Therefore, this study aimed i) at developing a population pharmacokinetic model for ER-Tac in de novo adult kidney transplant patients ii) and identifying genetic factors and time-varying covariates predictive of pharmacokinetic variability to guide tacrolimus dosage during the early post-transplant period. A total of 1,067 blood tacrolimus concentrations from 138 kidney transplant patients were analyzed. A total of 29 out of 138 patients were intensively sampled for 24h on the day 5 post-transplantation; meanwhile, for the remaining patients, concentrations were collected on days 5, 10, and 15 after transplantation. Tacrolimus daily doses and genetic and demographic characteristics were retrieved from the medical files. Biochemistry time-varying covariates were obtained on different days over the pharmacokinetic (PK) study. A simultaneous PK analysis of all concentrations was carried out using the non-linear mixed-effects approach with NONMEM 7.5. A two-compartment model with linear elimination and delayed absorption best described the tacrolimus pharmacokinetics. Between-patient variability was associated with oral blood clearance (CL/F) and the central compartment distribution volume (Vc/F). Tacrolimus concentrations standardized to a hematocrit value of 45% significantly improved the model (p < 0.001). This method outperformed the standard covariate modeling of the hematocrit-blood clearance relationship. The effect of the CYP3A5 genotype was statistically (p < 0.001) and clinically significant on CL/F. The CL/F of patients who were CYP3A5*1 carriers was 51% higher than that of CYP3A5*1 non-carriers. Age also influenced CL/F variability (p < 0.001). Specifically, CL/F declined by 0.0562 units per each increased year from the value estimated in patients who were 60years and younger. The 36% between-patient variability in CL/F was explained by CYP3A5 genotype, age, and hematocrit. Hematocrit standardization to 45% explained the variability of tacrolimus whole-blood concentrations, and this was of utmost importance in order to better interpret whole-blood tacrolimus concentrations during therapeutic drug monitoring. The dose requirements of CYP3A5*/1 carriers in patients aged 60years or younger would be highest, while CYP3A5*/1 non-carriers older than 60years would require the lowest doses.

Prediction of the Intra-T Lymphocyte Tacrolimus Concentration after Kidney Transplantation with Population Pharmacokinetic Modeling.

The intracellular tacrolimus concentration in CD3+ T lymphocytes is proposed to be a better representative of the active component of tacrolimus than the whole blood concentration. However, intracellular measurements are complicated. Therefore, the aim of this study was to describe the relationship between intracellular and whole blood tacrolimus concentrations in a population pharmacokinetic model. Twenty-eight de novo kidney transplant recipients, treated with a once-daily oral extended-release tacrolimus formulation, were followed during the first-month post-transplantation. Additional whole blood and intracellular tacrolimus concentrations were measured at day 6 ± 1 (pre-dose, 4 and 8 hours post-dose) and day 14 ± 3 (pre-dose) post-transplantation. Pharmacokinetic analysis was performed using nonlinear mixed effects modeling software (NONMEM). The ratio between intracellular (n = 109) and whole blood (n = 248) concentrations was best described by a two-compartment whole blood model with an additional intracellular compartment without mass transfer from the central compartment. The ratio remained stable over time. Prednisolone dose influenced the absorption rate of tacrolimus, while hemoglobin, CYP3A4*22 allele carrier, and CYP3A5 expresser status were associated with the oral clearance of tacrolimus (P-value < 0.001). Furthermore, the intracellular tacrolimus concentrations were correlated with the intracellular production of interleukin-2 (P-value 0.015). The intracellular tacrolimus concentration can be predicted from a measured whole blood concentration using this model, without the need for repeated intracellular measurements. This knowledge is particularly important when the intracellular concentration is ready to be implemented into clinical practice, to overcome the complexities of cell isolation and analytical methods.

Expert opinion on the prescription practice of vildagliptin and its combinations in managing type 2 diabetes mellitus in Indian settings

Background: The aim of the study was to gather expert opinion regarding the use of vildagliptin and its combinations in T2DM in Indian settings. Methods: This cross-sectional study involved 24 questions and collected perspectives of experts across various clinical settings in India regarding the use of vildagliptin and its combinations for the management of type 2 diabetes mellitus (T2DM) in their clinical practice. Results: Among 195 participants, most clinicians (73%) advocated vildagliptin once-daily formulation for newly diagnosed young diabetics, elderly patients with long-standing diabetes, and those with uncontrolled diabetes as an add-on therapy. Around 92% favored vildagliptin for its weight-neutral nature, preservation of beta-cell function, minimal glycemic variation, and low risk of adverse effects. Most clinicians (66%) preferred initiating vildagliptin and metformin combination therapy in diabetic individuals aged 40 to 50 years, with 53% opting for it when HbA1c levels exceeded 8%. Approximately 83% favored this combination for young, elderly, and long-standing diabetic individuals. More than half (54%) of the clinicians preferred prescribing the fixed-dose combination (FDC) of vildagliptin and dapagliflozin to 11-25% of the patients. Conclusions: The survey underscored the effectiveness of vildagliptin and its combinations in managing T2DM. Clinicians widely endorsed vildagliptin once-daily formulation and vildagliptin and metformin therapy for diverse diabetic populations due to their efficacy and tolerability. They also advocated the use of vildagliptin and dapagliflozin therapy, especially in patients with specific comorbidities or higher HbA1c levels, citing its benefits in achieving better glycemic control and reducing disease progression.

The use of once-daily LCP-Tacrolimus with adolescent and young adult solid organ transplant recipients.

Adolescent and young adult (AYA) solid organ transplant (SOT) recipients experience increased rates of rejection and graft loss surrounding the time of health care transition, in part due to poor medication adherence. This study aims to examine the impact of a once-daily formulation of tacrolimus, LCP-tacrolimus (LCPT), on medication adherence for AYA SOT patients. A retrospective descriptive analysis was performed for all patients who underwent SOT and were prescribed LCPT after the age of 12 at our single-center pediatric hospital. Medication adherence was assessed via provider documentation and the medication level variability index (MLVI). Twenty-nine patients were prescribed LCPT as part of their immunosuppression regimen. Twenty patients were converted to LCPT from immediate-acting (IR) tacrolimus; six patients were initiated immediately following transplant, and three patients were unable to receive LCPT due to insurance denial. There was a numeric improvement in medication adherence for converted patients when measured by provider assessment (45.0% vs. 68.4%, p = .140) and MLVI (40.0% vs. 71.4%, p = .276), though these did not reach statistical significance. There were no differences in episodes of rejection or adverse effects. LCPT prescription was not associated with decreased medication burden, and two patients transitioned back to IR tacrolimus due to increased cost. LCPT use did not significantly improve patient adherence; however, it resulted in numerically higher perceived and measured adherence rates. LCPT appears to be safe and effective in the management of SOT recipients; however, it may not affect pill burden and may result in a higher financial burden. Use may be considered for a select group of AYA SOT recipients.

A multi-center interventional study to assess pharmacokinetics, effectiveness, and tolerability of prolonged-release tacrolimus after pediatric kidney transplantation: study protocol for a prospective, open-label, randomized, two-phase, two-sequence, single dose, crossover, phase III b trial.

Tacrolimus, a calcineurin inhibitor (CNI), is currently the first-line immunosuppressive agent in kidney transplantation. The therapeutic index of tacrolimus is narrow due to due to the substantial impact of minor variations in drug concentration or exposure on clinical outcomes (i.e., nephrotoxicity), and it has a highly variable intra- and inter-individual bioavailability. Non-adherence to immunosuppressants is associated with rejection after kidney transplantation, which is the main cause of long-term graft loss. Once-daily formulations have been shown to significantly improve adherence compared to twice-daily dosing. Envarsus®, the once-daily prolonged-release formulation of tacrolimus, offers the same therapeutic efficacy as the conventional twice-daily immediate-release tacrolimus formulation (Prograf®) with improved bioavailability, a more consistent pharmacokinetic profile, and a reduced peak to trough, which may reduce CNI-related toxicity. Envarsus® has been approved as an immunosuppressive therapy in adults following kidney or liver transplantation but has not yet been approved in children. The objective of this study is to evaluate the pharmacokinetic profile, efficacy, and tolerability of Envarsus® in children and adolescents aged ≥ 8 and ≤ 18 years to assess its potential role as an additional option for immunosuppressive therapy in children after kidney transplantation. The study is designed as a randomized, prospective crossover trial. Each patient undergoes two treatment sequences: sequence 1 includes 4 weeks of Envarsus® and sequence 2 includes 4 weeks of Prograf®. Patients are randomized to either group A (sequence 1, followed by sequence 2) or group B (sequence 2, followed by sequence 1). The primary objective is to assess equivalency between total exposure (of tacrolimus area under the curve concentration (AUC0-24)), immediate-release tacrolimus (Prograf®) therapy, and prolonged-release tacrolimus (Envarsus®) using a daily dose conversion factor of 0.7 for prolonged- versus immediate-release tacrolimus. Secondary objectives are the assessment of pharmacodynamics, pharmacogenetics, adherence, gut microbiome analyses, adverse events (including tacrolimus toxicity and biopsy-proven rejections), biopsy-proven rejections, difference in estimated glomerular filtration rate (eGFR), and occurrence of donor-specific antibodies (DSAs). This study will test the hypothesis that once-daily prolonged-release tacrolimus (Envarsus®) is bioequivalent to twice-daily intermediate-release tacrolimus after pediatric kidney transplantation and may reduce toxicity and facilitate medication adherence. This novel concept may optimize immunosuppressive therapy for more stable graft function and increased graft survival by avoiding T-cell mediated and/or antibody-mediated rejection due to improved adherence. In addition, the study will provide data on the pharmacodynamics and pharmacogenetics of prolonged-release tacrolimus in children and adolescents. EUDRA-CT 2019-003710-13 and ClinicalTrial.gov, identifier NCT06057545.

Inhibition of Receptor-Interacting Protein Kinase1 in Chronic Plaque Psoriasis: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study.

Receptor-interacting protein kinase1 (RIPK1), a key mediator of inflammation through necroptosis and proinflammatory cytokine production, may play a role in the pathogenesis of immune-mediated inflammatory diseases such as chronic plaque psoriasis. An experimental medicine study of RIPK1 inhibition with GSK2982772 immediate-release formulation at doses up to 60mg three times daily in mild to moderate plaque psoriasis indicated that efficacy may be improved with higher trough concentrations of GSK2982772. This multicenter, randomized, double-blind, placebo-controlled, repeat-dose study (NCT04316585) assessed the efficacy, safety, pharmacokinetics, and pharmacodynamics of 960mg GSK2982772 (once-daily modified-release formulation) in patients with moderate to severe plaque psoriasis. Twenty-nine patients were randomized 2:1 to GSK2982772 (N = 19) or placebo (N = 10) for 12weeks. GSK2982772 was well tolerated with trough concentrations greater than tenfold higher than the previous phase1 study with immediate release. Despite near complete RIPK1 target engagement in blood and modest reduction in circulating inflammatory cytokines, the proportion of patients achieving 75% improvement from baseline in Psoriasis Area Severity Index score at week12 was similar between GSK2982772 and placebo (posterior median 1.8% vs 4.9%, respectively), with an estimated median treatment difference of - 2.3%. This analysis incorporated historical placebo data through the use of an informative prior distribution on the placebo arm. Week4 changes in skin biopsy gene expression suggested sufficient local drug exposure to elicit a pharmacodynamic response. Administration of the RIPK1 inhibitor GSK2982772 to patients with moderate to severe plaque psoriasis did not translate into meaningful clinical improvements.

A Bioequivalence Comparison Between the Once-Daily Extended-Release Tablet and the Twice-Daily Tablet Formulations of Deutetrabenazine at Steady State.

Deutetrabenazine is approved for the treatment of tardive dyskinesia and chorea associated with Huntington's disease. This study compared the exposure between the once-daily (test) and twice-daily (reference) formulations of deutetrabenazine under fed conditions. Using a randomized crossover design, healthy adults (n = 262) received the 24mg of the test formulation once daily and 12 mg of the reference formulation twice daily, each for 7days. Plasma concentrations were collected on Days 4-6 before dose intake, and frequently for pharmacokinetic evaluation on Days 6 and 7 for determination of deutetrabenazine and active metabolites, deuterated α-dihydrotetrabenazine (α-HTBZ) and β-dihydrotetrabenazine (β-HTBZ). Geometric mean ratios (GMRs, test/reference) were computed for all analytes, and bioequivalence was tested for area under the plasma concentration-time curve over 24 hours at steady state (AUC0-24h,ss ) and for maximum plasma concentrations at steady state (Cmax,ss ). The GMRs for AUC0-24h,ss were 115% for deutetrabenazine and 95% for deuterated total (α+β)-HTBZ; and the GMR for Cmax,ss for deutetrabenazine was 95%. Relative bioavailability was assessed for Cmax,ss of the active metabolites; the GMR was 78% for total (α+β)-HTBZ. At steady state, deutetrabenazine administered as the once-daily formulation was bioequivalent to the twice-daily formulation for both AUC and Cmax, and the active metabolites were bioequivalent with regard to AUC0-24h,ss .

Pemafibrate has a novel mechanism of action to lower LDL-C and ApoB in patients with higher LDL-C levels: Insights from a phase 2 exploratory clinical pharmacology crossover study

Abstract Background Pemafibrate, a selective PPARα modulator (SPPARMα), decreases plasma TG and increases HDL-C. The effects of pemafibrate on cardiovascular outcomes were examined in patients with type 2 diabetes, moderately high TG, and low HDL-C who were on statin therapy (the PROMINENT trial) [1]. Against our expectation, the intervention with pemafibrate did not reduce the outcomes. The increases in LDL-C and ApoB observed in the trial may have mitigated the beneficial effects of lowering TG and remnants. On the contrary, pemafibrate decreased LDL-C and ApoB in some of the clinical trials conducted in Japanese population [2, 3], suggesting that the effects of pemafibrate on LDL-C and ApoB may vary depending on the target patient population. Purpose To clarify the mechanisms behind the LDL-C-lowering effects of pemafibrate, we evaluated the effects of pemafibrate on serum levels of lathosterol, beta-sitosterol and campesterol, surrogate markers for cholesterol synthesis and absorption. Methods This is a post hoc analysis of a Phase 2 study comparing a once-daily extended-release formulation (ER) of pemafibrate to a twice-daily immediate-release formulation (IR). The study was a multicentre, randomized, single-blind, 3-treatment, 2-period crossover clinical trial. Patients with fasting serum TG &amp;gt;150 mg/dL were treated with IR 0.2 mg/day (IR0.2), ER 0.4 mg/day (ER0.4), or ER 0.8 mg/day (ER0.8) for 4 weeks in each treatment period. We measured serum levels of TG, LDL-C, ApoB, lathosterol (a cholesterol synthesis marker), and beta-sitosterol and campesterol (cholesterol absorption markers) before and after the intervention and evaluated their correlations. Results Among 63 patients randomized, 60 received the study drug. At baseline, the mean TG was 221.3 mg/dL, LDL-C was 134.5 mg/dL, and 10% of patients were concomitantly treated with a statin. The least squares mean percentage changes from baseline at 4 weeks were -43.6%, -41.1%, and -39.7% for TG, -3.5%, -7.0%, and -11.3% for LDL-C, and -9.8%, -11.9%, and -13.4% for ApoB with IR0.2, ER0.4, and ER0.8, respectively, which were significant except for LDL-C with IR0.2. Lathosterol, beta-sitosterol, and campesterol significantly decreased with each dose (see Fig.). The percentage change in LDL-C was positively correlated with those in the synthesis and absorption markers. There was a trend that the reductions in LDL-C and lathosterol increased in a dose-dependent manner. The reduction in LDL-C was larger in the subgroup with higher baseline levels than those with lower baseline levels. Conclusion Pemafibrate reduced serum levels of LDL-C and ApoB. In parallel, they reduced serum markers for cholesterol synthesis and absorption. Because the percentage changes in LDL-C were significantly correlated with those in the absorption and synthesis markers, we would propose that pemafibrate reduced LDL-C by inhibiting both synthesis and absorption of cholesterol.

A Review ofOmadacycline forPotential Utility inthe Military Health System forthe Treatment ofWound Infections.

Combat-related wound infections complicate the recovery of wounded military personnel, contributing to overall morbidity and mortality. Wound infections in combat settings present unique challenges because of the size and depth of the wounds, the need to administer emergency care in the field, and the need for subsequent treatment in military facilities. Given the increase in multidrug-resistant pathogens, a novel, broad-spectrum antibiotic is desired across this continuum of care when the standard of care fails. Omadacycline was FDA-approved in 2018 for treatment of adults with acute bacterial skin and skin structure infections (ABSSSI), as well as community-acquired bacterial pneumonia (CABP). It is a broad-spectrum antibiotic with activity against gram-positive, gram-negative, and atypical bacterial pathogens, including multidrug-resistant species. Omadacycline can overcome commonly reported tetracycline resistance mechanisms, ribosomal protection proteins, and efflux pumps, and is available in once-daily intravenous or oral formulations. In this review, we discuss the potential role of omadacycline, which is included in the Department of Defense Formulary, in the context of combat wound infections. A literature review was undertaken for manuscripts published before July 21, 2023. This included a series of publications found via PubMed and a bibliography made publicly available on the Paratek Pharmaceuticals, Inc. website. Publications presenting primary data published in English on omadacycline in relation to ESKAPEE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Escherichia coli, and Enterobacter species) pathogens and Clostridioides difficile, including in vitro, in vivo, and clinical data were included. Of 260 identified records, 66 were included for evidence review. Omadacycline has in vitro activity against almost all the ESKAPEE pathogens, apart from P. aeruginosa. Importantly, it has activity against the four most prevalent bacterial pathogens that cause wound infections in the military healthcare system: S. aureus, including methicillin-resistant S. aureus, A. baumannii, K. pneumoniae, and E. coli. In vivo studies in rats have shown that omadacycline is rapidly distributed in most tissues, with the highest tissue-to-blood concentration ratios in bone mineral. The clinical efficacy of omadacycline has been assessed in three separate Phase 3 studies in patients with ABSSSI (OASIS-1 and OASIS-2) and with CABP (OPTIC). Overall, omadacycline has an established safety profile in the treatment of both ABSSSI and CABP. Omadacycline has broad-spectrum activity, the option to be orally administered and an established safety profile, making it a potentially attractive replacement for moxifloxacin in the military individual first aid kit, especially when accounting for the increasing resistance to fluoroquinolones. Further studies and clinical evaluation are warranted to support broader use of omadacycline to treat combat wound infections in the military healthcare system.

Effectiveness and safety of once-daily tacrolimus formulations in de novo liver transplant recipients: The PRETHI study.

Data comparing long-term effectiveness and safety of once-daily tacrolimus formulations in de novo liver transplantation are scarce. We compared the effectiveness, pharmacokinetic profile, and safety of LCPT (Envarsus) and PR-Tac (Advagraf) for up to 12months post-transplant. Adult de novo liver transplant recipients who started IR-Tac (Prograf) and were converted to LCPT or PR-Tac 3-5days post-transplant were included. Data from 163 patients were analyzed, 87 treated with LCPT and 76 with PR-Tac. The incidence of treatment failure was 30.5% in the LCPT group versus 23.0% in the PR-Tac group (p=.291). Biopsy-proven acute rejection (BPAR) was reported in 26.8% of patients in the LCPT group and 17.6% in the PR-Tac group (p=.166). Graft loss was experienced in one patient (1.2%) in the LCPT group and three patients (4.1%) in the PR-Tac group (p=.346). Death was registered in three patients (3.7%) in the LCPT group and three patients (4.1%) in the PR-Tac group (p>.999). Patients in the LCPT group showed 45.7% higher relative bioavailability (Cmin /total daily dose [TDD]; p<.01) with similar Cmin and 33.3% lower TDD versus PR-Tac (p<.01). The evolution of renal function, safety profile, and the incidence of post-transplant renal failure, dyslipidemia, obesity, hypertension, and diabetes mellitus were similar in patients treated with LCPT and PR-Tac. In de novo liver transplant patients, LCPT and PR-Tac showed comparable effectiveness with higher relative bioavailability, similar Cmin and lower TDD in the LCPT group. Renal function, safety, and post-transplant complications were comparable in LCPT and PR-Tac groups.

Tremor Induced by Cyclosporine, Tacrolimus, Sirolimus, or Everolimus: A Review of the Literature.

Calcineurin inhibitors such as cyclosporine and tacrolimus are immunosuppressant drugs that are known to induce tremors. Non-calcineurin inhibitors such as sirolimus and everolimus have also reportedly been accompanied by tremors, albeit less likely. However, the prevalence rates reported in the literature are notably wide, and the risk profiles for these drug-induced tremors are less understood. We searched PubMed to extract data on the risk of tremors with these drugs when prescribed for various transplant and non-transplant indications. We ascertained whether the risk of drug-induced tremor is influenced by the underlying diagnosis, dosing formulations, drug concentrations, and blood monitoring. We extracted data on treatment strategies and outcomes for tremors. Articles were primarily screened based on English language publications, abstracts, and studies with n ≥ 5, which included case series, retrospective studies, case-controlled studies, and prospective studies. We found 81 eligible studies comprising 33 cyclosporine, 43 tacrolimus, 6 sirolimus, and 1 everolimus that discussed tremor as an adverse event. In the pooled analysis of studies with n > 100, the incidence of tremor was 17% with cyclosporine, 21.5% with tacrolimus, and 7.8% with sirolimus and everolimus together. Regarding the underlying diagnosis, tremor was more frequently reported in kidney transplant (cyclosporine 28%, tacrolimus 30.1%) and bone marrow transplant (cyclosporine 40%, tacrolimus 41.9%) patients compared with liver transplant (cyclosporine 9%, tacrolimus 11.5%) and nontransplant indications (cyclosporine 21.5%, tacrolimus 11.3%). Most studies did not report whether the risk of tremors correlated with drug concentrations in the blood. The prevalence of tremors when using the twice-daily formulation of tacrolimus was nearly the same as the once-daily formulation (17% vs 18%). Data on individual-level risk factors for tremors were lacking. Except for three studies that found some benefit to maintaining magnesium levels, there were minimal data on treatments and outcomes. A large body of data supports a substantive and wide prevalence of tremor resulting from tacrolimus use followed by cyclosporine, especially in patients receiving a kidney transplant. However, there is little reporting on the patient-related risk factors for tremor, risk relationship with drug concentrations, treatment strategies, and outcomes.

Efficacy of once-daily ophthalmic bilastine for the treatment of allergic conjunctivitis: a dose-finding study.

Bilastine is a non-sedating second-generation antihistamine for the symptomatic treatment of allergic rhinoconjunctivitis and urticaria. This trial aimed to evaluate the optimal dose, efficacy, and safety of a newly developed once-daily preservative-free ophthalmic formulation of bilastine for allergic conjunctivitis. This phase 2, single-center, double-masked, randomized study evaluated the efficacy of 3 doses of a bilastine ophthalmic formulation (0.2%, 0.4%, and 0.6%) compared to vehicle for the treatment of allergic conjunctivitis. The primary efficacy endpoint was ocular itching reduction. The Ora-CAC® Conjunctival Allergen Challenge model was used to assess ocular and nasal symptoms at the onset of action (15 minutes), 8- and 16-hours post-treatment. Tolerance and safety were also evaluated. A total of 121 adults with seasonal and/or perennial ocular allergy were randomized. Bilastine ophthalmic formulation 0.2%, 0.4% and 0.6% were significantly superior (p>0.001) to vehicle for the treatment of ocular itching at 3, 5 and 7 minutes post-challenge at onset of action (15 minutes) and 8 hours post-treatment. Bilastine 0.6% was also effective at 16 hours post-treatment. Treatment differences for bilastine 0.6% were statistically significant (p<0.001) compared to vehicle at all timepoints for tearing, eyelid swelling, and nasal symptoms. No relevant adverse events were observed. All the tested ophthalmic bilastine doses were efficacious in rapidly reducing ocular itching. The 0.6% formulation was effective up to 16 hours post-treatment, making it suitable for once-daily administration. The new formulation was safe and well tolerated.

Efficacy and safety of once-daily prolonged-release tacrolimus versus twice-daily tacrolimus in kidney transplant recipients: A meta-analysis and trial sequential analysis.

Kidney transplantation is the most important treatment for end-stage renal disease. Immunosuppressive therapies can prevent acute rejection for kidney transplant recipients. Tacrolimus is usually administered to prevent graft rejection after transplantation. Previous studies have indicated that once-daily tacrolimus may improve medication adherence. Therefore, this meta-analysis aimed to compare clinical outcomes between once-daily and twice-daily tacrolimus in de novo renal transplant patients. Eligible studies were identified from the Cochrane Library Database, PubMed, and Embase until July 2022. Those randomized controlled trials (RCTs) evaluating once-daily versus twice-daily tacrolimus formulations in de novo renal transplantation were included. A summary risk ratio (RR) and standardized mean difference (SMD) with the 95% confidence interval (CI) were estimated using a random-effects model. In total, nine RCTs were included. There were no differences in biopsy-confirmed acute rejection rates between patients with once-daily and those with twice-daily tacrolimus (RR, 0.91; 95% CI, 0.73-1.13) in 12 months. Regarding renal function, there was no significant difference between the once-daily and twice-daily tacrolimus groups (SMD, -0.03; 95% CI, -0.12 to 0.07). In addition, the risk of graft failure, death, and adverse events in the first year was similar for the once-daily and twice-daily tacrolimus groups. Our major findings suggest that de novo renal transplantation recipients receiving once-daily tacrolimus immediately after transplantation have comparable efficacy and safety with those recipients who received twice-daily tacrolimus. Therefore, once-daily tacrolimus medication can be an alternative for de novo renal transplantation recipients.

Safety and Efficacy of Conversion to Once-Daily Tacrolimus from Twice-Daily Tacrolimus in Pediatric Liver Transplant Recipients

BackgroundNonadherence to immunosuppression is the most common cause of late acute rejection in pediatric liver transplant (LT) recipients. A prolonged-release once-daily tacrolimus formulation was developed to improve adherence and long-term allograft survival. MethodsWe screened 179 pediatric LT recipients who converted from twice-daily tacrolimus (TD-TAC) to once-daily tacrolimus (OD-TAC) between February 2011 and September 2019. ResultsOne hundred seventy-nine recipients converted to OD-TAC and were followed for 18 months. 152 OD-TAC-converted recipients (84.9%) experienced uneventful follow-up, while 21 recipients showed LFT elevation. Four recipients had biopsy-proven acute rejection within six months of conversion, all of which were successfully treated with steroid pulse. 166 recipients (92.7%) remain on OD-TAC and 13 (7.3%) were switched back to TD-TAC. The mean tacrolimus trough level significantly decreased three months following conversion (3.14 ± 1.9 ng/mL) compared with pre-conversion levels (3.69 ± 1.98 ng/mL). Mean tacrolimus trough levels remained unchanged from 3 months to 12 months following conversion. Percent coefficient of variation of tacrolimus trough levels decreased significantly from 32.5 ± 16.4 ng/mL to 27.5 ± 15.6 ng/mL after conversion to OD-TAC, reflecting a decrease in variation of tacrolimus trough levels following conversion. ConclusionsConversion to OD-TAC in pediatric LT recipients with stable graft function is safe and effective. Level of evidenceLevel IV.

EnGraft: a multicentre, open-label, randomised, two-arm, superiority study protocol to assess bioavailability and practicability of Envarsus® versus Advagraf™ in liver transplant recipients

BackgroundGraft rejection and chronic CNI toxicity remain obstacles to organ transplant success. Current formulations of tacrolimus, such as Prograf® and Advagraf™, exhibit limitations in terms of pharmacokinetics and tolerability, related in part to suboptimal bioavailability. As dosing non-compliance can result in graft rejection, the once daily formulation of tacrolimus, Advagraf™, was developed (vs 2x/day Prograf®). Benefits of Advagraf™ are counterbalanced by delayed achievement of therapeutic trough levels and need for up to 50% higher doses to maintain Prograf®-equivalent troughs. Envarsus® is also a prolonged-release once-daily tacrolimus formulation, developed using MeltDose™ drug-delivery technology to increase drug bioavailability; improved bioavailability results in low patient drug absorption variability and less pronounced peak-to-trough fluctuations. In phase III de novo kidney transplant studies, Envarsus® proved non-inferior to twice-daily tacrolimus; however, no phase IV studies show superiority of Envarsus® vs Advagraf™ in de novo liver transplant (LTx) recipients.MethodsThe EnGraft compares bioavailability and tests superiority of Envarsus® (test arm) versus Advagraf™ (comparator arm) in de novo LTx recipients. A total of 268 patients from 15 German transplant centres will be randomised 1:1 within 14 days post-LTx. The primary endpoint is dose-normalised trough level (C/D ratio) measured 12 weeks after randomisation. Secondary endpoints include the number of dose adjustments, time to reach first defined trough level and incidence of graft rejections. Additionally, clinical and laboratory parameters will be assessed over a 3-year period.DiscussionC/D ratio is an estimate for tacrolimus bioavailability. Improving bioavailability and increasing C/D ratio using Envarsus could reduce renal dysfunction and other tacrolimus-related toxicities; previous trials have shown that a higher C/D ratio (i.e. slower tacrolimus metabolism) is not only associated with improved renal function but also linked to reduced neurotoxic side effects. A higher C/D ratio could improve clinical outcomes for LTx recipients; EnGraft has begun, with one third of patients recruited by January 2022.Trial registrationThis trial has been registered (4 May 2020) in the EU Clinical Trials Register, EudraCT-Nummer: 2020–000796-20. Additionally, this trial has been registered (22 January 2021) at ClinicalTrials.gov: NCT04720326. The trial received a favourable opinion from the concerned lead ethics committee at the University of Regensburg, under the reference 20–1842-112.

Intestinal Permeability in Patients Early after Kidney Transplantation Treated with Two Different Formulations of Once-Daily Tacrolimus.

Adequate tacrolimus blood exposure is crucial in the early post-renal transplant period and a gut epithelial barrier integrity may play a role. We prospectively investigated several markers of intestinal permeability in recent kidney transplant recipients (KTRs) treated with different tacrolimus extended-release formulations. Within each of the 49 KTR pairs that received grafts from the same donor, an early randomized conversion was performed from twice-daily (Prograf) to once-daily tacrolimus formulation: Advagraf or Envarsus. Plasma zonulin, calprotectin, circulating lipopolysaccharide (LPS), LPS-binding protein (LBP), intestinal fatty acid binding protein (FABP-2), and CD-14 levels were measured. There was no difference in the recipient age, dialysis vintage, BMI, and residual diuresis between Advagraf and Envarsus groups. FABP-2 and LPS levels were significantly associated with tacrolimus trough level, 3-h level, and area under the curve (AUC) in the Envarsus but not in the Advagraf group. AUC was independently increased by LPS and decreased by age, FABP-2 concentration, and the use of Envarsus formulation as compared with Advagraf. Functional changes of gastrointestinal tract in patients treated with Envarsus may influence intestinal tacrolimus absorption to a greater extent than in Advagraf-treated KTRs and may lead to inadequate variability of tacrolimus exposure early after kidney transplantation.

Assessment of Dose Proportionality of Three Dose Strengths (6 mg, 12 mg and 24 mg) over the Clinical Dose Range (6–48 mg) of the Newly Developed Once-Daily Extended Release Tablet Formulation of Deutetrabenazine (P2-11.016)

<h3>Objective:</h3> To assess dose proportionality of three dose strengths (6mg, 12mg and 24mg), and across recommended clinical dose range (6mg – 48mg), for the once-daily (QD) extended-release tablet formulation of deutetrabenazine. <h3>Background:</h3> Deutetrabenazine (Austedo, Teva), a twice-daily (BID) formulation, is an approved treatment (daily doses 6–48mg) for tardive dyskinesia and chorea associated with Huntington disease. The new QD formulation has shown to deliver similar daily exposure to the BID formulation. <h3>Design/Methods:</h3> In a randomized phase 1 study (Study TV50717-PK-10175), healthy adult males and females (n=116) received single administrations of the QD formulation in a fed state (2×6mg, 1×12mg, 1×24mg, 2×24mg). Safety was assessed, and pharmacokinetic (PK) blood samples were collected pre-dose and up to 96 hours post-dose. Geometric mean ratios (GMRs) and 90% CIs were computed for PK parameters (maximum plasma concentration [C_max], area under the plasma concentration curve from time 0 to 36 hours [AUC_0–36h] and extrapolated to infinity [AUC_0-inf]) of deutetrabenazine, and active metabolites, deuterated α-HTBZ and β-HTBZ (individually and as a sum). A power model was fitted to describe the relationship between dose and PK parameters using a mixed model with sequence, period, and dose as fixed effects; and subject as random effect. To determine dose proportionality starting at 6mg, relative bioavailability was assessed between 2×6mg and 1×12mg. <h3>Results:</h3> GMRs and 90% CIs for C_max and AUCs fell within the bioequivalence limits of 80.00%–125.00%, demonstrating similarity between 2×6mg and 1×12mg tablets. Dose proportionality was demonstrated for all PK parameters and all analytes for QD formulation dose strengths 6mg, 12mg, and 24mg; and over the clinical dose range (6–48mg), as the 90% CIs for the slopes were contained within 0.839 to 1.161 and 0.839 to 1.107, respectively. <h3>Conclusions:</h3> The QD formulation of deutetrabenazine exhibits dose proportional pharmacokinetics for dose strengths (6mg, 12mg and 24mg), and across the full clinical dose range (6mg – 48mg). <b>Disclosure:</b> Dr. Sunzel has received personal compensation for serving as an employee of Teva Pharmaceuticals. Dr. Sunzel has stock in Teva Pharmaceuticals. An immediate family member of Dr. Sunzel has stock in Incyte. Dr. Ghibellini has received personal compensation for serving as an employee of Teva Pharmaceutical. Dr. Ghibellini has stock in Teva Pharmaceuticals. Ms. Iyengar has received personal compensation for serving as an employee of Teva. Ms. Iyengar has stock in Teva. Dr. Gutierrez has stock in Teva. Mrs. Ruffo has nothing to disclose. Dr. Gordon has received personal compensation for serving as an employee of Teva. Dr. Gordon has stock in Teva. Laura Rabinovich-Guilatt has received personal compensation for serving as an employee of Teva Pharmaceuticals. Laura Rabinovich-Guilatt has stock in Teva Pharmaceuticals.