Significant Food Effect Research Articles

Contrasting the pharmacokinetic performance and gut microbiota effects of an amorphous solid dispersion and lipid nanoemulsion for a poorly water-soluble anti-psychotic

Increasing attention is being afforded to understanding the bidirectional relationship that exists between oral drugs and the gut microbiota. Often overlooked, however, is the impact that pharmaceutical excipients exert on the gut microbiota. Subsequently, in this study, we contrasted the pharmacokinetic performance and gut microbiota interactions between two commonly employed formulations for poorly soluble compounds, namely 1) an amorphous solid dispersion (ASD) stabilised by poly(vinyl pyrrolidone) K-30, and 2) a lipid nanoemulsion (LNE) comprised of medium chain glycerides and lecithin. The poorly soluble antipsychotic, lurasidone, was formulated with ASD and LNE due to its rate-limiting dissolution, poor oral bioavailability, and significant food effect. Both the ASD and LNE were shown to facilitate lurasidone supersaturation within in vitro dissolution studies simulating the gastrointestinal environment. This translated into profound improvements in oral pharmacokinetics in rats, with the ASD and LNE exerting comparable ∼ 2.5-fold improvements in lurasidone bioavailability, compared to the pure drug. The oral formulations imparted contrasting effects on the gut microbiota, with the LNE depleting the richness and abundance of the microbial ecosystem, as evidenced through reductions in alpha diversity (Chao1 index) and operational taxonomical units (OTUs). In contrast, the ASD exerted a ‘gut neutral’ effect, whereby a mild enrichment of alpha diversity and OTUs was observed. Importantly, this suggests that ASDs are effective solubility-enhancing formulations that can be used without comprising the integrity of the gut microbiota – an integral consideration in the treatment of mental health disorders, such as schizophrenia, due to the role of the gut microbiota in regulating mood and cognition.

Food Effect and Pharmacokinetic Bridging of Avacopan in Caucasian and Japanese Healthy Participants.

Avacopan 30mg twice daily (BID) is approved for the treatment of severe active antineutrophil cytoplasmic autoantibody-associated vasculitis (granulomatosis with polyangiitis and microscopic polyangiitis). Food effect on avacopan pharmacokinetics (PKs) and PK bridging in Japanese participants were examined through 2 phase 1 studies involving healthy adult participants. In Study 1, an open-label, crossover trial, participants received oral administration of a single 30-mg dose of avacopan under fasted and fed conditions. Study 2 was a randomized, single-blind, placebo-controlled trial in Caucasian and Japanese participants: Part A investigated single doses of 10 and 30mg of avacopan under fasted and fed conditions and Part B investigated 30 and 50mg BID avacopan. The PKs of single-dose administrations of 10 and 30mg in Japanese participants was compared with that in Caucasian participants under fasted conditions. Food substantially increased plasma avacopan area under the plasma concentration-time curve from time 0 to time infinity (AUC0-inf) by 1.72-fold, supporting the recommendation of taking avacopan with food. Maximum plasma concentration (Cmax) remained relatively unchanged. The median time to reach Cmax (tmax) was delayed by 3hours. No significant food effect was observed on the active metabolite CCX168-M1 (M1) AUC. Avacopan and M1 exposures were <1.5-fold higher in Japanese participants than in Caucasian participants following multiple-dose administration of avacopan.

Inulin‐Lipid Core–Shell Microcapsules Target the Gut Microbiota and Mimic the Pharmaceutical Food Effect for Improved Oral Antipsychotic Delivery

AbstractThe oral delivery of most atypical antipsychotics is severely challenged by their low oral bioavailability and significant food effects that necessitate patient compliance. Lipid formulations are an attractive delivery system for overcoming the dosing challenges of antipsychotics, but their negative impact on the gut microbiota can interfere with the pharmacodynamic response through disruption of the gut‐brain axis. Here, novel gut microbiota‐targeting microcapsules are engineered to provide a multifunctional approach for improving both the pharmacokinetic and pharmacodynamic properties of the antipsychotic, lurasidone. The microcapsules are comprised of a lipid core that facilitates the solubilization and oral absorption of the lipophilic drug and an outer carbohydrate polymer (inulin) shell that positively modulates the gut microbiota by facilitating microbial fermentation. Fed‐fasted variability in lurasidone solubilization is mitigated through microencapsulation with inulin‐lipid microcapsules (ILM), while microbiota enrichment is coupled with enhanced serotonin levels in the small intestine, faeces, and plasma. The realization of multifunctional ILM confirms the pharmacokinetics and efficacy of mental health therapies, such as antipsychotics, can be optimized through strategic encapsulation within functional formulations that target the gut microbiota for effective modulation of the gut‐brain axis.

1-Deoxynojirimycin containing Morus alba leaf-based food modulates the gut microbiome and expression of genes related to obesity

BackgroundObesity is a serious disease with an alarmingly high incidence that can lead to other complications in both humans and dogs. Similar to humans, obesity can cause metabolic diseases such as diabetes in dogs. Natural products may be the preferred intervention for metabolic diseases such as obesity. The compound 1-deoxynojirimycin, present in Morus leaves and other sources has antiobesity effects. The possible antiobesity effect of 1-deoxynojirimycin containing Morus alba leaf-based food was studied in healthy companion dogs (n = 46) visiting the veterinary clinic without a history of diseases. Body weight, body condition score (BCS), blood-related parameters, and other vital parameters of the dogs were studied. Whole-transcriptome of blood and gut microbiome analysis was also carried out to investigate the possible mechanisms of action and role of changes in the gut microbiome due to treatment.ResultsAfter 90 days of treatment, a significant antiobesity effect of the treatment food was observed through the reduction of weight, BCS, and blood-related parameters. A whole-transcriptome study revealed differentially expressed target genes important in obesity and diabetes-related pathways such as MLXIPL, CREB3L1, EGR1, ACTA2, SERPINE1, NOTCH3, and CXCL8. Gut microbiome analysis also revealed a significant difference in alpha and beta-diversity parameters in the treatment group. Similarly, the microbiota known for their health-promoting effects such as Lactobacillus ruminis, and Weissella hellenica were abundant (increased) in the treatment group. The predicted functional pathways related to obesity were also differentially abundant between groups.Conclusions1-Deoxynojirimycin-containing treatment food have been shown to significantly improve obesity. The identified genes, pathways, and gut microbiome-related results may be pursued in further studies to develop 1-deoxynojirimycin-based products as candidates against obesity.

Quality by design (QbD) commended exploration of bosutinib loaded lipid nanocarriers for food effect attenuation and bioavailability enhancement in breast cancer

Bosutinib (BOS), a BCS class IV drug suffers from poor aqueous solubility and bioavailability along with significant food effect. Lipid nanocarriers (LNC) have the potential to circumvent bioavailability related issues associated with hydrophobic moieties. In this endeavor, we explore the potential of novel lipid nanocarriers to circumvent the bioavailability pitfalls, while minimizing food effect and pharmacokinetic variability. Quality by design and multi-variate analysis was adopted for the optimization of various process parameters during nanoparticle fabrication. The optimized particle size, polydispersity index (PDI) and zeta potential were found to be 131.7 nm, 0.105 and −9.29 mV respectively. Ex vivo studies revealed improved intestinal permeation of LNC. Enhancements in cytotoxicity, ROS generation and apoptosis were observed against MCF-7 cells that could be attributed to elevated intracellular drug accumulation using LNC. Pharmacokinetic studies revealed a 2.6-fold increase in the bioavailability of BOS during fasted state and a 1.36-fold increase during fed state when BOS was administered via LNC, indicating superior oral bioavailability. Cmax fast/fed was found to be 0.94 while, AUC fast/fed was 0.9258 which was close to 1, indicating attenuation of the food effect by BOS LNC. Therefore, LNCs can serve as promising delivery carriers for attenuation of food effect during breast cancer therapy.

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.

Comparative Bioequivalence of Tablet and Capsule Formulations of Ulotaront and the Effect of Food on the Pharmacokinetics of the Tablet Form in Humans.

Ulotaront (SEP-363856), a dual trace animeassociated receptor 1 (TAAR1) and 5-HT1A receptor agonist, is in phase 3 clinical development for the treatment of schizophrenia. This study evaluated the comparative bioequivalence (BE) between tablet and capsule formulations of ulotaront and the food effect (FE) on pharmacokinetics (PK) of tablet form in healthy adult human subjects. The BE study applied an open-label two-period crossover design in 24 healthy volunteers. Subjects were randomly assigned (1:1) to dosing sequence AB or BA (A, 25 mg ulotaront tablet; B, 25 mg ulotaront capsule). The FE study also used an open-label randomized two-period crossover design in 20 healthy volunteers. Subjects were fasted overnight then randomly assigned (1:1) to dosing sequence AB or BA (A, fasted condition; B, fed condition). Dosing periods were separated by 1 week for both studies. Serial plasma samples from each period were collected and analyzed by LC-MS/MS. PK parameters were calculated using Phoenix WinNonlin® software. For the BE study, geometric mean ulotaront Cmax values were 93.28 and 86.98 ng/mL for tablet and capsule, respectively. Cmax ratio was 107.25% (90% CI 101.84-112.94%). Geometric mean ulotaront area under the plasma concentration-time curve from time 0 to infinity (AUC0-∞) values were 868.8 and 829.3 ng·h/mL for tablet and capsule, respectively. AUC0-∞ ratio was 104.76% (90% CI 100.68109.01%). For the FE study, geometric mean ulotaront Cmax was 157.89 and 157.95 ng/mL under fed and fasted conditions, respectively. Geometric mean ratio of Cmax was 99.96% (90% CI 94.48-105.77%). Geometric mean ulotaront AUC0-∞ was 1584.2 ng·h/mL fed and 1589.2 ng·h/mL fasted. Geometric mean ratio for AUC0-∞ was 99.69% (90% CI 95.02-104.58%). There was a delay in tmax (median difference 1.47 h) in the fed condition. The results showed geometric mean ratios and 90% CIs for both Cmax and AUC0-∞ for ulotaront were well within typical bioequivalence criteria of 80-125% for both the BE and FE studies, thereby confirming the bioequivalence of the two dosage forms and no significant food effect.

SATELLITE IMAGE-DERIVED NEIGHBORHOOD CHARACTERICS EXPLAIN REGIONAL VARIATION IN CARDIOMETABOLIC DISEASE

We are aware of no study indicating the effects of synbiotic food consumption on metabolic profiles, inflammation and oxidative stress among diabetic patients. The aim of the current study was to investigate the effects of synbiotic food consumption on metabolic profiles, hs-CRP and biomarkers of oxidative stress in diabetic patients.This randomized double-blinded cross-over controlled clinical trial was performed among 62 diabetic patients aged 35–70 y. After a 2-wk run-in period, subjects were randomly assigned to consume either a synbiotic (n = 62) or control food (n = 62) for 6 weeks. A 3-week washout period was applied following which subjects were crossed over to the alternate treatment arm for an additional 6 weeks. The synbiotic food consisted of a probiotic viable and heat-resistant Lactobacillus sporogenes (1 × 107 CFU), 0.04 g inulin (HPX) as prebiotic with 0.38 g isomalt, 0.36 g sorbitol and 0.05 g stevia as sweetener per 1 g. Control food (the same substance without probiotic bacteria and prebiotic inulin) was packed in identical 9-gram packages. Patients were asked to consume the synbiotic and control foods three times a day. Fasting blood samples were taken at baseline and after a 6-wk intervention to measure metabolic profiles, hs-CRP and biomarkers of oxidative stress.Consumption of a synbiotic food, compared to the control, resulted in a significant decrease in serum insulin levels (changes from baseline: −1.75 ± 0.60 vs. +0.95 ± 1.09 μIU/mL, P = 0.03). Although we failed to find a significant effect of synbiotic food consumption on total- and LDL-cholesterol levels and HOMA-IR, the effects on FPG (22.3 vs. 4.2 mg/dL, P = 0.09), serum triglycerides (45.9 vs. 20.6 mg/dL, P = 0.08) and HDL-cholesterol levels (3.1 vs. −2 mg/dL, P = 0.06) tended to be significant. A significant reduction in serum hs-CRP levels (−1057.86 ± 283.74 vs. 95.40 ± 385.38 ng/mL, P = 0.01) was found following the consumption of synbiotic food compared with the control group. Supplementation with the synbiotic food led to a significant increase in plasma total GSH (319.98 vs. 19.73 μmol/L, P < 0.001) and serum uric acid levels (+0.7 vs. −0.1 mg/dL, P = 0.04) compared to the control food. No significant effect of the synbiotic food was observed on plasma TAC levels.In conclusion, consumption of a synbiotic food for 6 weeks among diabetic patients had significant effects on serum insulin, hs-CRP, uric acid and plasma total GSH levels.Clinical trial registration number: www.irct.ir: IRCT201201195623N1.

SDI-118, a novel procognitive SV2A modulator: First-in-human randomized controlled trial including PET/fMRI assessment of target engagement.

Background: Current treatments for progressive neurodegenerative disorders characterized by cognitive impairment either have limited efficacy or are lacking altogether. SDI-118 is a small molecule which modulates the activity of synaptic vesicle glycoprotein 2A (SV2A) in the brain and shows cognitive enhancing effects in a range of animal models of cognitive deficit. Methods: This first-in-human study evaluated safety, tolerability, and pharmacokinetics/pharmacodynamics of SDI-118 in single ascending oral doses up to 80mg administered to 32 healthy male subjects. Brain target occupancy was measured in eight subjects using positron emission tomography with PET-ligand [11C]-UCB-J. Food effect was assessed in seven subjects. Mood state was regularly evaluated using standardized questionnaires, and resting state fMRI data were analyzed as exploratory objectives. Key Results: At all doses tested, SDI-118 was well tolerated and appeared safe. Adverse events were mainly dizziness, hypersomnia, and somnolence. All were mild in intensity and increased in frequency with increasing administered dose. No dose-limiting adverse reactions were observed at any dose. SDI-118 displayed a linear pharmacokinetic profile with no significant food effect. Brain penetration and target engagement were demonstrated by a dose-proportional SV2A occupancy. Conclusion: Single oral doses of SDI-118 up to 80mg were very well tolerated in healthy male subjects. Dose-proportional SV2A occupancy in the brain was demonstrated with brain imaging. Adverse effects in humans mainly occurred in higher dose ranges, with high occupancy levels, and were all mild and self-limiting. These data support further clinical exploration of the compound in patients with cognitive disorders. Clinical Trial Registration: https://clinicaltrials.gov/, identifier NCT05486195.

Effect of Food (Low and High Fat) on Pharmacokinetics of FCN-159, a Selective MEK Inhibitor, in Healthy Chinese Males.

FCN-159 is a novel, oral, potent, selective MEK1/2 inhibitor in clinical development for the treatment of NRAS-mutant advanced melanoma and neurofibromatosis type 1. We investigated the effect of food on the pharmacokinetics (PK), safety, and tolerability of FCN-159. In this single-center, open-label, phase 1 study with a three-period, three-sequence, crossover design, healthy Chinese male subjects (n = 24) were randomized (1:1:1) to receive a single, oral 8mg dose of FCN-159 in the fasted state (overnight, > 10h), and with a low-fat and a high-fat meal, separated by a 10-day washout. PK parameters including time to maximum plasma concentration (Cmax) and area under the concentration-time curve (AUC) were compared using geometric least-squares mean ratios (GLSMR), with the fasted state as the reference. A 90% CI for the GLSMR within 80-125% indicated no significant food effect. A low-fat meal (n = 23) did not affect the PK profile of FCN-159: G LSMR for AUC from time 0 to t (AUC0-t), 106.9% (90% CI 99.9-114.4%); AUC from time 0 to infinity (AUC0-∞), 106.8% (90% CI 100.0-114.0%); Cmax, 96.4% (90% CI 83.9-110.8%). A high-fat meal (n = 24) did not affect exposure to FCN-159 (GLSMR for AUC0-t, 99.4%; 90% CI 99.0-106.3%; AUC0-∞, 99.5 5%; 90% CI 93.2-106.1%), but modestly reduced Cmax by 15% (GLSMR 84.9%; 90% CI 74.0-97.3%). Both the low-fat and high-fat meals slightly prolonged the median time to Cmax by 0.5h (90% CI 0.5-1.0h). FCN-159 was generally well tolerated, with a lower incidence of treatment-emergent adverse events following administration in the fasted state than with a low-fat or high-fat meal (20.8%, 39.1%, and 37.5%, respectively). Food did not affect the PK profile of FCN-159 to a clinically meaningful extent compared with administration in the fasted state.

Novel Salts of the Atypical Antipsychotic Drug Lurasidone with Improved Solubility and Bioavailability

Lurasidone is an atypical antipsychotic drug for treating schizophrenia and bipolar disorder. The commercial form of lurasidone hydrochloride performs poor bioavailability and significant food effect owing to its poor water solubility. In this study, three novel salts of lurasidone, namely, lurasidone–ketoglutaric acid (LUD–KTA), lurasidone–trans-aconitic acid (LUD–TAA), and lurasidone–maleic acid (LUD–MA–H2O), were obtained and characterized by powder X-ray diffraction and thermal analyses. The molecular components and structures were confirmed by single-crystal X-ray diffraction. The results of the stability experiment showed that LUD–KTA and LUD–TAA exhibited satisfying physical stabilities. Based on in vitro powder dissolution experiments, the new salts achieved remarkably higher solubility than LUD-HCl. In addition, in vivo studies also showed that LUD–KTA and LUD–TAA provided superior bioavailability.

Phase II therapeutic equivalence study of Abiraterone Acetate Tablets (I) vs. ZYTIGA® in patients with metastatic castration-resistant prostate cancer.

e17040 Background: Abiraterone acetate is approved for the treatment of metastatic castration-resistant prostate cancer (mCRPC). However, the originator abiraterone acetate (ZYTIGA) is observed to be with relatively low bioavailability and high pharmacokinetic variability. Abiraterone Acetate Tablets (I), in which Sodium N-[8-(2-hydroxy-benzoyl) amino] caprylate (SNAC) was added in the formulation as an absorption enhancer, was therefore developed by using nanocrystal technology to enhance the dissolution rate of pharmaceutical compounds, leading to the improvement of the low oral bioavailability and significant food effects. Methods: Patients with mCRPC were randomized (1:1) to receive either Abiraterone Acetate Tablets (I) 300 mg daily plus 5 mg prednisone orally twice daily, or ZYTIGA 1000 mg once daily plus 5 mg prednisone orally twice daily for 84 days. The primary endpoint was serum testosterone concentration (Day 9/10). Secondary endpoints included serum prostate-specific antigen (PSA), pharmacokinetics and adverse events. Results: 68 patients with a median age of 71 (52-84 yrs) (n = 34 in each group) were enrolled in the full analysis set (FAS). The least square geometric mean of Day 9/10 serum testosterone concentration (rounded-up by 1 ng/dl) in Abiraterone Acetate Tablets (I) and ZYTIGA groups was 1.053 (95% CI, 1.006-1.102) and 1.000 (95% CI, 0.956-1.046), respectively. The geometric mean ratio between two groups was 1.053 (90% CI, 0.998-1.110) and the 90% CI fell within 80.0% to 125.0% equivalence limits. The PSA-50 response rate was also similar on Days 28, 56 and 84 (46.9% vs 50.0%, 65.6% vs 57.6%, 71.9% vs 67.7%). Compared with ZYTIGAlabel, no new safety concerns were observed in Abiraterone Acetate Tablets (I). In addition, Abiraterone Acetate Tablets (I) group was observed to be with lower frequency of treatment-emergent adverse events (TEAEs) of any grade (76.5% vs 85.7%), grade ≥3 TEAEs (8.8% vs 22.9%), and grade ≥3 treatment-related adverse events (TRAEs) (5.9% vs 14.3%). Conclusions: Therapeutic equivalence between Abiraterone Acetate Tablets (I) 300 mg and ZYTIGA 1000 mg was confirmed by Day 9/10 serum testosterone concentration in mCRPC patients. Abiraterone Acetate Tablets (I) also showed a trend of improvement in safety profile. Clinical trial information: NCT04862091.

Clinical Formulation Bridging of Gefapixant, a P2X3-Receptor Antagonist, for the Treatment of Chronic Cough.

Gefapixant is a P2X3‐receptor antagonist being developed for treatment of refractory or unexplained chronic cough. Four phase 1 studies were conducted in healthy participants that bridged the early‐phase gefapixant formulation (F01) to the phase 3 (F04A) and intended commercial (F04B) formulations. In addition, food and proton pump inhibitor (PPI) coadministration effects on gefapixant exposure were assessed. The gefapixant free base formulation (F01) was used in the initial early‐phase clinical studies. Adding citric acid to the F01 formulation (to generate F02) enhanced drug solubilization, resulting in similar bioavailability and mitigating food and gastric pH effects. The subsequently developed gefapixant citrate salt formulation (F04) achieved exposures that were comparable to F02 in the fed state (90%CIs of geometric mean ratios for area under the plasma concentration–time curve from time 0 extrapolated to infinity and maximum observed concentration were within 0.80 and 1.25) and were not meaningfully affected by food or PPIs (90%CIs of geometric mean ratios for area under the plasma concentration–time curve from time 0 extrapolated to infinity and maximum observed concentration were within 0.80 and 1.25). Minor compositional changes were made to generate the F04A and F04B formulations. In vitro dissolution studies were used to bridge F04 to F04A, and clinical bioequivalence was then established between F04A and F04B. These data support use of the proposed commercial gefapixant formulation without significant food and PPI effects.

Development and Introduction of Fexinidazole into the Global Human African Trypanosomiasis Program.

ABSTRACT.In this article, the authors show the strategy used to streamline the introduction of fexinidazole, the first all oral treatment of human African trypanosomiasis (HAT) caused by Trypanosoma brucei gambiense. The dose range was determined in phase 1 studies and a significant food effect was observed, which was tested with field-adapted meals. The pharmacokinetic profile required definition of a higher loading dosage for the first 4 days and administration of the daily dose together with a typical local meal to optimize product absorption and rapidly achieve drug steady state. This allowed for a combined phase II/III pivotal study directly after phase I trials. Partnerships with highly engaged actors from endemic country control programs and international research institutions started early through the HAT platform, building on an agreed target product profile (TPP), establishing a regulatory plan early and transparently including endemic countries in the research and data flow. A key element that enabled a quick start to access activities was preparing for World Health Organization guidelines early and starting the process prior to registration. Distribution plans were identified and supply was established from the start, by taking advantage of the existing supply agreement between the producers of all HAT drugs (Sanofi and Bayer) and the WHO. Pharmacovigilance and phase 4 studies were nested into wider implementation activities. Targeted sequential introduction into national programs was prioritized, based on medical need and epidemiologically updated information.

Redefining in-room amenities for hotel staycationers in the new era of tourism: A deep dive into guest well-being and intentions

Three separate studies were undertaken in this study. Study I is motivated to explore and redefine the in-room amenities and the underlying dimension structure of the in-room amenities for the post-pandemic era. Study II is mapped out to assess the customer evaluations of each in-room amenity in order to compare its importance and performance. Study III is designed to examine the role of the in-room amenities in regard to building a customer’s sense of well-being that in turn increases intentions to return. The findings captured a total of twenty-eight in-room amenities, which were categorized by six factors. Also, the results observed the significant effect of protective amenities, sensory amenities, and food & beverage amenities on the sense of well-being, which in turn improves intentions to return. The discussion and implications are made for the academic and industry practitioners to use in the post-pandemic world.

Effects of food on the pharmacokinetics of ensartinib in healthy Chinese subjects.

Ensartinib is a promising, aminopyridazine-based small molecule that potently inhibits anaplastic lymphoma kinase. This random, two-period, crossover study evaluated the effects of food on the pharmacokinetics of ensartinib after a single dose (225mg) in healthy Chinese subjects. The pharmacokinetic parameters of ensartinib were calculated using non-compartmental analysis. Twenty-four healthy Chinese subjects age 20-44years were included in this study. The area under the concentration-time curve of ensartinib was ~25% lower after the intake of a high-fat, high-calorie meal before dosing, whereas the maximum plasma concentration was decreased by ~37%, illustrating the statistically significant effect of food on ensartinib pharmacokinetics. In addition, food intake prolonged the absorption phase of ensartinib (median time to maximum plasma concentration, from 4.5 to 6hours). Population pharmacokinetic (PopPK) analysis was conducted using NONMEM, and the influences of food, age, sex, body weight and body mass index were studied via covariate analysis. In this analysis, ensartinib plasma concentrations were best described by a one-compartment model with Weibull absorption. The final model included food and age as covariates on apparent distribution and apparent clearance. Based on the final PopPK model, food was identified as a significant covariate for apparent clearance, apparent volume of distribution and absorption rate constant, consistent with the results of non-compartmental pharmacokinetic analysis.

Pharmacokinetics and Bioequivalence of Two Amoxicillin 500mg Products: Effect of Food on Absorption and Supporting Scientific Justification for Biowaiver.

Aims of this study were to compare the bioequivalence of two formulations of amoxicillin 500mg capsules under fasted and fed conditions in the same set of healthy volunteers, compare pharmacokinetics of amoxicillin under the two conditions and to assess the possibility of predicting in vivo bioequivalence of the two formulations using in vitro dissolution data. The innovator product of amoxicillin was used as the reference formulation and a test product, which showed in vitro equivalence after a biowaiver study with the same reference product was used in the bioequivalence study. Altogether 16 subjects were randomized to the reference and test products in the fasted study and 12 of them participated in the fed study. Plasma concentration of amoxicillin was analyzed by a validated Liquid chromatography coupled with two mass spectrometry (LC-MS/MS) method. Noncompartmental analysis was used to determine the pharmacokinetic parameters. Average bioequivalence method was used to evaluate the bioequivalence of the two formulations and statistical significance of the pharmacokinetic parameters were tested to study the effect of food on amoxicillin absorption. The Geometric Mean Ratio (GMR) for the test/reference product for the maximum drug concentrations (Cmax) was 102.77% and 97.38% in fasted and fed conditions respectively which was within 80.00-125.00% range required to demonstrate bioequivalence. The GMR for test/reference products for the area under the curve (AUC0-8,) was 100.05% and 96.91% in fasted and fed conditions respectively meeting the bioequivalence criteria. For the reference product, the Cmax was 9.38 and 7.61µg x mL-1(p =0.0224), time to reach maximum concentration (Tmax) was 1.73 and 3.02h (p=0.0005) and AUC0-8 was 26.02 and 25.54µg/h-1mL-1p=0.672) under fasted and fed conditions respectively. The test and the reference formulations were bioequivalent under both fasted and fed conditions. Although the Cmax was significantly lower and Tmax was significantly delayed under fed conditions, it did not affect the AUC. Therefore, being a time dependent antibiotic, clinically significant effect of food on efficacy of amoxicillin is unlikely. As the selected products were equivalent in vitro, these findings support scientific justification for conducting in vitro dissolution studies for solid oral amoxicillin products as a surrogate for in vivo bioequivalence studies.

Safety, Tolerability, and Pharmacokinetics of a Novel Mitochondrial Modulator, TRC150094, in Overweight and Obese Subjects: A Randomized Phase-I Clinical Trial.

TRC150094, a novel mitochondrial modulator, can restore metabolic flexibility by improving insulin resistance in preclinical studies. This study primarily aims to evaluate the safety, tolerability, and pharmacokinetics (PK) of oral TRC150094 after conducting two double-blind, randomized, Phase-I studies, single ascending dose (SAD) and multiple ascending dose (MAD), with n = 46, in overweight/obese adult and elderly subjects. In addition, the effect of TRC150094 on pharmacodynamic (PD) efficacy markers was evaluated. PK assessments, including maximum concentration (Cmax), area under the plasma concentration (AUC), time to Cmax (Tmax), and elimination half-life (t½), were assessed at pre-specified time points. PD assessments included apolipoprotein B (ApoB), triglycerides, hepatic fat by magnetic resonance spectroscopy (MRS) and cardiopulmonary exercise testing (CPET) parameters. TRC150094 was rapidly absorbed, and the AUC of TRC150094 increased in a dose-dependent manner across all doses in non-elderly and elderly cohorts. Cmax was more than the dose-proportional for all doses in all cohorts. Tmax ranged from 0.25 to 4 h, and t½ ranged from 15 to 18 h, making TRC150094 suitable for once-daily dosing. Food did not interfere with the overall absorption of the drug. The metabolites of TRC150094 were glucuronide and sulfate conjugates, and 20% of the drug was excreted unchanged in the urine. TRC150094 at 50 mg showed an improving trend in triglycerides. A significant reduction in Apo B was observed after 50 mg dose (−2.34 vs. 13.24%, p = 0.008), which was, however, not the case after 150 mg (8.78 vs. 13.24%, p = 0.1221). Other parameters such as hepatic fat and insulin sensitivity indices (HOMA-IR, MATSUDA Index derived from OGTT) showed an improving trend for the dose of 50 mg. In terms of safety, all the AEs reported were mild to moderate in severity. None of the adverse events was considered definitely or probably related to treatment, and there were no abnormal laboratory findings. In conclusion, the PK of TRC150094 was linear with no clinically significant food effect. TRC150094 and its metabolites suggest a lesser likelihood of drug-drug interactions. Overall, TRC150094 ensured safety and exhibited suitability for all subjects.Clinical Trial Registration: EUDRA CT: 2009-014941-10 (SAD) and CTR-India registration: CTRI/2009/091/000601 (MAD)

Safety, Pharmacokinetics, Pharmacodynamics, and Formulation of Liver‐Distributed Farnesoid X‐Receptor Agonist TERN‐101 in Healthy Volunteers

TERN-101 is a nonsteroidal farnesoid X-receptor agonist being developed for the treatment of nonalcoholic steatohepatitis (NASH). We assessed the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of TERN-101 capsule and tablet formulations in healthy volunteers. In a randomized, double-blind, placebo-controlled study, 38 participants were enrolled and randomized to receive placebo or 25-, 75-, or 150-mg TERN-101 capsules orally once daily for 7 days. In a separate open-label PK and formulation-bridging study, 16 participants received single doses of TERN-101 tablets (5 and 25 mg) or capsules (25 mg). TERN-101 was overall well-tolerated in this healthy volunteer population; no pruritus was reported. TERN-101 capsule administration over 7 days resulted in decreases in serum 7α-hydroxy-4-cholesten-3-one that were sustained for 24 hours after the last dose (maximum suppression 91% from baseline), indicating target engagement in the liver. TERN-101 capsules exhibited less than dose-proportional PK. Relative to capsules, TERN-101 tablets showed increased bioavailability, with 24-hour plasma exposure of the 5-mg tablet similar to that of the 25-mg capsule. There was no significant effect of food on exposure. The overall safety, PK, and PD profiles of TERN-101 support its further evaluation for the treatment of NASH.

Molecular Responses after Switching from a Standard-Dose Twice-Daily Nilotinib Regimen to a Reduced-Dose Once-Daily Schedule in Patients with Chronic Myeloid Leukemia: A Real Life Observational Study (NILO-RED)

IntroductionStandard dosing regimen for the BCR-ABL1 tyrosine kinase inhibitor (TKI) nilotinib in chronic myeloid leukemia (CML) is 300mg twice daily (BID) in the frontline setting and 400mg BID in the 2nd line setting or beyond. Patients (pts) are instructed to fast within 2 hours before and 1 hour after medication intake due to significant high-fat food effects on drug bioavailability. On-label dose adjustments to a lower-dose once-daily (QD) regimen are recommended solely in case of significant toxicity.Study goalThe primary aim of our observational two-center study was to ask whether nilotinib-treated adult CML pts were able to maintain major molecular responses (MMR) within 1 year after conversion to a more convenient nilotinib QD regimen at reduced doses, regardless of reasons for tapering nilotinib. Pts with minor transcripts or a history of blast crisis or allogeneic stem cell transplantation were excluded.PatientsEighty one pts in chronic phase were identified and included and results from the first 67 pts with a follow-up of at least 12 months after the switch to the once-daily dose-reduced nilotinib regimen are presented. Median age at study entry was 52 years (range: 19-82). There were 25 males (37.3%) and the Sokal score was low, intermediate, high or unknown in 43.3%, 37.3%, 13.4% and 6% of pts, respectively. All pts had major-type BCR-ABL1 transcripts. Nilotinib was started as 1st line TKI at 300mg BID in 68.6% of pts and as 2nd or subsequent line TKI at 400 or 300 mg BID in 31.4% of pts due to intolerance, warning, resistance or absence of a deep molecular response on prior therapy. Median duration of nilotinib prior switching to a reduced QD dosing was 29 months (range: 1-94) and median duration of MMR was 25 months (range: 3-212). Primary reason for the switch to a reduced QD nilotinib dosing was non-serious adverse events in 37.3% of pts and improvement in pts convenience in 62.7% of pts. Nilotinib was reduced down to 450mg QD, 400mg QD or 300mg QD in 86.6%, 10.4% and 3% of pts, respectively. A 2nd dose reduction from 450mg to 300mg QD was performed in 30 pts after a median time of 18 months (range: 4-37). The median duration of low-dose nilotinib QD was 24 months (5-54). No severe tolerance issues were encountered and no ischemic cardiovascular events occurred. Eleven pts stopped nilotinib due to treatment-free remission attempt (n=10) or persistent adverse event (n=1). All pts were alive at last follow-up.Evolution of molecular responsesAt baseline, the number of pts in MMR, MR4 and ≥MR4.5 was 9 (13.4%), 17 (25.4%) and 41 (61.2%), respectively and 32 pts (47.8%) had undetectable BCR-ABL1 transcripts. Median BCR-ABL1/ABL1 % IS was 0.006% (range: 0.0007-0.063) and median ABL1 copy number in pts with undetectable transcripts was 87259 (range: 36018-921339). Only 2 pts treated with 1st line nilotinib lost MMR 4 and 6 months after QD dose reduction of nilotinib with BCR-ABL1/ABL1 % IS at 0.13 and 0.11%, respectively. Both pts spontaneously regained MMR 4 months later without any treatment modification. Kaplan-Meier analysis of survival without unconfirmed MMR loss was 97% (95% CI: 92.9-100) at 12 months and analysis by molecular response category showed that none of the pts who were at least in MR4 at baseline lost MMR (Figure 1). At last follow-up on low-dose QD nilotinib, the number of pts in MMR, MR4 and ≥MR4.5 was 4 (6.3%), 11 (16.4%) and 52 (77.6%), respectively and 37 pts had undetectable transcripts (55.2%). Median BCR-ABL1/ABL1 % IS was 0.0035% (range: 0.00025-0.058) and median ABL1 copy number in pts with undetectable transcripts was 96000 (range: 23285-472000).Ten pts in long-lasting deep molecular response stopped nilotinib without further treatment after a median duration of TKI and of nilotinib of 60 months (range: 50-149) and 56 months (range: 42-87), respectively. Their follow-up after nilotinib discontinuation was 18 months (range: 5-33). Only 1 of them lost MMR and restarted therapy 5 months later while the others remained treatment-free.ConclusionSwitching to a nilotinib QD regimen at reduced doses as maintenance therapy after achievement of a MMR on standard-dose nilotinib BID schedule is feasible and safe in chronic phase CML pts regardless of prior treatment history and does not compromise the anti-leukemic efficacy of nilotinib. Our results may pave the way for clinical trials aiming at systematic avoidance of overtreatment and improvement of pts convenience in treatment with nilotinib. [Display omitted] DisclosuresRea:Pfizer: Honoraria; BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Incyte: Honoraria. Cayuela:BMS: Honoraria; Novartis: Honoraria. Etienne:BMS: Speakers Bureau; Incyte: Speakers Bureau; Novartis: Consultancy, Research Funding.