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The four cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulators, ivacaftor, lumacaftor, tezacaftor, and elexacaftor, have revolutionised the treatment of CF by direct action on the protein target behind the disease's development. The aim was to develop and validate a quantification method for these CFTR modulators in plasma and breast milk to better understand inter-patient variability in pharmacokinetics and treatment outcome, including the risk of adverse drug reactions. The ability to monitor CFTR modulators in breast milk enables the estimation of the exposure of breastfed infant, with a potential concern for CFTR modulator-induced liver injury. The analysis was performed on a Thermo Vanquish Flex Binary UHPLC system coupled to a high-resolution mass spectrometer (HRMS), Thermo Q Exactive. The analytes were detected using positive electrospray ionisation in full scan mode. After sample preparation by protein precipitation, the supernatant was injected onto the LC system and the analytes were separated using a Zorbax SB-C18 Rapid Res HPLC column (3.5 µm, 4.6 × 75 mm). This is the first published method for CFTR modulators in breast milk. The validated quantification range for ivacaftor is 0.0050-10 µg/mL with a coefficient of variation < 6% and a mean accuracy of 97-106%; for lumacaftor, tezacaftor, and elexacaftor, the validated quantification range is 0.050-100 µg/mL with a coefficient of variation < 8% and a mean accuracy 93-106%. A simple and sensitive quantification method for CFTR modulators has been developed and used for routine analysis of human plasma and breast milk samples since 2022., (© 2024. The Author(s).)

This study investigated the formulation and characterization of rebamipide nanocrystals (REB-NCs) to enhance the solubility and permeability of rebamipide, an anti-ulcer medication known for its low aqueous solubility and permeability, classified as BCS class IV. Employing high-pressure homogenization and wet milling techniques, we successfully achieved nanonization of rebamipide, resulting in stable nanosuspensions that were subsequently freeze-dried to produce REB-NCs with an average particle size of 223 nm. Comprehensive characterization techniques, including Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), X-ray diffraction (XRD), and differential scanning calorimetry (DSC) confirmed the crystalline nature of the nanocrystals and their compatibility with the selected excipients. The saturation solubility study revealed a remarkable three-fold enhancement in PBS pH 7.4 compared to rebamipide API, indicating the effectiveness of the nanocrystal formulation in improving drug solubility. Furthermore, 3D in-vitro permeability assessments conducted on Caco-2 cell monolayers demonstrated an noticeable increase in the permeability of REB-NCs relative to the pure active pharmaceutical ingredient (API), highlighting the promise of this formulation to enhance drug absorption. The dissolution profile of the nanocrystal tablets exhibited immediate release characteristics, significantly outperforming conventional formulations in terms of the dissolution rate. This research underscores the potential of nanomilling as a scalable, environment-friendly, and less toxic approach to significantly enhance the bioavailability of rebamipide. By addressing the challenges associated with the solubility and permeability of poorly water-soluble drugs, our outcome offers insightful information into developing efficient nanomedicine strategies for enhancing therapeutic outcomes.

Background and Objectives : Dovitinib (DVB) is a pan-tyrosine kinase inhibitor (TKI) that can be administered orally. In September 2023, the FDA granted Oncoheroes approval to proceed with an Investigational New Drug (IND) application for dovitinib. This application is intended for the treatment of relapsed or advanced juvenile solid tumors, namely, osteosarcoma. Materials and Methods : The target of the present study was to develop a rapid, green, accurate, and sensitive UHPLC-MS/MS method for measuring DVB levels in human liver microsomes (HLMs). The validations of the HLMs were performed via the established UHPLC-MS/MS approach, as stated in the US FDA reported guidelines for the standards of bioanalytical method validation protocol. The StarDrop in silico software package (version 6.6), which involves the DEREK and WhichP450 in silico modules, was used to check the DVB structure for hazardous alerts and metabolic instability. The DVB and encorafenib (EFB), internal standard, and chromatographic peaks were successfully separated using a reversed phase column (an Eclipse Plus Agilent C8 column) and an isocratic mobile phase. The production of DVB parent ions was accomplished by utilizing the positive ionization mode of an ESI source. The identification and measurement of DVB daughter ions were conducted using the MRM mode. Results : The inter-day accuracy and precision exhibited a spectrum of values in the range of -0.56% to 9.33%, while the intra-day accuracy and precision showcased a range of scores between 0.28% and 7.28%. The DVB calibration curve showed a linear relationship that ranged from 1 to 3000 ng/mL. The usefulness of the currently validated UHPLC-MS/MS method was approved by the lower limit of quantification (LLOQ) of 1 ng/mL. The AGREE findings demonstrate that the UHPLC-MS/MS method had a noteworthy degree of ecological greenness. The in vitro half-life (t 1/2 ) and intrinsic clearance (Cl int ) of DVB were calculated to be 15.48 min and 52.39 mL/min/kg, respectively, which aligned with the findings from the WhichP450 software (version 6.6). Conclusions : Via the usage of in silico software, it has been observed that making small changes to the structure of the aryl piperazine ring and quinolinone moieties, or replacing these groups in the drug design process, shows potential for enhancing the metabolic safety and stability of newly developed derivatives compared to DVB.

Indacaterol, a β 2 agonist prescribed for long-term management of patients with chronic obstructive pulmonary disease and asthma. In this study the first MISPE cartridges was developed using indacaterol as a template for its selective extraction from rat lung tissues, enabling precise pharmacokinetic evaluation at the drug's site of action. A molecular imprinting polymer was synthesized using indacaterol as a template, methacrylic acid as a functional monomer and ethylene glycol dimethacrylate as a cross-linker with a molar ratio (1: 4: 20). The polymer was characterized by a high binding capacity of 9840 ± 0.86 and high selectivity with an imprinting factor of 4.53 ± 0.12. The synthesized polymer was utilized as a sorbent in solid-phase extraction to purify and extract indacaterol from lung tissue matrix. The optimum molecularly imprinted solid-phase extraction (MISPE) conditions were 20.0 mg of molecular imprinting polymer and non-imprinting polymer, acetonitrile as the loading solvent, acetonitrile: water (20: 80; by volume) as the washing solvent, and methanol: acetic acid (90: 10; by volume) as the eluting solvent. A pharmacokinetic study was performed for indacaterol in rat lungs using the synthesized and optimized MISPE cartridge as a tool for sample purification. These parameters were determined in the lung tissues of rats emphasizing the local exposure of indacaterol to its target organ. The C max and T max were 51.020 ± 2.810 µg mL - 1 and 0.083 ± 0.001 h, respectively. The AUC 0-24 and AUC 0 - inf were 175.920 ± 1.053 and 542.000 ± 5.245 µg h mL - 1 , respectively. The elimination rate constant was 0.014 ± 0.00012 h - 1 and the half-life time was 48.510 ± 0.012 h. This study successfully developed and optimized MISPE cartridges using indacaterol as a template, enabling precise pharmacokinetic evaluation in rat lung tissues. The cartridges demonstrated high binding capacity and selectivity, providing crucial insights into the local exposure of indacaterol at its site of action., (© 2024. The Author(s).)

Background: Brexpiprazole is a second-generation antipsychotic approved in Japan in 2018; however, information on placental passage and breast milk transfer remains limited. In this report, the patient, a 30-year-old pregnant woman with schizophrenia, was medicated with brexpiprazole, risperidone, and quetiapine., Methods: The study used high-performance liquid chromatography-tandem mass spectrometry to determine the concentrations of brexpiprazole, quetiapine, risperidone, and its active metabolite (paliperidone) in maternal and neonatal plasma, cord venous plasma, and breast milk. Maternal plasma samples were obtained approximately 2 and 8 hours after the last administration of antipsychotics on the day of delivery and at the estimated drugs' trough time on days 1, 3, and 5 after delivery., Results: The maternal plasma concentrations of brexpiprazole, quetiapine, and paliperidone increased by approximately 3.5-fold on the fifth day compared with those on the day of delivery, whereas the risperidone concentration remained almost constant. Moreover, the neonatal plasma concentrations of the 4 drugs immediately after birth were indistinguishable from the umbilical cord concentrations and gradually decreased, except for risperidone. Relative infant doses of these compounds were below 1.1%., Conclusions: Pregnancy status notably alters the pharmacokinetic properties of antipsychotics. Therefore, close and careful monitoring of clinical symptoms should be considered during pregnancy and after delivery. Although brexpiprazole is transferred to neonates through the placenta, breastfeeding is still possible because the relative infant dose value of this drug was much less than 10%., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: On-demand topical products could be an important tool for human immunodeficiency virus (HIV) prevention. We evaluated the safety, pharmacokinetics, and ex vivo pharmacodynamics of a tenofovir alafenamide/elvitegravir (TAF/EVG, 20 mg/16 mg) insert administered rectally., Methods: MTN-039 was a phase 1, open-label, single-arm, 2-dose study. Blood, rectal fluid, and rectal tissue were collected over 72 hours following rectal administration of 1 and 2 TAF/EVG inserts for each participant., Results: TAF/EVG inserts were safe and well tolerated. EVG and tenofovir (TFV) were detected in blood plasma at low concentrations: median peak concentrations after 2 inserts were EVG 2.4 ng/mL and TFV 4.4 ng/mL. Rectal tissue EVG peaked at 2 hours (median, 2 inserts = 9 ng/mg) but declined to below limit of quantification in the majority of samples at 24 hours, whereas tenofovir diphosphate (TFV-DP) remained high >2000 fmol/million cells for 72 hours with 2 inserts. Compared to baseline, median cumulative log10 HIV p24 antigen of ex vivo rectal tissue HIV infection was reduced at each time point for both 1 and 2 inserts (P < .065 and P < .039, respectively)., Discussion: Rectal administration of TAF/EVG inserts achieved high rectal tissue concentrations of EVG and TFV-DP with low systemic drug exposure and demonstrable ex vivo inhibition of HIV infection for 72 hours. Clinical Trials Registration . NCT04047420., Competing Interests: Potential conflicts of interest. S. A. R. received research grants from Gilead Sciences and Merck. P. L. A. received research contracts from Gilead Sciences paid to his institution. S. L. H. received research grants and consulting fees from Merck. G. F. D. received research grants from Gilead Sciences. C. W. H. has received clinical research funding from Gilead Sciences and Merck; he is a coinventor of 2 issued US patents related to microbicides; and is founder of Prionde BioPharma, LLC, a microbicide company. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Cystic fibrosis is one of the most common genetic diseases among caucasian population. This disease is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene encoding for the CFTR protein. Lumacaftor, elexacaftor, tezacaftor, and ivacaftor were currently used as the treatment to Cystic fibrosis. In this study, we describe a new method for the simultaneous quantification of four molecules: lumacaftor, elexacaftor, tezacaftor, and ivacaftor, alongside two metabolites of ivacaftor, specifically hexyl-methyl ivacaftor and ivacaftor carboxylate by liquid chromatography-tandem mass spectrometry. This method holds significant utility for therapeutic drug monitoring and the optimization of treatments related to CFTR modulators. Molecules were extracted from 100 µL of plasma by a simple method of protein precipitation using acetonitrile. Following extraction, chromatographic separation was carried out by reverse chromatography on a C18 analytical column, using a gradient elution of water (0.05 % formic acid, V/V) and acetonitrile (0.05 % formic acid, V/V). The run time was 7 minutes at a flow rate of 0.5 mL/min. After separation, molecules were detected by electrospray ionization on a Xevo TQD triple-quadrupole-mass-spectrometer (Waters®, Milford, USA). The calibration range were: 0.053-20.000 mg/L for elexacaftor, tezacaftor and lumacaftor, 0.075-14.000 mg/L for ivacaftor, and 0.024-6.500 mg/L for hexyl-methyl ivacaftor and ivacaftor carboxylate. The proposed method underwent throughout validation demonstrating satisfactory precision (inter- and intra-day coefficients of variation less than 14.3 %) and a good accuracy (inter- and intra-day bias ranging between -13.7 % and 14.7 %) for all the analytes. The presented method for the simultaneous quantification of CFTR modulators and their metabolites in human plasma has undergone rigorous validation process yielding good results including strong precision and accuracy for all analytes. This method has been effectively used in routine analytical analysis and clinical investigations within our laboratory., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Elexacaftor, tezacaftor, ivacaftor (ETI) is a CFTR modulator combination approved for use in ∼90 % of people with cystic fibrosis (pwCF) over 2 years old. While most pwCF tolerate this therapy well, some are intolerant to standard dosing, and others show little response. Clinical providers may adjust ETI dosing to combat these issues, but these adjustments are not well guided by pharmacokinetic evidence. Our post-approval study aimed to describe pharmacokinetic variability of ETI plasma concentrations in 15 participants who were administered a standard or reduced dose. ETI were quantified by LC-MS/MS in plasma samples taken prior to the morning dose. Results showed non-significant differences for each compound regardless of dosing regimen and after dose equivalence normalization. The majority of participants in both dosing groups had concentrations expected to elicit clinical response to ETI therapy. These findings indicate that dose reduction may be a viable strategy to maintain clinical benefit while managing intolerance., Competing Interests: Declaration of competing interest Dr. Guimbellot reports consulting fees from Vertex Pharmaceuticals Incorporated, outside the submitted work. All other authors have no conflicts of interest to report., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Therapeutic drug monitoring (TDM) of elexacaftor, tezacaftor, ivacaftor (ETI) could be a useful tool to increase efficacy and decrease the risk of adverse effects in people with Cystic Fibrosis (pwCF). It is however unclear whether drug exposure should be monitored by assessment of trough (C min ) levels or determination of the area under the curve (AUC). Hence, in this study the correlation between measured C min concentration and AUC was evaluated. Serial plasma samples, including C min , were drawn after administration of ETI in order to calculate the AUC and assess the correlation between the two parameters. A linear correlation between C min and AUC 0-24h was found, with Pearson's r correlation coefficients of 0.963, 0.908 and 0.860 for elexacaftor, tezacaftor and ivacaftor, respectively. Exposure of ETI may be monitored by assessment of C min levels., Competing Interests: Declaration of competing interest The authors have no conflict of interest to declare., (Copyright © 2024. Published by Elsevier B.V.)

Aripiprazole once-monthly (AOM) exhibits an important interindividual pharmacokinetic variability with significant implications for its clinical use. CYP2D6 and CYP3A4 highly contributes to this variability, as they metabolize aripiprazole (ARI) into its active metabolite, dehydroaripiprazole (DHA) and the latter into inactive metabolites. This study aims to evaluate the effect of CYP2D6 and CYP3A4 polymorphisms in combination and the presence of concomitant inducers and inhibitors of this cytochromes on ARI and DHA plasma concentrations in a real clinical setting. An observational study of a cohort of 74 Caucasian patients under AOM treatment was conducted. Regarding CYP2D6, higher concentrations were found for active moiety (ARI plus DHA) (AM) (67 %), ARI (67 %) and ARI/DHA ratio (77 %) for poor metabolizers (PMs) compared to normal metabolizers (NMs). No differences were found for DHA. PMs for both CYP2D6 and CYP3A4 showed a 58 % higher AM and 66 % higher plasma concentration for ARI compared with PMs for CYP2D6 and NMs for CYP3A4. In addition, PMs for both CYP2D6 and CYP3A4 have 45 % higher DHA concentrations than NMs for both cytochromes and 41 % more DHA than PMs for CYP2D6 and NMs for CYP3A4, suggesting a significant role of CYP3A4 in the elimination of DHA. Evaluating the effect of CYPD26 and CYP3A4 metabolizing state in combination on plasma concentrations of ARI, DHA and parent-to-metabolite ratio, considering concomitant treatments with inducers and inhibitor, could optimize therapy for patients under AOM treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

A physiologically-based pharmacokinetic (PBPK) model for tipifarnib, which included mechanistic absorption, was built and verified by integrating in vitro data and several clinical data in healthy subjects and cancer patients. The final PBPK model was able to recover the clinically observed single and multiple-dose plasma concentrations of tipifarnib in healthy subjects and cancer patients under several dosing conditions, such as co-administration with a strong CYP3A4 inhibitor and inducer, an acid-reducing agent (proton pump inhibitor and H2 receptor antagonist), and with a high-fat meal. In addition, the model was able to accurately predict the effect of mild or moderate hepatic impairment on tipifarnib exposure. The appropriately verified model was applied to prospectively simulate the liability of tipifarnib as a victim of CYP3A4 enzyme-based drug-drug interactions (DDIs) with a moderate inhibitor and inducer as well as tipifarnib as a perpetrator of DDIs with sensitive substrates of CYP3A4, CYP2B6, CYP2D6, CYP2C9, and CYP2C19 in healthy subjects and cancer patients. The effect of a high-fat meal, acid-reducing agent, and formulation change at the therapeutic dose was simulated. Finally, the model was used to predict the effect of mild, moderate, or severe hepatic, and renal impairment on tipifarnib PK. This multipronged approach of combining the available clinical data with PBPK modeling-guided dosing recommendations for tipifarnib under several conditions. This example showcases the totality of the data approach to gain a more thorough understanding of clinical pharmacology and biopharmaceutic properties of oncology drugs in development., (© 2024 The Author(s). CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

ELQ-300 is a potent antimalarial drug with activity against blood, liver, and vector stages of the disease. A prodrug, ELQ-331 , exhibits reduced crystallinity and improved in vivo efficacy in preclinical testing, and currently, it is in the developmental pipeline for once-a-week dosing for oral prophylaxis against malaria. Because of the high cost of developing a new drug for human use and the high risk of drug failure, it is prudent to have a back-up plan in place. Here we describe ELQ-596 , a member of a new subseries of 3-biaryl-ELQs, with enhanced potency in vitro against multidrug-resistant Plasmodium falciparum parasites. ELQ-598 , a prodrug of ELQ-596 with diminished crystallinity, is more effective vs murine malaria than its progenitor ELQ-331 by 4- to 10-fold, suggesting that correspondingly lower doses could be used to protect and cure humans of malaria. With a longer bloodstream half-life in mice compared to its progenitor, ELQ-596 highlights a novel series of next-generation ELQs with the potential for once-monthly dosing for protection against malaria infection. Advances in the preparation of 3-biaryl-ELQs are presented along with preliminary results from experiments to explore key structure-activity relationships for drug potency, selectivity, pharmacokinetics, and safety.

Acute myelogenous leukemia (AML), a heterogeneous disease of the blood and bone marrow, is characterized by the inability of myeloblasts to differentiate into mature cell types. Dihydroorotate dehydrogenase (DHODH) is an enzyme well-known in the pyrimidine biosynthesis pathway and preclinical findings demonstrated that DHODH is a metabolic vulnerability in AML as inhibitors can induce differentiation across multiple AML subtypes. As a result of virtual screening and structure-based drug design approaches, a novel series of isoquinolinone DHODH inhibitors was identified. Further lead optimization afforded JNJ-74856665 as an orally bioavailable, potent, and selective DHODH inhibitor with favorable physicochemical properties selected for clinical development in patients with AML and myelodysplastic syndromes (MDS).

A pharmacokinetic (PK) bridging approach was successfully employed to support the dosing regimen and approval of brexpiprazole in pediatric patients aged 13-17 years with schizophrenia. Brexpiprazole was approved in 2015 for the treatment of schizophrenia and the adjunctive treatment of major depressive disorder in adults based on efficacy and safety data from clinical trials. On January 13, 2020, the US Food and Drug Administration issued a general advice letter to sponsors highlighting the acceptance of efficacy extrapolation of certain atypical antipsychotics from adult patients to pediatric patients considering the similarity in disease and exposure-response relationships. Brexpiprazole is the first atypical antipsychotic approved in pediatrics using this approach. The PK data available from pediatric patients aged 13-17 years have shown high variability due to the limited number of PK evaluable subjects, which limits a robust estimation of differences between adult and pediatric patients. The PK model-based approach was thus utilized to evaluate the appropriateness of the dosing regimen by comparing PK exposures in pediatric patients aged 13-17 years with exposures achieved in adults at the approved doses. In addition to exposure matching, safety data from a long-term open-label clinical study in pediatric patients informed the safety profile in pediatric patients. This report illustrates the potential of leveraging previously collected efficacy, safety, and PK data in adult patients to make a regulatory decision in pediatric patients for the indication of schizophrenia., (© 2024, The American College of Clinical Pharmacology.)

Background and Objective: Managing drug-food interactions is essential for optimizing the effectiveness and safety profile of quinolones. Following PRISMA guidelines, we systematically reviewed the influence of dietary interventions on the bioavailability of 22 quinolones., Methods: All studies describing or investigating the impact of food, beverages, antacids, and mineral supplements on pharmacokinetic parameters or pharmacokinetic/pharmacodynamic indices of orally taken quinolones were considered for inclusion. We excluded reviews, in vitro and in silico studies, studies performed on animals, and those involving alcohol. We performed the search in Medline (via PubMed), Embase, and Cochrane Library, covering reports from database inception to December 2022. We used the following tools to assess the risk of bias: version 2 of the Cochrane risk-of-bias tool for parallel trials, the Cochrane risk-of-bias tool for cross-over studies, and the NIH quality assessment tool for before-after studies. We performed quantitative analyses for each quinolone if two or more food-effect studies with specified and comparable study designs were available. If meta-analyses were not applicable, we qualitatively summarized the results., Results: We included 109 studies from 101 reports. Meta-analyses were conducted for 12 antibiotics and qualitative synthesis was employed for the remaining drugs. Of the studies, 60.5% were open-label, cross-over, as recommended by FDA. We judged 46% of studies as having a high risk of bias and only 4% of having a low risk of bias. Among 19 quinolones with available food impact data, 14 (74%) had potentially clinically important interactions. For nalidixic acid, oxolinic acid, and tosufloxacin, food exerted a high positive impact on bioavailability (AUC or C max increased by > 45%), whereas, for all the remaining drugs, postprandial absorption was lower. The most significant negative influence of food (AUC or C max decreased by > 40%) occurred for delafloxacin capsules and norfloxacin, whereas the moderate influence (AUC or C max decreased by 30-40%) occurred for nemonoxacin and rufloxacin. All 14 analysed quinolones showed a substantial reduction in bioavailability when co-administered with antacids and mineral supplements, except for calcium preparations. The impact of beverages was evaluated for 10 quinolones, with 50% experiencing significantly reduced absorption in the presence of milk (the highest negative impact for ciprofloxacin). Moreover, both ciprofloxacin and levofloxacin demonstrated compromised bioavailability when consumed with orange juice, particularly calcium-fortified., Discussion: Several factors may influence interactions, including the physicochemical characteristics of quinolones, the type of intervention, drug formulation, and the patient's health status. We assessed the quality of evidence as low due to the poor actuality of included studies, their methodological diversity, and uneven data availability for individual drugs., (© 2024. The Author(s).)

Background: The use of elexacaftor/tezacaftor/ivacaftor (ETI) in people with cystic fibrosis (pwCF) after solid organ transplantation is controversial because of potential drug-drug interactions (DDI) with tacrolimus. We aimed to improve insight into the safety and clinical benefits of co-administration of ETI and tacrolimus in liver or kidney transplanted adult pwCF., Methods: In 5 pwCF, tacrolimus concentrations were monitored during 2 weeks before and 4 weeks after starting ETI treatment. Trough levels, area under the curve (AUC) and clinical effect of ETI were investigated. During the study (6 weeks in total) adverse events were monitored., Results: The DDI between tacrolimus and ETI resulted in an increased exposure of tacrolimus in all subjects, the dose adjusted AUC 0-24h was 1.79 (median) times higher at the end of the study. Five dose adjustments were performed in 4 subjects in order to attain tacrolimus target range. No adverse events were reported and all subjects showed clinical improvement during ETI treatment., Conclusion: The clinical value of ETI treatment in kidney and liver transplanted pwCF is clear. The use of ETI may increase tacrolimus levels moderately. Therefore, we recommend close monitoring of tacrolimus trough levels in patients who start ETI., Competing Interests: Declaration of competing interest We hereby declare that none of the authors have received any financial support or other benefits from commercial sources for the work reported in this manuscript; neither do they have any financial interest which could create a potential conflict of interest., (Copyright © 2024 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Background: Ivacaftor (IVA) has been shown to be safe and efficacious in children aged ≥4 months with cystic fibrosis (CF) and CFTR gating variants. We evaluated safety, pharmacokinetics (PK), and efficacy of IVA in a small cohort of infants aged 1 to <4 months with CF., Methods: In this phase 3, open-label study, infants 1 to <4 months with CF and an IVA-responsive CFTR variant received an initial low dose of IVA based on age and weight. Because IVA is a sensitive CYP3A substrate and CYP3A maturation is uncertain in infants, doses were adjusted at day 15 to better match median adult exposures based on individual PK measurements taken on day 4. Primary endpoints were safety and PK measurements., Results: Seven infants (residual function CFTR variants [n=5]; minimal function CFTR variants [n=2]) received ≥1 dose of IVA. Six infants had doses adjusted at day 15 and one infant did not require dose adjustment; subsequent PK analyses showed mean trough concentrations for IVA and metabolites were within range of prior clinical experience. Four infants (57.1%) had adverse events (AEs); no serious AEs were noted. One infant discontinued study drug due to a non-serious AE of elevated alanine aminotransferase >8x the upper limit of normal. Mean sweat chloride concentration decreased (-40.3 mmol/L [SD: 29.2]) through week 24. Improvements in biomarkers of pancreatic function and intestinal inflammation, as well as growth parameters, were observed., Conclusions: In this small, open-label study, IVA dosing in infants achieved exposures previously shown to be safe and efficacious. Because PK was predictable, a dosing regimen based on age and weight is proposed. IVA was generally safe and well tolerated, and led to improvements in CFTR function, markers of pancreatic function and intestinal inflammation, and growth parameters, supporting use in infants as young as 1 month of age., Competing Interests: Declaration of competing interest MR has received research grant funding and an advisory board role for Vertex Pharmaceuticals Incorporated for which her institution received payment. AS has received grants/contracts as a principal investigator from Vertex Pharmaceuticals Incorporated. SAM has received compensation to institution as principal investigator and advisory board consulting fees from Vertex Pharmaceuticals Incorporated. PM has received compensation to his institution as co-investigator, advisory board participation, and honoraria for speaker events from Vertex Pharmaceuticals Incorporated. JD has received payment for clinical trial leadership, advisory board participation, and speaker events from Vertex Pharmaceuticals Incorporated. MH, ML, JL, and VR-R are employees of Vertex Pharmaceuticals Incorporated and may own stock or stock options., (Copyright © 2024. Published by Elsevier B.V.)

Lumacaftor/ivacaftor (Orkambi®, LUM/IVA) is indicated for the treatment of cystic fibrosis (CF) patients aged ≥ 2 years with homozygous F580del mutation in the CFTR gene. Triazole fungal agents are used to treat fungal disease in CF. The use of triazoles is limited by pharmacokinetic challenges, such as drug-drug interactions. The most notable drug-drug interaction between triazoles and LUM/IVA is due to strong induction of CYP3A4 and UGT by LUM. In this real-world retrospective observational study, we described the effect of LUM/IVA on the trough concentration of triazoles. Concomitant use of LUM/IVA with itraconazole, posaconazole or voriconazole resulted in subtherapeutic triazole levels in 76% of the plasma samples. In comparison, in patients with triazole agents without LUM/IVA only 30.6% of the plasma samples resulted in subtherapeutic concentrations. Subtherapeutic plasma concentrations of triazoles should be considered in CF patients on LUM/IVA and further research is warranted for other dosing strategies and alternative antifungal therapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

To formulate and optimize Ozenoxacin nano-emulsion using Quality by Design (QbD) concept by means of Box-Behnken Design (BBD) and converting it to a gel to form Ozenoxacin nano-emulgel followed by physico-chemical, in-vitro, ex-vivo and in-vivo evaluation. This study demonstrates the application of QbD methodology for the development and optimization of an effective topical nanoemulgel formulation for the treatment of Impetigo focusing on the selection of appropriate excipients, optimization of formulation and process variables, and characterization of critical quality attributes. BBD was used to study the effect of "% of oil, % of S mix and homogenization speed" on critical quality attributes "globule size and % entrapment efficiency" for the optimisation of Ozenoxacin Nano-emulsion. Ozenoxacin loaded nano-emulgel was characterized for "description, identification, pH, specific gravity, amplitude sweep, viscosity, assay, organic impurities, antimicrobial effectiveness testing, in-vitro release testing, ex-vivo permeation testing, skin retention and in-vivo anti-bacterial activity". In-vitro release and ex-vivo permeation, skin retention and in-vivo anti-bacterial activity were found to be significantly (p < 0.01) higher for the nano-emulgel formulation compared to the innovator formulation (OZANEX™). Antimicrobial effectiveness testing was performed and found that even at 70% label claim of benzoic acid is effective to inhibit microbial growth in the drug product. The systematic application of QbD principles facilitated the successful development and optimization of a Ozenoxacin Nano-Emulsion. Optimised Ozenoxacin Nano-Emulgel can be considered as an effective alternative and found to be stable at least for 6 months at 40 °C / 75% RH and 30 °C / 75% RH., (© 2024. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.)

Eye drops, including solutions and suspensions, are essential dosage forms to treat ophthalmic diseases, with poorly water-soluble drugs typically formulated as ophthalmic suspensions. In addition to low bioavailability, suspensions exhibit limited efficacy, safety, and usability due to the presence of drug particles. Improving bioavailability can reduce the drug concentrations and the risk of problems associated with suspended drug particles. However, practical penetration enhancers capable of improving bioavailability remain elusive. Herein, we focused on penetratin (PNT), a cell-penetrating peptide (CPP) that promotes active cellular transport related to macromolecule uptake, such as micropinocytosis. According to the in vitro corneal uptake study using a reconstructed human corneal epithelial tissue model, LabCyte CORNEA-MODEL24, PNT enhanced the uptake of Fluoresbrite ® YG carboxylate polystyrene microspheres without covalent binding. In an ex vivo porcine eye model, the addition of 10 µM PNT to rebamipide ophthalmic suspension markedly improved the corneal uptake of rebamipide; however, the addition of 100 µM PNT was ineffective due to potentially increased particle size by aggregation. This article provides basic information on the application of PNT as a penetration enhancer in ophthalmic suspensions, including the in vitro and ex vivo studies mentioned above, as well as the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cytotoxicity assay and storage stability at different pH values.

Aim: The relationship between CYP1A2 polymorphisms and the steady-state plasma levels of aripiprazole and its active metabolite, dehydroaripiprazole, were investigated in Japanese schizophrenic patients., Background: It has been implied that cytochrome P450 (CYP) 1A2 may play a role in the metabo-lism of aripiprazole. Genetic variations in the CYP1A2 gene have been reported., Objective: The authors investigated the relationship between 2 CYP1A2 polymorphisms, CYP1A2*C (-3860G>A) and CYP1A2*F (-163C>A) , and the steady-state plasma levels/dose (C/D) ratios of aripiprazole and dehydroaripiprazole in Japanese schizophrenic patients., Methods: All 89 subjects (46 males and 43 females) had been receiving 2 fixed daily doses of aripiprazole (24 mg; n=56 and 12 mg: n=33) for more than 2 weeks. No other drugs were used except flunitrazepam and biperiden. The plasma drug levels were determined by LC/MS/MS. These CYP1A2 polymorphisms were detected using polymerase chain reaction analysis., Results: The mean C/D ratios of dehydroaripiprazole were significantly (P < 0.05) lower in patients with the A/A allele of CYP1A2*F than in those without the allele. No differences were found in the values of aripiprazole and the combination of aripiprazole and dehydroaripiprazole among the CYP1A2 *F genotype. There were no differences in the values of aripiprazole, dehydroaripiprazole, or the combination of the 2 compounds among the CYP1A2 *C genotype. The absence of the A allele of CYP1A2 *F was correlated with the mean C/D ratios of dehydroaripiprazole (standardized partial correlation coefficient = 0.276, P < 0.01) by multiple regression analysis., Conclusion: The findings of this study suggest that the CYP1A2 *F polymorphism contributes at least partially to the variability in the steady-state plasma levels of dehydroaripiprazole., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Objective: We aimed to unravel potential pharmacokinetic interactions between aripiprazole and duloxetine., Methods: Plasma concentrations of aripiprazole in two groups of 78 patients each, receiving aripiprazole as a monotherapy or combined with duloxetine, were compared. A potential impact of duloxetine on the metabolism of aripiprazole was expected in higher plasma concentrations of aripiprazole and higher dose-adjusted plasma concentrations., Results: Patients co-medicated with duloxetine showed significantly higher plasma concentrations of aripiprazole by 54.2% (p = 0.019). Dose-adjusted plasma concentrations were 45.6% higher (p = 0.001); 12.8% of these patients exhibited aripiprazole plasma concentrations above the upper limit of the therapeutic reference range, in the control group this was only the case for 10.3% of the patients. A positive relationship was found between the daily dose of duloxetine and dose-adjusted plasma concentrations of aripiprazole (p = 0.034). As dehydroaripiprazole concentrations were not available, conclusions for the active moiety (aripiprazole plus dehydroaripiprazole) could not be drawn., Conclusions: Combining duloxetine and aripiprazole leads to significantly higher drug concentrations of aripiprazole, most likely via an inhibition of cytochrome P450 CYP2D6 and to a lesser extent of CYP3A4 by duloxetine. Clinicians have to consider increasing aripiprazole concentrations when adding duloxetine to a treatment regimen with aripiprazole., (© 2023 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society). Published by John Wiley & Sons Ltd.)

The MedLine database contains 570 publications, including 71 randomized clinical trials and 6 meta-analyses on the rebamipide molecule in 2022. Indications for the use of rebamipide are gastric ulcer, chronic gastritis with hyperacidityin the acute stage, erosive gastritis, prevention of damage to the gastrointestinal mucosa while taking non-steroidal anti-inflammatory drugs, eradication of Helicobacter pylori . Currently trials are studying the efficacy and safety of the drug in gouty and rheumatoid arthritis, osteoarthritis, Sjögren's syndrome, bronchial asthma, vitiligo, atherosclerosis, diseases of the kidneys and liver; using in traumatology to accelerate bone regeneration; in ophthalmology to improve the regeneration of corneal epithelium; in oncology to reduce inflammatory changes in the oral mucosa after chemoradiotherapy. The review article is about the main pharmacokinetic and pharmacodynamic characteristics of rebamipide. A detailed understanding of pharmacodynamics and pharmacokinetics allows for individual selection of therapy based on the characteristics of the patient's body - gender, age, comorbidities; choose the optimal route of administration and dosing regimen; predict adverse effects and drug interactions; be determined with new clinical indications.

An intramuscular formulation of aripiprazole monohydrate dosed once monthly (AOM) was developed to address nonadherence with the approved oral tablets. A 3-compartment linear population pharmacokinetic model for oral and AOM doses was developed; relative bioavailability was estimated for AOM relative to oral dosing and body mass index and sex were significant predictors of AOM absorption rate constant (longer absorption half-life for women and absorption half-life increases with increasing body mass index). Aripiprazole apparent oral clearance for subjects with cytochrome P450 (CYP) 2D6 poor metabolizer status and in the presence of strong CYP2D6 inhibitors was approximately half that of subjects with CYP2D6 extensive metabolizer status and 24% lower in the presence of strong CYP3A4 inhibitors. Simulations of the population pharmacokinetics were conducted to evaluate the effect of different dose initiation strategies for AOM, the effects of CYP2D6 metabolizer status, coadministration of CYP2D6 and CYP3A4 inhibitors, and missed doses. An exposure-response model with an exponential hazard function of the model-predicted minimum concentration (C min ) described the time to relapse. The hazard ratio (95% confidence interval) was 4.41 (2.89-6.75). Thus, a subject with a diagnosis of schizophrenia and C min  ≥ 95 ng/mL is 4.41 times less likely to relapse relative to a subject with C min  < 95 ng/mL., (© 2022 The Authors. Clinical Pharmacology in Drug Development published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

Brexpiprazole is an oral antipsychotic agent indicated for use in patients with schizophrenia or as adjunctive treatment for major depressive disorder. As obesity (body mass index ≥35 kg/m 2 ) has the potential to affect drug pharmacokinetics and is a common comorbidity of both schizophrenia and major depressive disorder, it is important to understand changes in brexpiprazole disposition in this population. This study uses a whole-body physiologically based pharmacokinetic model to compare the pharmacokinetics of brexpiprazole in obese and normal-weight (body mass index 18-25 kg/m 2 ) individuals known to be cytochrome P450 2D6 extensive metabolizers (EMs) and poor metabolizers (PMs). The physiologically based pharmacokinetic simulations demonstrated significant differences in the time to effective concentrations between obese and normal-weight individuals within metabolizer groups according to the label-recommended titration. Simulations using an alternative dosing strategy of 1 week of twice-daily dosing in obese EMs or 2 weeks of twice-daily dosing in obese poor metabolizers, followed by a return to once-daily dosing, yielded more consistent plasma concentrations between normal-weight and obese patients without exceeding the area under the plasma concentration-time curve observed in the normal-weight EMs. These alternative dosing strategies reduce the time to effective concentrations in obese patients and may improve clinical response to brexpiprazole., (© 2021, The American College of Clinical Pharmacology.)

Brexpiprazole is an oral antipsychotic agent indicated for use in patients with schizophrenia, or as adjunctive treatment for major depressive disorder. As cytochrome P450 (CYP) 2D6 contributes significantly to brexpiprazole metabolism, there is a label-recommended 50% reduction in dose among patients with the CYP2D6 poor metabolizer phenotype. This study uses a whole-body physiologically based pharmacokinetic (PBPK) model to compare the pharmacokinetics of brexpiprazole in patients known to be extensive metabolizers (EMs) and poor metabolizers (PMs). A PBPK model was constructed, verified, and validated against brexpiprazole clinical data, and simulations of 500 subjects were performed to establish the median time to effective concentrations in EMs and PMs. The PBPK simulations captured brexpiprazole PK well and demonstrated significant differences in the time to effective concentrations between EMs and PMs according to the label-recommended titration. Additionally, these simulations suggest that CYP2D6 PMs consistently achieve lower minimum concentrations during the dosing interval than CYP2D6 EMs. Simulations using an alternative dosing strategy of twice-daily dosing (as opposed to once daily) in PMs during the first week of brexpiprazole dosing yielded more consistent plasma concentrations between EMs and PMs, without exceeding the area under the plasma concentration-time curve observed in the EMs. Taken together, the results of these PBPK simulations suggest that product labeling for brexpiprazole titration in CYP2D6 PMs likely overcompensates for the decreased clearance seen in this population. We propose an alternative dosing strategy that decreases the time to effective concentrations and recommend a reevaluation of steady-state PK in this population to potentially allow for higher daily doses in CYP2D6 PMs., (© 2021, The American College of Clinical Pharmacology.)

The big problem of antimicrobial resistance is that it requires great efforts in the design of improved drugs which can quickly reach their target of action. Studies of antibiotic uptake and interaction with their target it is a key factor in this important challenge. We investigated the accumulation of ozenoxacin (OZN), moxifloxacin (MOX), levofloxacin (LVX), and ciprofloxacin (CIP) into the bacterial cells of 5 species, including Staphylococcus aureus (SA4-149), Staphylococcus epidermidis (SEP7602), Streptococcus pyogenes (SPY165), Streptococcus agalactiae (SAG146), and Enterococcus faecium (EF897) previously characterized.The concentration of quinolone uptake was estimated by agar disc-diffusion bioassay. Furthermore, we determined the inhibitory concentrations 50 (IC 50 ) of OZN, MOX, LVX, and CIP against type II topoisomerases from S. aureus .The accumulation of OZN inside the bacterial cell was superior in comparison to MOX, LVX, and CIP in all tested species. The accumulation of OZN inside the bacterial cell was superior in comparison to MOX, LVX, and CIP in all tested species. The rapid penetration of OZN into the cell was reflected during the first minute of exposure with antibiotic values between 190 and 447 ng/mg (dry weight) of bacteria in all strains. Moreover, OZN showed the greatest inhibitory activity among the quinolones tested for both DNA gyrase and topoisomerase IV isolated from S. aureus with IC50 values of 10 and 0.5 mg/L, respectively. OZN intracellular concentration was significantly higher than that of MOX, LVX and CIP. All of these features may explain the higher in vitro activity of OZN compared to the other tested quinolones.

Purpose: Rebamipide (REB) a potent anti-ulcer agent, has not been exploited to its full potential, owing to it extremely poor solubility, leading to highly diminutive bioavailability (<10%). The purpose is to carry out its solid-state modification., Method: Cocrystallisation was done with three GRAS coformers namely citric acid (CA), 3,4-dihydroxybenzoic acid (DHBA) and oxalic acid (OXA) employing the liquid-assisted grinding method. Cocrystal formation was based upon amide-carboxyl and amide-hydroxyl supramolecular synthons. Characterization of novel cocrystals i.e. RCA, RDHBA and ROXA was carried out by DSC, PXRD and additionally by FT-IR spectroscopy. Chemical structures have been determined utilizing the PXRD pattern by Material Studio®. Furthermore, cocrystals were subjected to solubility and intrinsic dissolution rate (IDR) evaluation. Also, pharmacodynamic and pharmacokinetic studies were performed and compared with pure rebamipide., Result: The appearances of a single sharp melting endotherm in DSC, along with novel characteristic peaks in PXRD infer the existence of a new crystalline form. Shifting in characteristic vibrations in FT-IR spectroscopy supports the establishment of distinct hydrogen-bonded networks. Structural determination revealed that RCA crystallizes in 'Bb2b' space groups whereas RDHBA in 'P1' and ROXA crystallize out in the 'P-1' space group. All the cocrystals exhibited superior apparent solubility and almost 7-13 folds increase in IDR. Furthermore, 1.6-2.5 folds enhancement in relative bioavailability and remarkable amplification in anti-ulcer, anti-inflammatory and the antioxidant potential of these cocrystals were observed., Conclusion: The study ascertains the advantages of cocrystallization, with RCA showing greatest potential and suggests a viable alternative approach for improved formulation of rebamipide., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Brexpiprazole (BRX) is approved for the treatment of schizophrenia and major depressive disorders and it is mainly metabolized by CYP3A4 and CYP2D6. Grapefruit juice (GFJ), pomegranate juice (PJ) and tomato juice (TJ) have the potential to inhibit CYP3A4 enzymes in the body. However, fruit juice-drug interactions between BRX and GFJ, PJ and TJ have not been studied extensively. The present study describes the influence of GFJ, PJ and TJ on the pharmacokinetic parameters of BRX in rats. The study samples were analyzed using a mass-accurate and single-step bioanalytical method by ultra-high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry over a wide calibration range of 20-1,500 ng/ml. The results of the pharmacokinetic study denoted that the combined administration of GFJ and PJ could increase systemic exposure of BRX. The area under the curve of BRX increased 3.43- and 1.88-fold with co-administration of GFJ and PJ, respectively, while TJ with BRX had no effect on the area under the curve. Time to peak concentration and half-life were not significantly changed by any juice co-administration. The results show that GFJ and PJ affect the pharmacokinetic profile of BRX and hence advice needs to be given to patients., (© 2021 John Wiley & Sons, Ltd.)

Background: The potential effects of ivacaftor during pregnancy and breastfeeding on the offspring are still unknown. This study aimed to investigate pre-/postnatal age-related entry into the brain and lungs and transfer of maternally administered drug by the placental and via the milk., Methods: In acute experiments Sprague Dawley rats at embryonic day (E) 19, postnatal days (P) 4, 9, 16, and adult were administered an intraperitoneal injection of ivacaftor (40 mg/kg) traced with [3H] ivacaftor. To determine tissue entry, plasma, cerebrospinal fluid (CSF), lungs and brains were collected, and radioactivity measured using liquid scintillation counting. For long term experiments pregnant dams were orally treated at 25 mg/kg/day for 7 days and pups collected at E19. For postnatal pups, dams received treatment for 7 or 14 days and pups were collected at P6, 9, 13 and 16. To estimate placental and milk transfer concentration of ivacaftor in pup & maternal plasma was determined by liquid chromatography-mass spectrometry., Results: At all ages, entry of ivacaftor into lungs, following either acute or prolonged exposure, was much higher than into brain & CSF. Brain entry appeared higher at earlier ages. Transfer across the placenta and breast milk. was estimated to be around ~40% of maternal plasma., Conclusions: Fetal and postnatal rats were exposed to maternally administered ivacaftor via placental and milk transfer. Preferential entry in the lungs at all ages suggests the possibility that exposing CF babies to maternally administered ivacaftor could be beneficial for limiting progression of CF pathology in early development., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: The novel cystic fibrosis transmembrane conductance regulator (CFTR) modulators, ivacaftor, lumacaftor, and tezacaftor, are the first drugs directly targeting the underlying pathophysiological mechanism in cystic fibrosis (CF); however, independent studies describing their pharmacokinetics are lacking. The aim of this study was to develop a quantification method for ivacaftor and its 2 main metabolites, lumacaftor and tezacaftor, in plasma and sputum using liquid chromatography with tandem mass spectrometry., Methods: The developed method used a small sample volume (20 µL) and simple pretreatment method; protein precipitation solution and internal standard were added in one step to each sample. Liquid chromatography with tandem mass spectrometry was performed for a total run time of 6 minutes. The method was validated by assessing selectivity, carryover, linearity, accuracy and precision, dilution, matrix effects, and stability., Results: The selectivity was good as no interference from matrices was observed. In the concentration range from 0.01 to 10.0 mg/L, calibration curves were linear with a correlation coefficient >0.9997 for all compounds. The within-run and between-run accuracy were between 99.7% and 116% at the lower limit of quantitation (LLOQ) and between 95.8% and 112.9% for all concentrations above LLOQ for all analytes in plasma and sputum. Within-run and between-run precisions were <12.7% for LLOQ and <6.7% for the higher limit of quantitation. Samples were stable, with no significant degradation at examined temperatures and time points. Clinical applicability was revealed by analyzing samples from 2 patients with CF., Conclusions: The presented method enables simultaneous quantification of ivacaftor, lumacaftor, and tezacaftor in plasma and sputum and is an improvement over previous methods because it uses smaller sample volumes, a simple pretreatment protocol, and includes tezacaftor. In future studies, it can be applied for examining pharmacokinetics characteristics of new CF transmembrane conductance regulator modulators., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology.)

In this study, a novel rebamipide-loaded spray-dried microsphere (RSM) with enhanced drug solubility and oral bioavailability has been developed utilizing meglumine, an alkalizing agent. The influence of carriers on the drug solubility alone, and the solubility and dissolution of the drug in the RSM was investigated. Among the alkalizing agents and hydrophilic polymers tested, meglumine and polyvinyl alcohol (PVA) showed the highest drug solubility and dissolution rate, respectively. Many RSMs were manufactured with various amounts of meglumine and PVA using distilled water, and their drug solubility and dissolution were determined. The physicochemical properties, dissolution and pharmacokinetics of the chosen RSM in rats were assessed compared to the rebamipide powder and commercial tablet. Among the RSMs tested, the one composed of rebamipide, meglumine and PVA at a weight ratio of 3:1.75:6 showed the highest drug solubility and dissolution. This RSM with a smooth spherical form significantly decreased the particle size and modified the amorphous rebamipide. Furthermore, the drug solubility, dissolution, plasma concentrations, AUC and C max values of RSM were significantly higher than those of drug powder and commercial tablet. Thus, this RSN system developed with distilled water and meglumine is recommended as an oral water-soluble rebamipide-loaded pharmaceutical product.

Background and Objective: Clinical evidence suggests no clinically relevant pharmacokinetic interactions between indacaterol (IND), glycopyrronium (GLY) and mometasone furoate (MF). A population pharmacokinetic (popPK) analysis was conducted to identify structural models describing systemic pharmacokinetic profiles of IND, GLY and MF, and estimate the effect of covariates on their pharmacokinetics following inhalation as IND/GLY/MF., Methods: Pharmacokinetic data from 698 patients with asthma were pooled from two Phase III studies that evaluated IND/MF medium- (150/160 µg) and high-dose (150/320 µg), IND/GLY/MF medium- (150/50/80 μg) and high-dose (150/50/160 μg), and a device bridging Phase II study with MF. One popPK model was developed each for IND, GLY and MF using a nonlinear mixed-effect modelling approach. Maximal and trough plasma concentrations were compared across formulations and studies, including data for IND/GLY from chronic obstructive pulmonary disease (COPD) patients. The effect of predefined covariates on the pharmacokinetics of components was evaluated using a full covariate modelling approach., Results: The final pharmacokinetic models were two-compartment disposition models with first-order elimination and sequential zero-order/first-order absorption (IND), with bolus administration and first-order elimination (GLY), and with mixed zero-order/first-order absorption and first-order elimination (MF). All model parameters were estimated with good precision (% relative standard error: IND and MF ≤25%; GLY <10%). No clinically relevant covariate effect was observed on the pharmacokinetics of IND, GLY and MF. IND and GLY pharmacokinetic profiles were similar across different formulations., Conclusion: Two-compartment popPK models adequately described the pharmacokinetics of IND, GLY and MF. The effect of covariates was not clinically relevant. The pharmacokinetic profiles of MF were comparable for combination products at corresponding medium- or high-dose inhaled corticosteroids. On a population level, the pharmacokinetics of IND and GLY were comparable between patients with asthma and COPD., (© 2021. The Author(s).)

Rationale: Elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was shown to be efficacious and safe in patients ≥12 years of age with cystic fibrosis and at least one F508del-CFTR (cystic fibrosis transmembrane conductance regulator) allele, but it has not been evaluated in children <12 years of age. Objectives: To assess the safety, pharmacokinetics, and efficacy of ELX/TEZ/IVA in children 6 through 11 years of age with F508del -minimal function or F508del - F508del genotypes. Methods: In this 24-week open-label phase 3 study, children ( N  = 66) weighing <30 kg received 50% of the ELX/TEZ/IVA adult daily dose (ELX 100 mg once daily, TEZ 50 mg once daily, and IVA 75 mg every 12 h) whereas children weighing ⩾30 kg received the full adult daily dose (ELX 200 mg once daily, TEZ 100 mg once daily, and IVA 150 mg every 12 h). Measurements and Main Results: The primary endpoint was safety and tolerability. The safety and pharmacokinetic profiles of ELX/TEZ/IVA were generally consistent with those observed in older patients. The most commonly reported adverse events included cough, headache, and pyrexia; in most of the children who had adverse events, these were mild or moderate in severity. Through Week 24, ELX/TEZ/IVA treatment improved the percentage of predicted FEV 1 (10.2 percentage points; 95% confidence interval [CI], 7.9 to 12.6), Cystic Fibrosis Questionnaire-Revised respiratory domain score (7.0 points; 95% CI, 4.7 to 9.2), lung clearance index 2.5 (-1.71 units; 95% CI, -2.11 to -1.30), and sweat chloride (-60.9 mmol/L; 95% CI, -63.7 to -58.2); body mass index-for-age z -score increased over the 24-week treatment period when compared with the pretreatment baseline. Conclusions: Our results show ELX/TEZ/IVA is safe and efficacious in children 6 through 11 years of age with at least one F508del-CFTR allele, supporting its use in this patient population. Clinical trial registered with www.clinicaltrials.gov (NCT03691779).

Preclinical and clinical development of numerous small molecules is prevented by their poor aqueous solubility, limited absorption, and oral bioavailability. Herein, we disclose a general prodrug approach that converts promising lead compounds into aminoalkoxycarbonyloxymethyl (amino AOCOM) ether-substituted analogues that display significantly improved aqueous solubility and enhanced oral bioavailability, restoring key requirements typical for drug candidate profiles. The prodrug is completely independent of biotransformations and animal-independent because it becomes an active compound via a pH-triggered intramolecular cyclization-elimination reaction. As a proof-of-concept, the utility of this novel amino AOCOM ether prodrug approach was demonstrated on an antimalarial compound series representing a variety of antimalarial 4(1 H )-quinolones, which entered and failed preclinical development over the last decade. With the amino AOCOM ether prodrug moiety, the 3-aryl-4(1 H )-quinolone preclinical candidate was shown to provide single-dose cures in a rodent malaria model at an oral dose of 3 mg/kg, without the use of an advanced formulation technique.

Purpose: The aim of this Phase 1, open-label, positron emission tomography (PET) study was to determine the degree of striatal D 2 /D 3 receptor occupancy induced by the serotonin-dopamine activity modulator, brexpiprazole, at different single dose levels in the range 0.25-6 mg., Methods: Occupancy was measured at 4 and 23.5 h post-dose using the D 2 /D 3 receptor antagonist [ 11 C]raclopride. The pharmacokinetics, safety and tolerability of brexpiprazole were assessed in parallel., Results: Fifteen healthy participants were enrolled (mean age 33.9 years; 93.3% male). Mean D 2 /D 3 receptor occupancy in the putamen and caudate nucleus increased with brexpiprazole dose, leveled out at 77-88% with brexpiprazole 5 mg and 6 mg at 4 h post-dose, and remained at a similar level at 23.5 h post-dose (74-83%). Estimates of maximum obtainable receptor occupancy (O max ) were 89.2% for the putamen and 95.4% for the caudate nucleus; plasma concentrations predicted to provide 50% of O max (EC 50 ) were 8.13 ng/mL and 7.75 ng/mL, respectively. Brexpiprazole area under the concentration-time curve (AUC ∞ ) and maximum plasma concentration (C max ) increased approximately proportional to dose. No notable subjective or objective adverse effects were observed in this cohort., Conclusion: By extrapolating the observed single-dose D 2 /D 3 receptor occupancy data in healthy participants, multiple doses of brexpiprazole 2 mg/day and above are expected to result in an efficacious brexpiprazole concentration, consistent with clinically active doses in schizophrenia and major depressive disorder., Trial Registration: ClinicalTrials.gov NCT00805454 December 9, 2008.

The hiccup (Latin singultus ) is an involuntary periodic contraction of the diaphragm followed by glottic closure, which can be a rare side effect of aripiprazole. In contrast to the structurally closely related aripiprazole, brexpiprazole was not associated with this particular adverse drug reaction. Having two very similar drugs that differ in their ability to induce hiccups represents a unique opportunity to gain insight into the receptors involved in the pathophysiology of the symptom and differences in clinical effects between aripiprazole and brexpiprazole. The overlap between maneuvers used to terminate paroxysmal supraventricular tachycardia and those employed to terminate bouts of hiccups suggests that activation of efferent vagal fibers can be therapeutic in both instances. Recent work seems to support a pivotal role for serotonin receptors in such vagal activation. It is unlikely that a unique receptor-drug interaction could explain the different effects of the examined drugs on hiccup. The different effect is most likely the consequence of several smaller effects at more than one receptor. Brexpiprazole is a highly affine (potent) α 2C antagonist and, therefore, also an indirect 5-HT 1A agonist. In contrast, aripiprazole is a partial 5-HT 1A agonist (weak antagonist) and an HT 3 antagonist. Activation of 5-HT 1A receptors enhances vagal activity while HT 3 blockade reduces it. Vagus nerve activation is therapeutic for hiccups. A definitive answer continues to be elusive., Competing Interests: The authors declare no conflict of interest., (© 2021 The Authors. Published by IMR Press.)

Rationale: We previously reported that ivacaftor was safe and well tolerated in cohorts aged 12 to <24 months with cystic fibrosis and gating mutations in the ARRIVAL study; here, we report results for cohorts aged 4 to <12 months. Objectives: To evaluate the safety, pharmacokinetics, and pharmacodynamics of ivacaftor in infants aged 4 to <12 months with one or more gating mutations. Methods: ARRIVAL is a single-arm phase 3 study. Infants received 25 mg or 50 mg ivacaftor every 12 hours on the basis of age and weight for 4 days in part A and 24 weeks in part B. Measurements and Main Results: Primary endpoints were safety (parts A and B) and pharmacokinetics (part A). Secondary/tertiary endpoints (part B) included pharmacokinetics and changes in sweat chloride levels, growth, and markers of pancreatic function. Twenty-five infants received ivacaftor, 12 in part A and 17 in part B (four infants participated in both parts). Pharmacokinetics was consistent with that in older groups. Most adverse events were mild or moderate. In part B, cough was the most common adverse event ( n  = 10 [58.8%]). Five infants (part A, n  = 1 [8.3%]; part B, n  = 4 [23.5%]) had serious adverse events, all of which were considered to be not or unlikely related to ivacaftor. No deaths or treatment discontinuations occurred. One infant (5.9%) experienced an alanine transaminase elevation >3 to ≤5× the upper limit of normal at Week 24. No other adverse trends in laboratory tests, vital signs, or ECG parameters were reported. Sweat chloride concentrations and measures of pancreatic obstruction improved. Conclusions: This study of ivacaftor in the first year of life supports treating the underlying cause of cystic fibrosis in children aged ≥4 months with one or more gating mutations.Clinical trial registered with clinicaltrials.gov (NCT02725567).

In this paper, we present a copper(I)-catalyzed nitrile-addition/ N -arylation ring-closure cascade for the synthesis of 5,11-dihydro-6 H -indolo[3,2- c ]quinolin-6-ones from 2-(2-bromophenyl)- N -(2-cyanophenyl)acetamides. Using CuBr and t -BuONa in dimethylformamide (DMF) as the optimal reaction conditions, the cascade reaction gave the target products, in high yields, with a good substrate scope. Application of the cascade reaction was demonstrated on the concise total syntheses of alkaloid isocryptolepine. Further optimization of the products from the cascade reaction led to 3-chloro-5,12-bis[2-(dimethylamino)ethyl]-5,12-dihydro-6 H -[1,3]dioxolo[4',5':5,6]indolo[3,2- c ]quinolin-6-one ( 2k ), which exhibited the characteristic DNA topoisomerase-I inhibitory mechanism of action with potent in vitro anticancer activity. Compound 2k actively inhibited ARC-111- and SN-38-resistant HCT-116 cells and showed in vivo activity in mice bearing human HCT-116 and SJCRH30 xenografts. The interaction of 2k with the Top-DNA cleavable complex was revealed by docking simulations to guide the future optimization of 5,11-dihydro-6 H -indolo[3,2- c ]quinolin-6-ones as topoisomerase-I inhibitors.

Background: A once-daily (o.d.) fixed-dose combination of indacaterol acetate (IND), glycopyrronium bromide (GLY), and mometasone furoate (MF) delivered via the Breezhaler ® device (IND/GLY/MF) is being developed for treatment of asthma. This study compared steady-state pharmacokinetics of IND, GLY and MF between Japanese and Caucasian male subjects after multiple inhalations of IND/GLY/MF o.d., Methods: This was a single-center, open-label, 2-treatment crossover study with a 21-day washout period. Japanese and Caucasian subjects received IND/GLY/MF 150/50/80 μg (inhaled corticosteroid [ICS] medium-dose) or 150/50/160 μg o.d. (ICS high-dose) for 14 days in each period. Pharmacokinetics were characterized up to 24 h post-dose on Days 1 and 14., Results: In total, 16 Japanese (median age 31 years [range 20-40 years], mean weight 68.3 kg) and 17 Caucasian subjects (median age 27 years [range 21-43 years], mean weight 75.0 kg) were randomized. Geometric mean ratios (Japanese/Caucasian) [90% confidence interval (CI)] for C max for IND, GLY and MF at the high ICS dose on Day 14 were 1.31 [1.13, 1.51] 1.38 [1.13, 1.69] and 1.07 [0.969, 1.18], respectively. Geometric mean ratios (Japanese/Caucasian) [90% CI] for AUC 0-24h on Day 14 for IND, GLY and MF at the high ICS dose were 1.17 [1.01, 1.35], 1.05 [0.920, 1.20] and 1.15 [1.05, 1.27] respectively. Similar trends were noted for all components for the medium ICS dose treatment. IND/GLY/MF was safe and well tolerated; no AEs suspected to be study drug-related were observed., Conclusion: Pharmacokinetics of IND, GLY and MF (high and medium dose) when delivered as a fixed-dose combination were comparable between Japanese and Caucasian subjects. The IND/GLY/MF combination at the administrated doses was safe and well tolerated in both ethnic groups., Trial Registration: Japan Registry of Clinical Trial: jRCT2031200227, retrospectively registered on 04, December, 2020.

Ceranib-2 is a recently discovered, poorly water-soluble potent ceramidase inhibitor, with the ability to suppress cancer cell proliferation and delay tumor growth. However, its poor water solubility and weak cellular bioavailability hinder its use as a therapeutic agent for cancer. PEGylated rosin esters are an excellent platform as a natural polymer for drug delivery applications, especially for controlling drug release due to their degradability, biocompatibility, capability to improve solubility, and pharmacokinetics of potent drugs. In this study, stable aqueous amphiphilic submicron-sized PEG400-rosin ester-ceranib-2 (PREC-2) particles, ranging between 100 and 350 nm in a 1:1 mixture, were successfully synthesized by solvent evaporation mediated by sonication.Conclusion: Stable aqueous PEGylated rosin ester nanocarriers might present a significant solution to improve solubility, pharmacokinetic, and bioavailability of ceranib-2, and hold promises for use as an anticancer adjacent drug after further investigations.

LY3023414 is an oral, selective adenosine triphosphate-competitive inhibitor of class I phosphatidylinositol 3-kinase isoforms, mammalian target of rapamycin, and DNA-protein kinase in clinical development. We report results of a 3 + 3 dose-escalation Phase 1 study for twice-daily (BID) dosing of LY3023414 monotherapy in Japanese patients with advanced malignancies. The primary objective was to evaluate tolerability and safety of LY3023414. Secondary objectives were to evaluate pharmacokinetics and to explore antitumor activity. A total of 12 patients were enrolled and received 150 mg (n = 3) or 200 mg (n = 9) LY3023414 BID. Dose-limiting toxicities were only reported at 200 mg LY3023414 for 2 patients with Grade 3 stomatitis. Common treatment-related adverse events (AEs) across both the dose levels included stomatitis (75.0%), nausea (66.7%), decreased appetite (58.3%), diarrhea, and decreased platelet count (41.7%), and they were mostly mild or moderate in severity. Related AEs Grade ≥ 3 reported for ≥1 patient included anemia, stomatitis, hypophosphatemia, and hyperglycemia (n = 2, 16.7%). Two patients discontinued due to AEs (interstitial lung disease and stomatitis). No fatal events were reported. The pharmacokinetic profile of LY3023414 was characterized by rapid absorption and elimination. Five patients had a best overall response of stable disease (150 mg, n = 3; 200 mg, n = 2) for a 55.6% disease control rate. LY3023414 up to 200 mg BID is tolerable and safe in Japanese patients with advanced malignancies.

Background: The natural food supplements curcumin and genistein, and the drug ivacaftor were found effective as CFTR potentiators in the organoids of individuals carrying a S1251N gating mutation, possibly in a synergistic fashion. Based on these in vitro findings, we evaluated the clinical efficacy of a treatment with curcumin, genistein and ivacaftor, in different combinations., Methods: In three multi-center trials people with CF carrying the S1251N mutation were treated for 8 weeks with curcumin+genistein, ivacaftor and ivacaftor+genistein. We evaluated change in lung function, sweat chloride concentration, CFQ-r, BMI and fecal elastase to determine the clinical effect. We evaluated the pharmacokinetic properties of the compounds by evaluating the concentration in plasma collected after treatment and the effect of the same plasma on the intestinal organoids., Results: A clear clinical effect of treatment with ivacaftor was observed, evidenced by a significant improvement in clinical parameters. In contrast we observed no clear clinical effect of curcumin and/or genistein, except for a small but significant reduction in sweat chloride and airway resistance. Plasma concentrations of the food supplements were low, as was the response of the organoids to this plasma., Conclusions: We observed a clear clinical effect of treatment with ivacaftor, which is in line with the high responsiveness of the intestinal organoids to this drug. No clear clinical effect was observed of the treatment with curcumin and/or genistein, the low plasma concentration of these compounds emphasizes that pharmacokinetic properties of a compound have to be considered when in vitro experiments are performed., Competing Interests: Declaration of Competing Interest J.M.B. and C.K.v.d.E are inventors on a patent application related to these findings. GHK reports research funding from the Lung Foundation of the Netherlands, GSK, Ubbo Emmius Foundation, Vertex, TEVA the Netherlands, TETRI Foundation, outside the submitted work and participation in advisory boards from GSK and PureIMS, outside the submitted work., (Copyright © 2020. Published by Elsevier B.V.)

Laquinimod, a neuroimmunomodulator, is extensively metabolized by cytochrome P450 (CYP) 3A4, and modulations of CYP3A4 activity may lead to alterations in the pharmacokinetics and/or clinical effects of laquinimod. To determine the drug-drug interaction potential of laquinimod with CYP3A inhibitors and inducers, interaction assessments were conducted in healthy volunteers using single-dose administration of laquinimod before and after multiple dosing of CYP3A inhibitors (ketoconazole, fluconazole, and cimetidine) or a CYP3A4 inducer (rifampin). For ketoconazole, subjects (n = 14) received laquinimod 0.6 mg following 1 day of ketoconazole (400 mg daily) pretreatment, a single concomitant dose, and 28 additional days. For fluconazole, subjects (n = 14) received laquinimod 0.6 mg after a single fluconazole dose of 400 mg followed by 200-mg daily fluconazole administration for 20 additional days. For cimetidine, subjects (n = 14) received laquinimod 0.6 mg following 1 day of cimetidine (800 mg twice daily) pretreatment, a single concomitant dose, and 21 additional days. For rifampin, subjects (n = 14) received laquinimod 0.6 mg following 9 days of rifampin (600 mg daily) pretreatment, a single concomitant dose, and 12 additional days. Coadministration of laquinimod with CYP3A inhibitors, ketoconazole, fluconazole, and cimetidine increased laquinimod area under the plasma concentration-time curve from time zero to infinity by approximately 3.1-, 2.5-, and 1.1-fold, respectively. Coadministration of laquinimod with rifampin decreased laquinimod area under the plasma concentration-time curve from time zero to infinity by 5-fold. These results indicate that coadministration of laquinimod with moderate to strong inhibitors of CYP3A or strong inducers of CYP3A may give rise to significant pharmacokinetic drug interactions., (© 2020, The American College of Clinical Pharmacology.)

There is a pressing need to improve the efficiency of drug development, and nowhere is that need more clear than in the case of neglected diseases like malaria. The peculiarities of pyrimidine metabolism in Plasmodium species make inhibition of dihydroorotate dehydrogenase (DHODH) an attractive target for antimalarial drug design. By applying a pair of complementary quantitative structure-activity relationships derived for inhibition of a truncated, soluble form of the enzyme from Plasmodium falciparum (s-PfDHODH) to data from a large-scale phenotypic screen against cultured parasites, we were able to identify a class of antimalarial leads that inhibit the enzyme and abolish parasite growth in blood culture. Novel analogs extending that class were designed and synthesized with a goal of improving potency as well as the general pharmacokinetic and toxicological profiles. Their synthesis also represented an opportunity to prospectively validate our in silico property predictions. The seven analogs synthesized exhibited physicochemical properties in good agreement with prediction, and five of them were more active against P. falciparum growing in blood culture than any of the compounds in the published lead series. The particular analogs prepared did not inhibit s-PfDHODH in vitro, but advanced biological assays indicated that other examples from the class did inhibit intact PfDHODH bound to the mitochondrial membrane. The new analogs, however, killed the parasites by acting through some other, unidentified mechanism 24-48 h before PfDHODH inhibition would be expected to do so.

In this study, a series of 3,4-dihydroquinolin-2(1H)-one derivatives were designed and synthesized using two experimental models, namely maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ), to test the anticonvulsant activity of the target compound in vivo (i.p. in Kunming mice). The neurotoxicity (NT) of the target compound was measured by the rotating rod method (i.p. in Kunming mice). Six compounds with potential activity were selected from the two experimental models to test the 50% effective dose (ED 50 ). In vitro binding experiments with the GABA A receptor were also performed. The results of the pharmacological experiments showed that compound 7-((5-(pentylthio)-1,3,4-oxadiazol-2-yl)methoxy)-3,4-dihydroquinolin-2(1H)-one (5b) showed the best anticonvulsant activity (MES, ED 50  = 10.1 mg/kg; scPTZ, ED 50  = 9.3 mg/kg), which was superior to activities shown by carbamazepine and ethosuximide, and it also exhibited the most potent binding affinity to GABA A receptors (IC 50  = 0.12 μM). The GABA content in Wistar rat brains (i.p.) was also investigated, and the results showed that compound 5b may have a certain effect on the GABA system, as it increased the GABA concentration in the brain of rats. Molecular docking was used to study the binding mode of compound 5b and the GABA A receptor. Compound 5b showed significant interactions with residues at the benzodiazepines binding site on the GABA A receptor. The physicochemical and pharmacokinetic properties of the target compounds were predicted using Discovery Studio 2019 and ChemBioDraw Ultra 14.0., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Indacaterol maleate delivered with the Breezhaler® inhalation device is a long-acting β 2 -agonist approved for chronic obstructive pulmonary disease. In the development of a once daily, inhaled fixed dose combination (FDC) of indacaterol, glycopyrronium bromide (a long-acting muscarinic antagonist), and mometasone furoate (an inhaled corticosteroid [ICS]) for the treatment of patients with asthma, the acetate salt of indacaterol is used instead of the maleate salt. Here, we investigated the lung function, pharmacokinetics (PK) and safety of indacaterol maleate 150 μg once daily (o.d.) and indacaterol acetate 150 μg o.d. in comparison with placebo., Methods: This was a randomised, double-blind, three-period crossover study (ClinicalTrials.gov identifier, NCT03257995) in patients with asthma on background ICS therapy. Patients with percent predicted pre-bronchodilator forced expiratory volume per second (FEV 1 ) ≥50% and ≤ 90% were included in the study. Patients received indacaterol maleate 150 μg o.d., indacaterol acetate 150 μg o.d., or placebo on top of stable background ICS in randomised sequence. Trough FEV 1 was assessed after 14 days of treatment. PK of indacaterol salts were assessed at steady state after 14 days of treatment; peak expiratory flow (PEF) rate and rescue medication use were collected with a combined PEF-meter/electronic diary throughout the study., Results: Of the 54 adult patients (median age of 48 years), 51 patients completed the study. Both indacaterol salts demonstrated statistically significant improvements in trough FEV 1 of 186 mL (maleate) and 146 mL (acetate) compared with placebo (both P < 0.001). FEV 1 AUC 0-4h improved by 248 mL (maleate) and 245 mL (acetate), and PEF by 33 L/min (maleate) and 30.8 L/min (acetate) versus placebo. Systemic exposure of indacaterol (AUC 0-24h,ss and C max,ss on Day 14) was comparable after administration of both salt forms. Both salt forms demonstrated a good safety profile and were well tolerated, with a difference in the reporting frequency of AEs of coughing (maleate, 23.5%; acetate, 0%)., Conclusions: In patients with asthma, indacaterol maleate and acetate elicited comparable and significant improvements in lung function compared with placebo and achieved comparable systemic exposure. Both indacaterol salts were safe and well tolerated., Trial Registration: ClinicalTrials.gov NCT03257995 June 06, 2017.