New Horizons of Model Informed Drug Development in Rare Diseases Drug Development.

Model-informed approaches provide a quantitative framework to integrate all available nonclinical and clinical data, thus furnishing a totality of evidence approach to drug development and regulatory evaluation. Maximizing the use of all available data and information about the drug enables a more robust characterization of the risk-benefit profile and reduces uncertainty in both technical and regulatory success. This offers the potential to transform rare diseases drug development, where conducting large well-controlled clinical trials is impractical and/or unethical due to a small patient population, a significant portion of which could be children. Additionally, the totality of evidence generated by model-informed approaches can provide confirmatory evidence for regulatory approval without the need for additional clinical data. In the article, applications of novel quantitative approaches such as quantitative systems pharmacology, disease progression modeling, artificial intelligence, machine learning, modeling of real-world data using model-based meta-analysis and strategies such as external control and patient-reported outcomes as well as clinical trial simulations to optimize trials and sample collection are discussed. Specific case studies of these modeling approaches in rare diseases are provided to showcase applications in drug development and regulatory review. Finally, perspectives are shared on the future state of these modeling approaches in rare diseases drug development along with challenges and opportunities for incorporating such tools in the rational development of drug products.

Ab-initio insights into the mechanical, phonon, bonding, electronic, optical and thermal properties of hexagonal W2N3 for prospective applications.

We thoroughly investigated the structural, mechanical, electronic, vibrational, optical, thermodynamic, and a number of thermophysical properties of W2N3 compound through first-principles calculations using the DFT based formalism. The calculated structural parameters show very good agreement with the available theoretical and experimental results. The mechanical and dynamical stabilities of this compound have been investigated theoretically from the elastic constants and phonon dispersion curves. The Pugh's and Poisson's ratios of W2N3 are located quite close to the brittle/ductile borderline. W2N3 is elastically anisotropic. The calculated electronic band structure and density of states reveal that W2N3 is conducting in nature. The Fermi surface topology has also been explored. The analysis of charge density distribution map shows that W atoms have comparatively high electron density around compared to the N atoms. Presence of covalent bondings between W-N, W-W, and N-N atoms are anticipated. High melting temperature and high phonon thermal conductivity of W2N3 imply that the compound has potential to be used as a heat sink system. The optical characteristics show anisotropy. The compound can be used in optoelectronic devices due to its high absorption coefficient and low reflectivity in the visible to ultraviolet spectrum. Furthermore, the quasi-harmonic Debye model is used to examine temperature and pressure dependent thermal characteristics of W2N3 for the first time.

Impact of Socio-demographic Variables, Surgical Techniques and Risk Factors on the Outcome of Coronary Artery Bypass Graft Surgery among Bangladeshi Population.

This study was intended to evaluate the pathological outcome of cardiopulmonary bypass whilst considering socio-demographic variables and surgical technique on early postoperative results following coronary artery bypass graft (CABG) surgery in patients at a tertiary level hospital in Bangladesh. This observational study evaluated a total of 880 patients with ischemic heart disease in Bangabandhu Sheikh Mujib Medical University, Bangladesh from 2011 to 2019 who were undergoing an isolated CABG surgery. In this current study, the population divided into two groups- Group A: Off-pump CABG (n=440) and Group B: On-pump CABG (n=440). The mean age of the patients was 55.25±5.0 years in off-pump and 50.75±5.2 years in the on-pump group. Risk factors, including smoking, hypertension, and hyperlipidemia, were predominant in both study groups. Total operative time was notably higher in the on-pump CABG group. However, grafting time was more in the off-pump CABG procedures. Postoperative neurological deficits were higher amongst the on-pump CABG population. The mean time of mechanical ventilation, intensive care unit (ICU) stay, total hospital stay, and mortality was notably higher in the on-pump CABG group. Moreover, the number of mortalities in on-pump CABG patients was primarily due to the low output syndrome, failure of weaning from cardiopulmonary bypass (CPB) and sudden cardiac arrest. Off-pump CABG is now more acceptable due to its potentiality to avoid CPB induced complications, aortic cannulation, and cross-clamping. Cardiac arrest in on-pump CABG induces global ischemia and reperfusion injury to the cardiac muscle. Besides, the Off-pump CABG provides a conspicuous survival advantage compared to the on-pump CABG, in association with a notable reduction in postoperative morbidity and mortality.

Steric, Synergetic, Energetic Studies on the Impact of the Type of the Hybridized Polymers (Chitosan and ß-Cyclodextrin) on the Adsorption Properties of Zeolite-A for Congo Red Dye.

Zeolite-A was synthesized successfully from kaolinite and hybridized with two species of biopolymers (chitosan (CH/Z) and ß-cyclodextrin (CD/Z)). The obtained hybridized forms were assessed as potential adsorbents of Congo red synthetic dye (CR) with enhanced affinities and elimination capacities. The synthesized CD/Z and CH/Z hybrids demonstrated uptake capacities of 223.6 and 208.7 mg/g, which are significantly higher than single-phase zeolite-A (140.3 mg/g). The integrated polymers change the surface area, surface reactivity, and number of free active receptors that are already present. The classic isotherm investigations validate Langmuir equilibrium behavior for ZA and Freundlich properties for CD/Z and CH/Z. The steric parameters validate a strong increase in the existing active receptors after the incorporation of CD (CD/Z) to be 98.1 mg/g as compared to 83 mg/g for CH/Z and 60.6 mg/g for ZA, which illustrate the detected uptake behaviors. Moreover, the CR dye was adsorbed as several molecules per single site, reflecting the vertical uptake of these molecules by multimolecular mechanisms. The energetic assessment, considering both Gaussian energies and adsorption energies (<40 kJ/mol), validates the dominant impact of the physical mechanism during the sequestration of CR (dipole binding interactions (2-29 kJ/mol) and hydrogen bonds (<30 kJ/mol)), in addition to the considerable effect of ion exchange processes. Based on the thermodynamic parameters, the CR molecules were adsorbed by exothermic and spontaneous reactions.

Pharmacokinetics and Safety of Firsocostat, an Acetyl-Coenzyme A Carboxylase Inhibitor, in Participants with Mild, Moderate, and Severe Hepatic Impairment.

Firsocostat is an oral, liver-targeted inhibitor of acetyl-coenzyme A carboxylase in development for the treatment of metabolic dysfunction-associated steatohepatitis. Hepatic organic anion transporting polypeptides play a significant role in the disposition of firsocostat with minimal contributions from uridine diphospho-glucuronosyltransferase and cytochrome P450 3A enzymes. This phase 1 study evaluated the pharmacokinetics and safety of firsocostat in participants with mild, moderate, or severe hepatic impairment. Participants with stable mild, moderate, or severe hepatic impairment (Child-Pugh A, B, or C, respectively [n = 10 per cohort]) and healthy matched controls with normal hepatic function (n = 10 per cohort) received a single oral dose of firsocostat (20 mg for mild and moderate hepatic impairment; 5 mg for severe hepatic impairment) with intensive pharmacokinetic sampling over 96 h. Safety was monitored throughout the study. Firsocostat plasma exposure (AUCinf) was 83%, 8.7-fold, and 30-fold higher in participants with mild, moderate, and severe hepatic impairment, respectively, relative to matched controls. Firsocostat was generally well tolerated, and all reported adverse events were mild in nature. Dose adjustment is not necessary for the administration of firsocostat in patients with mild hepatic impairment. However, based on the observed increases in firsocostat exposure, dose adjustment should be considered for patients with moderate or severe hepatic impairment, and additional safety and efficacy data from future clinical trials will further inform dose adjustment.

Higher testosterone is associated with higher HDL-cholesterol and lower triglyceride concentrations in older women: an observational study.

OBJECTIVE: This study aimed to determine whether concentrations of testosterone and its main precursor after menopause, dehydroepiandrosterone (DHEA), are associated with lipoproteins and other lipids in community-dwelling older women. METHODS: The Sex Hormones in Older Women (SHOW) study was an observational study of 6358 Australian women, aged at least 70 years, with no prior major adverse cardiovascular event who had sex hormones measured by liquid chromatography-tandem mass spectrometry. Associations between hormones and lipids were examined using multilinear regression adjusted for potential confounders. RESULTS: The cross-sectional analyses included 3231 participants, median age 74.0 (interquartile range 71.7-77.9) years. Compared with concentrations in the lowest quartile (Q1), testosterone concentrations in the highest quartiles (Q3 and Q4) were positively associated with high-density lipoprotein cholesterol (HDL-C) (p = 0.002 and p < 0.001, respectively) while Q4 testosterone concentrations were positively associated with total cholesterol (p = 0.038). Q2, Q3 and Q4 testosterone concentrations were significantly inversely associated with triglycerides (TG) (p = 0.024, p = 0.003 and p < 0.001, respectively). For DHEA, Q4 concentrations was positively associated with non-HDL-C (p = 0.024). CONCLUSIONS: In older women, higher endogenous testosterone concentrations are significantly associated with higher HDL-C and lower TG, indicating a less atherogenic profile. These findings suggest a neutral, or potentially protective, cardiovascular disease effect of testosterone in older women.

Feasibility of Using Population Pharmacokinetics-Based Virtual Control Groups in Organ Impairment Studies.

This work aimed to assess the feasibility of using population pharmacokinetics (popPK) to generate virtual healthy control groups in organ impairment studies. Data from 11 organ impairment studies containing 18 organ impairment arms and 13 healthy control groups across 7 drugs were analyzed. Area under the concentration-time curve (AUC) and maximum concentration (Cmax) were calculated from popPK-simulated individual concentration-time profiles for participants in the healthy control groups, accounting for the participant's specific covariate(s) (N = 1000 replicates). The AUC and Cmax geometric mean ratios (GMRs; simulated healthy control/observed healthy control and observed organ impairment/simulated healthy control) were calculated. The simulated healthy control group geometric mean exposures were within 30% of the observed geometric mean exposures in 8 of the 11 studies (73%). The number of organ impairment arms for which the observed GMR (observed organ impairment/observed healthy control) and median of simulation-based GMRs (observed organ impairment/simulated healthy control) for AUC and Cmax being within the same fold change were 12 (67%) and 13 (72%) arms, respectively. The number of organ impairment arms for which the median of simulation-based AUC and Cmax GMRs were within the 90% confidence interval of the observed GMRs were 14 (72%) and 15 (83%), respectively. Poor concordance was observed for 1 drug (3 arms), where healthy participants' data were not incorporated in the popPK model. This work supports using popPK-based virtual control groups in organ impairment studies. Subsequent work should aim to establish best practices for constructing popPK-based virtual control groups.

Evaluation of the Effects of Meal Type and Acid-Reducing Agents on the Pharmacokinetics of Cilofexor, a Selective Nonsteroidal Farnesoid X Receptor Agonist.

Cilofexor is a nonsteroidal farnesoid X receptor agonist being developed in combination with firsocostat/semaglutide for the treatment of nonalcoholic steatohepatitis. This phase 1 study evaluated the effects of food and acid-reducing agents (ARAs) on the pharmacokinetics of cilofexor (100- or 30-mg fixed-dose combination with firsocostat) in healthy participants. Cohorts 1 (n = 20, 100 mg) and 2 (n = 30, 30 mg) followed a 3-period, 2-sequence crossover design and evaluated effects of light-fat and high-fat meals. Cohort 3 (n = 30, 100 mg fasting) followed a 2-period, 2-sequence crossover design and evaluated the effects of a 40-mg single dose of famotidine. Cohort 4 (n = 18, 100 mg) followed a 3-period, 2-sequence crossover design and evaluated the effects of a 40-mg once-daily regimen of omeprazole administered under fasting conditions or following a light-fat meal. Administration with light-fat or high-fat meals resulted in no change and an ∼35% reduction in cilofexor AUC, respectively, relative to the fasting conditions. Under fasting conditions, famotidine increased cilofexor AUC by 3.2-fold and Cmax by 6.1-fold, while omeprazole increased cilofexor AUC by 3.1-fold and Cmax by 4.8-fold. With a low-fat meal, omeprazole increased cilofexor exposure to a lesser extent (Cmax 2.5-fold, AUC 2.1-fold) than fasting conditions. This study suggests that caution should be exercised when cilofexor is administered with ARAs under fed conditions; coadministration of cilofexor (100 or 30 mg) with ARAs under fasting conditions is not recommended with the current clinical trial formulations.

A Systematic Review Evaluating the Efficacy, Immunogenicity and Safety of the Biosimilar FKB327 in Treating Rheumatoid Arthritis.

Biosimilars are known to be pharmaceutical products which are very similar to a biologic drug. FKB327 is one such biosimilar of the drug Adalimumab which is prescribed in treating autoimmune diseases like Rheumatoid Arthritis. The aim of this review is to evaluate the efficacy, immunogenicity and safety of the drug FKB327 in treating patients with mild to moderate Rheumatoid Arthritis and compare the same with that of the drug Adalimumab. Two databases (PubMed and Cochrane Library) were used to screen relevant publications using pre-determined inclusion and exclusion criteria. Of the 12 studies found to be relevant, 3 were found to be eligible for the review. The data were extracted for the study characteristics, outcome measures, complications, and safety. The quality of the papers was assessed through Jadad scoring. Three (3) papers were reviewed in the study although there were limitations in reviewing efficacy as one of the papers lacked required data for efficacy. Efficacy was observed through ACR20 response and DAS28 score in the 24th week of all the three studies and immunogenicity was reviewed through the presence of Anti-drug antibody in patients after administration of both the drugs in same dosage. Safety was assessed through the development of complications after the administration of the drugs. The review concludes that there are similarities in efficacy, immunogenicity and safety between FKB327 but could not adequately prove the superiority of FKB327 over Adalimumab.

Synthesis and characterization of chitosan hybridized zinc phosphate/hydroxyapatite core shell nanostructure and its potentiality as delivery system of oxaliplatin drug.

An advanced form of zinc phosphate/hydroxyapatite nanorods with a core-shell structure (ZPh/HPANRs) was made and then hybridized with chitosan polymeric chains to make a safe biocomposite (CH@ZPh/HPANRs) that improves the delivery structure of traditional oxaliplatin (OXPN) chemotherapy during the treatment of colorectal cancer cells. The qualifications of CH@ZPh/HPANRs in comparison with ZPh/HPANRs as a carrier for OXPN were followed based on loading, release, and cytotoxicity. CH@ZPh/HPANRs composite exhibits a notably higher OXPN loading capacity (321.75 mg/g) than ZPh/HPANRs (127.2 mg/g). The OXPN encapsulation processes into CH@ZPh/HPANRs display the isotherm behavior of the Langmuir model (R2 = 0.99) and the kinetic assumptions of pseudo-first-order kinetics (R2 > 0.89). The steric studies reflect a strong increment in the quantities of the free sites after the chitosan hybridization steps (Nm = 34.6 mg/g) as compared to pure ZPh/HPANRs (Nm = 18.7 mg/g). Also, the capacity of each site was enhanced to be loaded by 10 OXPN molecules (n = 9.3) in a vertical orientation. The OXPN loading energy into CH@ZPh/HPANRs (<40 KJ/mol) reflects physical loading reactions involving van der Waals forces and hydrogen bonding. The OXPN release profiles of CH@ZPh/HPANRs exhibit slow and controlled properties for about 140 h at pH 7.4 and 80 h at pH 5.5. The release kinetics and diffusion exponent (>0.45) signify non-Fickian transport and a complex erosion/diffusion release mechanism. The free CH@ZPh/HPANRs particles display a considerable cytotoxic effect on the HCT-116 cancer cells (9.53 % cell viability), and their OXPN-loaded product shows a strong cytotoxic effect (1.83 % cell viability).

Ethnicity-specific BRCA1, BRCA2, PALB2, and ATM pathogenic alleles in breast and ovarian cancer patients from the North Caucasus.

BACKGROUND: Mountain areas of the North Caucasus host several large ethnic communities that have preserved their national identity over the centuries. METHODS: This study involved high-grade serous ovarian cancer (HGSOC) and breast cancer (BC) patients from Dagestan (HGSOC: 37; BC: 198), Kabardino-Balkaria (HGSOC: 68; BC: 155), North Ossetia (HGSOC: 51; BC: 104), Chechnya (HGSOC: 68; BC: 79), Ingushetia (HGSOC: 19; BC: 103), Karachay-Cherkessia (HGSOC: 13; BC: 47), and several Armenian settlements (HGSOC: 16; BC: 101). The group of BC patients was enriched by young-onset and/or family history-positive and/or bilateral and/or receptor triple-negative cases. The entire coding region of BRCA1, BRCA2, PALB2, and ATM genes was analyzed by next-generation sequencing. RESULTS: A significant contribution of BRCA1/2 pathogenic variants (PVs) to HGSOC and BC development was observed across all North Caucasus regions (HGSOC: 19-39%; BC: 6-13%). Founder alleles were identified in all ethnic groups studied, e.g., BRCA1 c.3629_3630delAG in Chechens, BRCA2 c.6341delC in North Ossetians, BRCA2 c.5351dupA in Ingush, and BRCA1 c.2907_2910delTAAA in Karachays. Some BRCA1/2 alleles, particularly BRCA2 c.9895C > T, were shared by several nationalities. ATM PVs were detected in 14 patients, with c.1673delG and c.8876_8879delACTG alleles occurring twice each. PALB2 heterozygosity was observed in 5 subjects, with one variant seen in 2 unrelated women. CONCLUSION: This study adds to the evidence for the global-wide contribution of BRCA1/2 genes to HGSOC and BC morbidity, although the spectrum of their PVs is a subject of ethnicity-specific variations. The data on founder BRCA1/2 alleles may be considered when adjusting the BRCA1/2 testing procedure to the ethnic origin of patients.

The 2023 Practitioner's Toolkit for Managing Menopause.

OBJECTIVE: The Practitioner's Toolkit for Managing the Menopause, developed in 2014, provided an accessible desk-top tool for health-care practitioners caring for women at midlife. To ensure the Toolkit algorithms and supporting information reflect current best practice, the Toolkit has been revised in accordance with the published literature. METHODS: A systematic search for guidelines, position and consensus statements pertaining to the menopause and published after 2014 was undertaken, and key recommendations extracted from the Clinical Practice Guidelines determined to be the most robust by formal evaluation. The peer-reviewed literature was further searched for identified information gaps. RESULTS: The revised Toolkit provides algorithms that guide the clinical assessment and care of women relevant to menopause. Included are the reasons why women present, information that should be ascertained, issues that may influence shared decision-making and algorithms that assist with determination of menopausal status, menopause hormone therapy (MHT) and non-hormonal treatment options for symptom relief. As clear guidelines regarding when MHT might be indicated to prevent bone loss and subsequent osteoporosis in asymptomatic women were found to be lacking, the Toolkit has been expanded to support shared decision-making regarding bone health. CONCLUSIONS: The 2023 Toolkit and supporting document provide accessible desk-top information to support health-care providers caring for women at midlife.The Toolkit has been endorsed by the International Menopause Society, Australasian Menopause Society, British Menopause Society, Endocrine Society of Australia and Jean hailes for Women's Health.

How Did Mortality Rates from Covid-19 Differ between Vaccinated and Unvaccinated People in a Tertiary Level Hospital of Bangladesh?

This study aims to find out the difference in mortality rates between vaccinated & non-vaccinated Covid-19 positive patients who were admitted in a tertiary centre (Ward and Intensive care unit) of Bangladesh. Retrospective analysis of data over 6 weeks in February 2022- March 2022, 100 confirmed Covid-19 positive patients were included- 50 patients from ICU and 50 patients from ward irrespective of age, gender, vaccination status and co-morbidities. Seventy five percent (75.0%) of all confirmed Covid-19 positive patients were vaccinated. Mortality among vaccinated people was less compared to non-vaccinated population 41.3% vs. 52%. Interestingly it was found pregnancy was the most significant risk factor in childbearing age female group- 86.7% of patients (pregnant and peripartum) required Intensive care admission and mortality was 40.0% although none of them had any recorded co-morbidities. Again, mortality among vaccinated was significantly less (35.7%) compared to 100.0% mortality among unvaccinated. Mortality rate among patient admitted in intensive care was significantly high compared to patients treated in ward- 72.0% vs. 16.0%. In ICU 83.0% of patients who died were vaccinated (90.0% had 2 doses and 10.0% had 3 doses). On the other hand, 87.5% who died in ward were unvaccinated. Among the survivors from intensive care units- 93.0% were vaccinated compared to 7.0% unvaccinated. Pre-existing co-morbidities increased mortality (59.0%) compared to 40.9% mortality in patients without any previous medical conditions. We found vaccination against Covid-19 reduces the rate of death irrespective of co-morbidities or severity of disease. Recovery rate was significantly increased in vaccinated patients requiring intensive care support. Pregnancy was found to be the most important risk factor for Intensive care admission and mortality in otherwise healthy childbearing age females and mortality was significantly high (100.0% though limited data availability) in unvaccinated. These results require further revalidation on larger population.

Steric and Energetic Studies on the Synergetic Enhancement Effect of Integrated Polyaniline on the Adsorption Properties of Toxic Basic and Acidic Dyes by Polyaniline/Zeolite-A Composite.

The synergetic enhancement effect of the polyaniline (PANI) integration process on the adsorption properties of the PANI/zeolite-A composite (PANI/ZA) as an adsorbent for malachite green and Congo red synthetic dyes was evaluated based on classic equilibrium modelling in addition to the steric and energetic parameters of advanced isotherm studies. The PANI/ZA composite displays enhanced adsorption capacities for both methylene blue (270.9 mg/g) and Congo red (235.5 mg/g) as compared to ZA particles (methylene blue (179.6 mg/g) and Congo red (140.3 mg/g)). The reported enhancement was illustrated based on the steric parameters of active site density (Nm) and the number of adsorbed dyes per active site (n). The integration of PANI strongly induced the quantities of the existing active sites that have enhanced affinities towards both methylene blue (109.2 mg/g) and Congo red (92.9 mg/g) as compared to the present sites on the surface of ZA. Every site on the surface of PANI/ZA can adsorb about four methylene blue molecules and five Congo red molecules, signifying the vertical orientation of their adsorbed ions and their uptake by multi-molecular mechanisms. The energetic investigation of the methylene blue (-10.26 to -16.8 kJ/mol) and Congo red (-9.38 to -16.49 kJ/mol) adsorption reactions by PANI/ZA suggested the operation of physical mechanisms during their uptake by PANI/ZA. These mechanisms might involve van der Waals forces, dipole bonding forces, and hydrogen bonding (<30 kJ/mol). The evaluated thermodynamic functions, including enthalpy, internal energy, and entropy, validate the exothermic and spontaneous behaviours of the methylene blue and Congo red uptake processes by PANI/ZA.

Characterization of the US Food and Drug Administration Post-Marketing Commitments and Requirements for Pregnancy and Lactation.

Enactment of the US Food and Drug Administration Amendments Act (FDAAA) in 2007 and the Pregnancy and Lactation Labeling Rule (PLLR) in 2015 are important milestones giving the FDA the authority to request studies in pregnant and lactating women. Our objective was to characterize trends of pregnancy and lactation-related postmarketing commitments (PMCs) and postmarketing requirements (PMRs) for new molecular entities approved by the FDA between 2000 and 2022. Approval letters of original New Drug Applications (NDAs, N = 488) for new molecular entities were obtained from the FDA website. NDAs with pregnancy and lactation-based PMCs/PMRs were identified, and data extracted. Data included: PMC/PMR timelines and attributes of requested study(ies) (type, design elements, and outcomes) when available. Fifty-nine NDAs included 92 PMCs/PMRs related to pregnancy and lactation. Forty-one NDAs had pregnancy-related PMRs/PMCs, 4 had lactation-related PMRs, and 14 had both. Most PMRs/PMCs were for nervous system medications (N = 33). Forty-seven NDAs specified safety data collection in infants in at least the first year of life. All pregnancy-related PMRs were issued after 2008, most PMCs (N = 8) were issued before 2008. Only one PMC requested a pharmacokinetic study in pregnant women. All lactation-related PMRs (N = 18) requested measurement of drug concentrations in breast milk with one also requiring measurement of maternal blood concentrations. Eighty-nine percent of lactation-related PMRs were requested after 2015. There was a steady increase in pregnancy and lactation-related PMRs following enactment of FDAAA and PLLR. Additions involved information collection pertaining to safety of the medication in pregnant and lactating women and children exposed to medications during pregnancy and breastfeeding.

Endoscopic Orientation of Juxta-pituitary Carotid in Transsphenoidal Approaches: Critical Considerations for Clinical Applications

Abstract Introduction In sphenoid sinuses with ill-defined carotid bony landmarks, accidental injury of the internal carotid artery (ICA) remains one of the most challenging complications, which is particularly reported in the endoscopic endonasal transsphenoidal approaches (EETAs). Objectives To describe an anatomical model for the endoscopic orientation of the juxta-pituitary segment of the ICA in relation to the lateral opticocarotid recess (OCR) as a nearby bony landmark. Methods Dissection was performed progressively, simulating the EETA, in twenty fresh adult cadavers. After reducing the posterior and lateral walls of the sphenoid sinuses, various measurements were taken from both lateral OCRs to "contact points" on the juxta-pituitary segment of the ICA and lateral margins of the pituitary gland. Results The current results have enabled us to divide the region between the lateral OCRs into 3 compartments: 2 lateral parasellar compartments contain juxta-pituitary segments of the ICA with a mean width of 8 mm and a narrow range from 7 mm to 10 mm; and a central intercarotid sellar compartment represents the safe region for bone drilling, showing widely variable widths ranging from 9 mm to 20 mm. In all specimens, the variation in the width of the intercarotid compartment correlated with the distance between both lateral OCRs. Conclusion The present study improves surgeon awareness of the variations in the course of the ICA through the EETA along sphenoid sinuses with ill-defined bony landmarks. An appreciation of the measurements taken in the present study can help in operative training, and can also provide a base for future studies to confirm ICA courses associated with a higher risk of injury.

Endoscopic Orientation of Juxta-pituitary Carotid in Transsphenoidal Approaches: Critical Considerations for Clinical Applications.

Introduction In sphenoid sinuses with ill-defined carotid bony landmarks, accidental injury of the internal carotid artery (ICA) remains one of the most challenging complications, which is particularly reported in the endoscopic endonasal transsphenoidal approaches (EETAs). Objectives To describe an anatomical model for the endoscopic orientation of the juxta-pituitary segment of the ICA in relation to the lateral opticocarotid recess (OCR) as a nearby bony landmark. Methods Dissection was performed progressively, simulating the EETA, in twenty fresh adult cadavers. After reducing the posterior and lateral walls of the sphenoid sinuses, various measurements were taken from both lateral OCRs to "contact points" on the juxta-pituitary segment of the ICA and lateral margins of the pituitary gland. Results The current results have enabled us to divide the region between the lateral OCRs into 3 compartments: 2 lateral parasellar compartments contain juxta-pituitary segments of the ICA with a mean width of 8 mm and a narrow range from 7 mm to 10 mm; and a central intercarotid sellar compartment represents the safe region for bone drilling, showing widely variable widths ranging from 9 mm to 20mm. In all specimens, the variation in the width of the intercarotid compartment correlated with the distance between both lateral OCRs. Conclusion The present study improves surgeon awareness of the variations in the course of the ICA through the EETA along sphenoid sinuses with ill-defined bony landmarks. An appreciation of the measurements taken in the present study can help in operative training, and can also provide a base for future studies to confirm ICA courses associated with a higher risk of injury.

Model-Informed Approaches and Innovative Clinical Trial Design for Adeno-Associated Viral Vector-Based Gene Therapy Product Development: A White Paper.

The promise of viral vector-based gene therapy (GT) as a transformative paradigm for treating severely debilitating and life-threatening diseases is slowly coming to fruition with the recent approval of several drug products. However, they have a unique mechanism of action often necessitating a tortuous clinical development plan. Expertise in such complex therapeutic modality is still fairly limited in this emerging class of adeno-associated virus (AAV) vector-based gene therapies. Because of the irreversible mode of action and incomplete understanding of genotype-phenotype relationship and disease progression in rare diseases careful considerations should be given to GT product's benefit-risk profile. In particular, special attention needs to be paid to safe dose selection, reliable dose exposure response (including clinically relevant endpoints), or creative approaches in study design targeting small patient populations during clinical development. We believe that quantitative tools encompassed within model-informed drug development (MIDD) framework fits quite well in the development of such novel therapies, as they enable us to benefit from the totality of data approach in order to support dose selection as well as optimize clinical trial designs, end point selection, and patient enrichment. In this thought leadership paper, we provide our collective experiences, identify challenges, and suggest areas of improvement in applications of modeling and innovative trial design in development of AAV-based GT products and reflect on the challenges and opportunities for incorporating MIDD tools and more in rational development of these products.

Effect of Hepatic Impairment on the Pharmacokinetics and Pharmacodynamics of Cilofexor, a Selective Nonsteroidal Farnesoid X Receptor Agonist.

Cilofexor is a nonsteroidal farnesoid X receptor agonist in clinical development for treatment of nonalcoholic steatohepatitis. This work characterized the pharmacokinetics, pharmacodynamics, safety, and tolerability of cilofexor in participants with normal hepatic function or hepatic impairment (HI). Participants with stable mild, moderate, or severe HI (Child-Pugh [CP] A, B, or C, respectively, [n = 10/group]) and healthy matched controls with normal hepatic function received a single oral dose of cilofexor (30 mg for CP-A or B; 10 mg for CP-C) with a standardized meal. Overall, 56 participants received cilofexor and completed the study. Cilofexor area under the plasma concentration-time curve was 76%, 2.5-fold, and 6.3-fold higher in participants with mild, moderate, or severe HI, respectively, relative to the area under the plasma concentration-time curve in matched participants with normal hepatic function. Cilofexor unbound fraction was 38%, 2-fold, and 3.16-fold higher in participants with mild, moderate, and severe HI, respectively, relative to participants with normal hepatic function. Moderate correlations were identified between cilofexor exposure and CP score or laboratory tests components of CP score. Serum 7α-hydroxy-4-cholesten-3-one and plasma fibroblast growth factor 19 were similar in participants with mild, moderate, or severe HI and participants with normal hepatic function. Cilofexor was generally well tolerated; all cilofexor-related adverse events were mild in severity. Cilofexor can be administered to patients with mild HI without dose adjustment. Caution and dose modification are warranted when administering cilofexor to patients with moderate or severe HI.