Eman El-Khateeb

Background: Peroxisome proliferator‐activated receptor α (PPARα) has been reported to exert protective roles in immune‐mediated intestinal diseases through inhibition of interleukin‐6 (IL‐6)‐induced signal transducer and activator of transcription factor 3 (STAT3) activation. Aim: To investigate the potential anti‐inflammatory effect of fenofibrate, as an add‐on therapy to mesalamine, on IL‐6/STAT3 and nitric oxide (NO) in patients with ulcerative colitis (UC). Methods: This pilot, double‐blind, randomized, controlled trial included 60 patients diagnosed with mild‐to‐moderate UC. Patients were randomly allocated into two groups. The placebo group ( n = 30) received placebo plus mesalamine 1 g three times daily, and the fenofibrate group ( n = 30) received mesalamine 1 g three times daily and fenofibrate 160 mg once daily. The study duration was 6 months. The severity of UC was evaluated using the Disease Activity Index (DAI), and quality of life (QoL) was assessed using the Short Form‐36 questionnaire (SF‐36). Serum levels of IL‐6, NO, C‐reactive protein (CRP), and STAT3 were measured for all patients. Results: After treatment, both groups showed a significant reduction in DAI, IL‐6, STAT3, NO, and CRP, along with an increase in SF‐36 scores. Furthermore, the fenofibrate group demonstrated a significantly greater decrease in DAI ( p = 0.0002), IL‐6 ( p = 0.04), STAT3 ( p = 0.004), NO ( p = 0.013), and CRP ( p = 0.034), as well as a greater increase in SF‐36 ( p = 0.04) compared with the placebo group. Conclusion: Fenofibrate may represent a promising add‐on therapy in patients with mild‐to‐moderate UC by modulating inflammation and improving QoL. Trial Registration: NCT05753267

Concentration-dependent binding to red blood cells is a characteristic of several drugs, complicating the understanding of how pathophysiological factors influence drug behavior. This study utilized user-friendly, physiologically-based pharmacokinetic (PBPK) models to compare concentration-dependent and independent blood-to-plasma drug concentration ratios (B/P), using tacrolimus as a case study. Two models were developed and validated for tacrolimus using clinical data from healthy volunteers; Model 1 accounted for saturable blood binding, and Model 2 used a constant B/P level. The differences between the two models based on the two binding assumptions were also studied across clinically relevant hematocrit (HCT) and dose levels. For intravenous (IV) infusions, varying HCT from 15 to 45% resulted in a predicted difference in the area under the concentration-time curve (AUC) of 6–9% for total drug concentration in blood and 37–39% for unbound drug concentration in plasma. Increasing IV doses increased the predicted differences in blood AUC. For oral dosing to steady state, predicted differences in trough concentrations ranged between 50% and 130%, peak concentrations (78–284%), and AUC (up to 125%) according to HCT, dose, and biological medium, e.g., trough differences ranged from 50% (blood, 5 mg) to 130% (plasma, 10 mg). A hypothetical scenario of tacrolimus dose levels increasing above clinically relevant doses revealed a reducing difference in outcomes between the two binding assumptions. Although PBPK models ignoring concentration-dependent binding may adequately fit observed data, they can necessitate compensatory adjustments in disposition parameters, limiting their ability to predict clinical scenarios beyond the model’s original development settings.

Ethnic variabilities can affect the outcome of drug pharmacokinetics (PK) and drug–drug interactions (DDI). This work aimed to develop four North American (NA) sub‐populations: White, African American, Asian American, and Hispanic_Latino suitable for physiologically based pharmacokinetic (PBPK) modeling and simulations. Demographic data and tissue weight/volume, blood flows, cardiac output, plasma protein levels, hematocrit, enzyme and transporter abundances/frequencies, serum creatinine, glomerular filtration rate, and gastrointestinal transit times for the different populations were collated. Equations describing various covariate relationships for these physiological parameters were developed for each ethnicity. Some key population differences that can affect drug PK were higher CYP3A5 and OATP1B1 population mean abundances for African Americans and lower CYP3A4 and OATP1B1 population mean abundances for Asian Americans. The most common CYP2C9 alleles in the White as well as the Asian populations are the *1, *2, and *3 alleles. However, additional lower‐activity alleles (*5, *6, *8, and *11) were also shown to occur among the African Americans and Hispanic_Latino subjects. Clinical studies reporting population specific PK profiles (6 studies) or results from a mixed NA population (14 studies including 6 DDI studies) were simulated, and the simulated data were within two‐fold of the observed data. PBPK simulations using the 4 NA population files and repaglinide as a probe compound predicted significant differences in the drug exposure for the Asians, African Americans, and White subjects. In conclusion, the developed population files can aid drug development for specific subgroups of the diverse NA population by accounting for variabilities in drug kinetics and DDI consequences.

Background: The therapeutic potential of nifuroxazide in colitis has been explored in several experimental studies of ulcerative colitis (UC). Aim: To evaluate the efficacy of nifuroxazide in patients with UC. Methods: Fifty patients with mild to moderate UC were randomly assigned into two groups (n = 25 each). The placebo group received a placebo alongside mesalamine (1 g three times daily [t.i.d.]) for six months. The nifuroxazide group received nifuroxazide (200 mg twice daily) in combination with mesalamine (1 g t.i.d). A gastroenterologist assessed disease severity using the partial Mayo score (PMS). Serum levels of C-reactive protein (CRP), nuclear factor kappa B (NF-κB), interleukin-6 (IL-6), and signal transducer and activator of transcription 3 (STAT3) were measured before and after treatment. Quality of life was evaluated using the Inflammatory Bowel Disease Questionnaire (IBDQ-32). Primary outcomes: Change in PMS. Secondary outcomes: change in IBDQ-32 and in the level of measured biomarkers. Results: Baseline measurements were comparable between groups (p > 0.05). Post-treatment values showed significant improvements within both groups compared to baseline. However, the nifuroxazide group demonstrated significantly greater improvements than the placebo group, including reductions in PMS (p = 0.005) and increases in IBDQ scores (p = 0.002). Additionally, significant decreases were observed in IL-6 (p = 0.03), NF-κB (p = 0.03), CRP (p = 0.02), and STAT3 (p = 0.03) levels. The placebo group had a response rate of 56% (14/25) and a remission rate of 24% (6/25), whereas the nifuroxazide group achieved a response rate of 76% (19/25) and a remission rate of 56% (14/25), based on PMS. Conclusion: Co-administration of nifuroxazide with mesalamine improved clinical outcomes, including higher response and remission rates, reduced inflammation by reducing IL-6/STAT3, and enhanced quality of life in patients with UC, compared to mesalamine alone. Trial Registration Identifier: NCT05988528.

Background: The development of long-acting products of a characterized drug substance is of great interest. It is possible to support the development of these products with available clinical data by matching the exposure to a predefined bracket of a minimal concentration for efficacy and a maximal concentration for safety. This bracketing approach would cut down on the time and cost of new long-acting contraceptive products progressing to market. The current study describes the assessment of the data available to support a bracketing approach to conclude comparable levels of efficacy and safety for a postulated novel long-acting reversible contraceptive (LARC) product of levonorgestrel. Methods: Literature evidence of levonorgestrel efficacy, as quantified by the Pearl Index, was utilized and modeled by incorporating three LARC products for the estimation of a minimal concentration required for efficacy. Further literature was reviewed to quantify the maximal concentration required to ensure product safety. Additionally, a review of the regulatory precedence for the approach was conducted using European and UK databases. Results: There was a reasonable definition of the minimal concentrations for efficacy where the target concentrations of levonorgestrel were in the range of 200–400 pg/mL. Maximum concentrations for safety were less well defined. Although regulatory guidance supports the bracketing approach, there is little precedence for licensing new products based on pharmacokinetic data only, despite much reduced clinical and non-clinical packages being evidenced. Conclusions: Understanding of the exposure response is not currently considered sufficient to support a bracketing approach for a new levonorgestrel product. If additional safety data are established, current regulations may allow for a reduced application package. Additional work is needed to support the approach, and this could utilize the wealth of information in real-world datasets combined with systems models.

Background: Ulcerative colitis (UC) is an idiopathic chronic inflammation of colonic and rectal mucosa. The peroxisome proliferator-activated receptor α (PPARα) has been identified as having protective effects in UC. Aim: The study aimed to investigate the efficacy of fenofibrate, a PPARα agonist, in UC. Methods: A total of 70 patients with mild to moderate UC were allocated randomly and assigned to two groups (n = 35 each) from Gastroenterology Department, Faculty of Medicine, Menoufia University. The mesalamine group received a placebo along with 1 g of mesalamine three times daily, while the fenofibrate group received 1 g of mesalamine three times and fenofibrate 160 mg once daily. The study duration was for six months. A gastroenterologist assessed patients by non-invasive Partial Mayo Score (PMS) and the Inflammatory Bowel Disease Questionnaire (IBDQ) to evaluate clinical response and remission. The serum levels of silent information regulator 1 (SIRT1), NOD-like receptor protein 3 (NLRP3), and adenosine monophosphate activated protein kinase (AMPK), as well as fecal calprotectin levels were examined to determine the biological effect of fenofibrate. Results: After treatment, the fenofibrate group showed statistically significant reductions in PMS (p = 0.044) and improved digestive domain of IBDQ (p = 0.023). Additionally, there were significant decreases in serum NLRP3 (p = 0.041) and fecal calprotectin (p = 0.035), along with significant increases in SIRT1 (p = 0.002) and AMPK (p = 0.0003). The fenofibrate group also had higher response and remission rates compared to the mesalamine group. Conclusion: Fenofibrate may be a promising adjunct for improving clinical outcomes, quality of life, and modulating inflammation in mild to moderate patients with UC. Trial Registration Identifier: NCT05781698.

The Simcyp Simulator is a software platform widely used in the pharmaceutical industry to conduct stochastic physiologically‐based pharmacokinetic (PBPK) modeling. This approach has the advantage of combining routinely generated in vitro data on drugs and drug products with knowledge of biology and physiology parameters to predict a priori potential pharmacokinetic changes in absorption, distribution, metabolism, and excretion for populations of interest. Combining such information with pharmacodynamic knowledge of drugs enables planning for potential dosage adjustment when clinical studies are feasible. Although the conduct of dedicated clinical studies in some patient groups (e.g., with hepatic or renal diseases) is part of the regulatory path for drug development, clinical studies for all permutations of covariates potentially affecting pharmacokinetics are impossible to perform. The role of PBPK in filling the latter gap is becoming more appreciated. This tutorial describes the different input parameters required for the creation of a virtual population giving robust predictions of likely changes in pharmacokinetics. It also highlights the considerations needed to qualify the models for such contexts of use. Two case studies showing the step‐by‐step development and application of population files for obese or morbidly obese patients and individuals with Crohn's disease are provided as the backbone of our tutorial to give some hands‐on and real‐world examples.

Background: Acne vulgaris (AV) is an inflammatory skin disorder leading to scars and discomfort, its intensity has major psychological consequences such as depression.Aim: To investigate the effect of isotretinoin (ISO) on NF‐κB/NLRP3, biotinidase, and HMGB and correlation with depression.Patients and Methods: This was a case–control study that involved two groups. Group 1 is 20 healthy control, and group 2 is 20 patients diagnosed with AV according to Global Acne Grading System (GAGS) and received 20 mg ISO for 2 months. Before and after therapy, the Hamilton Depression Rating Scale (HDRS) was applied to assess each participant's level of depression. Nuclear factor kappa B (NF‐ĸB), biotinidase, high mobility group box protein (HMGB1), nucleotide‐binding domain, leucine‐rich–containing family, and pyrin domain–containing‐3 (NLRP–3) were measured in serum samples.Results: There was no significant difference in all measured markers of healthy group before and after 2 months. Regarding group 2, there was a statistically significant decrease in all measured markers after 2 months of treatment and significant correlations between GAGS, NF‐ĸB, HMGB1, NLRP3, biotinidase, and depression score.Conclusion: Increased GAGS, HMGB1, NLRP3, and biotinidase were associated with depression severity in AV patients and ISO treatment significantly reduced these parameters and reduced depressive symptoms.