Ahmed Nader - Academia.edu (original) (raw)

Papers by Ahmed Nader

Clinical and Translational Science, 2022

This study evaluated the effect of repeated doses of elagolix on the pharmacokinetics of omeprazo... more This study evaluated the effect of repeated doses of elagolix on the pharmacokinetics of omeprazole and its metabolites in healthy premenopausal female subjects. Adult premenopausal female subjects (N = 20) received a single oral dose of omeprazole (40 mg) on Day 1 and Day 11 and oral doses of elagolix (300 mg) twice-daily on Days 3 to 11. Serial blood samples for assay of omeprazole and its metabolites were collected for 24 hours after dosing on Days 1 and 11. Pharmacokinetic parameters were calculated for omeprazole, 5-hydroxyomeprazole and omeprazole sulfone; and were compared between Day 1 and Day 11. Pharmacogenetic testing was performed for CYP2C19 variant alleles and the results were used to compare the magnitude of elagolix-omeprazole DDI between the different genotype subgroups. Administration of elagolix 300 mg twice-daily for 9 days increased omeprazole exposure by 1.8-fold and decreased the metabolite-to-parent ratio for 5-hydroxyomeprazole by ~60%. Conversely, there was an increase in the metabolite-to-parent ratio for omeprazole sulfone by 25%. Elagolix increased omeprazole exposures by 2- to 2.5-fold in CYP2C19 Extensive and Intermediate Metabolizer subjects, but decreased omeprazole exposures by 40% in Poor Metabolizer subjects. Exposures of 5-hydroxyomeprazole decreased by 20-30% in all genotype subgroups, and omeprazole sulfone exposures increased by ~3-fold in Extensive and Intermediate Metabolizer subjects. Elagolix is a weak inhibitor of CYP2C19 and exposure of CYP2C19 substrates may be increased upon coadministration with elagolix. Omeprazole may exhibit drug interactions due to multiple mechanisms other than CYP2C19-mediated metabolism; complicating the interpretation of results from omeprazole DDI studies.

In this report, we present our research results for the fourth half-year phase of the project Cor... more In this report, we present our research results for the fourth half-year phase of the project Corporate Smart Content under the working package "Knowledge- based Mining of Complex Event Patterns". We present SpaceROAM, our new approach to Role Discovery that focuses on the domain of Collaborative Content Management Systems. The method tries to magnify users' characteristic features by positioning them among other one of the same user as well as among features of other users. Applied on real-life data, the method was able to recognize all typical roles and to detect new ones that differ from the known ones significantly. Finally, we provide a description of other research tasks that we started and whose results will be included in our next report.

CPT: Pharmacometrics & Systems Pharmacology, 2020

Elagolix is a novel oral gonadotropin releasing hormone receptor antagonist, that can suppress es... more Elagolix is a novel oral gonadotropin releasing hormone receptor antagonist, that can suppress estradiol in a dose‐dependent manner. It is indicated for management of moderate‐to‐severe pain associated with endometriosis. A population exposure‐response model describing the relationship between elagolix exposure and changes in bone mineral density (BMD) was developed using data from four phase III studies in premenopausal women with endometriosis‐associated pain. Elagolix pharmacokinetic exposure‐dependent changes in BMD were described by an indirect‐response maximum effect (Emax) model through stimulation of bone resorption. African American race, higher body mass index (BMI), and lower type‐I collagen C‐telopeptide concentrations were significantly associated with higher baseline BMD. Higher BMI was significantly associated with higher bone formation rates. Simulations using the final model demonstrated that elagolix 150 mg q.d. dosing for 24 months is predicted to result in −1.45%...

Clinical and Translational Science, 2021

Elagolix is a novel, oral gonadotropin‐releasing hormone receptor antagonist indicated for the ma... more Elagolix is a novel, oral gonadotropin‐releasing hormone receptor antagonist indicated for the management of moderate to severe pain associated with endometriosis and heavy menstrual bleeding associated with uterine fibroids. Consistent with its mechanism of action, elagolix exhibited dose‐dependent suppression of estradiol (E2) in clinical studies. A dose‐response model that describes the relationship between elagolix dosages and average E2 levels was combined with a previously published quantitative systems pharmacology (QSP) model of calcium homeostasis to predict bone mineral density (BMD) changes during and following elagolix treatment. In the QSP model, changes in E2 levels were linked to downstream changes in markers of bone resorption (carboxyterminal cross‐linked telopeptide of type 1 collagen [CTX]), formation (N‐terminal propeptide of type 1 procollagen [P1NP]) and BMD. The BMD, CTX, and P1NP predictions by the QSP model were validated against observed data from four phas...

Clinical Pharmacokinetics, 2020

CPT: Pharmacometrics & Systems Pharmacology, 2020

Elagolix is an oral gonadotropin‐releasing hormone antagonist approved by the US Food and Drug Ad... more Elagolix is an oral gonadotropin‐releasing hormone antagonist approved by the US Food and Drug Administration (FDA) for the management of moderate‐to‐severe pain associated with endometriosis and in combination with estradiol/norethindrone acetate approved for the management of heavy menstrual bleeding associated with uterine leiomyomas (fibroids) in premenopausal women. The objective of this work was to characterize the relationships between elagolix exposures and clinical efficacy response rates for dysmenorrhea (DYS) and nonmenstrual pelvic pain (NMPP) in premenopausal women enrolled in the pivotal phase III studies with moderate‐to‐severe pain associated with endometriosis. Relationships between elagolix average concentrations (Cavg) and efficacy responses (DYS and NMPP) were characterized using a nonlinear mixed‐effects discrete‐time first order Markov modeling approach. Only age was statistically significant for NMPP but not considered clinically relevant. This work indicates ...

JACCP: JOURNAL OF THE AMERICAN COLLEGE OF CLINICAL PHARMACY, 2020

IntroductionVancomycin is commonly used for the treatment of complicated infections caused by met... more IntroductionVancomycin is commonly used for the treatment of complicated infections caused by methicillin‐resistant Staphylococcus aureus. The impact of vancomycin therapeutic drug monitoring (TDM) quality indices on clinical outcomes has not been previously explored.ObjectivesThis study aims to relate routine vancomycin TDM service quality indices to clinical effectiveness outcomes and to develop a pragmatic vancomycin‐specific TDM quality assessment tool that can be used in quality audits.MethodsA retrospective chart review was conducted on adult non‐dialysis vancomycin TDM records documented between January 2014 and October 2016 in three tertiary care hospitals under Hamad Medical Corporation (HMC) in Qatar. Evidence‐based criteria and pilot‐testing were applied to develop a quality assessment tool. The appropriateness of vancomycin TDM service and clinical outcomes were simultaneously evaluated.ResultsA 13‐criterion vancomycin TDM quality assessment tool was developed and used t...

Clinical Pharmacokinetics, 2019

The clinical pharmacology of elagolix was extensively evaluated in clinical studies in healthy su... more The clinical pharmacology of elagolix was extensively evaluated in clinical studies in healthy subjects and in women with endometriosis. Elagolix pharmacokinetics (PK) show significant population variability, however they are minimally affected by patients' baseline characteristics and demographics, except for clinically relevant extrinsic and intrinsic factors such as coadministrated strong organic anion transporting polypeptide (OATP) 1B1 inhibitors and severe hepatic impairment, which are contraindications for the use of elagolix. These studies enabled a comprehensive understanding of elagolix mechanism of action and the downstream pharmacodynamic (PD) effects on gonadotropin and ovarian hormones, as well as full characterization of the PK/PD (PKPD) relationships of elagolix at various dosages, including the approved 150 mg once daily and 200 mg twice daily dosing regimens for the management of moderate to severe pain associated with endometriosis. Several model-based analyses have contributed to understanding of the benefit-risk profile of elagolix in patients with endometriosis, through characterization of the exposure relationship with responder rates, with changes in bone mineral density over time, as well as the interaction with coadministered drugs. Collectively, these studies and analyses served as supportive evidence for the effectiveness of the approved dosages and provided general dosing instructions of the first approved oral gonadotropin-releasing hormone receptor antagonist.

The Journal of Clinical Pharmacology, 2019

Upadacitinib (ABT‐494) is a selective Janus kinase (JAK)1 inhibitor being developed for treatment... more Upadacitinib (ABT‐494) is a selective Janus kinase (JAK)1 inhibitor being developed for treatment of several inflammatory disorders. A population pharmacokinetic model was developed for upadacitinib using 11,658 plasma concentrations from 1145 subjects from 4 phase 1 and 5 phase 2 studies in healthy subjects and subjects with rheumatoid arthritis, Crohn's disease, ulcerative colitis, or atopic dermatitis. A 2‐compartment model with first‐order absorption and lag time for the immediate‐release formulation and mixed zero‐ and first‐order absorption with lag time for the extended‐release formulation, and linear elimination adequately described upadacitinib plasma concentration–time profiles. The oral bioavailability of upadacitinib extended‐release formulation was estimated to be approximately 80% relative to the immediate‐release formulation. Covariates included in the final model were creatinine clearance, subject population (healthy subjects vs subjects with atopic dermatitis, u...

Clinical Pharmacokinetics, 2019

Background Venetoclax is a selective inhibitor of B-cell lymphoma-2, which plays a role in the de... more Background Venetoclax is a selective inhibitor of B-cell lymphoma-2, which plays a role in the development of various autoimmune diseases including systemic lupus erythematosus. The aim of these analyses was to quantify the exposure-response relationship for venetoclax effects on B-lymphocyte and total lymphocyte counts as pharmacodynamic markers of efficacy and safety, respectively, in women with systemic lupus erythematosus. The developed modeling framework was also used to evaluate venetoclax effects following cyclic, continuous, or induction/maintenance dosing paradigms as potential dosing alternatives in systemic lupus erythematosus. Methods Serial pharmacokinetic and lymphocyte count data from 73 women enrolled in a phase I study of venetoclax (single doses of 10-500 mg or two cycles of 30-600 mg or placebo once daily for 7 days followed by a 21-day washout) were analyzed using a sequential population pharmacokinetic/pharmacodynamic modeling approach. Simulations to evaluate changes in B-lymphocyte and total lymphocyte counts following different venetoclax dosing scenarios were conducted. Results Effect of venetoclax plasma exposures on B lymphocytes was described using an indirect linear response model and on total lymphocytes using a maximal response (E max) with an effect site compartment. Baseline lymphocyte counts were significant covariates on the slope and half maximal inhibitory concentration parameter estimates for the respective models; with higher baseline counts associated with a greater reduction upon treatment with venetoclax. Model simulations showed that continuous dosing with lower doses of venetoclax (e.g., 150 mg daily) are predicted to achieve similar maximal effects on B-lymphocyte counts compared to cyclic dosing with higher doses (e.g., 400 mg 1 week on/3 weeks off); with better recovery of total lymphocyte counts during off-treatment weeks for the cyclic regimens. Conclusions Venetoclax treatment in women with systemic lupus erythematosus was associated with exposure-dependent reductions in B lymphocytes, and to a lesser extent, total lymphocyte counts. Results from this study support evaluation of B-cell lymphoma-2 inhibitors as potential therapies for the treatment of systemic lupus erythematosus. Clinicaltrials.gov NCT01686555.

Journal of Clinical Pharmacy and Therapeutics, 2019

What is known and objective: High-dose methotrexate (HD-MTX) is associated with a plethora of adv... more What is known and objective: High-dose methotrexate (HD-MTX) is associated with a plethora of adverse drug reactions and potential drug interactions (DIs). But there is a paucity of information regarding the safety of co-administering primaquine with HD-MTX. Case summary: A 65-year-old male patient was diagnosed with mantle cell lymphoma (MCL) with CNS involvement and treated with three cycles of IV HD-MTX. His case was further complicated by fungal pneumonia treated with primaquine during cycle-2. Serial blood sampling and subsequent population pharmacokinetics (PK) modelling suggests a possible distribution-mediated DI between the two drugs. What is new and conclusion: This is the first case report to highlight the safe co-administration of MTX and primaquine, despite a possible PK interaction.

Journal of Investigative Dermatology, 2019

This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Clinical Pharmacology & Therapeutics, 2019

Exposure-response analyses of upadacitinib (UPA) key efficacy and safety end points (3,685 and 4,... more Exposure-response analyses of upadacitinib (UPA) key efficacy and safety end points (3,685 and 4,577 subjects for efficacy and safety, respectively) using data from phase II and phase III rheumatoid arthritis (RA) studies were conducted to support benefit-risk assessment. Percentage of subjects achieving American College of Rheumatology (ACR)20/50/70, disease activity score 28 (C-reactive protein) (DAS28-CRP) ≤ 3.2, and DAS28-CRP < 2.6 increased with increasing UPA plasma exposures. With the small number of observed safety events, no clear trends for exposure-response relationships were identified for pneumonia, herpes zoster infection, changes in platelet count, lymphopenia (Grade ≥ 4), or neutropenia (Grade ≥ 3) up to Week 26. Shallow exposure-response relationships were observed for > 2 g/dL decrease in hemoglobin, lymphopenia Grade ≥ 3 at Week 12/14, and serious infections at Week 24/26. Exposure-efficacy analyses demonstrate that UPA 15 mg q.d. (once daily) dose provided the optimal benefit-risk in RA through maximizing efficacy with only small incremental benefit with 30 mg q.d.; and with consistency across RA subpopulations and with UPA monotherapy or combination with conventional synthetic disease-modifying antirheumatic drugs. Upadacitinib (ABT-494) is a selective Janus kinase (JAK)1 inhibitor being developed for the treatment of several inflammatory disorders, including rheumatoid arthritis (RA), ulcerative colitis, atopic dermatitis, Crohn's disease, psoriatic arthritis, axial spondyloarthritis, and giant cell arteritis. 1-13 The JAKs are a family of tyrosine kinases (JAK1, 2, and 3 and tyrosine kinase 2) that mediate

Poster Presentations, 2019

models. The proportions of patients reporting improvements ! minimum clinically important differe... more models. The proportions of patients reporting improvements ! minimum clinically important differences (MCID) from BL to Week 12 or scores ! normative values were determined with UPA, PBO, and ADA treatment; comparisons used chi-square tests. Results: Data from 1629 patients (UPA: 651; PBO: 651; ADA: 327) were analysed. Mean age was 54 years; 79% were female; 54% had RA for !5 years. Baseline mean PRO scores were similar across treatment groups. At Week 12, UPA treatment resulted in statistically significant LSM changes from BL vs PBO across all PROs and statistically significant LSM changes from BL vs ADA in PtGA, pain, HAQ-DI, AM stiffness severity, FACIT-F, and SF-36 physical component summary (PCS) and 6/ 8 domain scores (Table). ADA treatment resulted in statistically significant LSM changes from baseline vs PBO in PtGA, pain, HAQ-DI, AM stiffness severity and duration, FACIT-F, and SF-36 PCS and 5/8 domain scores. Compared with PBO at Week 12, significantly more UPA-treated patients reported improvements ! MCID and scores ! normative values across all PROs with numbers needed to treat (NNTs) <10. The proportions of UPA-treated patients reporting improvements ! MCID were similar or numerically higher than ADA-treated patients. Importantly, the proportion of UPA vs ADA treated patients reporting improvements ! normative values were significantly greater (all p<0.05) in PtGA (36% vs 26%), HAQ-DI (21% vs 14%), SF-36 PCS (16% vs 11%), and SF-36 bodily pain (29% vs 21%) and vitality (42% vs 35%) domains. Conclusion: Among patients with active RA, treatment with UPA 15 mg QD on background MTX therapy for 12 weeks resulted in statistically significant and clinically meaningful improvements in PROs compared with PBO. Overall, PRO improvements with UPA treatment met or were superior to treatment with ADA, especially in key domains of pain, function and vitality.

European Journal of Drug Metabolism and Pharmacokinetics, 2019

Background Vancomycin therapeutic drug monitoring (TDM) is based on achieving 24-h area under the... more Background Vancomycin therapeutic drug monitoring (TDM) is based on achieving 24-h area under the concentration-time curve to minimum inhibitory concentration cure breakpoints (AUC 24 /MIC). Approaches to vancomycin TDM vary, with no head-to-head randomized controlled trial (RCT) comparisons to date. Objectives We aimed to compare clinical and pharmacokinetic outcomes between peak-trough-based and trough-only-based vancomycin TDM approaches and to determine the relationship between vancomycin AUC 24 /MIC and cure rates. Methods A multicentered pragmatic parallel-group RCT was conducted in Hamad Medical Corporation hospitals in Qatar. Adult non-dialysis patients initiated on vancomycin were randomized to peak-trough-based or trough-only-based vancomycin TDM. Primary endpoints included vancomycin AUC 24 /MIC ratio breakpoint for cure and clinical effectiveness (therapeutic cure vs therapeutic failure). Descriptive, inferential, and classification and regression tree (CART) statistical analyses were applied. NONMEM.v.7.3 was used to conduct population pharmacokinetic analyses and AUC 24 calculations. Results Sixty-five patients were enrolled [trough-only-based-TDM (n = 35) and peak-trough-based-TDM (n = 30)]. Peaktrough-based TDM was significantly associated with higher therapeutic cure rates compared to trough-only-based TDM [76.7% vs 48.6%; p value = 0.02]. No statistically significant differences were observed for all-cause mortality, neutropenia, or nephrotoxicity between the two groups. Compared to trough-only-based TDM, peak-trough-based TDM was associated with less vancomycin total daily doses by 12.05 mg/kg/day (p value = 0.027). CART identified creatinine clearance (CL CR), AUC 24 /MIC, and TDM approach as significant determinants of therapeutic outcomes. All patients [n = 19,100%] with CL CR ≤ 7.85 L/h, AUC 24 /MIC ≤ 1256, who received peak-trough-based TDM achieved therapeutic cure. AUC 24 /MIC > 565 was identified to be correlated with cure in trough-only-based TDM recipients [n = 11,84.6%]. No minimum AUC 24 /MIC breakpoint was detected by CART in the peak-trough-based group. Conclusion Maintenance of target vancomycin exposures and implementation of peak-trough-based vancomycin TDM may improve vancomycin-associated cure rates. Larger scale RCTs are warranted to confirm these findings.

Clinical pharmacokinetics, 2018

Elagolix is a novel, orally active, non-peptide, competitive gonadotropin-releasing hormone (GnRH... more Elagolix is a novel, orally active, non-peptide, competitive gonadotropin-releasing hormone (GnRH) receptor antagonist in development for the management of endometriosis with associated pain and heavy menstrual bleeding due to uterine fibroids. The pharmacokinetics of elagolix have been well-characterized in phase I studies; however, elagolix population pharmacokinetics have not been previously reported. Therefore, a robust model was developed to describe elagolix population pharmacokinetics and to evaluate factors affecting elagolix pharmacokinetic parameters. The data from nine clinical studies (a total of 1624 women) were included in the analysis: five phase I studies in healthy, premenopausal women and four phase III studies in premenopausal women with endometriosis. Elagolix population pharmacokinetics were best described by a two-compartment model with a lag time in absorption. Of the 15 covariates tested for effect on elagolix apparent clearance (CL/F) and/or volume of distri...

PloS one, 2018

Anti-drug antibody formation occurs with most biological agents across disease states, but the me... more Anti-drug antibody formation occurs with most biological agents across disease states, but the mechanism by which they are formed is unknown. The formation of anti-drug antibodies to adalimumab (AAA) may decrease its therapeutic effects in some patients. HLA alleles have been reported to be associated with autoantibody formation against interferons and other TNF inhibitors, but not adalimumab. We analyzed samples from 634 subjects with either rheumatoid arthritis (RA) or hidradenitis suppurativa (HS): 37 subjects (17 RA and 20 HS) developed AAA (AAA+) during adalimumab treatment and 597 subjects (348 RA, 249 HS) did not develop AAA (AAA-) during the clinical trials. Using next-generation sequencing-based HLA typing, we identified three protective HLA alleles (HLA-DQB1*05, HLA-DRB1*01,and HLA-DRB1*07) that were less prevalent in AAA+ than AAA-subjects (ORs: 0.4, 0.25 and 0.28, respectively; and P values: 0.012, 0.012 and 0.018, respectively) and two risk HLA alleles (HLA-DRB1*03 and ...

European Journal of Cancer, 2017

INTRODUCTION: Vulvar carcinoma accounts for about 4% of the female reproductive tract cancers and... more INTRODUCTION: Vulvar carcinoma accounts for about 4% of the female reproductive tract cancers and a total of 0.6% of all malignant cancers in females. PATIENTS AND METHODS: This retrospective study aimed to identify the possible risk factors which can impact survival in Egyptian patients with vulval cancer who received treatment at Ain Shams University department of clinical oncology and nuclear medicine in the period from 1-1-2007 till 1-1-2012. RESULTS: Our study included 64 patients [median age 63 years, median overall survival (OS) was 16.5 months]. The factors associated with favourable impact on OS were: Rural residence (17 versus 10 months for patients from urban residence, p=0.002), premenopausal status (19 versus 16 months in post menopausal patients, p<0.001), low grade histology (19 versus 10 months in patients with high grade, p<0.001) and negative resection margins (19 versus 10 months in case of positive margin, p<0.001). The factors associated with poor OS were: higher number of offspring (≥5 offspring, OS 10 versus 19 months if less than 5 offspring, p<0.001), patients presenting with ulcer rather than mass (11 versus 19 months, p<0.001 and those with bilateral disease (10 versus 17 months in unilateral disease, p=0.04), presence of ≥4 positive groin lymph nodes metastases (OS =16 months versus 17 months, p=0.047) tumor size ≥ 4 cm (10 versus 17 months in case of <4 cm, p=0.001) and depth of stromal invasion (17 versus 16 months in case of <1 cm and ≥ 1 cm respectively, p=0.015) CONCLUSION: Urbanization has been linked with more aggressive disease leading to decrease of OS. The age of onset of intercourse did not affect survival as was expected however multiple offspring which could be related to more frequent intercourse had an effect on survival. The offered treatment modalities did not show a superiority probably because all the patients presented in an advanced stage. The anatomical nature of this cancer might be the cause in delayed diagnosis which warrants health education projects for early detection. Further studies are required to assess the risk factors for development of vulval cancer in Egyptian patients.

The AAPS journal, Jul 22, 2016

Nifedipine is a BCS Class II drug used for treatment of hypertension and preterm labor. Large int... more Nifedipine is a BCS Class II drug used for treatment of hypertension and preterm labor. Large inter-patient variability in nifedipine absorption results in variable exposure among different patients. We conducted in vitro dissolution studies to compare nifedipine dissolution from immediate release (IR) capsules with different volumes of dissolution media. Results from dissolution studies were used to design a crossover study in healthy volunteers to evaluate the effect of coadministered water volume with nifedipine 10 mg IR capsules on nifedipine pharmacokinetics, especially absorption (C max, t max, and AUC0-6). Dissolution studies demonstrated that larger gastric fluid volumes result in enhanced nifedipine dissolution from 10 mg IR cosolvent capsules (73 vs. 17% in 200 and 100 mL simulated gastric fluid, respectively, at 30 min). The pharmacokinetic crossover study in healthy volunteers (N = 6) did not show a significant effect of the water volume administered with the capsule (50...

Clinical and Translational Science, 2022

This study evaluated the effect of repeated doses of elagolix on the pharmacokinetics of omeprazo... more This study evaluated the effect of repeated doses of elagolix on the pharmacokinetics of omeprazole and its metabolites in healthy premenopausal female subjects. Adult premenopausal female subjects (N = 20) received a single oral dose of omeprazole (40 mg) on Day 1 and Day 11 and oral doses of elagolix (300 mg) twice-daily on Days 3 to 11. Serial blood samples for assay of omeprazole and its metabolites were collected for 24 hours after dosing on Days 1 and 11. Pharmacokinetic parameters were calculated for omeprazole, 5-hydroxyomeprazole and omeprazole sulfone; and were compared between Day 1 and Day 11. Pharmacogenetic testing was performed for CYP2C19 variant alleles and the results were used to compare the magnitude of elagolix-omeprazole DDI between the different genotype subgroups. Administration of elagolix 300 mg twice-daily for 9 days increased omeprazole exposure by 1.8-fold and decreased the metabolite-to-parent ratio for 5-hydroxyomeprazole by ~60%. Conversely, there was an increase in the metabolite-to-parent ratio for omeprazole sulfone by 25%. Elagolix increased omeprazole exposures by 2- to 2.5-fold in CYP2C19 Extensive and Intermediate Metabolizer subjects, but decreased omeprazole exposures by 40% in Poor Metabolizer subjects. Exposures of 5-hydroxyomeprazole decreased by 20-30% in all genotype subgroups, and omeprazole sulfone exposures increased by ~3-fold in Extensive and Intermediate Metabolizer subjects. Elagolix is a weak inhibitor of CYP2C19 and exposure of CYP2C19 substrates may be increased upon coadministration with elagolix. Omeprazole may exhibit drug interactions due to multiple mechanisms other than CYP2C19-mediated metabolism; complicating the interpretation of results from omeprazole DDI studies.

In this report, we present our research results for the fourth half-year phase of the project Cor... more In this report, we present our research results for the fourth half-year phase of the project Corporate Smart Content under the working package "Knowledge- based Mining of Complex Event Patterns". We present SpaceROAM, our new approach to Role Discovery that focuses on the domain of Collaborative Content Management Systems. The method tries to magnify users' characteristic features by positioning them among other one of the same user as well as among features of other users. Applied on real-life data, the method was able to recognize all typical roles and to detect new ones that differ from the known ones significantly. Finally, we provide a description of other research tasks that we started and whose results will be included in our next report.

CPT: Pharmacometrics & Systems Pharmacology, 2020

Elagolix is a novel oral gonadotropin releasing hormone receptor antagonist, that can suppress es... more Elagolix is a novel oral gonadotropin releasing hormone receptor antagonist, that can suppress estradiol in a dose‐dependent manner. It is indicated for management of moderate‐to‐severe pain associated with endometriosis. A population exposure‐response model describing the relationship between elagolix exposure and changes in bone mineral density (BMD) was developed using data from four phase III studies in premenopausal women with endometriosis‐associated pain. Elagolix pharmacokinetic exposure‐dependent changes in BMD were described by an indirect‐response maximum effect (Emax) model through stimulation of bone resorption. African American race, higher body mass index (BMI), and lower type‐I collagen C‐telopeptide concentrations were significantly associated with higher baseline BMD. Higher BMI was significantly associated with higher bone formation rates. Simulations using the final model demonstrated that elagolix 150 mg q.d. dosing for 24 months is predicted to result in −1.45%...

Clinical and Translational Science, 2021

Elagolix is a novel, oral gonadotropin‐releasing hormone receptor antagonist indicated for the ma... more Elagolix is a novel, oral gonadotropin‐releasing hormone receptor antagonist indicated for the management of moderate to severe pain associated with endometriosis and heavy menstrual bleeding associated with uterine fibroids. Consistent with its mechanism of action, elagolix exhibited dose‐dependent suppression of estradiol (E2) in clinical studies. A dose‐response model that describes the relationship between elagolix dosages and average E2 levels was combined with a previously published quantitative systems pharmacology (QSP) model of calcium homeostasis to predict bone mineral density (BMD) changes during and following elagolix treatment. In the QSP model, changes in E2 levels were linked to downstream changes in markers of bone resorption (carboxyterminal cross‐linked telopeptide of type 1 collagen [CTX]), formation (N‐terminal propeptide of type 1 procollagen [P1NP]) and BMD. The BMD, CTX, and P1NP predictions by the QSP model were validated against observed data from four phas...

Clinical Pharmacokinetics, 2020

CPT: Pharmacometrics & Systems Pharmacology, 2020

Elagolix is an oral gonadotropin‐releasing hormone antagonist approved by the US Food and Drug Ad... more Elagolix is an oral gonadotropin‐releasing hormone antagonist approved by the US Food and Drug Administration (FDA) for the management of moderate‐to‐severe pain associated with endometriosis and in combination with estradiol/norethindrone acetate approved for the management of heavy menstrual bleeding associated with uterine leiomyomas (fibroids) in premenopausal women. The objective of this work was to characterize the relationships between elagolix exposures and clinical efficacy response rates for dysmenorrhea (DYS) and nonmenstrual pelvic pain (NMPP) in premenopausal women enrolled in the pivotal phase III studies with moderate‐to‐severe pain associated with endometriosis. Relationships between elagolix average concentrations (Cavg) and efficacy responses (DYS and NMPP) were characterized using a nonlinear mixed‐effects discrete‐time first order Markov modeling approach. Only age was statistically significant for NMPP but not considered clinically relevant. This work indicates ...

JACCP: JOURNAL OF THE AMERICAN COLLEGE OF CLINICAL PHARMACY, 2020

IntroductionVancomycin is commonly used for the treatment of complicated infections caused by met... more IntroductionVancomycin is commonly used for the treatment of complicated infections caused by methicillin‐resistant Staphylococcus aureus. The impact of vancomycin therapeutic drug monitoring (TDM) quality indices on clinical outcomes has not been previously explored.ObjectivesThis study aims to relate routine vancomycin TDM service quality indices to clinical effectiveness outcomes and to develop a pragmatic vancomycin‐specific TDM quality assessment tool that can be used in quality audits.MethodsA retrospective chart review was conducted on adult non‐dialysis vancomycin TDM records documented between January 2014 and October 2016 in three tertiary care hospitals under Hamad Medical Corporation (HMC) in Qatar. Evidence‐based criteria and pilot‐testing were applied to develop a quality assessment tool. The appropriateness of vancomycin TDM service and clinical outcomes were simultaneously evaluated.ResultsA 13‐criterion vancomycin TDM quality assessment tool was developed and used t...

Clinical Pharmacokinetics, 2019

The clinical pharmacology of elagolix was extensively evaluated in clinical studies in healthy su... more The clinical pharmacology of elagolix was extensively evaluated in clinical studies in healthy subjects and in women with endometriosis. Elagolix pharmacokinetics (PK) show significant population variability, however they are minimally affected by patients' baseline characteristics and demographics, except for clinically relevant extrinsic and intrinsic factors such as coadministrated strong organic anion transporting polypeptide (OATP) 1B1 inhibitors and severe hepatic impairment, which are contraindications for the use of elagolix. These studies enabled a comprehensive understanding of elagolix mechanism of action and the downstream pharmacodynamic (PD) effects on gonadotropin and ovarian hormones, as well as full characterization of the PK/PD (PKPD) relationships of elagolix at various dosages, including the approved 150 mg once daily and 200 mg twice daily dosing regimens for the management of moderate to severe pain associated with endometriosis. Several model-based analyses have contributed to understanding of the benefit-risk profile of elagolix in patients with endometriosis, through characterization of the exposure relationship with responder rates, with changes in bone mineral density over time, as well as the interaction with coadministered drugs. Collectively, these studies and analyses served as supportive evidence for the effectiveness of the approved dosages and provided general dosing instructions of the first approved oral gonadotropin-releasing hormone receptor antagonist.

The Journal of Clinical Pharmacology, 2019

Upadacitinib (ABT‐494) is a selective Janus kinase (JAK)1 inhibitor being developed for treatment... more Upadacitinib (ABT‐494) is a selective Janus kinase (JAK)1 inhibitor being developed for treatment of several inflammatory disorders. A population pharmacokinetic model was developed for upadacitinib using 11,658 plasma concentrations from 1145 subjects from 4 phase 1 and 5 phase 2 studies in healthy subjects and subjects with rheumatoid arthritis, Crohn's disease, ulcerative colitis, or atopic dermatitis. A 2‐compartment model with first‐order absorption and lag time for the immediate‐release formulation and mixed zero‐ and first‐order absorption with lag time for the extended‐release formulation, and linear elimination adequately described upadacitinib plasma concentration–time profiles. The oral bioavailability of upadacitinib extended‐release formulation was estimated to be approximately 80% relative to the immediate‐release formulation. Covariates included in the final model were creatinine clearance, subject population (healthy subjects vs subjects with atopic dermatitis, u...

Clinical Pharmacokinetics, 2019

Background Venetoclax is a selective inhibitor of B-cell lymphoma-2, which plays a role in the de... more Background Venetoclax is a selective inhibitor of B-cell lymphoma-2, which plays a role in the development of various autoimmune diseases including systemic lupus erythematosus. The aim of these analyses was to quantify the exposure-response relationship for venetoclax effects on B-lymphocyte and total lymphocyte counts as pharmacodynamic markers of efficacy and safety, respectively, in women with systemic lupus erythematosus. The developed modeling framework was also used to evaluate venetoclax effects following cyclic, continuous, or induction/maintenance dosing paradigms as potential dosing alternatives in systemic lupus erythematosus. Methods Serial pharmacokinetic and lymphocyte count data from 73 women enrolled in a phase I study of venetoclax (single doses of 10-500 mg or two cycles of 30-600 mg or placebo once daily for 7 days followed by a 21-day washout) were analyzed using a sequential population pharmacokinetic/pharmacodynamic modeling approach. Simulations to evaluate changes in B-lymphocyte and total lymphocyte counts following different venetoclax dosing scenarios were conducted. Results Effect of venetoclax plasma exposures on B lymphocytes was described using an indirect linear response model and on total lymphocytes using a maximal response (E max) with an effect site compartment. Baseline lymphocyte counts were significant covariates on the slope and half maximal inhibitory concentration parameter estimates for the respective models; with higher baseline counts associated with a greater reduction upon treatment with venetoclax. Model simulations showed that continuous dosing with lower doses of venetoclax (e.g., 150 mg daily) are predicted to achieve similar maximal effects on B-lymphocyte counts compared to cyclic dosing with higher doses (e.g., 400 mg 1 week on/3 weeks off); with better recovery of total lymphocyte counts during off-treatment weeks for the cyclic regimens. Conclusions Venetoclax treatment in women with systemic lupus erythematosus was associated with exposure-dependent reductions in B lymphocytes, and to a lesser extent, total lymphocyte counts. Results from this study support evaluation of B-cell lymphoma-2 inhibitors as potential therapies for the treatment of systemic lupus erythematosus. Clinicaltrials.gov NCT01686555.

Journal of Clinical Pharmacy and Therapeutics, 2019

What is known and objective: High-dose methotrexate (HD-MTX) is associated with a plethora of adv... more What is known and objective: High-dose methotrexate (HD-MTX) is associated with a plethora of adverse drug reactions and potential drug interactions (DIs). But there is a paucity of information regarding the safety of co-administering primaquine with HD-MTX. Case summary: A 65-year-old male patient was diagnosed with mantle cell lymphoma (MCL) with CNS involvement and treated with three cycles of IV HD-MTX. His case was further complicated by fungal pneumonia treated with primaquine during cycle-2. Serial blood sampling and subsequent population pharmacokinetics (PK) modelling suggests a possible distribution-mediated DI between the two drugs. What is new and conclusion: This is the first case report to highlight the safe co-administration of MTX and primaquine, despite a possible PK interaction.

Journal of Investigative Dermatology, 2019

This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Clinical Pharmacology & Therapeutics, 2019

Exposure-response analyses of upadacitinib (UPA) key efficacy and safety end points (3,685 and 4,... more Exposure-response analyses of upadacitinib (UPA) key efficacy and safety end points (3,685 and 4,577 subjects for efficacy and safety, respectively) using data from phase II and phase III rheumatoid arthritis (RA) studies were conducted to support benefit-risk assessment. Percentage of subjects achieving American College of Rheumatology (ACR)20/50/70, disease activity score 28 (C-reactive protein) (DAS28-CRP) ≤ 3.2, and DAS28-CRP < 2.6 increased with increasing UPA plasma exposures. With the small number of observed safety events, no clear trends for exposure-response relationships were identified for pneumonia, herpes zoster infection, changes in platelet count, lymphopenia (Grade ≥ 4), or neutropenia (Grade ≥ 3) up to Week 26. Shallow exposure-response relationships were observed for > 2 g/dL decrease in hemoglobin, lymphopenia Grade ≥ 3 at Week 12/14, and serious infections at Week 24/26. Exposure-efficacy analyses demonstrate that UPA 15 mg q.d. (once daily) dose provided the optimal benefit-risk in RA through maximizing efficacy with only small incremental benefit with 30 mg q.d.; and with consistency across RA subpopulations and with UPA monotherapy or combination with conventional synthetic disease-modifying antirheumatic drugs. Upadacitinib (ABT-494) is a selective Janus kinase (JAK)1 inhibitor being developed for the treatment of several inflammatory disorders, including rheumatoid arthritis (RA), ulcerative colitis, atopic dermatitis, Crohn's disease, psoriatic arthritis, axial spondyloarthritis, and giant cell arteritis. 1-13 The JAKs are a family of tyrosine kinases (JAK1, 2, and 3 and tyrosine kinase 2) that mediate

Poster Presentations, 2019

models. The proportions of patients reporting improvements ! minimum clinically important differe... more models. The proportions of patients reporting improvements ! minimum clinically important differences (MCID) from BL to Week 12 or scores ! normative values were determined with UPA, PBO, and ADA treatment; comparisons used chi-square tests. Results: Data from 1629 patients (UPA: 651; PBO: 651; ADA: 327) were analysed. Mean age was 54 years; 79% were female; 54% had RA for !5 years. Baseline mean PRO scores were similar across treatment groups. At Week 12, UPA treatment resulted in statistically significant LSM changes from BL vs PBO across all PROs and statistically significant LSM changes from BL vs ADA in PtGA, pain, HAQ-DI, AM stiffness severity, FACIT-F, and SF-36 physical component summary (PCS) and 6/ 8 domain scores (Table). ADA treatment resulted in statistically significant LSM changes from baseline vs PBO in PtGA, pain, HAQ-DI, AM stiffness severity and duration, FACIT-F, and SF-36 PCS and 5/8 domain scores. Compared with PBO at Week 12, significantly more UPA-treated patients reported improvements ! MCID and scores ! normative values across all PROs with numbers needed to treat (NNTs) <10. The proportions of UPA-treated patients reporting improvements ! MCID were similar or numerically higher than ADA-treated patients. Importantly, the proportion of UPA vs ADA treated patients reporting improvements ! normative values were significantly greater (all p<0.05) in PtGA (36% vs 26%), HAQ-DI (21% vs 14%), SF-36 PCS (16% vs 11%), and SF-36 bodily pain (29% vs 21%) and vitality (42% vs 35%) domains. Conclusion: Among patients with active RA, treatment with UPA 15 mg QD on background MTX therapy for 12 weeks resulted in statistically significant and clinically meaningful improvements in PROs compared with PBO. Overall, PRO improvements with UPA treatment met or were superior to treatment with ADA, especially in key domains of pain, function and vitality.

European Journal of Drug Metabolism and Pharmacokinetics, 2019

Background Vancomycin therapeutic drug monitoring (TDM) is based on achieving 24-h area under the... more Background Vancomycin therapeutic drug monitoring (TDM) is based on achieving 24-h area under the concentration-time curve to minimum inhibitory concentration cure breakpoints (AUC 24 /MIC). Approaches to vancomycin TDM vary, with no head-to-head randomized controlled trial (RCT) comparisons to date. Objectives We aimed to compare clinical and pharmacokinetic outcomes between peak-trough-based and trough-only-based vancomycin TDM approaches and to determine the relationship between vancomycin AUC 24 /MIC and cure rates. Methods A multicentered pragmatic parallel-group RCT was conducted in Hamad Medical Corporation hospitals in Qatar. Adult non-dialysis patients initiated on vancomycin were randomized to peak-trough-based or trough-only-based vancomycin TDM. Primary endpoints included vancomycin AUC 24 /MIC ratio breakpoint for cure and clinical effectiveness (therapeutic cure vs therapeutic failure). Descriptive, inferential, and classification and regression tree (CART) statistical analyses were applied. NONMEM.v.7.3 was used to conduct population pharmacokinetic analyses and AUC 24 calculations. Results Sixty-five patients were enrolled [trough-only-based-TDM (n = 35) and peak-trough-based-TDM (n = 30)]. Peaktrough-based TDM was significantly associated with higher therapeutic cure rates compared to trough-only-based TDM [76.7% vs 48.6%; p value = 0.02]. No statistically significant differences were observed for all-cause mortality, neutropenia, or nephrotoxicity between the two groups. Compared to trough-only-based TDM, peak-trough-based TDM was associated with less vancomycin total daily doses by 12.05 mg/kg/day (p value = 0.027). CART identified creatinine clearance (CL CR), AUC 24 /MIC, and TDM approach as significant determinants of therapeutic outcomes. All patients [n = 19,100%] with CL CR ≤ 7.85 L/h, AUC 24 /MIC ≤ 1256, who received peak-trough-based TDM achieved therapeutic cure. AUC 24 /MIC > 565 was identified to be correlated with cure in trough-only-based TDM recipients [n = 11,84.6%]. No minimum AUC 24 /MIC breakpoint was detected by CART in the peak-trough-based group. Conclusion Maintenance of target vancomycin exposures and implementation of peak-trough-based vancomycin TDM may improve vancomycin-associated cure rates. Larger scale RCTs are warranted to confirm these findings.

Clinical pharmacokinetics, 2018

Elagolix is a novel, orally active, non-peptide, competitive gonadotropin-releasing hormone (GnRH... more Elagolix is a novel, orally active, non-peptide, competitive gonadotropin-releasing hormone (GnRH) receptor antagonist in development for the management of endometriosis with associated pain and heavy menstrual bleeding due to uterine fibroids. The pharmacokinetics of elagolix have been well-characterized in phase I studies; however, elagolix population pharmacokinetics have not been previously reported. Therefore, a robust model was developed to describe elagolix population pharmacokinetics and to evaluate factors affecting elagolix pharmacokinetic parameters. The data from nine clinical studies (a total of 1624 women) were included in the analysis: five phase I studies in healthy, premenopausal women and four phase III studies in premenopausal women with endometriosis. Elagolix population pharmacokinetics were best described by a two-compartment model with a lag time in absorption. Of the 15 covariates tested for effect on elagolix apparent clearance (CL/F) and/or volume of distri...

PloS one, 2018

Anti-drug antibody formation occurs with most biological agents across disease states, but the me... more Anti-drug antibody formation occurs with most biological agents across disease states, but the mechanism by which they are formed is unknown. The formation of anti-drug antibodies to adalimumab (AAA) may decrease its therapeutic effects in some patients. HLA alleles have been reported to be associated with autoantibody formation against interferons and other TNF inhibitors, but not adalimumab. We analyzed samples from 634 subjects with either rheumatoid arthritis (RA) or hidradenitis suppurativa (HS): 37 subjects (17 RA and 20 HS) developed AAA (AAA+) during adalimumab treatment and 597 subjects (348 RA, 249 HS) did not develop AAA (AAA-) during the clinical trials. Using next-generation sequencing-based HLA typing, we identified three protective HLA alleles (HLA-DQB1*05, HLA-DRB1*01,and HLA-DRB1*07) that were less prevalent in AAA+ than AAA-subjects (ORs: 0.4, 0.25 and 0.28, respectively; and P values: 0.012, 0.012 and 0.018, respectively) and two risk HLA alleles (HLA-DRB1*03 and ...

European Journal of Cancer, 2017

INTRODUCTION: Vulvar carcinoma accounts for about 4% of the female reproductive tract cancers and... more INTRODUCTION: Vulvar carcinoma accounts for about 4% of the female reproductive tract cancers and a total of 0.6% of all malignant cancers in females. PATIENTS AND METHODS: This retrospective study aimed to identify the possible risk factors which can impact survival in Egyptian patients with vulval cancer who received treatment at Ain Shams University department of clinical oncology and nuclear medicine in the period from 1-1-2007 till 1-1-2012. RESULTS: Our study included 64 patients [median age 63 years, median overall survival (OS) was 16.5 months]. The factors associated with favourable impact on OS were: Rural residence (17 versus 10 months for patients from urban residence, p=0.002), premenopausal status (19 versus 16 months in post menopausal patients, p<0.001), low grade histology (19 versus 10 months in patients with high grade, p<0.001) and negative resection margins (19 versus 10 months in case of positive margin, p<0.001). The factors associated with poor OS were: higher number of offspring (≥5 offspring, OS 10 versus 19 months if less than 5 offspring, p<0.001), patients presenting with ulcer rather than mass (11 versus 19 months, p<0.001 and those with bilateral disease (10 versus 17 months in unilateral disease, p=0.04), presence of ≥4 positive groin lymph nodes metastases (OS =16 months versus 17 months, p=0.047) tumor size ≥ 4 cm (10 versus 17 months in case of <4 cm, p=0.001) and depth of stromal invasion (17 versus 16 months in case of <1 cm and ≥ 1 cm respectively, p=0.015) CONCLUSION: Urbanization has been linked with more aggressive disease leading to decrease of OS. The age of onset of intercourse did not affect survival as was expected however multiple offspring which could be related to more frequent intercourse had an effect on survival. The offered treatment modalities did not show a superiority probably because all the patients presented in an advanced stage. The anatomical nature of this cancer might be the cause in delayed diagnosis which warrants health education projects for early detection. Further studies are required to assess the risk factors for development of vulval cancer in Egyptian patients.

The AAPS journal, Jul 22, 2016

Nifedipine is a BCS Class II drug used for treatment of hypertension and preterm labor. Large int... more Nifedipine is a BCS Class II drug used for treatment of hypertension and preterm labor. Large inter-patient variability in nifedipine absorption results in variable exposure among different patients. We conducted in vitro dissolution studies to compare nifedipine dissolution from immediate release (IR) capsules with different volumes of dissolution media. Results from dissolution studies were used to design a crossover study in healthy volunteers to evaluate the effect of coadministered water volume with nifedipine 10 mg IR capsules on nifedipine pharmacokinetics, especially absorption (C max, t max, and AUC0-6). Dissolution studies demonstrated that larger gastric fluid volumes result in enhanced nifedipine dissolution from 10 mg IR cosolvent capsules (73 vs. 17% in 200 and 100 mL simulated gastric fluid, respectively, at 30 min). The pharmacokinetic crossover study in healthy volunteers (N = 6) did not show a significant effect of the water volume administered with the capsule (50...