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Article ; Online: Immunogenicity Considerations for Therapeutic Modalities Used in Rare Diseases.

Fathallah, Anas M / Oldfield, Philip / Fiedler-Kelly, Jill / Ramadan, Abdulraouf

2022 Volume 62 Suppl 2, Page(s) S110–S118

Abstract: New therapeutic modalities carry with them great promise for the treatment of rare diseases. They also present unique development challenges including immunogenicity, which can impact the safety and efficacy of those new modalities. In this review, an ... ...

Abstract	New therapeutic modalities carry with them great promise for the treatment of rare diseases. They also present unique development challenges including immunogenicity, which can impact the safety and efficacy of those new modalities. In this review, an overview of the basic function of the immune system and its possible interaction with new therapeutic modalities is presented. A juxtaposition of immunogenicity in the rare disease space versus traditional clinical programs is hereby being proposed. A clinical pharmacology viewpoint of immunogenicity, proposed approaches to account for immunogenicity in clinical data, bioanalytical considerations, and effects of route of administration and production changes on immunogenicity are discussed.
MeSH term(s)	Humans ; Rare Diseases/drug therapy ; Pharmacology, Clinical
Language	English
Publishing date	2022-12-03
Publishing country	England
Document type	Review ; Journal Article
ZDB-ID	188980-1
ISSN	1552-4604 ; 0091-2700 ; 0021-9754
ISSN (online)	1552-4604
ISSN	0091-2700 ; 0021-9754
DOI	10.1002/jcph.2166
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Article ; Online: Mechanistic Modeling of the Effect of Recombinant Human Hyaluronidase (rHuPH20) on Subcutaneous Delivery of Cetuximab in Rats.

Gao, Xizhe / Lee, Jongbong / Deshpande, Kiran / Kang, David W / Fathallah, Anas M / Kagan, Leonid

Pharmaceutical research

2022 Volume 39, Issue 8, Page(s) 1867–1880

Abstract: Purpose: To evaluate the duration of effect of rHuPH20 on SC absorption of cetuximab and to develop a mechanistic pharmacokinetic model linking the kinetics of rHuPH20 action with hyaluronan (HA) homeostasis and absorption of cetuximab from the SC space. ...

Abstract	Purpose: To evaluate the duration of effect of rHuPH20 on SC absorption of cetuximab and to develop a mechanistic pharmacokinetic model linking the kinetics of rHuPH20 action with hyaluronan (HA) homeostasis and absorption of cetuximab from the SC space. Methods: Serum pharmacokinetics of cetuximab was evaluated after IV and SC dosing at 0.4 and 10 mg/kg (control groups). In test groups, SC cetuximab was administered simultaneously with rHuPH20 (Co-Injection) or 12 h after injection of rHuPH20 (Pre-Injection). Mechanistic pharmacokinetic model was developed to simultaneously capture cetuximab kinetics in all groups. Results: Administration of rHuPH20 resulted in a faster absorption of cetuximab; the difference between co-injection and pre-injection groups appeared to be dependent on the dose level. The model combined three major components: kinetics of rHuPH20 at SC site; HA homeostasis and its disruption by rHuPH20; and cetuximab systemic disposition and the effect of HA disruption on cetuximab SC absorption. The model provided good description of experimental data obtained in this study and collected previously. Conclusions: Proposed model can serve as a potential translational framework for capturing the effect of rHuPH20 across multiple preclinical species and in human studies and can be used for optimization of SC delivery of biotherapeutics.
MeSH term(s)	Animals ; Cetuximab/pharmacology ; Humans ; Hyaluronic Acid ; Hyaluronoglucosaminidase ; Injections, Subcutaneous ; Rats ; Recombinant Proteins
Chemical Substances	Recombinant Proteins ; Hyaluronic Acid (9004-61-9) ; Hyaluronoglucosaminidase (EC 3.2.1.35) ; Cetuximab (PQX0D8J21J)
Language	English
Publishing date	2022-07-01
Publishing country	United States
Document type	Journal Article
ZDB-ID	843063-9
ISSN	1573-904X ; 0724-8741 ; 0739-0742
ISSN (online)	1573-904X
ISSN	0724-8741 ; 0739-0742
DOI	10.1007/s11095-022-03294-y
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Article ; Online: Bridging the Gap With Clinical Pharmacology in Innovative Rare Disease Treatment Modalities: Targeting DNA to RNA to Protein.

Lee, Lucy / Gollen, Rakesh / Fathallah, Anas M / Gao, Lan / Patil, Shivakumar

Journal of clinical pharmacology

2022 Volume 62 Suppl 2, Page(s) S95–S109

Abstract: Rare diseases are frequently caused by inherited 'monogenic' defects. Treatment interventions that target a specific genetic location or that replaces a specific protein provide rational therapeutic approaches. The current review discusses innovative ... ...

Abstract	Rare diseases are frequently caused by inherited 'monogenic' defects. Treatment interventions that target a specific genetic location or that replaces a specific protein provide rational therapeutic approaches. The current review discusses innovative targeted therapies that act or modulate at the level of DNA, RNA, or protein. They include DNA gene editing, small interference RNA (siRNA), antisense oligonucleotide (ASO), small molecule RNA splicing modifier, and bispecific antibody. With limited numbers of patients, testing multiple dose levels and regimens prior to making an informed dose decision remains one of the major challenges in rare disease drug development. Clinical pharmacology strategically bridges the gap to support drug development and regulatory approvals. Pharmacokinetic drug exposures are driven by absorption, distribution, metabolism, elimination, and in some cases immunogenicity. Drug responses are measured by pharmacodynamic biomarkers that are linked to either short- or long-term clinical outcomes. Understanding the drug exposure-response relationship lies at the heart of bridging the gap that enables a dose decision by balancing effectiveness and safety. Furthermore, and importantly, understanding the influence of intrinsic and extrinsic factors on drug pharmacokinetics enables dose adjustment decisions based on drug exposures. Case examples include the identification of doses and regimens without a formal dose-finding study, the support of new doses and regimens without conducting additional studies, and the extrapolation of adult drug-drug interaction (DDI) studies to pediatrics without performing a pediatric DDI study. With increasing discoveries of innovative treatment modalities, the responsibility of clinical pharmacologists is expected to grow and enhance the development of novel treatments for rare diseases.
MeSH term(s)	Adult ; Humans ; Child ; Pharmacology, Clinical ; Rare Diseases/drug therapy ; DNA ; RNA, Small Interfering ; Drug Development
Chemical Substances	DNA (9007-49-2) ; RNA, Small Interfering
Language	English
Publishing date	2022-12-03
Publishing country	England
Document type	Review ; Journal Article
ZDB-ID	188980-1
ISSN	1552-4604 ; 0091-2700 ; 0021-9754
ISSN (online)	1552-4604
ISSN	0091-2700 ; 0021-9754
DOI	10.1002/jcph.2172
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Article ; Online: Safety and efficacy of edaravone in patients with amyotrophic lateral sclerosis: a systematic review and meta-analysis.

Nourelden, Anas Zakarya / Kamal, Ibrahim / Hagrass, Abdulrahman Ibrahim / Tawfik, Abdelrahman G / Elhady, Mahmoud M / Fathallah, Ahmed Hashem / Eshag, Mona Muhe Eldeen / Zaazouee, Mohamed Sayed

Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology

2023 Volume 44, Issue 10, Page(s) 3429–3442

Abstract: Aim: The study aims to increase understanding of edaravone's efficacy and safety as an amyotrophic lateral sclerosis (ALS) treatment and provide significant insights regarding this field's future research.: Methods: We conducted a comprehensive ... ...

Abstract	Aim: The study aims to increase understanding of edaravone's efficacy and safety as an amyotrophic lateral sclerosis (ALS) treatment and provide significant insights regarding this field's future research. Methods: We conducted a comprehensive search of the Embase, PubMed, Cochrane Library, Web of Science, and Scopus databases for randomized controlled trials and observational studies up until September 2022. We evaluated the studies' quality using the Cochrane risk of bias tool and the National Institutes of Health tool. Results: We included 11 studies with 2845 ALS patients. We found that edaravone improved the survival rate at 18, 24, and 30 months (risk ratio (RR) = 1.03, 95% confidence interval (CI) [1.02 to 1.24], P = 0.02), (RR = 1.22, 95% CI [1.06 to 1.41], P = 0.007), and (RR = 1.17, 95% CI [1.01 to 1.34], P = 0.03), respectively. However, the administration of edaravone did not result in any significant difference in adverse effects or efficacy outcomes between the two groups, as indicated by a P value greater than 0.05. Conclusion: Edaravone improves survival rates of ALS patients at 18, 24, and 30 months with no adverse effects. However, edaravone does not affect functional outcomes. In order to ensure the validity of our findings and assess the results in accordance with the disease stage, it is essential to carry out additional prospective, rigorous, and high-quality clinical trials. The current study offers preliminary indications regarding the effectiveness and safety of edaravone. However, further comprehensive research is required to establish the generalizability and sustainability of the findings.
MeSH term(s)	United States ; Humans ; Edaravone/therapeutic use ; Amyotrophic Lateral Sclerosis/drug therapy ; Amyotrophic Lateral Sclerosis/chemically induced ; Prospective Studies ; Quality of Life ; Severity of Illness Index
Chemical Substances	Edaravone (S798V6YJRP)
Language	English
Publishing date	2023-05-30
Publishing country	Italy
Document type	Meta-Analysis ; Systematic Review ; Journal Article ; Review
ZDB-ID	2016546-8
ISSN	1590-3478 ; 1590-1874
ISSN (online)	1590-3478
ISSN	1590-1874
DOI	10.1007/s10072-023-06869-8
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Article ; Online: Efficacy and Safety of Therapeutic Hypothermia as an Adjuvant Therapy for Percutaneous Coronary Intervention in Acute Myocardial Infarction: A Systematic Review and Meta-Analysis.

Mir, Ali / Rahman, Mohammed Faraaz / Ragab, Khaled Mohamed / Fathallah, Ahmed Hashem / Daloub, Shaden / Alwifati, Nader / Hagrass, Abdulrahman Ibrahim / Nourelden, Anas Zakarya / Elsayed, Sarah Makram / Kamal, Ibrahim / Elhady, Mahmoud M / Khan, Raheel

Therapeutic hypothermia and temperature management

2023

Abstract: The study aims to compare the use of hypothermia in patients with myocardial infarction (MI) undergoing percutaneous coronary intervention (PCI) with control. We systematically searched four electronic databases until March 2022. The inclusion criteria ... ...

Abstract	The study aims to compare the use of hypothermia in patients with myocardial infarction (MI) undergoing percutaneous coronary intervention (PCI) with control. We systematically searched four electronic databases until March 2022. The inclusion criteria were any study design that compared hypothermia in patients with MI undergoing PCI with control. The risk of bias assessment of the included randomized controlled trials was conducted through Cochrane Tool, while the quality of the included cohort studies was assessed by the NIH tool. The meta-analysis was performed on RevMan. A total of 19 studies were entered. Regarding the mortality, there were nonsignificant differences between hypothermia and control (odds ratio [OR] = 1.06, 95% confidence interval [CI] 0.75 to 1.50,
Language	English
Publishing date	2023-10-04
Publishing country	United States
Document type	Journal Article
ZDB-ID	2609342-X
ISSN	2153-7933 ; 2153-7658
ISSN (online)	2153-7933
ISSN	2153-7658
DOI	10.1089/ther.2023.0007
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Article: Inhaled corticosteroids' effect on COVID-19 patients: A systematic review and meta-analysis of randomized controlled trials.

Badi, Yasra / Hammad, Mohamed / Tawfik, Abdelrahman G / Eshag, Mona Muhe Eldeen / Elhady, Mahmoud M / Ragab, Khaled Mohamed / Nourelden, Anas Zakarya / Gamal, Mohamed Hesham / Fathallah, Ahmed Hashem

Canadian journal of respiratory therapy : CJRT = Revue canadienne de la therapie respiratoire : RCTR

2023 Volume 59, Page(s) 154–166

Abstract: Background: More than six million people died due to COVID-19, and 10-15% of infected individuals suffer from post-covid syndrome. Corticosteroids are widely used in the management of severe COVID-19 and post-acute COVID-19 symptoms. This study ... ...

Abstract	Background: More than six million people died due to COVID-19, and 10-15% of infected individuals suffer from post-covid syndrome. Corticosteroids are widely used in the management of severe COVID-19 and post-acute COVID-19 symptoms. This study synthesizes current evidence of the effectiveness of inhaled corticosteroids (ICS) on mortality, hospital length-of-stay (LOS), and improvement of smell scores in patients with COVID-19. Methods: We searched Embase, Web of Science, PubMed, Cochrane Library, and Scopus until Aug 2022. The Cochrane risk of bias tool was used to assess the quality of studies. We evaluated the effectiveness of ICS in COVID-19 patients through measures of mortality, LOS, alleviation of post-acute COVID-19 symptoms, time to sustained self-reported cure, and sense of smell (visual analog scale (VAS)). Results: Ten studies were included in the meta-analysis. Our study showed a significant decrease in the LOS in ICS patients over placebo (MD = -1.52, 95% CI [-2.77 to -0.28], Conclusion: We concluded that the use of ICS decreased patient LOS and improved COVID-19-related symptoms. INC may have a role in improving the smell score. Therefore, using INC and ICS for two weeks or more may prove beneficial. Current data do not demonstrate an effect on mortality or time to sustained self-reported cure. However, the evidence is inconclusive, and more studies are needed for more precise data.
Language	English
Publishing date	2023-08-01
Publishing country	Canada
Document type	Systematic Review
ZDB-ID	1377251-x
ISSN	1205-9838
ISSN	1205-9838
DOI	10.29390/001c.84260
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Article ; Online: Chest pain in pediatric patients in the emergency department- Presentation, risk factors and outcomes-A systematic review and meta-analysis.

Alsabri, Mohammed / Elshanbary, Alaa Ahmed / Nourelden, Anas Zakarya / Fathallah, Ahmed Hashem / Zaazouee, Mohamed Sayed / Pincay, Jorge / Nakadar, Zaid / Wasem, Muhammad / Aeder, Lita

PloS one

2024 Volume 19, Issue 4, Page(s) e0294461

Abstract: Objective: This study aimed to assess and determine the presentation, risk factors, and outcomes of pediatric patients who were admitted for cardiac-related chest pain.: Background: Although chest pain is common in children, most cases are due to non- ...

Abstract	Objective: This study aimed to assess and determine the presentation, risk factors, and outcomes of pediatric patients who were admitted for cardiac-related chest pain. Background: Although chest pain is common in children, most cases are due to non-cardiac etiology. The risk of misdiagnosis and the pressure of potentially adverse outcomes can lead to unnecessary diagnostic testing and overall poorer patient experiences. Additionally, this can lead to a depletion of resources that could be better allocated towards patients who are truly suffering from cardiac-related pathology. Methods: This review was conducted per PRISMA guidelines. This systematic review used several databases including MEDLINE, Embase, Scopus, and Web of Science to obtain its articles for review. Results: A total of 6,520 articles were identified, and 11 articles were included in the study. 2.5% of our study population was found to have cardiac-related chest pain (prevalence = 0.025, 95% CI [0.013, 0.038]). The most commonly reported location of pain was retrosternal chest pain. 97.5% of the study population had a non-cardiac cause of chest pain, with musculoskeletal pain being identified as the most common cause (prevalence = 0.357, 95% CI [0.202, 0.512]), followed by idiopathic (prevalence = 0.352, 95% CI [0.258, 0.446]) and then gastrointestinal causes (prevalence = 0.053, 95% CI [0.039, 0.067]). Conclusions: The overwhelming majority of pediatric chest pain cases stem from benign origins. This comprehensive analysis found musculoskeletal pain as the predominant culprit behind chest discomfort in children. Scrutinizing our study cohort revealed that retrosternal chest pain stands as the unequivocal epicenter of this affliction. Thorough evaluation of pediatric patients manifesting with chest pain is paramount for the delivery of unparalleled care, especially in the context of potential cardiac risks in the emergency department.
MeSH term(s)	Humans ; Child ; Musculoskeletal Pain/complications ; Chest Pain/diagnosis ; Chest Pain/etiology ; Chest Pain/epidemiology ; Emergency Service, Hospital ; Risk Factors ; Hospitalization
Language	English
Publishing date	2024-04-16
Publishing country	United States
Document type	Meta-Analysis ; Systematic Review ; Journal Article
ZDB-ID	2267670-3
ISSN	1932-6203 ; 1932-6203
ISSN (online)	1932-6203
ISSN	1932-6203
DOI	10.1371/journal.pone.0294461
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Article ; Online: Anatomical, physiological, and experimental factors affecting the bioavailability of sc-administered large biotherapeutics.

Fathallah, Anas M / Balu-Iyer, Sathy V

Journal of pharmaceutical sciences

2015 Volume 104, Issue 2, Page(s) 301–306

Abstract: Subcutaneous route of administration is highly desirable for protein therapeutics. It improves patient compliance and quality of life (McDonald TA, Zepeda ML, Tomlinson MJ, Bee WH, Ivens IA. 2010. Curr Opin Mol Ther 12(4):461-470; Dychter SS, Gold DA, ... ...

Abstract	Subcutaneous route of administration is highly desirable for protein therapeutics. It improves patient compliance and quality of life (McDonald TA, Zepeda ML, Tomlinson MJ, Bee WH, Ivens IA. 2010. Curr Opin Mol Ther 12(4):461-470; Dychter SS, Gold DA, Haller MF. 2012. J Infus Nurs 35(3):154-160), while reducing healthcare cost (Dychter SS, Gold DA, Haller MF. 2012. J Infus Nurs 35(3):154-160). Recent evidence also suggests that sc administration of protein therapeutics can increase tolerability to some treatments such as intravenous immunoglobulin therapy by administering it subcutaneously (subcutaneous immunoglobulin therapy SCIG), which will reduce fluctuation in plasma drug concentration (Kobrynski L. 2012. Biologics 6:277-287). Furthermore, sc administration may reduce the risk of systemic infections associated with i.v. infusion (McDonald TA, Zepeda ML, Tomlinson MJ, Bee WH, Ivens IA. 2010. Curr Opin Mol Ther 12(4):461-470; Dychter SS, Gold DA, Haller MF. 2012. J Infus Nurs 35(3):154-160). This route, however, has its challenges, especially for large multidomain proteins. Poor bioavailability and poor scalability from preclinical models are often cited. This commentary will discuss barriers to sc absorption as well as physiological and experimental factors that could affect pharmacokinetics of subcutaneously administered large protein therapeutics in preclinical models. A mechanistic pharmacokinetic model is proposed as a potential tool to address the issue of scalability of sc pharmacokinetic from preclinical models to humans.
MeSH term(s)	Biological Availability ; Biological Products/administration & dosage ; Biological Products/metabolism ; Biological Products/pharmacokinetics ; Biological Therapy ; Humans ; Injections, Subcutaneous
Chemical Substances	Biological Products
Language	English
Publishing date	2015-02
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	3151-3
ISSN	1520-6017 ; 0022-3549
ISSN (online)	1520-6017
ISSN	0022-3549
DOI	10.1002/jps.24277
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Article ; Online: Safety and pharmacokinetics of docetaxel in combination with pegvorhyaluronidase alfa in patients with non-small cell lung cancer.

Heineman, Thomas / Baumgart, Megan / Nanavati, Charvi / Gabrail, Nash / Van Wart, Scott A / Mager, Donald E / Maneval, Daniel C / Fathallah, Anas M / Sekulovich, Rose E

Clinical and translational science

2021 Volume 14, Issue 5, Page(s) 1875–1885

Abstract: This open-label, phase Ib study (NCT02346370) assessed the effect of pegvorhyaluronidase alfa (PVHA; PEGPH20) on the plasma pharmacokinetics (PKs) and safety of docetaxel in 15 patients with stage IIIB/IV non-small cell lung cancer (NSCLC). The docetaxel ...

Abstract	This open-label, phase Ib study (NCT02346370) assessed the effect of pegvorhyaluronidase alfa (PVHA; PEGPH20) on the plasma pharmacokinetics (PKs) and safety of docetaxel in 15 patients with stage IIIB/IV non-small cell lung cancer (NSCLC). The docetaxel PK profile from this study was consistent with simulations from a published docetaxel population PK model, and did not demonstrate an effect of PVHA on docetaxel PK. A maximum a posteriori Bayesian fit of the literature PK model to the docetaxel PK appeared unbiased. Adverse events (AEs) were generally consistent with previous reports for docetaxel monotherapy in NSCLC, except for higher incidence of musculoskeletal events, including myalgias, with PVHA plus docetaxel. The most common AEs were fatigue (87%), muscle spasms (60%), and myalgia (53%). Four patients experienced thromboembolic events (27%), three leading to treatment discontinuation. PVHA appeared to demonstrate an acceptable safety profile when given with docetaxel without significantly changing the plasma PK of docetaxel in patients with stage IIIB/IV NSCLC.
Language	English
Publishing date	2021-07-30
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2433157-0
ISSN	1752-8062 ; 1752-8054
ISSN (online)	1752-8062
ISSN	1752-8054
DOI	10.1111/cts.13041
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Article ; Online: O-phospho-l-serine mediates hyporesponsiveness toward FVIII in hemophilia A-murine model by inducing tolerogenic properties in dendritic cells.

Fathallah, Anas M / Ramakrishnan, Radha / Balu-Iyer, Sathy V

Journal of pharmaceutical sciences

2014 Volume 103, Issue 11, Page(s) 3457–3463

Abstract: The clinical use of therapeutic proteins can be complicated by the development of anti-product antibodies. We have previously observed that O-phospho-l-serine (OPLS) reduced antibody response to FVIII in Hemophilia-A (HA) mice. However, the mechanism ... ...

Abstract	The clinical use of therapeutic proteins can be complicated by the development of anti-product antibodies. We have previously observed that O-phospho-l-serine (OPLS) reduced antibody response to FVIII in Hemophilia-A (HA) mice. However, the mechanism underlying this observation is not clear. We hypothesize that OPLS reduces immunogenicity by inducing tolerogenic properties in dendritic cells (DCs). We tested this hypothesis using in vivo, in vitro, and ex vivo methods. Naive HA mice that were pre-exposed to FVIII in the presence of OPLS showed substantially lower antibody response following rechallenge with OPLS free FVIII as compared with dexamethasone-pretreated mice. Exposure of OPLS to bone-marrow-derived dendritic cells (BMDCs) in culturing conditions resulted in an increase in the regulatory cytokine TGF-β and a decrease in proinflammatory cytokines TNF-α and IL12p70. This was accompanied by a significant reduction in upregulation of costimulatory marker CD40, as measured by flow cytometry. Furthermore, ex vivo matured BMDCs in the presence of FVIII and OPLS failed to elicit a robust immune response in HA mice compared with FVIII-treated BMDCs. Our data suggest that OPLS modulates the immune response by altering the function and maturation of DCs, resulting in the induction of tolerogenic properties. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:3457-3463, 2014.
MeSH term(s)	Adjuvants, Immunologic/pharmacology ; Animals ; Antibodies/blood ; CD40 Antigens/metabolism ; Cells, Cultured ; Coagulants/immunology ; Coagulants/pharmacology ; Dendritic Cells/drug effects ; Dendritic Cells/immunology ; Dendritic Cells/metabolism ; Disease Models, Animal ; Factor VIII/immunology ; Factor VIII/pharmacology ; Hemophilia A/blood ; Hemophilia A/drug therapy ; Hemophilia A/genetics ; Hemophilia A/immunology ; Immune Tolerance/drug effects ; Interleukin-12/metabolism ; Mice, Transgenic ; Phosphoserine/pharmacology ; Time Factors ; Transforming Growth Factor beta/metabolism ; Tumor Necrosis Factor-alpha/metabolism
Chemical Substances	Adjuvants, Immunologic ; Antibodies ; CD40 Antigens ; Coagulants ; Transforming Growth Factor beta ; Tumor Necrosis Factor-alpha ; Phosphoserine (17885-08-4) ; Interleukin-12 (187348-17-0) ; F8 protein, human (839MOZ74GK) ; Factor VIII (9001-27-8)
Language	English
Publishing date	2014-09-29
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	3151-3
ISSN	1520-6017 ; 0022-3549
ISSN (online)	1520-6017
ISSN	0022-3549
DOI	10.1002/jps.24173
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