Review
Biochemistry & Molecular Biology
Baoquan Chen, Wenqiang Liu, Yaohao Li, Bo Ma, Shiying Shang, Zhongping Tan
Summary: Therapeutic proteins are increasingly valued for their unique advantages in the treatment of various diseases, but their intrinsic limitations often restrict their wider applications. Glycosylation, as a crucial post-translational modification, has positive effects on protein properties. Glycoengineering, involving changing glycosylation patterns, is expected to be an effective means of improving the performance of therapeutic proteins.
Article
Chemistry, Analytical
Gang Wu, Chuanfei Yu, Wenbo Wang, Jialiang Du, Zhihao Fu, Gangling Xu, Meng Li, Lan Wang
Summary: Imaged capillary isoelectric focusing (icIEF) and ion exchange chromatography (IEX) are routinely used for charge variant analysis of therapeutic monoclonal antibodies (mAbs). In this study, icIEF-MS and strong cation exchange (SCX)-MS were compared, and it was found that icIEF-MS outperformed SCX-MS in terms of sensitivity, carryover effect, protein identification, and separation resolution.
ANALYTICAL CHEMISTRY
(2023)
Article
Chemistry, Multidisciplinary
Paul R. Malik, Abdullah Hamadeh, Andrea N. Edginton
Summary: Modeling study suggests that a high concentration of circulating monocytes and macrophages is unlikely to explain the fast weight-based clearance of monoclonal antibodies in very young children.
PHARMACEUTICAL RESEARCH
(2022)
Review
Pharmacology & Pharmacy
Andrew Lim, Pradeep Sharma, Oleg Stepanov, Venkatesh Pilla Reddy
Summary: Ethical regulations and limited paediatric participants contribute to a 6-year delay in paediatric mAb approval. Modelling and simulation methodologies, specifically PBPK modelling, offer alternative strategies to design optimized paediatric clinical studies and improve pharmacokinetic predictions. This review consolidates data on the ontogeny of key physiological processes in paediatric mAb disposition and discusses the complementary use of pop-PK and PBPK modelling to increase confidence in pharmacokinetic predictions.
Article
Pharmacology & Pharmacy
Zinnia P. Parra-Guillen, Aymara Sancho-Araiz, Kapil Mayawala, Sara Zalba, Maria J. Garrido, Dinesh de Alwis, Inaki F. Troconiz, Tomoko Freshwater
Summary: This study developed a mechanistic modeling framework to quantitatively characterize the kinetics and distribution of V937 oncolytic virus in cancer patients. The model accurately described the changes in V937 mRNA levels and tumor size and revealed the importance of viral distribution and infectivity in clinical therapy.
CLINICAL PHARMACOLOGY & THERAPEUTICS
(2023)
Review
Pharmacology & Pharmacy
Katherine L. Gill, Hannah M. Jones
Summary: Testing new drugs in paediatric and pregnant patients can be difficult due to recruitment challenges and ethical issues. Modelling and simulation can aid in designing clinical trials and bridging recruitment gaps. Currently, there are more published PBPK models for paediatrics than for pregnant women. Challenges include limited knowledge of relevant physiological processes and availability of clinical data.
Article
Pharmacology & Pharmacy
Matthias van der Veken, Joachim Brouwers, Agustos Cetin Ozbey, Kenichi Umehara, Cordula Stillhart, Noel Knops, Patrick Augustijns, Neil John Parrott
Summary: This study investigates the age dependency of tacrolimus exposure in pediatric patients, focusing on absorption, metabolism, and distribution. A physiologically based pharmacokinetic (PBPK) model was developed based on adult data and extrapolated to the pediatric population using kidney transplant patients' data. Selecting appropriate ontogeny profiles for hepatic and intestinal CYP3A4 was crucial for the model's applicability in children. The study also found that the dissolution profiles of tacrolimus could be adequately represented by diffusion-layer-based dissolution modeling in both adult and pediatric PBPK models. Differences in blood plasma partitioning of tacrolimus may contribute to the variability in exposure in pediatric patients.
Review
Chemistry, Medicinal
Kenta Haraya, Haruka Tsutsui, Yasunori Komori, Tatsuhiko Tachibana
Summary: This review summarizes the recent advances and future direction of modeling and simulation-based approaches to the quantitative prediction of human pharmacokinetics and pharmacodynamics of therapeutic monoclonal antibodies (mAbs).
Review
Medicine, Research & Experimental
Sean Chia, Shi Jie Tay, Zhiwei Song, Yuansheng Yang, Ian Walsh, Kuin Tian Pang
Summary: The circulatory half-life of recombinant therapeutic proteins is important for determining dosing frequency and treatment cost. Manipulating the N-glycan composition, particularly sialic acid, can extend the half-life by masking the terminal galactose recognized by the hepatic asialoglycoprotein receptor. This review provides an illustrative overview of strategies to enhance pharmacokinetic/ pharmacodynamic properties through manipulation of sialic acid content in recombinant therapeutic proteins.
BIOMEDICINE & PHARMACOTHERAPY
(2023)
Article
Chemistry, Analytical
Felix Kuhne, Katrin Heinrich, Martin Winter, Juergen Fichtl, Gabriel Hoffmann, Franziska Zaehringer, Katharina Spitzauer, Monika Meier, Tarik A. Khan, Lea Bonnington, Katharina Wagner, Jan Olaf Stracke, Dietmar Reusch, Harald Wegele, Michael Mormann, Patrick Bulau
Summary: Antibody combination therapies have emerged as viable treatment options for severe diseases like cancer. However, the co-formulation production approach poses challenges for the analytical control of drug product quality due to complex variant profiles. This study developed a multi-dimensional liquid chromatography with tandem mass spectrometry method to characterize antibody homo- and hetero-aggregates. The results showed that the co-formulation of trastuzumab and pertuzumab, two monoclonal antibodies with similar properties, exhibited high stability with minimal aggregate formation under storage and stress conditions. The formation of homo- and hetero-aggregates was not significantly affected by formulation and storage conditions.
ANALYTICAL CHEMISTRY
(2023)
Review
Nutrition & Dietetics
Sara Manti, Giulia Pecora, Francesca Patane, Alessandro Giallongo, Giuseppe Fabio Parisi, Maria Papale, Amelia Licari, Gian Luigi Marseglia, Salvatore Leonardi
Summary: Food allergy is a pathological immune response triggered by exposure to specific food allergens, with no specific treatment available yet. Dietary avoidance and symptomatic medications are the main treatment methods currently employed. Recent therapeutic strategies like monoclonal antibodies have shown long-term safety and benefits in clinical practice.
Review
Pharmacology & Pharmacy
Kevin Roe
Summary: Several fungal pathogens are resistant to traditional treatments and some have become multidrug-resistant. Alternative treatments such as vaccines, monoclonal antibody injections, or mRNA injections can mask fungal surface proteins and target pathogenic proteins to combat infections. Combining antifungal drugs with mRNA instructions for patient synthesis of conventional or synthetic monoclonal antibodies offer potential advantages over existing treatments.
DRUG DISCOVERY TODAY
(2023)
Review
Pharmacology & Pharmacy
Claudia Ceci, Pedro Miguel Lacal, Grazia Graziani
Summary: Antibody-drug conjugates (ADCs) are a new group of anticancer agents that combine the selectivity of monoclonal antibodies with the cell killing properties of chemotherapeutic agents. However, the development of ADCs faces challenges such as low tumor selectivity, premature release of drugs, and tumor resistance mechanisms. The design of inert antibodies and the discovery of innovative targets and drugs have led to the development of next-generation ADCs with improved therapeutic properties.
PHARMACOLOGY & THERAPEUTICS
(2022)
Article
Critical Care Medicine
David J. Douin, Lianne Siegel, Greg Grandits, Andrew Phillips, Neil R. Aggarwal, Jason Baker, Samuel M. Brown, Christina C. Chang, Anna L. Goodman, Birgit Grund, Elizabeth S. Higgs, Catherine L. Hough, Daniel D. Murray, Roger Paredes, Mahesh Parmar, Sarah Pett, Mark N. Polizzotto, Uriel Sandkovsky, Wesley H. Self, Barnaby E. Young, Abdel G. Babiker, Victoria J. Davey, Virginia Kan, Annetine C. Gelijns, Gail Matthews, B. Taylor Thompson, H. Clifford Lane, James D. Neaton, Jens D. Lundgren, Adit A. Ginde
Summary: Due to the uncertainty of COVID-19's natural history, it is challenging to assess the clinical recovery of hospitalized patients. This study compared three different definitions of recovery and found that 20% of the patients had clinically significant events after discharge within 90 days.
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
(2022)
Article
Multidisciplinary Sciences
Emanuele Andreano, Ida Paciello, Giulia Piccini, Noemi Manganaro, Piero Pileri, Inesa Hyseni, Margherita Leonardi, Elisa Pantano, Valentina Abbiento, Linda Benincasa, Ginevra Giglioli, Concetta De Santi, Massimiliano Fabbiani, Ilaria Rancan, Mario Tumbarello, Francesca Montagnani, Claudia Sala, Emanuele Montomoli, Rino Rappuoli
Summary: Research suggests that individuals who have been infected or vaccinated for the first time will produce antibodies with increased potency and breadth, allowing for better control of emerging SARS-CoV-2 variants.
Article
Pharmacology & Pharmacy
Khaled Abduljalil, Amita Pansari, Jia Ning, Masoud Jamei
Summary: This study used a physiologically based pharmacokinetic (PBPK) modeling approach to predict maternal and fetal drug disposition during pregnancy. The PBPK models were validated using observed data and showed accurate predictions. The findings of this study are important for improving the understanding of drug exposure during pregnancy and for clinical trials and risk assessment.
CLINICAL PHARMACOKINETICS
(2022)
Article
Pharmacology & Pharmacy
Khaled Abduljalil, Jia Ning, Amita Pansari, Xian Pan, Masoud Jamei
Summary: This study developed a PBPK model to predict the disposition of certain drugs in maternal and fetal tissues. The model accurately predicted the exposure levels in both the mother and fetus, and could be used for clinical trial design and risk assessment for maternal-fetal exposure.
DRUG METABOLISM AND DISPOSITION
(2022)
Article
Pharmacology & Pharmacy
Helen Humphries, Lisa Almond, Alexander Berg, Iain Gardner, Oliver Hatley, Xian Pan, Ben Small, Mian Zhang, Masoud Jamei, Klaus Romero
Summary: This study demonstrated the utility of physiologically-based pharmacokinetic modeling in predicting plasma and lung concentrations of tuberculosis therapies. The models showed high accuracy in comparison with clinical data, suggesting their potential for evaluating drug efficacy and interactions.
CPT-PHARMACOMETRICS & SYSTEMS PHARMACOLOGY
(2021)
Review
Pharmacology & Pharmacy
Katherine L. Gill, Hannah M. Jones
Summary: Testing new drugs in paediatric and pregnant patients can be difficult due to recruitment challenges and ethical issues. Modelling and simulation can aid in designing clinical trials and bridging recruitment gaps. Currently, there are more published PBPK models for paediatrics than for pregnant women. Challenges include limited knowledge of relevant physiological processes and availability of clinical data.
Article
Pediatrics
Khaled Abduljalil, Iain Gardner, Masoud Jamei
Summary: Perinatal pharmacology plays a crucial role in predicting the pharmacokinetics of drugs during pregnancy and lactation. This study utilized a physiological-based pharmacokinetic (PBPK) model to predict the concentrations of theophylline, a model drug, before, during, and after pregnancy, as well as in breast milk and neonates. The results showed that the PBPK model accurately predicted the concentrations of theophylline in pregnant populations and breast milk, providing a method for estimating the daily dose of theophylline for infants.
FRONTIERS IN PEDIATRICS
(2022)
Article
Pediatrics
Udoamaka Ezuruike, Alexander Blenkinsop, Amita Pansari, Khaled Abduljalil
Summary: Accurate prediction of fetal exposure to drugs excreted by the kidney requires considering the time-varying renal function parameters. This study collected and integrated data on fetal urinary production rate (FUPR) and creatinine measured at different gestational ages, and compared the predicted fetal glomerular filtration rate (GFR) with neonatal values. The results showed that 3D ultrasound methods yielded higher estimates of FUPR compared to 2D methods, and a power law function accurately captured the change in FUPR with fetal age. The predicted FUPR based on 3D data showed a strong linear relationship with amniotic creatinine concentration, and the predicted fetal GFR values were in good agreement with neonatal values at birth.
FRONTIERS IN PEDIATRICS
(2022)
Article
Pharmacology & Pharmacy
Hanadi H. Alrammaal, Khaled Abduljalil, Victoria Hodgetts Morton, R. Katie Morris, John F. Marriott, Hsu P. Chong, Hannah K. Batchelor
Summary: This study used a PBPK approach to predict the pharmacokinetics of cefazolin and cefuroxime in obese pregnant women during cesarean section. The study found that higher doses and longer administration times may be necessary for obese pregnant women to achieve target drug concentrations. Further clinical research is needed to validate these predictions.
Article
Pharmacology & Pharmacy
Janak R. Wedagedera, Anthonia Afuape, Siri Kalyan Chirumamilla, Hiroshi Momiji, Robert Leary, Mike Dunlavey, Richard Matthews, Khaled Abduljalil, Masoud Jamei, Frederic Y. Bois
Summary: Physiologically-based pharmacokinetic (PBPK) models often involve uncertain extrapolation from in vitro to in vivo conditions. This uncertainty can be reduced by incorporating clinical observations to estimate unknown or uncertain parameters using a population pharmacokinetics inferential framework. Different methods, such as QRPEM, NPAG, Bayesian MH, and Hamiltonian Markov Chain Monte Carlo sampling, have been compared in a minimal PBPK model study using theophylline dataset. The results showed that QRPEM and NPAG provided consistent parameter estimates, mostly in agreement with Bayesian estimates, while MH simulations had faster runtime but similar performance to the other methods.
CPT-PHARMACOMETRICS & SYSTEMS PHARMACOLOGY
(2022)
Editorial Material
Pharmacology & Pharmacy
Xian Pan, Karen Rowland Yeo
CPT-PHARMACOMETRICS & SYSTEMS PHARMACOLOGY
(2022)
Article
Pharmacology & Pharmacy
Udoamaka Ezuruike, Mian Zhang, Amita Pansari, Mailys De Sousa Mendes, Xian Pan, Sibylle Neuhoff, Iain Gardner
Summary: The Simcyp Simulator is a software platform used for population PBPK modeling and simulation, which connects in vitro data to in vivo pharmacokinetic outcomes. This tutorial explains the required input parameters and considerations for developing a PBPK model in the Simulator, using a case study on ondansetron as an example.
CPT-PHARMACOMETRICS & SYSTEMS PHARMACOLOGY
(2022)
Editorial Material
Pharmacology & Pharmacy
Kuan-Fu Chen, Hannah M. Jones, Katherine L. Gill
Summary: Drugs that modulate cytokine levels are commonly used for cancer treatment and inflammatory or immunologic disorders. There is clear evidence linking elevated IL-6 levels to P450 suppression, although the clinical significance of these interactions remains uncertain. PBPK modeling has been successful in predicting the impact of raised IL-6 on P450 activities. However, evidence regarding the direct effect of other cytokines on P450 activity is inconclusive.
DRUG METABOLISM AND DISPOSITION
(2022)
Article
Pharmacology & Pharmacy
Amita Pansari, Muhammad Faisal, Masoud Jamei, Khaled Abduljalil
Summary: Medication use during breastfeeding can potentially expose infants to drugs through breast milk. This study developed a physiologically based Pharmacokinetic Model (PBPK) to predict drug exposure in breast milk and estimate the potential infant dose. The model showed accurate predictions for the four drugs tested and can assist in evaluating the risk to infants from maternal exposure to these drugs.
BIOPHARMACEUTICS & DRUG DISPOSITION
(2022)
Article
Pharmacology & Pharmacy
Rachel H. H. Rose, Armin Sepp, Felix Stader, Katherine L. L. Gill, Cong Liu, Iain Gardner
Article
Pharmacology & Pharmacy
Weize Huang, Felix Stader, Phyllis Chan, Colby S. Shemesh, Yuan Chen, Katherine L. Gill, Hannah M. Jones, Linzhong Li, Gianluca Rossato, Benjamin Wu, Jin Y. Jin, Pascal Chanu
Summary: Using mechanistic physiologically-based pharmacokinetic (PBPK) modeling, this study predicted the exposure of pediatric patients to atezolizumab and found that a dose of 15 mg/kg provides comparable exposure to a dose of 1,200 mg in adults.
FRONTIERS IN PHARMACOLOGY
(2022)
Article
Pharmacology & Pharmacy
Xian Pan, Karen Rowland Yeo
Summary: The safety of using efavirenz during breastfeeding in tuberculosis-endemic areas was evaluated using physiologically-based PK modeling. The model predicted the exposure of efavirenz in vulnerable populations, including children, mothers, and breastfeeding infants. The model also showed the influence of CYP2B6 genotype on infant efavirenz exposure and the adequacy of weight-based dosing regimens for children according to CYP2B6 genotype.
CLINICAL PHARMACOLOGY & THERAPEUTICS
(2023)