The AAPS Journal[JOURNAL]
Sun
200 papers
Effect of Incentivizing Pediatric Studies on the Development of Pediatric-Friendly Formulations.
Abdel-Rahman SM, Burckart GJ
AAPS J · 2026 Mar · PMID 41882479 · Publisher ↗
Challenges to medication administration arise in children when pediatric-friendly (PF) formulations are lacking. This study examines the extent to which PF formulations were developed for use in pediatric trials of drugs...
Challenges to medication administration arise in children when pediatric-friendly (PF) formulations are lacking. This study examines the extent to which PF formulations were developed for use in pediatric trials of drugs awarded 6-months of patent extension under a written request (WR). Publicly accessible and proprietary data were aggregated to characterize the formulations used in studies submitted to the U.S. FDA in support of pediatric labeling for WRs issued through September 2025. From 1998-2025, exclusivity was awarded to 321 unique sponsor:drug pairs satisfying the requirements of a WR. A majority, (235/321), received a new or updated pediatric indication and nearly all (310/321) resulted in pediatric labeling. Drugs intended for oral administration (n = 213) were supported by 304 studies. The majority (173/304) exclusively studied adult solid dosage forms (SDF), a minority (129/304) used at least one PF dosage form, and 2 accomplished labeling without the conduct of clinical trials. SDF were exclusively used in 26.3%, 44.9%, 85.1%, and 94.1% of studies in children < 2 yr, 2-5 yr, 6-12 yr and > 12 yr, respectively. Of trials employing an oral PF formulation, 85% were associated with a marketed PF product at labeling. Marketed oral PF formulations were also associated with 8% of cases where studies relied exclusively on a s SDF. Nearly all non-enteral drug studies were supported by existing commercial formulations with only investigational inhalation formulations making their way to market. Legislative provisions enacted to incentivize pediatric drug development incompletely extend to pediatric reformulation efforts despite the associated financial gains.
Multicomponent Interactive Release (MIR) Model for Herbal Extract/Multidrug-Loaded Electrospun Nanofibers: A Mechanistic Framework Integrating Diffusion, Swelling, and Erosion.
Supaphol P
AAPS J · 2026 Mar · PMID 41882320 · Publisher ↗
Controlled release of multiple herbal bioactives from electrospun polymeric fibers involves complex coupling of diffusion, polymer relaxation, swelling, and erosion within porous mat architectures. This work establishes...
Controlled release of multiple herbal bioactives from electrospun polymeric fibers involves complex coupling of diffusion, polymer relaxation, swelling, and erosion within porous mat architectures. This work establishes the Multicomponent Interactive Release (MIR) model, a comprehensive framework integrating component-specific transport mechanisms with molecular interactions and mat-scale structural effects. I revisited first-principles constitutive equations for three physicochemical regimes: rigid matrices (diffusion-controlled), swollen matrices (anomalous transport), and eroding matrices (degradation-controlled). The model addresses multi-scale release from intra-fiber radial diffusion to inter-fiber transport through tortuous pore networks governed by mat porosity (ε), tortuosity (τ), fiber diameter, and packing density. Critical analysis reveals that established empirical models (Higuchi, Korsmeyer-Peppas, Peppas-Sahlin, Hopfenberg) emerge as limiting cases, with the release exponent n arising from the Deborah number. Validation against dexamethasone/PLGA and dual contraceptive drug systems demonstrates superior predictive capability (R = 0.9847-0.9992) compared to seven conventional models. Additional model selection criteria including adjusted R (0.9762-0.9988), root mean square error (RMSE = 0.89-2.47%), and Akaike Information Criterion (AIC) confirmed MIR superiority while accounting for model complexity. Mechanistic weighting functions deconvolute transport contributions, revealing that fiber diameter governs diffusion-erosion balance while polymer composition dictates degradation kinetics. A practical workflow for implementing the MIR model and sensitivity analysis of key parameters are provided to guide rational formulation design. This framework enables rational design of electrospun systems for complex herbal formulations and combination therapies, directly linking electrospinning process parameters to controlled release performance.
Exploring Digestion-Induced Fed-State Simulated Intestinal Media with a Lipid Fraction and Compositional Variability.
Goovaerts B, De Bie J, Vinarov Z … +6 more , López Mármol Á, Borchardt TB, Indulkar AS, Koziolek M, Augustijns P, Brouwers J
AAPS J · 2026 Mar · PMID 41882303 · Publisher ↗
Food effects on intestinal drug solubility and dissolution are a critical consideration in drug development, commonly investigated using simulated intestinal fluids (SIF) such as FaSSIF and FeSSIF. While these media repr...
Food effects on intestinal drug solubility and dissolution are a critical consideration in drug development, commonly investigated using simulated intestinal fluids (SIF) such as FaSSIF and FeSSIF. While these media represent average fasted- and fed-state conditions, their lack of a lipid fraction and disregard for compositional variability limit their physiological relevance and predictive power. To address these limitations, this proof-of-concept study introduces a novel set of fed-state SIF, termed digestion-induced SIF (DiSIF), featuring two key enhancements: (i) inclusion of a physiologically relevant lipid fraction generated through in vitro digestion of a liquid meal, and (ii) incorporation of variability via modulation of bile salt concentration and stage of digestion. Nine DiSIF media were developed to reflect both the average composition and the variability observed in fed-state human intestinal fluids (HIF). Overall, DiSIF media adequately predicted the micellar solubility of seven poorly water-soluble model compounds. Unlike commonly used SIF, they also enabled estimation of drug solubilization in total samples containing both micellar and lipid fractions, as observed in fed-state HIF. Furthermore, the media's compositional variability allowed for the prediction of compound sensitivity to physiological variability with relative accuracy. These findings support further refinement and validation of DiSIF media as a versatile tool for formulation development and food-effect prediction in oral drug delivery.
Physiologically Based Pharmacokinetic (PBPK) Modeling of Oral Drug Absorption for Integrating Nonclinical Data into Human Pharmacokinetic Predictions.
Liang X, Fraczkiewicz G, Harish Jain KM … +3 more , Wan B, Ishida K, Lai Y
AAPS J · 2026 Mar · PMID 41857302 · Publisher ↗
Accurate prediction of oral drug absorption is essential for anticipating variability in bioavailability and guiding clinical development. Physiological factors, such as gastric pH, gastric emptying, and intestinal trans...
Accurate prediction of oral drug absorption is essential for anticipating variability in bioavailability and guiding clinical development. Physiological factors, such as gastric pH, gastric emptying, and intestinal transit time, influenced by food intake and acid-reducing agents (ARAs), play critical roles in the dissolution and absorption of drugs with pH-dependent solubility. Intestinal transporters and metabolizing enzymes also affect systemic exposure by regulating drug absorption, metabolism, and excretion in the intestine. Species differences in gastrointestinal physiology, including pH profiles, transporter expression, and motility patterns, present challenges when translating nonclinical data to humans. Physiologically based pharmacokinetic (PBPK) modeling offers a mechanistic framework to address these variations by integrating drug- and species-specific parameters. By calibrating in vitro and in vivo data, PBPK models can simulate human gastrointestinal conditions and more accurately predict oral absorption dynamics, enhancing translational relevance. These models facilitate early evaluation of food and ARA impacts, transporter-related absorption variabilities, and drug-drug interactions (DDIs), supporting the rational development of formulation and dose selection. Verifying model performance in nonclinical species, commonly in dogs, can further enhance confidence in human predictions. This review highlights drug- and species-specific factors and illustrates how PBPK modeling can address uncertainties regarding drug absorption in humans using nonclinical in vitro and in vivo data. Despite challenges such as parameter uncertainty and interspecies differences, PBPK modeling remains a valuable tool for estimating drug exposure and informing biopharmaceutical and clinical pharmacology strategies.
Industry Practices in Monoclonal Antibody Tissue Biodistribution Assessment: An IQ Consortium Cross-Industry Survey of Current Approaches and Emerging Trends.
Tang H, McCoy M, Leonard A … +5 more , Mohan K, Sane R, Guan C, Thomas MK, Koep K
AAPS J · 2026 Mar · PMID 41854808 · Publisher ↗
Tissue biodistribution characterization represents a critical component of monoclonal antibody (mAb) development, yet industry practices remain fragmented despite regulatory emphasis on comprehensive exposure assessment....
Tissue biodistribution characterization represents a critical component of monoclonal antibody (mAb) development, yet industry practices remain fragmented despite regulatory emphasis on comprehensive exposure assessment. The IQ Consortium Tissue Concentration Working Group surveyed eleven pharmaceutical companies to evaluate current methodologies in mAb tissue concentration analysis and establish consensus recommendations. Organizations demonstrated heterogeneous portfolio compositions, with traditional monospecific IgG1 and IgG4 platforms dominating 81.8% of companies while next-generation multispecific formats and antibody-drug conjugates gained prominence. Strategic approaches to biodistribution evaluation differed markedly, as 72.7% implemented compound-dependent assessment protocols versus systematic screening paradigms. Peak measurement activity occurred during lead optimization phases (63.6%) and pre-clinical candidate advancement (54.5%), reflecting resource optimization rather than mechanistic investigation priorities. Universal adoption of ligand binding methodologies complemented mass spectrometry integration in 81.8% of programs, though analytical validation standards exhibited substantial inconsistency. Blood contamination correction procedures were systematically implemented by merely 18.2% of respondents, indicating widespread methodological gaps. While tissue concentration datasets informed translational pharmacokinetic modeling across 81.8% of organizations, physiologically-based modeling frameworks remained underutilized. Results underscore urgent requirements for analytical harmonization to strengthen regulatory submissions and accelerate therapeutic development timelines.
Evaluating the PDA Quality Culture Assessment Tool as a Foundation to Advance Quality Management Maturity.
Kerr J, Polonsky M
AAPS J · 2026 Mar · PMID 41851582 · Publisher ↗
The U.S. Food and Drug Administration (FDA) introduced the Quality Management Maturity (QMM) initiative to promote quality practices in pharmaceutical manufacturing that extend beyond basic good manufacturing practices (...
The U.S. Food and Drug Administration (FDA) introduced the Quality Management Maturity (QMM) initiative to promote quality practices in pharmaceutical manufacturing that extend beyond basic good manufacturing practices (GMP), as a response to the ongoing drug shortage crisis. As the FDA has yet to formalize a QMM assessment tool, this study evaluated the Parenteral Drug Association's (PDA) Quality Culture Assessment Tool (QCAT) as a potential surrogate framework. Using anonymized data from 58 life sciences companies, we assessed internal consistency and examined whether the QCAT constructs differentiated responses across organizational, regional, and manufacturing modalities characteristics. Four of five domains-Employee Ownership and Engagement, Continuous Improvement, Technical Excellence, and Communication & Collaboration-demonstrated acceptable internal consistency (Cronbach's α ≥ 0.70), whereas Leadership Commitment yielded a lower reliability coefficient (α = 0.49). Technical Excellence scores significantly differed by business function (p = 0.02), with higher ratings reported by innovator firms compared to contract manufacturing organizations (CMO). These findings suggest that the PDA QCAT offers a promising model for operationalizing QMM principles, although refinement may be needed to enhance measurement of leadership constructs.
Correction: Affinity Capture Elution Coupled with Cell-based Cyclic Adenosine Monophosphate Assay as a Platform Method for Detection of Neutralizing Antibodies to Incretin Molecules.
Reynolds NA, Chen YQ, Higgs RE … +14 more , Calderon B, Cramer JW, Bivi N, Hodsdon ME, Bullock HA, Shockley TE, Peek VL, Mack JK, Lemen D, Copeland V, Ferrante A, Konrad RJ, Mullins GR, Wen Y
AAPS J · 2026 Mar · PMID 41851562 · Publisher ↗
Abstract loading — click title to view on PubMed.
Innovative In Vitro-In Silico Platform for Dose-Response Modeling in Canine Bladder Cancer: A 3D Organoid- and Mathematics-Based Approach.
Long M, Peng Y, Gade S … +15 more , Nicholson H, Catucci M, Zdyrski C, Pawlak A, Corbett M, Saba C, Laver T, Rawlings E, Orbay-Cerrato M, Christianson N, Elbadawy M, Nagata K, Woodward A, Allenspach K, Mochel JP
AAPS J · 2026 Mar · PMID 41851390 · Publisher ↗
Approximately 25% of human urothelial carcinoma (UC) cases progress to high-grade, muscle-invasive bladder cancer (MIBC), for which treatment response remains difficult to predict. To address the need for more predictive...
Approximately 25% of human urothelial carcinoma (UC) cases progress to high-grade, muscle-invasive bladder cancer (MIBC), for which treatment response remains difficult to predict. To address the need for more predictive platforms, we developed an integrated in vitro-in silico system using canine UC derived organoids, which closely mirror human MIBC at the histological, molecular, and clinical levels. Organoids were irradiated at doses of 0, 5, 9, or 15 Gy and cisplatin was administered at concentrations of 0, 10, 25, 50, or 100 μM at 24 and 72 h post-plating, respectively. Cell viability was assessed one week later using a PrestoBlue metabolic activity assay. Combined effects of radiation and cisplatin were estimated using a two-dimensional Hill model, which disentangles synergism in magnitude of effect (efficacy) and potency, with directly interpretable parameters. Implementation within a Bayesian hierarchical model accommodated both between-subject and between-assay variation. The model showed inter-patient variability in response to both radiation and cisplatin, with varying potency for the radiation dose (posterior median ED50: 0.55-7.6 Gy) and cisplatin concentration (posterior median EC50: 40-174 μM), although in some cases the maximum effect fell outside the observed data range. Radiation had a generally greater contribution to the combined inhibitory effect than cisplatin. In selected cases, synergistic effects of chemoradiation were also identified, primarily in the efficacy dimension. These preliminary results establish a robust in vitro platform for assessing chemoradiation efficacy and potency, and provide essential data for the future development of personalized and optimized chemoradiation strategies in canine and human. UC.
The Influence of Occlusion on Oxybutynin Absorption from Gel-Deposited Excipients Using Ex Vivo Skin and Healthy Human Volunteers.
Reginauld B, Thomas S, Karra VK … +4 more , Fox D, Hammell DC, Kane M, Stinchcomb AL
AAPS J · 2026 Mar · PMID 41826576 · Publisher ↗
While external factors can significantly influence the rate and extent of drug absorption from transdermal products, some of these factors are not typically accounted for in the development process. In this study, oxybut...
While external factors can significantly influence the rate and extent of drug absorption from transdermal products, some of these factors are not typically accounted for in the development process. In this study, oxybutynin gel (OXY GEL) was used as a model formulation to understand the impact of a short 3 h occlusion period on the oxybutynin absorption profile both in vitro and in vivo. Using the in vitro permeation test (IVPT) design with skin from 4 human donors, OXY GEL provided significantly greater flux and cumulative amounts of oxybutynin after occlusion was applied, as compared to the unoccluded formulation. These results were in agreement with the clinical pharmacokinetic (PK) study conducted with 12 healthy volunteers when temperature, dosing, and timepoints were harmonized between in vitro and in vivo studies to help develop an in vitro-in vivo correlation (IVIVC). Described herein are the IVPT and clinical PK study methods and results used to establish the Level A IVIVC.
Development of an In Vitro Release Test to Characterize Onivyde® Using Bio-Beads SM-2 Resin.
Juang V, Phoo MT, Yang HW … +5 more , Mei L, Wang X, Li J, Wang Y, Schwendeman A
AAPS J · 2026 Mar · PMID 41826575 · Publisher ↗
The development of generic versions of Onivyde® (irinotecan liposome injection) requires a reliable and discriminative in vitro release test (IVRT) to ensure product quality and support regulatory approval. Conventional...
The development of generic versions of Onivyde® (irinotecan liposome injection) requires a reliable and discriminative in vitro release test (IVRT) to ensure product quality and support regulatory approval. Conventional dialysis-based IVRT often is limited in maintaining sink conditions and is affected by membrane-related variability and batch inconsistency. To overcome these challenges, we developed an IVRT using Bio-Beads SM-2 Resin (BioBeads), which rapidly adsorb released free irinotecan via hydrophobic interactions. Key parameters, including BioBeads concentration, agitation speed and angle, temperature, and formulation concentration, were systematically optimized. Identified optimized conditions were 50 mg/mL BioBeads, vertical rotation at 10 rpm, 25°C, and an Onivyde® concentration of 45 µg/mL. Under these conditions, the method achieved > 90% drug release within 24 h with minimal liposomal disruption. Among all parameters, mechanical agitation had the greatest impact on release kinetics by promoting liposomal destabilization and cholesterol depletion. Using the similarity factor (f2) as a quantitative criterion, the method demonstrated high reproducibility and effectively distinguished between non-stressed and stressed formulations. Compared to dialysis-based approaches, this method more effectively maintains sink conditions, eliminates membrane-related diffusion limitations, and simplifies sample handling by avoiding separation steps. Overall, the BioBeads-based IVRT offers a practical, robust, and sensitive platform for accelerated release testing and quality control of liposomal irinotecan, with strong potential for use in generic drug development and regulatory evaluation.
PBPK Modelling of Antisense Oligonucleotide Therapeutics: Application for Predicting Plasma and Tissue Pharmacokinetics of Bepirovirsen.
Salem F, Stader F, Youssef AS … +4 more , Derbalah A, Nader A, Hood S, Taskar K
AAPS J · 2026 Mar · PMID 41826491 · Publisher ↗
Antisense oligonucleotide (ASO) therapeutics present new opportunities for treating challenging-to-treat diseases. Prediction of concentration-time course in systemic circulation and tissues within the context of large m...
Antisense oligonucleotide (ASO) therapeutics present new opportunities for treating challenging-to-treat diseases. Prediction of concentration-time course in systemic circulation and tissues within the context of large molecule physiologically based pharmacokinetic (PBPK) modelling has proven to be useful in animal-to-human extrapolation and first-in-human dose selection. A human PBPK model was developed and verified using bepirovirsen clinical data to predict plasma pharmacokinetics (PK) and tissue concentrations. Liver and kidney partition coefficient ratios from monkey studies, corrected for plasma unbound fraction in monkeys and humans, informed bepirovirsen concentration predictions in the human liver and kidney. Liver and kidney partition coefficients were calculated to be 2147 and 2822, respectively. All predicted PK parameters in healthy volunteers (except t) were within two-folds of observed data. Predicted vs. observed clearance (L/h), AUC (µg.h/mL) and C (µg/mL) for the 300 mg single dose in healthy volunteers were 2.94, 114.43, and 10.56 vs. 2.25, 136.6, and 6.5, respectively. The majority of observed plasma concentrations for all doses were within the 5th and 95th percentiles of the predictions. The evaluated model was used to predict the impact of moderate hepatic impairment on bepirovirsen PK in virtual patients. The predicted vs. observed bepirovirsen exposure in moderate hepatic impairment was 0.9 and 0.7-fold lower, respectively, compared with healthy volunteers. The PBPK model predicted the liver and kidney tissue C values to be 172 and 132 µg/mL, respectively. In conclusion, a PBPK modelling approach for bepirovirsen, an ASO, is presented in this article and offers opportunities for future applications to other oligonucleotide therapeutics.
Application of a Modified In Situ Perfusion Model to Quantify Intestinal Drug Excretion and Transporter-Mediated Interactions after Intravenous Administration.
Sun R, Li L, Wang L … +10 more , Xie Z, Bui D, Zheng Z, Zhao X, Hao J, Chen J, Yin T, Hu Y, Lai Y, Hu M
AAPS J · 2026 Mar · PMID 41813996 · Publisher ↗
Intestinal excretion (IE), one of the under-investigated mechanisms of drug elimination, has been identified as the loci of drug-drug interactions (DDIs) within the intestinal tract. Here, we employed a modified rat in s...
Intestinal excretion (IE), one of the under-investigated mechanisms of drug elimination, has been identified as the loci of drug-drug interactions (DDIs) within the intestinal tract. Here, we employed a modified rat in situ intestinal perfusion model to examine of the drug clearance of apixaban, talinolol, and irinotecan in the short time drug recovery study. The influence of specific efflux transporter inhibitors, including P-glycoprotein (P-gp) inhibitor elacridar, multidrug resistance-associated protein 2 (Mrp2) inhibitor MK571, and breast cancer resistance protein (Bcrp) inhibitor KO143, on IE, systemic exposure and metabolite ratio were accessed using a 2.5-h constant-rate intravenous infusion. IE plays a major role in the elimination of apixaban (36 ± 14% of the total amount eliminated estimated using the sum of biliary, renal, and intestinal excretion), but only a minor role in the excretion of talinolol (11 ± 3.9%) and irinotecan (22 ± 3.1%). Efflux transporter inhibitors of P-gp/Mrp2 significantly reduced the apixaban's intestine clearance without substantially affecting its biliary excretion or metabolite ratio, accompanied by increased systemic exposure or plasma area under the curve (AUC). However, the systemic PKs of talinolol and irinotecan were not altered, likely due to low IE. The drug's IE was temperature- and dose-dependent but not intestinal segmental-dependent. The modified perfusion model provides a robust framework for characterizing intestinal clearance and assessing transporter-mediated interactions for drugs undergoing intestinal clearance following i.v. administration. Similar to other routes, intestinal clearance can be a critical elimination pathway, and apixaban is a suitable reference "victim" drug for intestinal clearance inhibition studies.
Minimizing in Source Fragmentation for Mass Spectrometry Based NDSRI Analytical Procedures: A Case Study of Nitroso-bumetanide.
Zhang J, Shih M, Yang J … +3 more , Keire DA, Xu X, Faustino PJ
AAPS J · 2026 Mar · PMID 41807876 · Full text
Liquid chromatography-mass spectrometry (LC-MS) is the standard instrumental procedure for quantitating nitrosamine drug substance-related impurities (NDSRIs) due to its superior specificity and sensitivity. Electrospray...
Liquid chromatography-mass spectrometry (LC-MS) is the standard instrumental procedure for quantitating nitrosamine drug substance-related impurities (NDSRIs) due to its superior specificity and sensitivity. Electrospray (ESI) is the most used ionization source in LC-MS. However, analytes can undergo fragmentation directly within the ESI source before reaching the collision cell. This phenomenon is known as in source fragmentation (ISF). To our knowledge, the impact of ISF on analytical procedure performance for NDSRI measurements has not been explored. Thus, here, we present a case study on an NDSRI (nitroso-bumetanide) to illustrate how efforts can be taken during analytical procedure development to minimize ISF while still achieving the analytical target profile (ATP) measurement goals. In addition, we share some thoughts about incorporating risk assessment and leveraging prior knowledge for analytical procedure development for NDSRI LC-MS technology-based testing purposes.
PQRI Workshop: Model-Informed Drug Development (MIDD) Approaches in Pediatric Formulation Development.
Burckart GJ, Abdel-Rahman S, Choi C … +9 more , Cober MP, Cummins JE, Fotaki N, Gonzalez D, Harris D, Parrott N, Patel H, Wu F, Abend A
AAPS J · 2026 Mar · PMID 41803558 · Publisher ↗
In February of 2024, the Product Quality Research Institute held a virtual workshop entitled "Model-Informed Drug Development (MIDD) Approaches in Pediatric Formulation Development." The workshop covered a range of topic...
In February of 2024, the Product Quality Research Institute held a virtual workshop entitled "Model-Informed Drug Development (MIDD) Approaches in Pediatric Formulation Development." The workshop covered a range of topics related to pediatric formulation development and testing, including dissolution testing and applications to modeling drug absorption in developing pediatric patients. Workshop speakers reviewed the progress that has been made to advance our understanding of ontogeny related processes that drive interactions with product formulations and inform pediatric product development. They discussed recently constructed pediatric biorelevant models that provide more realistic information about drug dissolution in pediatric patients and their use in physiologically based models to produce data for regulatory submissions. Despite the progress, opportunities remain to expand the fund of knowledge on pediatric absorptive processes that will support the development of pediatric-friendly drug formulations.
Simultaneous LC-MS/MS Quantification Method for Cassette-Dosing Pharmacokinetics Study of Monoclonal Antibodies Using Alanine Modifications in Constant Region.
Ichikawa T, Hironiwa N, Murao N … +6 more , Noguchi Y, Gotanda K, Nagaya N, Kuramochi T, Kudo T, Ito K
AAPS J · 2026 Mar · PMID 41776134 · Publisher ↗
We developed a novel cassette-dosing pharmacokinetic (PK) evaluation method that combines antibody engineering with multiplex liquid chromatography-tandem mass spectrometry (LC-MS/MS). The antibody was engineered by intr...
We developed a novel cassette-dosing pharmacokinetic (PK) evaluation method that combines antibody engineering with multiplex liquid chromatography-tandem mass spectrometry (LC-MS/MS). The antibody was engineered by introducing alanine mutations or insertions into the GPSVFPLAPSSK sequence on the CH1 domain of IgG1, thereby enabling clear differentiation and simultaneous measurement of multiple antibodies recognizing the same antigen. Twelve antibodies, one unmodified and eleven modified, were selected for this study and evaluated for assay performance and PK. The method was validated with intra-day and inter-day assay data, which demonstrated accuracy ranging from 70.3% to 128.4% and precision (%CV) less than or equal to 28.7% for all antibodies. The mouse PK profiles of modified antibodies after intravenous administration were comparable to that of the unmodified antibody, with no statistical differences in key PK parameters (t, C, AUC, and V). These results indicate that the modifications had no substantial impact on PK profiles. Furthermore, cassette-dosing PK results were also consistent with those of single-dosing PK studies for six antibodies, indicating that there were no drug-drug interactions among antibodies. This method enables the efficient selection of lead/clinical candidates and the prediction of human PK for IgG1-type antibodies, which are the most widely used subtype in antibody therapeutics. Consequently, this novel approach complies with the 3Rs principle (Reduction, Refinement, and Replacement) in animal research and can substantially reduce costs in antibody drug development.
In-depth Evaluation of the Olink Target 48 Cytokine Panel: Inter-Laboratory Evaluation of Performance and Reliability for Biomarker Studies in Oncology.
Xiang Y, Beaver C, Su Z … +5 more , Yeung D, Chen J, Li B, Ciotti S, Myler H
AAPS J · 2026 Mar · PMID 41775992 · Publisher ↗
Olink Target 48 Cytokine (Thermo Fisher Scientific) is a biomarker panel and assay kit frequently used to characterize the pharmacodynamic effects of novel therapeutics and predict treatment outcomes. We have assessed as...
Olink Target 48 Cytokine (Thermo Fisher Scientific) is a biomarker panel and assay kit frequently used to characterize the pharmacodynamic effects of novel therapeutics and predict treatment outcomes. We have assessed assay performance across four commercial laboratories to determine the consistency of results. Overall reliability of individual biomarkers and the performance of controls were also assessed, and data were used for an exploratory assessment of differential biomarker expression in patients with head and neck cancer or lung cancer, relative to healthy donors. Reproducibility between operators was found to be good for three of the four laboratories, although the median coefficient of variation between operators for laboratory 4 was above the threshold of acceptability (30%) in the first half of the study. Performance across serial dilutions was also good for all laboratories except laboratory 2. Overall, data were statistically concordant for all laboratories except laboratory 4. Olink sample and calibrator controls performed well, and 43 of the 45 biomarkers in the panel were found to have good or moderate reliability. In total, 21 biomarkers were found to be upregulated or downregulated in patients with cancer relative to healthy donors. This comprehensive evaluation supports the use of Olink Target 48 Cytokine for use in biomarker studies and clinical applications, and highlights the need for standardization in sample handling and assay execution across providers.
The Need for Clinical Trial Dataset Specifications to Support Clinical Pharmacology Review of Immunogenicity.
Shubow S, Abhari MR, Ta A … +3 more , Florian J, Lee P, Wang YC
AAPS J · 2026 Feb · PMID 41735721 · Publisher ↗
Assessment of product immunogenicity in clinical trials via characterization of the anti-drug antibody (ADA) response to the drug, is an important component of biological license applications (BLA). The clinical pharmaco...
Assessment of product immunogenicity in clinical trials via characterization of the anti-drug antibody (ADA) response to the drug, is an important component of biological license applications (BLA). The clinical pharmacology review of immunogenicity focuses on the impact of ADA on pharmacokinetics (PK) based on data from three analysis datasets: Analysis Dataset (AD) for Subject Level data (ADSL), AD for Pharmacokinetic Concentrations (ADPC), and AD for Immunogenicity Specimens (ADIS). These datasets are derived from tabulation datasets that conform with the Clinical Data Interchange Standards Consortium (CDISC) Study Data Tabulation Model (SDTM) as requested by FDA and follow the CDISC Analysis Data Model (ADaM). Because no guidance is available on how to derive the ADIS dataset from the SDTM IS domain, BLAs submitted to the Food and Drug Administration (FDA) Center for Drug Evaluation and Research (CDER) vary in the completeness and quality of their ADIS datasets. This challenge has been addressed by information requests that can extend time of the clinical pharmacology review of immunogenicity. We analyzed the availability and content of ADIS, ADPC, and ADSL datasets in 48 BLAs submitted to CDER between 2019 and 2022. 75% of BLAs had at least one type of dataset issue. 50% of all BLAs had data reporting issues specifically (data format issues and/or missing data), 17% had data structure issues (where immunogenicity data were not reported in the dataset where the reviewer expected it, and/or a dataset does not follow the ADaM basic data structure), and 8% had more than one type of dataset issue. Our findings suggest that the publication of clinical trial dataset specifications to support the clinical pharmacology review of immunogenicity data could improve the efficiency of the regulatory review of CDER BLAs.
In Vivo Clearance of Immune Complexes: Insights Into Human Drug/Anti-Drug Antibody Complex Clearance Dynamics.
Opolka-Hoffmann E, Fowler S, Bach T … +2 more , Jordan G, Staack RF
AAPS J · 2026 Feb · PMID 41721139 · Publisher ↗
Immunogenicity of monoclonal antibodies (mAbs) and other biotherapeutics remains a significant clinical challenge. The resulting anti-drug antibodies (ADAs) can neutralize the drug, accelerate its clearance, diminish eff...
Immunogenicity of monoclonal antibodies (mAbs) and other biotherapeutics remains a significant clinical challenge. The resulting anti-drug antibodies (ADAs) can neutralize the drug, accelerate its clearance, diminish efficacy, and potentially trigger hypersensitivity reactions via the formation of immune complexes (ICs). Current pharmacokinetic (PK) and ADA assays typically measure the drug or ADAs but provide limited information on IC structure, concentration, and duration of exposure in humans. While rat studies suggest larger ICs are rapidly cleared, human dynamics are less understood. This study investigated IC formation and clearance in patients enrolled in a terminated Phase 1 clinical trial of TYRP1-TCB, a novel T-cell engager. Analysis of patient samples revealed that six patients, treated with 0.4 mg every three weeks, developed ADAs, resulting in IC formation. These complexes were evaluated using size exclusion chromatography (SEC) and enzyme-linked immunosorbent assay (ELISA). ICs of diverse sizes were detected, with larger ICs cleared faster than smaller ones. These findings highlighted the need for appropriate PK assays in clinical studies. Total drug PK assays alone may overestimate drug exposure during an immune response, as they do not distinguish between binding competent and ADA-bound drug. In contrast, active drug assays do not give any information on circulating drug that can no longer bind to the target. Neither approach gives information on circulating ICs, which may represent the majority of the drug administered following a strong ADA response. This study underscores the importance of understanding ADA and IC dynamics for ensuring the safe and effective use of biotherapeutics.
Best Practices for Performing Analytical and Functional Biosimilarity Assessment of Recombinant Monoclonal Antibody Biosimilars.
Rathore AS, Suryanarayanan R, Nejadnik R … +3 more , Gurvich VJ, Singh SK, Sarin D
AAPS J · 2026 Feb · PMID 41709016 · Publisher ↗
Biotherapeutic products have revolutionized the diagnosis and treatment of numerous complex to manage diseases, such as cancer, autoimmune disorders, and infectious diseases. When compared with small molecules (pharmaceu...
Biotherapeutic products have revolutionized the diagnosis and treatment of numerous complex to manage diseases, such as cancer, autoimmune disorders, and infectious diseases. When compared with small molecules (pharmaceuticals), this class of therapeutic agents has proven to be more effective and, in general, have fewer side effects. However, they are more expensive (typically 10-1000 times more) and this limits their global affordability and accessibility. This realization has driven the rise of biosimilars, which are products that have been deemed to be highly similar to a reference product that has been already approved in the regulatory jurisdiction under consideration. A key element in receiving approval for a biosimilar product is for the manufacturer to successfully demonstrate its biosimilarity, an exercise comprising extensive characterization using a gamut of orthogonal, high-resolution analytical and functional tools. Once biosimilarity has been demonstrated, the extent of clinical evaluation that the manufacturer has to perform is significantly curtailed. In this white paper, we discuss various challenges that a manufacturer faces when performing these biosimilarity exercises for monoclonal antibody (mAb) products. Particular attention has been paid to the impact of excipients on these assessments. Using multiple case studies, we elucidate the impact of the removal of these excipients on product stability as well as the impact of their presence on the outcome from any of the analytical and functional tools that are commonly used in these biosimilarity assessments. We also offer best practices for the manufacturers of biosimilars to overcome the challenges associated with the presence of excipients in mAb formulations. Finally, we discuss the number of batches, the development of acceptance criteria and the importance of orthogonal methods in the demonstration of biosimilarity using examples from regulatory filings and guidances.
Flux Matters: IVIVC-Based Prediction of Occlusion Effects on Transdermal Oxybutynin.
Tobin KV, Reginauld B, Hammell DC … +2 more , Stinchcomb AL, Gopalakrishnan M
AAPS J · 2026 Feb · PMID 41708883 · Publisher ↗
Oxybutynin (OXB), an antimuscarinic agent used to treat overactive bladder, is available as oral tablets, transdermal patches, and transdermal gels. In a recent clinical study involving the transdermal products, ~ 15-fol...
Oxybutynin (OXB), an antimuscarinic agent used to treat overactive bladder, is available as oral tablets, transdermal patches, and transdermal gels. In a recent clinical study involving the transdermal products, ~ 15-fold higher OXB exposures were observed during and following occlusion (i.e., creating a significant barrier to transepidermal water loss) potentially elevating the risk of adverse events. To better understand and predict these occlusion effects, a transdermal in vitro-in vivo correlation (IVIVC) model was developed. In vitro OXB permeation from a transdermal gel was characterized based on in vitro permeation tests using excised human skin without occlusion or with occlusion application from 7 to 10 h. OXB disposition was characterized by using digitized data from literature following intravenous administration. In vivo OXB absorption was characterized by using deconvolution techniques on data from a clinical study under similar occlusion conditions. In vitro and in vivo flux and occlusion-related parameters were correlated in an IVIVC model. While the in vitro flux showed a mean lag time of 3.5 h (21% variability), in vivo flux had no lag. The skin exit rate constant was similar in vitro (0.17 h, 61% variability) and in vivo (0.16 h, 79% variability). In vivo occlusion effects increased on average by 18-fold and 30-fold during occlusion and after occlusion removal, respectively. The IVIVC model predictions adequately described the observed data with precisely estimated parameters. This work establishes a new framework for developing transdermal IVIVCs and demonstrates the feasibility of predicting in vivo OXB concentrations while accounting for occlusion effects.
About
- Frequency
- Sun
- Papers found
- 200
- RSS feed
- Subscribe