The AAPS Journal[JOURNAL]
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200 papers
One-step Immobilization of Human α-1-acid Glycoprotein on Magnetic Beads: A Rapid Method for Small Molecule hAGP Binding Study.
Wang T, Samareh Afsari H, Anderlot S … +2 more , Teitelbaum AM, Taub ME
AAPS J · 2025 Sep · PMID 40968334 · Publisher ↗
Human α-1-acid glycoprotein (hAGP) immobilized directly on NHS ester (N-hydroxysuccinimide) activated magnetic beads (hAGP-beads) was developed as a novel tool for studying small molecule hAGP binding. This method offers...
Human α-1-acid glycoprotein (hAGP) immobilized directly on NHS ester (N-hydroxysuccinimide) activated magnetic beads (hAGP-beads) was developed as a novel tool for studying small molecule hAGP binding. This method offers a straightforward, one-step immobilization process compared to traditional biotin-streptavidin immobilization technique. The hAGP-beads system provides a rapid and convenient alternative to conventional methods like equilibrium dialysis (ED) or ultracentrifugation (UF) for assessing hAGP small molecule interactions. Characterization and evaluation of the hAGP-beads system revealed that equilibrium dissociation constant (K) values of various small molecules obtained by hAGP-beads method correlated well with those determined by ED. This result suggests that the conformation of hAGP binding site is not altered after hAGP covalently binds to magnetic beads through NHS ester conjugation. Key advantages of the hAGP-beads method include shorter assay incubation times compared to ED (~ 3 min versus 4-6 h) and the ability to quantify both free and hAGP-bound small molecule species, facilitated by simple magnetic separation. Furthermore, long-term storage tests demonstrated that hAGP-beads remain stable and retain its binding functionality at -80°C, significantly reducing the need for frequent preparations. These properties make the hAGP-beads system not only well-suited for general hAGP-related studies, such as small molecule binding, but especially advantageous for high-throughput screening applications.
Technical Considerations of Pharmacokinetic Assays for LNP-mRNA Drug Products by RT-qPCR.
Pennucci J, Hays A, Adamowicz W … +39 more , Azadeh M, Benhammadi M, Portabella EB, Cheng M, Colletti K, Dholakiya SL, Doddareddy R, Duchstein L, Durham J, Guelman S, Gullick B, Herr K, Jani D, Jani N, Johansson O, John K, Kubista M, Lavelle A, Li G, Li Y, Liu HY, Lochmann T, Ma H, Moritz B, Murphy J, Park A, Peddigari S, Piche MS, Ramaswamy SS, Reddy A, Smet M, Stanta J, Valentine J, Veirs K, Vepachedu V, Wissel M, Wu M, Xu B, Zondlo S
AAPS J · 2025 Sep · PMID 40968313 · Publisher ↗
Lipid nanoparticle-messenger RNA (LNP-mRNA) drug products are a growing class of drug modalities. The unique composition of these drug products requires multiple measurements to account for the different components of th...
Lipid nanoparticle-messenger RNA (LNP-mRNA) drug products are a growing class of drug modalities. The unique composition of these drug products requires multiple measurements to account for the different components of these drug modalities. Pharmacokinetic (PK) measurements include measurement of the encapsulated mRNA and components of the LNP in circulation to understand the effectiveness of the therapeutic mRNA. The PK measurements can utilize many different platforms including PCR. Current regulatory guidance documents for bioanalytical method validation are specific to ligand binding and chromatographic assay methods and difficult to interpret for use with molecular workflows. The purpose of this paper is to provide information on considerations for validation of regulated reverse transcription quantitative PCR (RT-qPCR) assays that are used to support the pharmacokinetic analysis of LNP-mRNA drug products.
Advanced P407/Tw80/βCD based Nasal Powders of Ropinirole Hydrochloride for Nose-to-Brain Delivery in Parkinson's Disease: Preparation and Comprehensive In Vitro and Ex Vivo Evaluation.
Saitani EM, Papakyriakopoulou P, Kikionis S … +3 more , Pippa N, Pispas S, Valsami G
AAPS J · 2025 Sep · PMID 40968216 · Publisher ↗
This study focuses on the development of lyophilized nasal powders of ropinirole hydrochloride (RH), composed of Poloxamer 407 triblock copolymer (P407), surfactant Tween 80 (Tw80) and derivatives of βCD [methyl-β-CD (Mβ...
This study focuses on the development of lyophilized nasal powders of ropinirole hydrochloride (RH), composed of Poloxamer 407 triblock copolymer (P407), surfactant Tween 80 (Tw80) and derivatives of βCD [methyl-β-CD (MβCD) or hydroxy-propyl-β-CD (HPβCD)] for managing Parkinson's disease. The lyophilized compositions were produced by freeze-drying of the corresponding colloidal dispersions. The innovative aspect of this research lies in the integration of these diverse biomaterials to develop advanced drug delivery systems for nasal administration. The optimal lyophilized formulations were blended with spray-dried microparticles of mannitol and lecithin (MLMPs) in various ratios. The blending process resulted in powders with improved morphological characteristics, as evidenced by Scanning Electron Microscopy analysis. Nasal powders were characterized through in vitro diffusion and ex vivo permeation studies. Finally, a comparison between the nasal powders and the corresponding colloidal dispersions was held. Results showed that the lyophilized powders had a superior release profile compared to colloidal dispersions, and blending with MPMPs further enhanced this effect. Ex vivo powders' permeation across rabbit nasal mucosa was found to be more efficient compared to pure RH solution. In particular, the lyophilized formulation of (P407/Tw80/HPβCD)/RH 10:5 blended with MLMPs (25:75) achieved 54.40 ± 3.30% permeation of the loading dose and a mass balance of 98.15 ± 1.61%. This study demonstrates the potential of these formulations for effective nose-to-brain drug delivery. Ongoing in vivo pharmacokinetic studies are being conducted to assess the performance of the optimal formulations in an appropriate animal model.
Insights from a Survey of Drug Formulation Experts: Challenges and Preferences in High-Concentration Subcutaneous Biologic Drug Development.
Desai M, Kundu A, Hageman M … +5 more , Lou H, Tenjarla S, Sun CC, Zhang F, Rahman O
AAPS J · 2025 Sep · PMID 40935928 · Publisher ↗
Increasing the concentration of intravenous (IV) biologic formulations to render them appropriate for subcutaneous (SC) delivery is challenging because it impacts many interrelated variables, including volume, viscosity,...
Increasing the concentration of intravenous (IV) biologic formulations to render them appropriate for subcutaneous (SC) delivery is challenging because it impacts many interrelated variables, including volume, viscosity, and stability. This study gathered drug formulation expert insights regarding these challenges as well as development approach preferences and perceptions concerning formulation volume. Biotechnology and pharmaceutical industry experts familiar with creating high-concentration (≥ 100 mg/mL) biologic drug formulations for SC delivery completed an online survey between 26 April and 7 May 2024. In total, there were 100 respondents included. When asked to rank seven approaches to transitioning a formulation from IV to SC administration, responses showed that increasing drug concentrations to reduce injection volume and/or changing the primary container were considered riskier, more time-consuming, and more costly than maintaining the concentration and using an on-body delivery system (OBDS). The greatest challenges mentioned were solubility issues (75%), viscosity-related challenges (72%), and aggregation issues (68%). Most respondents (69%) reported delays in clinical trials or product launches due to high-concentration SC formulation challenges. Of these, 33.3% experienced delays of 6-9 months (weighted mean: 11.3 months), while 4.3% indicated that trials or launches were canceled entirely due to formulation difficulties. In conclusion, making minimal drug formulation concentration changes to an IV biologic formulation may reduce the risk, time commitment, and cost associated with developing a SC biologic formulation. Further education is needed around the transition of traditional IV formulations to low-concentration, large-volume SC formulations utilizing delivery formats such as an SC infusion pump or OBDS.
Can Sex-based Variations in the Immune Responses to AAV Gene Therapy Affect Safety and Efficacy? A Review of Current Understanding.
Abdelhamid L, Mazor R
AAPS J · 2025 Sep · PMID 40931296 · Publisher ↗
As the field of gene therapy advances and as the importance of sex as a biological variable in shaping viral immune responses is recognized, the impact of sex on adeno-associated virus (AAV) vectors mediated gene therapi...
As the field of gene therapy advances and as the importance of sex as a biological variable in shaping viral immune responses is recognized, the impact of sex on adeno-associated virus (AAV) vectors mediated gene therapies remain largely unexplored. Here we review current understanding of the immune response against AAV gene therapy as well as the knowledge of sex differences observed in viral responses. We discuss sex differences in innate immune mechanisms such as Toll-like receptor recognition and complement activation, as well as the functional responses of key immune cells such as dendritic cells, macrophages, and T/B cells that are involved in AAV immunogenicity. Variations in pre-existing immunity, including differences in antibody levels and neutralizing activity among sexes, are also described. Additionally, we investigate evidence in the literature of sex differences in AAV transduction in animal and suggest a potential link between the immune responses and higher transductions in males.
Cellular Immunogenicity Assessments in CAR-T Cell Therapies: Current Insights and Future Directions.
Masilamani M, Balasubramanian N, Mora J … +2 more , Park A, Jawa V
AAPS J · 2025 Sep · PMID 40908464 · Publisher ↗
CAR-T-cells can drive MHC class-I-mediated CD8 + cytotoxic T-cell response towards CAR constructs in addition to an antibody response. Immune response may also develop towards residuals present in the CAR-T cell product...
CAR-T-cells can drive MHC class-I-mediated CD8 + cytotoxic T-cell response towards CAR constructs in addition to an antibody response. Immune response may also develop towards residuals present in the CAR-T cell product such as AAV, CRISPR/CAS9, and expamers. Health authorities recommend developing assays to assess both humoral and cellular immunogenicity towards the CAR-T protein. For the assessment of a humoral response, scientists can leverage the guidance and experience from anti-drug antibody (ADA) assays being developed for biologics. However, measuring CAR-T induced cellular immune responses may be challenging due to factors like cell survival, assay variability, lack of relevant positive controls, reagents, etc. This commentary overviews the strategy for investigating cellular immunogenicity for CAR-T products in development, describing the process for risk assessment, guidance on sample collection, including logistics of cell processing and handling, and design of CAR domain related peptides to elicit the memory response from dosed subjects. The experience gained from cellular immunogenicity assessments implemented for ongoing CAR-T-cell therapies and challenges encountered are presented with concrete recommendations, without disclosure of proprietary data. The clinical relevance/impact of assessing cellular immunogenicity for CAR-T therapies and any association with humoral response will also be delineated.
Pharmacokinetics of Racemic Eflornithine in Human Plasma and Cerebrospinal Fluid: Clinical Perspectives for L-eflornithine Against Human African Trypanosomiasis.
Boberg M, Na-Bangchang K, Ashton M … +1 more , Jansson-Löfmark R
AAPS J · 2025 Sep · PMID 40908438 · Publisher ↗
Intravenous dosing of L- and D-eflornithine in a racemic mixture is a currently recommended late-stage gambiense human African trypanosomiasis (g-HAT) treatment, either as 14-day monotherapy or in combination with oral n...
Intravenous dosing of L- and D-eflornithine in a racemic mixture is a currently recommended late-stage gambiense human African trypanosomiasis (g-HAT) treatment, either as 14-day monotherapy or in combination with oral nifurtimox for seven days. However, an oral eflornithine treatment against late-stage g-HAT would be preferable. Pharmacokinetics of eflornithine are enantioselective with different oral absorption of the enantiomers. L-eflornithine has a greater in vitro antitrypanosomal potency than D-eflornithine. This study aimed to integrate knowledge about in vitro potency and literature data from the only clinical study with enantiospecific pharmacokinetic oral data to predict L-eflornithine concentrations in plasma and cerebrospinal fluid to estimate the probability of target attainment. L- and D-eflornithine concentrations in cerebrospinal fluid from the clinical study with enantiospecific data were described with a compartment model that was validated using external data with total eflornithine concentrations. Simulations were performed with oral L-eflornithine doses ranging between 125 to 1000 mg/kg/day administered twice to twelve times daily. The probability of target attainment analysis showed that oral L-eflornithine doses of 750 mg/kg/day administered four or twelve times daily (i.e., drinking a solution every 2nd hour) as monotherapy would be needed to acquire efficacious exposures. In combination with nifurtimox, L-eflornithine dosed at 375 mg/kg/day four or twelve times daily would give exposures over the threshold concentration in cerebrospinal fluid. The presented simulation framework may serve as a starting point to find a suitable oral dose regimen to assess the clinical potential for an oral L-eflornithine-based combination treatments against late-stage g-HAT.
Recent Advances in Bioanalytical Methods for Quantification and Pharmacokinetic Analyses of Antibody-Drug Conjugates.
Khan RMN, Zeng Y, Lanihun AA … +3 more , Arisa OT, Horner JL, Figg WD
AAPS J · 2025 Sep · PMID 40908395 · Full text
Antibody-drug conjugates (ADCs) represent a rapidly expanding class of therapeutics, uniquely combining the specificity of monoclonal antibodies with the potency of cytotoxic small-molecule payloads. Due to their inheren...
Antibody-drug conjugates (ADCs) represent a rapidly expanding class of therapeutics, uniquely combining the specificity of monoclonal antibodies with the potency of cytotoxic small-molecule payloads. Due to their inherent structural complexity and heterogeneous composition, accurate characterization and quantification of ADCs pose significant bioanalytical challenges. This review discusses recent advancements in bioanalytical methodologies, including ligand binding assays (LBAs), liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based approaches, and emerging hybrid LBA-LC-MS/MS platforms. In addition, this review will discuss pharmacokinetic (PK) modeling approaches essential to ADC development, ranging from population PK models to mechanistic frameworks, including physiologically based pharmacokinetic (PBPK) and quantitative systems pharmacology (QSP) models. These modeling strategies allow detailed characterization of ADC absorption, distribution, metabolism, and elimination processes while also accounting for complexities introduced by payload deconjugation and drug-to-antibody ratio variability. By integrating robust bioanalytical methods with advanced modeling techniques, this review provides researchers with essential insights to enhance ADC characterization, inform experimental design, and ultimately facilitate the development of safer, more effective therapeutic candidates.
Commentary and Review on Prospective Prediction of Bioequivalence of Oral Dosage Forms using Compendial Dissolution Testing and PBPK Modeling.
Sagawa K, Thipsay P
AAPS J · 2025 Sep · PMID 40903672 · Publisher ↗
A virtual bioequivalence (VBE) approach utilizing physiologically based pharmacokinetic (PBPK) modeling presents a compelling alternative for pharmaceutical industries. This method can significantly reduce the time and c...
A virtual bioequivalence (VBE) approach utilizing physiologically based pharmacokinetic (PBPK) modeling presents a compelling alternative for pharmaceutical industries. This method can significantly reduce the time and cost associated with clinical bioequivalence (BE) trials while minimizing the risk of detecting a type II error (a false negative), as well as a type I error (a false positive). Additionally, it aligns with ethical considerations by obviating the need to expose healthy volunteers to investigational drugs. To secure a biowaiver through the VBE approach, it is essential to translate compendial in vitro dissolution data into pharmacokinetic (PK) parameters using PBPK modeling to evaluate BE. This article reflects three concepts: compendial dissolution test, PBPK modeling, and BE, reviewing their historical development and current research. It highlights the gaps and challenges and discusses potential future opportunities to strengthen clear linkage among three concepts. A deeper understanding of the mechanisms and mathematical translation of dosage form disintegration and API particle dissolution can enhance the prediction of dosage form performance in both in vivo and in vitro settings. Future advancement of PBPK modeling should incorporate these developments to improve confidence in correlating compendial dissolution data with quantitative risk assessments of BE outcomes.
Comparison of Branched DNA to RT-qPCR Technology for the Quantitation of mRNA from mRNA-LNP Drug Product in Human Serum.
Luongo CA, Wright AD, Lochmann TL … +5 more , Al Rihani SB, Marshall JC, Jani D, Pennucci J, Ortiz J
AAPS J · 2025 Sep · PMID 40903636 · Publisher ↗
Accurate quantitation of circulating messenger RNA (mRNA) is critical for the quantitation of lipid nanoparticle-formulated mRNA (mRNA-LNP) drug products. This study evaluated the concordance between branched DNA (bDNA)...
Accurate quantitation of circulating messenger RNA (mRNA) is critical for the quantitation of lipid nanoparticle-formulated mRNA (mRNA-LNP) drug products. This study evaluated the concordance between branched DNA (bDNA) and reverse transcription quantitative polymerase chain reaction (RT-qPCR) assays for quantifying mRNA in human serum from a phase 1 clinical trial. We compared analytical performance across bDNA and two RT-qPCR workflows-RNA purification and a simplified NP-40 detergent-based treatment. A total of 77 clinical serum samples were analyzed. Method performance was assessed using assay precision, accuracy, and total error, along with linear regression and Bland-Altman analyses to evaluate inter-platform concordance. Noncompartmental PK analysis was performed on a subset of samples from four subjects. Results showed that RT-qPCR methods yielded lower mRNA concentrations than bDNA, with a consistent negative bias more pronounced in NP-40-treated samples. The purification RT-qPCR method showed closer agreement with bDNA across the quantitative range (R = 0.878) than NP-40 treated RT-qPCR (R = 0.736). Despite quantitative differences, PK parameters derived from all methods were comparable, supporting RT-qPCR's suitability for clinical mRNA quantification. NP-40 treatment offered workflow efficiency and lower sample volume requirements, whereas mRNA purification had improved concordance with bDNA. These findings support the feasibility of adopting RT-qPCR as a viable alternative to bDNA method for mRNA quantification, with method selection guided by study phase, throughput needs, and available matrix volume. Cross-platform comparability ensures robust bioanalytical support for clinical development of mRNA drug candidates.
The Impact of Using Measured In Vitro Data to Develop Physiologically Based Pharmacokinetic Models of Dermal Absorption: An IVIVE Case Study.
Zhang Y, Clarke JF, Dancik Y
AAPS J · 2025 Sep · PMID 40892119 · Publisher ↗
In vitro permeation testing (IVPT) is commonly used to assess dermal drug delivery, yet its utility can be challenged by high variability and the need for large sample sizes to achieve sufficient statistical power. Derma...
In vitro permeation testing (IVPT) is commonly used to assess dermal drug delivery, yet its utility can be challenged by high variability and the need for large sample sizes to achieve sufficient statistical power. Dermal physiologically based pharmacokinetic (PBPK) models provide a mechanistic approach to better interpret IVPT results and to extrapolate in vitro to in vivo. In the present work, a dermal PBPK model for caffeine was developed using a bottom-up approach with minimal parameter optimization. The model incorporated formulation characteristics, experimentally measured skin partition coefficients, and predicted diffusion coefficients, while explicitly accounting for the constraints associated with the analytical methods used in each IVPT, improving the model's predictive reliability compared to previous work. After validation against literature IVPT data for aqueous solutions, the model was extended to simulate permeation from ointments and emulsions. The model was used to extrapolate and predict in vivo skin concentrations following application of gel formulations containing a chemical penetration enhancer, propylene glycol. For the emulsion formulations, the model was utilised to explore virtual bioequivalence and define a preliminary "safe space" for bioequivalence, offering insights to support both drug product development and regulatory submissions.
Beyond Accuracy, Precision and TAE: Direct assay Validation Against Product Specification Aligned with USP <1033> .
Josipovic D
AAPS J · 2025 Aug · PMID 40830303 · Publisher ↗
Traditional validation methodologies - whether based on accuracy and precision or total analytical error (TAE) and risk - focus primarily on the intrinsic performance of an analytical procedure, largely disregarding its...
Traditional validation methodologies - whether based on accuracy and precision or total analytical error (TAE) and risk - focus primarily on the intrinsic performance of an analytical procedure, largely disregarding its intended use environment. In contrast, this paper introduces a novel validation methodology that evaluates whether a procedure performs sufficiently well when integrated into its actual context of use. This approach aligns more closely with the intent of USP <1033> , where the Analytical Target Profile (ATP) is stated in terms of product and process requirements, rather than abstract analytical procedure requirements. By shifting the focus from theoretical performance to practical applicability, the proposed methodology ensures that analytical procedures meet quality requirements in practice - not just in principle. Although demonstrated here for potency assay validation in accordance with the USP <1033> guideline, the methodology is broadly applicable to other analytical procedures governed by ICH Q2(R2), with only minor adaptation. A freely accessible online application is provided to facilitate discussion and adoption of the novel methodology in practice.
Case Studies on the Use of Patient-centric Sampling for Clinical Studies in Pharmaceutical Drug Development.
Patel S, Baratta M, Bryan P … +8 more , Kopel H, Lowes S, Luo L, Spooner N, Stieltjes H, Wan K, Wickremsinhe E, Wilson A
AAPS J · 2025 Aug · PMID 40830292 · Publisher ↗
The current gold standard of blood sample collection in clinical trials involves venous draws performed by trained phlebotomists in clinical settings. However, recent technological advancements have enabled the emergence...
The current gold standard of blood sample collection in clinical trials involves venous draws performed by trained phlebotomists in clinical settings. However, recent technological advancements have enabled the emergence of patient-centric sampling (PCS) methods, offering more flexible and accessible alternatives. This paper examines the motivation behind the pharmaceutical industry's growing interest in PCS devices and explores their application in drug development through seven case studies. The case studies highlight the benefits and practical challenges of PCS strategies, including remote (at-home) sample collection, use in pediatric populations, advantages during COVID-19 pandemic, and implementation across trials involving small molecules, biotherapeutics, biomarkers and vaccines. Several studies assess the concordance between traditional venous sampling and PCS methods, while also addressing logistical considerations for remote sampling with and without nurse support. A central theme across the case studies is the importance of designing trials that prioritize patient convenience and engagement. Examples such as an early-phase asthma trial exemplify how PCS can enhance study design. The findings underscore the clear advantages of PCS in improving trial recruitment, increasing participant diversity, minimizing discomfort, reducing sample volumes and enhancing operational efficiency. The paper provides practical insights and recent examples to guide the integration of PCS technologies into clinical trial protocols, emphasizing the value of early planning and strategic implementation.
Assessment of Neutralizing Antibody Activity in Clinical Studies: Use of Surrogate Measurements Instead of Stand-alone Assays.
Partridge MA, Kamen L, Wu B … +8 more , Solberg H, McNally J, Stevenson L, Gupta S, Liu S, Xu W, Wu Y, White J
AAPS J · 2025 Aug · PMID 40804295 · Publisher ↗
Neutralizing antibodies (NAbs) to protein therapeutics have traditionally been assumed to be the most impactful subset of anti-drug-antibodies (ADA). NAbs can block the biotherapeutic from engaging its target impacting e...
Neutralizing antibodies (NAbs) to protein therapeutics have traditionally been assumed to be the most impactful subset of anti-drug-antibodies (ADA). NAbs can block the biotherapeutic from engaging its target impacting efficacy and may also cause serious safety events. Stand-alone NAb assays have been employed to detect neutralizing responses, often with reconfigured versions of other assays. These methods have historically been implemented in registrational trials for all molecules, and in early-stage studies for high risk biotherapeutics. However, data has demonstrated that NAb response and ADA magnitude are highly correlated. Additionally, the use of other markers to identify clinically relevant immunogenicity, such as apparent impact on pharmacokinetics (PK) or pharmacodynamics (PD), has been increasing. This manuscript reviews the available data on clinically meaningful immunogenic responses to biologics and proposes a risk-based strategy to determine if and when to employ a stand-alone NAb assay. For molecules with a high risk of safety consequences of immunogenicity (e.g., biological mimics) a NAb assay is recommended. However, for lower-safety risk molecules a stand-alone NAb assay does not enhance the interpretation of clinical data and is likely not needed. A combination of other assessments including ADA status, magnitude and persistence, PK, and PD (and efficacy) can be used as a surrogate for NAb assay data. Integration of data from all clinical evaluations is recommended by Health Authorities and can provide a more accurate overall assessment of neutralizing activity. This approach identifies clinically impactful downstream readouts of neutralizing activity without the need for a stand-alone NAb assay.
Optimization of In Vitro CYP3A4 TDI Assay Conditions and Use of Derived Parameters for Clinical DDI Risk Assessment Using Static and Dynamic Models.
Pugliano A, Ekiciler A, Preiss L … +3 more , Parrott NJ, Annaert P, Umehara K
AAPS J · 2025 Aug · PMID 40804139 · Publisher ↗
Cytochrome P450 3A4 (CYP3A4) is a key target for time-dependent inhibition (TDI) assessment during drug development. However, translating in vitro TDI data to in vivo drug-drug interaction (DDI) risk remains challenging...
Cytochrome P450 3A4 (CYP3A4) is a key target for time-dependent inhibition (TDI) assessment during drug development. However, translating in vitro TDI data to in vivo drug-drug interaction (DDI) risk remains challenging due to the acknowledged overestimation when incorporating in vitro kinetics in predictive models. We investigated different in vitro TDI assay conditions in human liver microsomes (HLM) and evaluated their impact on the predictive accuracy for CYP3A4-related DDI for 32 marketed drugs. Considering assay sensitivity and in vivo DDI prediction accuracy with mechanistic static modeling (MSM), optimal incubation parameters were identified as: a pre-incubation time of 40 min for precipitants and 10 min incubation time for CYP3A4 substrate midazolam (10 μM) at 0.1 mg/mL HLM. A tendency to overestimate the DDI magnitude (AFE = 4.83, AAFE = 4.87) was still observed in MSM when using the unbound drug inhibition constant (KI,) and maximum inactivation rate (k), measured under optimized incubation conditions. Improved predictions were achieved when applying the same parameters in physiologically-based pharmacokinetic (PBPK) models (AFE = 1.94, AAFE = 2.13), with 60% of predicted AUCR falling in the twofold range. These findings highlighted the importance of optimizing in vitro TDI incubation conditions, together with evaluating the benefits and limitations of numerical prediction approaches for predicting clinically significant CYP3A4 TDI effects with mechanistic static and PBPK models.
Novel Pharmacokinetic Bridging Strategy for Locally Acting Intravitreal Drug Products.
Ji P, Boyd WM, Sahajwalla C
AAPS J · 2025 Aug · PMID 40790008 · Publisher ↗
A clinical development program for follow-on locally acting intravitreal drug products typically includes a comparative efficacy study. Pharmacokinetic assessment is often considered of limited value because systemic exp...
A clinical development program for follow-on locally acting intravitreal drug products typically includes a comparative efficacy study. Pharmacokinetic assessment is often considered of limited value because systemic exposure is low and/or not predictive of efficacy at the site of action. In this commentary, we evaluated the relevance of pharmacokinetics for locally acting intravitreal large molecule drug products. Our assessment showed that systemic pharmacokinetic information including the rate constant could provide valuable insights into estimating local exposure of intravitreally administered drugs. This information has the potential to introduce a novel approach to clinical development programs for follow-on locally acting intravitreal drug products.
A Microemulsion for Oral Delivery of Nintedanib - QbD-Enabled Formulation Development, In-Vitro Characterization & In-Vivo Pharmacokinetic Assessment.
Gadhave D, Quadros M, Goyal M … +2 more , Ugale AR, Gupta V
AAPS J · 2025 Aug · PMID 40789799 · Publisher ↗
Nintedanib (Nint) is a potent tyrosine kinase inhibitor recently approved by the US FDA to treat idiopathic pulmonary fibrosis (IPF). Delivery of Nint through available approaches is highly challenging because of its poo...
Nintedanib (Nint) is a potent tyrosine kinase inhibitor recently approved by the US FDA to treat idiopathic pulmonary fibrosis (IPF). Delivery of Nint through available approaches is highly challenging because of its poor solubility and rapid metabolic degradation via hydrolytic ester cleavage, thereby reflecting poor oral bioavailability (< 5%). Hence, the current study was focused on formulating a Nint-loaded microemulsion (Nint-ME) and investigating its therapeutic potential in experimental animals to overcome the constraints of available therapies. Nint-ME was prepared via low-energy O/W emulsification aqueous titration techniques and optimized using QbD approach. Optimized ME subjected to screen for globule size, polydispersity index, encapsulation efficiency, transmittance, surface charge, and viscosity and were found to be 23.8 ± 1.4 nm, 0.18 ± 0.03, 99.8 ± 2.4%, 99.4 ± 0.1%, -0.7 ± 0.01 mV, and 1.5 ± 0.3 cP, respectively. Additionally, 94.5 ± 3.1% Nint was released from Nint-ME through the dialysis cassette within 72 h, demonstrating first-order kinetics with R of 0.966. First-order and Higuchi release kinetic patterns support concentration-dependent release and Fickian diffusion from the matrix of Nint-ME. In-vitro permeation study of Nint across Caco2 colon epithelial cell monolayer depicted 48.1 ± 1.5 µg of cellular permeation out of 50 µg, ensuring the permeation potential of Nint-ME. Concurrently, an in-vivo pharmacokinetic study for optimized Nint-ME against Nint suspension reflected 41.0 ± 12.5% oral bioavailability, a 2-fold enhancement compared to plain Nint suspension. Existing work demonstrated the successful development of oral Nint-ME as a novel formulation for safe and effective delivery of Nint in IPF.
Long-term Storage Stability of Inhalable Phage Powder Formulations: A Four-Year Study.
Li M, Ke WR, Chang RYK … +1 more , Chan HK
AAPS J · 2025 Aug · PMID 40760229 · Publisher ↗
The growing potential of bacteriophage therapy as an alternative treatment for pulmonary infections caused by multidrug-resistant bacteria has been increasingly recognized. This study aimed to evaluate the long-term stab...
The growing potential of bacteriophage therapy as an alternative treatment for pulmonary infections caused by multidrug-resistant bacteria has been increasingly recognized. This study aimed to evaluate the long-term stability of spray-dried phage powder formulations for pulmonary delivery, focusing on both biological activity and physicochemical properties. Three phages, PEV1, PEV20, and PEV61, were selected for formulation based on their host range against clinical strains of Pseudomonas aeruginosa. Eight spray-dried formulations, developed with varying proportions of lactose as a stabilizer and leucine as a moisture protectant and powder dispersion enhancer, were stored under controlled conditions at 4°C/15% relative humidity (RH) and 20°C/15% RH for four years. Over this period, phage titers declined with reduction ranging from 0.97 log in the most stable formulation to 2.49 log in the least stable one. Formulations with higher lactose concentrations (70-80%) demonstrated better preservation of biological activity. While the overall particle morphology remained unchanged, some thread-like elongated features protruding from the particle surfaces were observed, particularly in powders stored at 20°C/15% RH. However, there was a decline in the fine particle fraction (FPF) 50 - 60% to 27-44%. These findings showed the potential of spray-dried phage powders as a viable option for long-term storage to retain bioactivity, but the aerosol performance can be compromised.
Correction: Cellular Kinetics and Biodistribution of Adoptive T Cell Therapies: from Biological Principles to Effects on Patient Outcomes.
Li R, Grosskopf AK, Joslyn LR … +2 more , Stefanich EG, Shivva V
AAPS J · 2025 Jul · PMID 40745107 · Publisher ↗
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Development of a Multi-Purpose Comprehensive Physiologically Based Pharmacokinetic Model for Crizotinib: An Example Application in Bioequivalence Assessment between Oral Solution and Granules in Pediatric Subjects.
Sagawa K, Purohit V, Le V … +5 more , Hsu HJ, Ebrahimi E, Piscitelli J, Xu H, Johnson T
AAPS J · 2025 Jul · PMID 40721974 · Publisher ↗
Crizotinib exhibits a complex drug-drug interaction as it is a CYP3A4 substrate and acts as both a time-dependent inhibitor and inducer of the enzyme. Absorption of crizotinib is also complex as it exhibits a prolonged a...
Crizotinib exhibits a complex drug-drug interaction as it is a CYP3A4 substrate and acts as both a time-dependent inhibitor and inducer of the enzyme. Absorption of crizotinib is also complex as it exhibits a prolonged absorption phase. The primary objective of this research was to develop a comprehensive physiologically based pharmacokinetic (PBPK) model to mechanistically describe both metabolism and absorption of crizotinib. The established crizotinib adult PBPK model was extrapolated to pediatric population using the modified CYP3A4 ontogeny profile to evaluate the pharmacokinetic (PK) profile after a single dose administration of crizotinib under the fasted condition in pediatric population age between 1 to 6 years old. The model was further applied to conduct virtual bioequivalence (BE) trials including clinically observed intra-subject coefficient of variation (ICV%) in both adult and pediatric populations. In adult subjects, the estimated geometric mean ratio for AUC and C for oral solution (OS) vs granules formulation was 98.33 and 89.94, respectively with probability of demonstrating BE in adults of 100% for AUC and 90.3% for C. In pediatric subjects, the probability of demonstrating BE success was 99.7% for both AUC and C. The high probability of BE was replicated with the assumed higher ICV of 29% in pediatrics for both AUCinf and C. The granules (commercial formulation) can be considered BE to OS (Phase 3 clinical formulation) in adults, as well as pediatric subjects aged between 1 to 6 years old.
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