The AAPS Journal[JOURNAL]
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200 papers
Leveraging in vitro Tumor Cell Killing and Cytokine Release to Predict Cytokine Release Syndrome Associated with CD3 T-cell Bispecifics in Oncology: a Retrospective Analysis.
Lefèvre A, Parra-Guillen ZP, Trocóniz IF … +2 more , Boetsch C, Frances N
AAPS J · 2025 Nov · PMID 41254345 · Publisher ↗
While T-cell Bispecifics (TCBs) are promising molecules for cancer treatment, their clinical development remains challenging due to Cytokine Release Syndrome (CRS). There is currently no method to accurately predict the...
While T-cell Bispecifics (TCBs) are promising molecules for cancer treatment, their clinical development remains challenging due to Cytokine Release Syndrome (CRS). There is currently no method to accurately predict the doses expected to trigger CRS from pre-clinical data, resulting in the selection of non optimal First-In-Human (FIH) doses, far from the doses expected to show clinical benefit, to address safety concerns. In this work, a retrospective analysis aiming to identify which in vitro assay (focusing on tumor cell killing and cytokine release) is predictive of CRS at the first administration of TCBs developed for oncology indications at Roche is presented. A concentration threshold of C 25-times the in vitro tumor cell killing EC50 from the most sensitive assay (or 96% of the maximum killing effect) has been identified and can be used to guide the selection of clinical dose associated with no CRS. Above this concentration threshold, any CRS without distinction from grades 1-3 have been observed. This work demonstrates that in vitro tumor cell killing assay can be used to determine a FIH for TCBs at which no CRS is expected (at least for TCBs similar to the one used in this analysis). It also suggests that CRS events are connected to the intended pharmacological effect (tumor cell killing). This work can guide the selection of TCB FIH clinical doses, allowing higher starting dose compared to the minimum anticipated biological effect approach, therefore increasing patients' benefit.
Opportunities for AI-based Model-informed Drug Development: A Comparative Analysis of NONMEM and AI-based Models for Population Pharmacokinetic Prediction.
Mao B, Gao Y, Xu C … +3 more , Macha S, Shao S, Ahamadi M
AAPS J · 2025 Nov · PMID 41254220 · Publisher ↗
Model-informed drug development (MIDD) plays an important role in pharmacometrics by leveraging mathematical models to optimize drug dosing strategies. Traditional methods such as nonlinear mixed effects modeling (NONMEM...
Model-informed drug development (MIDD) plays an important role in pharmacometrics by leveraging mathematical models to optimize drug dosing strategies. Traditional methods such as nonlinear mixed effects modeling (NONMEM) have long been the gold standard in population pharmacokinetic (PPK) modeling. However, the development of artificial intelligence (AI) presents a potential improvement in predictive performance and computational efficiency. This study evaluates the effectiveness of AI-based MIDD methods for PPK analysis by comparing them against traditional nonlinear mixed-effects (NLME)-based methods (e.g., NONMEM). We tested five machine learning (ML) models, three deep learning (DL) models, and a neural ordinary differential equations (ODE) model on both simulated and real clinical datasets under different scenarios, assessing predictive performance with metrics such as root mean squared error (RMSE), mean absolute error (MAE), and coefficient of determination (R). Simulated datasets with known ground truth were created using a two-compartment model, while the real clinical dataset included data from 1,770 patients pooled from multiple clinical trials. Results indicate that AI/ML models often outperform NONMEM, with variations in performance depending on model type and data characteristics. Neural ODE models showed good performance, providing strong performance and explainability with large datasets. These findings underscore the potential of AI/ML methodologies to complement or enhance traditional PPK modeling approaches in MIDD, highlighting their applicability in future pharmacometrics workflows.
From AUC/MIC to AUCss and Cmin: Optimizing Micafungin Therapy in the Critically Ill through Model-Informed Precision Dosing.
Berrah R, Saint-Marcoux F, Monchaud C … +5 more , Cointault O, Conseil M, Jaber S, Jung B, Woillard JB
AAPS J · 2025 Nov · PMID 41219680 · Publisher ↗
Micafungin is an important echinocandin for invasive fungal infections, but its pharmacokinetics (PK) in critically ill patients is highly variable. This study aimed to characterize micafungin population PK in intensive...
Micafungin is an important echinocandin for invasive fungal infections, but its pharmacokinetics (PK) in critically ill patients is highly variable. This study aimed to characterize micafungin population PK in intensive care unit (ICU) patients, identify clinical covariates influencing exposure, and evaluate practical PK/pharmacodynamic (PD) indices, steady-state area under the curve (AUCss) and trough concentration (Cmin), as alternatives to the traditional AUC/minimum inhibitory concentration (MIC) ratio for therapeutic drug monitoring (TDM). Sixty critically ill adults received 100 mg/day intravenous micafungin, with rich PK sampling on Days 0, 4, and 14. Data were analyzed using a two-compartment model with first-order elimination in Monolix, and covariates were identified via forward-backward stepwise selection. The typical clearance was 1.56 L/h with high interindividual variability (coefficient of variation 59.9%), and total bilirubin was a significant predictor of clearance. Among 30 evaluable patients, the AUC/MIC ratio was a poor predictor of microbiological eradication (receiver operating characteristic [ROC] AUC = 0.579), whereas AUCss (ROC AUC = 0.656) and Cmin (ROC AUC = 0.641) demonstrated better performance. Time-to-event analysis showed that achieving AUCss > 90.15 mg·h/L (p = 0.045) or Cmin > 1.22 mg/L (p = 0.036) was significantly associated with faster eradication. In this heterogeneous ICU cohort, AUCss and Cmin were associated with microbiological outcomes and may offer pragmatic, MIC-independent monitoring metrics. These exploratory findings warrant prospective validation but incorporating simplified, exposure-guided dosing strategies may improve micafungin optimization and clinical outcomes in critically ill populations.
Regulatory Divergence in Narrow Therapeutic Index Drugs: A Comparative Review of the US, EU, Japan, Canada, and South Korea.
Lee S, Baek J, Kang W … +1 more , Kim E
AAPS J · 2025 Nov · PMID 41219563 · Publisher ↗
Generic drugs offer cost-effective alternatives to brand-name medications while ensuring comparable safety and efficacy. However, narrow therapeutic index drugs (NTIDs), which require precise dosing due to narrow margins...
Generic drugs offer cost-effective alternatives to brand-name medications while ensuring comparable safety and efficacy. However, narrow therapeutic index drugs (NTIDs), which require precise dosing due to narrow margins between therapeutic and toxic concentrations, present additional regulatory challenges. Concerns regarding the interchangeability of generic NTIDs are amplified by international variation in definitions, bioequivalence (BE) standards, and regulatory approaches. This systematic review compares NTID-related regulatory frameworks across major authorities to inform the development of the ICH M13C guideline and foster global harmonization of evaluation standards for generic NTIDs. A comprehensive comparative analysis was conducted of NTID-related regulatory frameworks in five ICH member countries (United States [US], European Union [EU], Japan, Canada, and South Korea), with Egypt, Jordan, and Saudi Arabia included as reference countries. Data were obtained from literature searches and official regulatory sources, focusing on NTID definitions, BE standards, and NTID lists. Marked regulatory divergence was observed. South Korea uniquely incorporates quantitative pharmacological and toxicological criteria into NTID definitions. The US employs the most stringent NTID BE standards, utilizing a fully replicated design, reference-scaled average bioequivalence (RSABE), and variability assessment. Only cyclosporine and tacrolimus are classified as NTIDs by all five core countries. Variability in NTID lists and evaluation criteria complicates global harmonization efforts. Achieving consistent evaluation and safe international use of generic NTIDs requires global alignment on definitions, BE criteria, and NTID lists. This review supports integrating real-world data into regulatory decision-making and advances the ICH M13C guideline.
Development, Verification, and Application of a Chinese Pediatric Physiologically Based Pharmacokinetic Model: Emphasis on CYP Metabolism and Renal Elimination.
Southall RL, Dinh J, Pan X … +2 more , Ning J, Johnson TN
AAPS J · 2025 Nov · PMID 41214361 · Publisher ↗
Physiologically based pharmacokinetics (PBPK) models are increasingly being used in pediatric drug development and with the conduct of clinical studies in specific countries, the development of such models to describe bo...
Physiologically based pharmacokinetics (PBPK) models are increasingly being used in pediatric drug development and with the conduct of clinical studies in specific countries, the development of such models to describe both age and ethnicity related differences is a logical step forward. This study described the development, verification, and application of a Chinese pediatric PBPK (p-PBPK) model. Chinese pediatric physiological systems parameters and clinical data was derived from public databases and the literature, the PBPK model was assembled so that demographic and physiological outputs such as height, cardiac output, and liver size with age represented the Chinese pediatric population. The model was tested using two drugs predominately metabolized by CYP3A4 (fentanyl and midazolam), one dual CYP3A4/CYP2C9 substrate (ruxolitinib), two by other CYPs (efavirenz and theophylline), and two by renal elimination (ceftazidime and vancomycin). Overall, 79% of all pharmacokinetic parameters were predicted within 0.8 to 1.25-fold, and 100% within 0.67 to 1.5-fold of the observed data. The application of the Chinese p-PBPK model is demonstrated with two bridging scenarios, by investigating whether recommended dosing regimens for efavirenz and theophylline are suitable for Chinese pediatric subjects. Given the increased regulatory use of pediatric PBPK models in drug development, expanding these models to other ethnic groups is important. There is a need to further develop the current model across a wider range of drugs with different elimination pathways, to increase model confidence, this should involve academia, industry, model providers, and regulatory agencies.
Dissolution Profile of Ionizable Drugs in Biorelevant Bicarbonate Buffer at Intermediate Gastrointestinal pH Level.
Okamoto N, Sugano K
AAPS J · 2025 Nov · PMID 41214267 · Publisher ↗
This study aimed to investigate the dissolution profiles of ionizable drugs in biorelevant bicarbonate buffer (BCB) at the intermediate gastrointestinal pH level. For the pH maintenance tests, BCB was prepared by adjusti...
This study aimed to investigate the dissolution profiles of ionizable drugs in biorelevant bicarbonate buffer (BCB) at the intermediate gastrointestinal pH level. For the pH maintenance tests, BCB was prepared by adjusting the pH and the ionic strength (I) of NaHCO/NaCO solutions using HCl and NaCl (BCB: 5-20 mM, pH 3.0-5.0, I = 0.14 M). The floating lid method was used to prevent CO loss. For the dissolution tests, febuxostat (FBX), dipyridamole (DPM), dantrolene Na (DNT Na), pioglitazone HCl (PIO HCl), and tosufloxacin tosylate monohydrate (TFLX TS) were employed. The dissolution profiles were measured at pH 4.5 (10 mM BCB, I = 0.14 M). Compendial citrate-phosphate buffer (CPB) and acetate buffer (ACB) were used for comparison. In the pH maintenance test, the pH change was ≤ + 0.11 for 2 h in all conditions. The dissolution rates of FBX and DPM were slower in BCB than in CPB and ACB. DNT Na showed slightly less supersaturation in CPB than in BCB and ACB. In contrast, PIO HCl showed markedly higher supersaturation in BCB than in CPB and ACB. TFLX TS showed higher and lower supersaturation in the absence and presence of Cl, respectively. The hemi-hydrochloride salt formed in the latter case. The dissolution profiles of ionizable drugs in BCB differed from those in CPB and ACB, especially in the case of the salt-form drugs with an acidic counterion. The floating lid method enables dissolution testing using BCB in the intermediate pH range.
Utilizing Minimal Physiologically Based Pharmacokinetic Modeling to Bridge Bevacizumab Pharmacokinetics from Adult to Pediatric Patients.
Sule O, Stader F, Kassir N … +3 more , Li J, Chan P, Huang W
AAPS J · 2025 Nov · PMID 41196551 · Publisher ↗
Bevacizumab is a humanized monoclonal antibody (mAb) approved to treat various cancers in adults and was investigated in pediatric patients. While the drug development of small molecules in pediatrics has greatly benefit...
Bevacizumab is a humanized monoclonal antibody (mAb) approved to treat various cancers in adults and was investigated in pediatric patients. While the drug development of small molecules in pediatrics has greatly benefited from the use of physiologically-based pharmacokinetic (PBPK) modeling for pharmacokinetic (PK) extrapolation, such application remains relatively limited in mAbs. In this study, our objective was to evaluate the applicability of PBPK modeling in characterizing the age-dependent PK of bevacizumab. A minimal PBPK model was developed incorporating bevacizumab-specific drug parameters, with age-dependent physiological changes such as tissue volume, blood and lymphatic flow, and endogenous immunoglobulin G (IgG) levels, and validated using observed PK data in 786 adult and 141 pediatric patients from 23 bevacizumab clinical studies. The final model was applied to predict the exposure of bevacizumab in pediatric patients ranging from six months to 18 years old. Clinically observed bevacizumab PK data in adults following single or multiple dosing of 5, 10, and 15 mg/kg were generally within the 95% model prediction intervals. In pediatrics, the individually simulated bevacizumab concentrations were consistent with the individual observed data, including the pediatric patients as young as six months old. Sensitivity analysis revealed that endogenous IgG concentration and neonatal Fc receptors abundance play critical roles in bevacizumab PK in children. Overall, the PBPK model successfully bridges the bevacizumab PK from adult to pediatric patients by incorporating age-dependent physiological changes. This work represents a significant step forward in advancing the application of PBPK modeling of mAbs in children.
Comparative Evaluation of Approaches to Convert Microsampled Capillary Blood Concentrations to Plasma Concentrations: Paracetamol and Metabolites as a Case Study.
Boffel L, De Sutter PJ, De Baerdemaeker L … +1 more , Stove CP
AAPS J · 2025 Nov · PMID 41196542 · Publisher ↗
The past decades have witnessed a growing interest in patient-centric sampling, including dried capillary blood microsampling. Despite its advancements, a key issue lies in interpreting dried capillary blood results agai...
The past decades have witnessed a growing interest in patient-centric sampling, including dried capillary blood microsampling. Despite its advancements, a key issue lies in interpreting dried capillary blood results against existing plasma-based reference ranges. To address this challenge, various methodologies to convert dried capillary blood concentrations to plasma equivalents have been proposed. This study systematically evaluates and compares different methodologies for converting dried capillary blood results to venous plasma results using clinical pharmacokinetic (PK) data of paracetamol and metabolites as a case study. Paired capillary volumetric absorptive microsampling (cVAMS) and venous plasma samples were collected from 55 patients. For each analyte, cVAMS results were converted using multiple approaches, including conversion based on the median (time-dependent) capillary-to-plasma ratio, Passing-Bablok regression analysis, linear mixed-effects modeling and the hematocrit (Hct). Performance was assessed by comparing the agreement between converted cVAMS concentrations and actual plasma results to pre-defined analytical and clinical acceptance criteria. All approaches, except Hct-based conversion, yielded acceptable results for all analytes, with minor variations in analytical performance. Estimated C and AUC values (and corresponding 90% confidence intervals) calculated based on the converted cVAMS results were within bio-equivalence criteria for all conversion approaches, except Hct-based conversion for one analyte. Both from analytical and clinical perspectives, this study demonstrated the reliability of different approaches to convert capillary blood microsampling-based to plasma-based results. The framework utilized in this study may guide future microsampling (PK) studies aiming at switching from collecting samples from the reference matrix to an alternative capillary blood matrix.
Investigating Sulfotransferase Mediated Drug Interactions of Ethinylestradiol using a Physiologically Based Pharmacokinetic Model.
Moore HP, Chen KF, Heikkinen AT … +6 more , Neuhoff S, Ezuruike U, Dinh J, Gardner I, Jones HM, Stader F
AAPS J · 2025 Nov · PMID 41188642 · Publisher ↗
Ethinylestradiol (EE) is a common estrogen used in combined oral contraceptives. CYP3A4 and SULT1E1 are the major enzymes that metabolize EE, while CYP2C9 and UGT1A1 have minor contributions. Drug-drug interactions (DDIs...
Ethinylestradiol (EE) is a common estrogen used in combined oral contraceptives. CYP3A4 and SULT1E1 are the major enzymes that metabolize EE, while CYP2C9 and UGT1A1 have minor contributions. Drug-drug interactions (DDIs) mediated by inhibition or induction of metabolism can adversely impact the safety and efficacy of EE. A physiologically-based pharmacokinetic (PBPK) model was previously developed and extensively verified to predict CYP3A4-mediated DDIs of EE. Recent clinical evidence showed increased EE exposure following coadministration with the SULT1E1 inhibitors etoricoxib and ziritaxestat, highlighting the need to expand the PBPK model to allow for predictions of SULT1E1-mediated DDIs. A PBPK model including SULT metabolism of EE was constructed and the interactions with PBPK models developed for etoricoxib and ziritaxestat were simulated. The observed EE concentrations were within the simulated 95% percentiles for the control and the DDI scenario. The predicted ratios for peak concentration (C) and area under concentration-time curve (AUCt) were within 1.5-fold of the observed data. The simulations demonstrated that clinically relevant DDIs may not be expected when EE is co-administered with 120 mg etoricoxib QD but may be expected with 600 mg QD ziritaxestat QD. A simulated dose reduction from 35 µg to 20 µg, when co-administered with ziritaxestat, was predicted to produce EE exposures in a similar range to when 35 µg is administered alone. The developed PBPK models for etoricoxib and ziritaxestat can be used in future applications as probe SULT1E1 precipitants. Incorporation of SULT metabolism into the EE PBPK model may support a more comprehensive assessment of the DDI liability of investigational drugs that affect multiple EE metabolic pathways.
Establishing the Human Duodenum Chip as a Surrogate for Effective Human Permeability: In Vitro and In Silico Assessment.
Zagaja KMP, Kopec AK, Harney J … +3 more , Hardink MA, Middleton J, Hens B
AAPS J · 2025 Oct · PMID 41168619 · Publisher ↗
Drug permeability across epithelial barriers is critical for predicting oral bioavailability and efficacy. Conventional models, including animals and simple cell cultures, lack intestinal complexity and translational val...
Drug permeability across epithelial barriers is critical for predicting oral bioavailability and efficacy. Conventional models, including animals and simple cell cultures, lack intestinal complexity and translational value. Organoids and organ-on-a-chip technologies address these limitations, offering physiologically relevant, human-specific platforms for more accurate drug permeability assessment [1]. Intestinal organoids, derived from stem cells, reproduce key structural and functional features of the gut, including crypt-villus organization, transporter and enzyme expression, and absorptive and secretory functions. Organoids are grown inside of microfluidic chips under dynamic media flow that attempt to recapitulate one or more tissue-specific functions, thereby supporting epithelial maturation and enabling more predictive drug transport measurements. Permeability can be studied by introducing compounds at the apical surface and quantifying their translocation to the basolateral compartment using analytical techniques. Compared with animal models, these approaches yield data of greater human relevance while reducing ethical concerns [2]. Furthermore, they enable the evaluation of passive permeability, active transport, intestinal metabolism, and interactions with microbial products [3]. In this study, permeability was investigated for three model compounds with distinct properties: lisinopril (low permeability), metoprolol (moderate permeability), and fluconazole (high permeability). Experiments were conducted using the Emulate human duodenum-on-a-chip platform and benchmarked against the Ralph Russ Canine Kidney (RRCK) cell line. Apparent permeability (P) values were correlated with literature-reported effective permeability (P) using linear regression. This regression was implemented in Simcyp® Simulator and GastroPlus™ to predict systemic exposure, which was compared against observed plasma concentration-time profiles.
From Liquid SNEDDS to Solid SNEDDS: A Comprehensive Review of Their Development and Pharmaceutical Applications.
Tanga S, Ramburrun P, Aucamp M
AAPS J · 2025 Oct · PMID 41168544 · Publisher ↗
The liquid and solid formulations of self-nano-emulsifying drug delivery systems (SNEDDS) have garnered significant attention in the pharmaceutical field for their ability to enhance the solubility and absorption of hydr...
The liquid and solid formulations of self-nano-emulsifying drug delivery systems (SNEDDS) have garnered significant attention in the pharmaceutical field for their ability to enhance the solubility and absorption of hydrophobic drugs. While both liquid and solid SNEDDS result in improved bioavailability; portability, patient compliance, desired administration route, and ease of preparation are some factors that contribute to the decision-making of the final SNEDDS dosage form. This review provides a comprehensive analysis of SNEDDS formulations in the liquid and solid state, including production and performance factors that researchers ought to consider when developing their final dosage form. We investigate excipient characteristics, stability concerns, liquid-to-solid preparation methods and their challenges, and in vivo and in vitro comparisons of both dosage forms. Finally, we explore the potential of artificial intelligence in the design of SNEDDS formulations.
Integrated Physiologically-based Pharmacokinetic Model with a Quantitative Systems Pharmacology and Toxicology Model for Statins in Disease Population. Part 2: MIDD and MIPD Applications.
Prieto Garcia L, Nordell P, Ahlström C … +2 more , Lennernäs H, Sjögren E
AAPS J · 2025 Oct · PMID 41168542 · Publisher ↗
The conventional strategy of prescribing the same dosage to all patients can result in suboptimal efficacy and safety. This is particularly true when considering drug-gene interactions (DGIs), drug-drug interactions (DDI...
The conventional strategy of prescribing the same dosage to all patients can result in suboptimal efficacy and safety. This is particularly true when considering drug-gene interactions (DGIs), drug-drug interactions (DDIs), or in individuals with compromised organ function. Precision medicine, which aims to tailor drug regimens based on individual patient characteristics, offers a promising alternative by focusing on drug disposition, efficacy, and safety. However, clinical trials face ethical and practical challenges and cannot cover all real-world patient scenarios. Thus, physiological based pharmacokinetic (PBPK) modeling offers a unique framework for enhancing model-informed drug development (MIDD) and precision dosing (MIPD). Despite this, most PBPK applications primarily assess drug pharmacokinetics without evaluating efficacy or safety outcomes. This limits the full potential of mechanistic models. In this study we used integrated PBPK, Quantitative Systems Pharmacology (QSP), and toxicology models to predict risks in scenarios like DGIs, DDIs, and varied renal impairment by simultaneously assessing drug PK, pharmacological effect, and toxicity. The findings underscore the importance of considering pharmacological effects and myotoxicity risks, which differed from changes seen in plasma exposure. This study demonstrates the value of PBPK-QSP models in guiding dose adjustments to optimize the efficacy and safety balance in target patient populations, showcasing their strength in MIDD and MIPD strategies.
Randomized-Exposure Mixture-Model Analysis (REMIX) allowing Type-1 Error Controlled Exposure-Response Modelling.
Wojtyniak D, Guk J, Wicha SG
AAPS J · 2025 Oct · PMID 41168535 · Publisher ↗
In drug development, exposure-response models are widely used to inform decisions in dose optimization processes. Type I error (T1) due to misspecified models can lead to critical and costly decisions. Therefore, a new a...
In drug development, exposure-response models are widely used to inform decisions in dose optimization processes. Type I error (T1) due to misspecified models can lead to critical and costly decisions. Therefore, a new approach called: "Randomized-exposure mixture-model analysis with type 1 error control (REMIX)" to account for model misspecification is proposed and compared against the standard approach (STA). A total of 82 simulation-estimation scenarios for a hypothetical antidiabetic drug were investigated. T1 rate and power was tested in presence or absence of model misspecification. Moreover, predictive performance of both approaches and accurary of the drug-effec parameter estimates was assessed. Precision and accuracy for the drug-effect parameter were compared to the STA parameter estimates for each structural model with the most patients. REMIX outperformed STA regarding T1 rate inflation (21/82, 44/82 for REMIX and STA, respectively) but led to lower power. In a case study with an example of a clear drug effect and no model misspecification, 27 patients were needed for REMIX compared to 17 for STA to reach 80% power. rRMSE and rBias for full REMIX and STA models were similar in most scenarios if a drug effect was present, but REMIX outperformed STA when no real drug effect was present. Precision and accuracy of parameter estimates were similar for REMIX and STA. Application of REMIX in further studies and comparison to other approaches to control T1 are warranted.
The Role of Early Exposure Metrics (pAUC and C) in Assessing the Bioequivalence of Methylphenidate Extended-release Products_A Sensitivity Analysis.
Hsu LF
AAPS J · 2025 Oct · PMID 41168527 · Publisher ↗
Methylphenidate extended-release (ER) products are used in the treatment of attention-deficit/hyperactivity disorder (ADHD). These products exhibit diverse pharmacokinetic (PK) profiles that influence early systemic expo...
Methylphenidate extended-release (ER) products are used in the treatment of attention-deficit/hyperactivity disorder (ADHD). These products exhibit diverse pharmacokinetic (PK) profiles that influence early systemic exposure and clinical response. To ensure bioequivalence (BE) for products such as Concerta and Ritalin LA, both the FDA and EMA recommend the use of pAUC, with the EMA additionally suggesting the inclusion of C. However, it remains unclear whether C offers added discriminatory value beyond pAUC in BE evaluation. The objective was to assess the sensitivity of early exposure metrics (pAUC, C, and C) to changes in the SKAMP (Swanson, Kotkin, Agler, M-Flynn, and Pelham rating scale) response, a pharmacodynamic (PD) endpoint commonly used to assess clinical response in ADHD. PK/PD model simulations were performed for seven methylphenidate ER products. These products were categorized by PK absorption model: parallel dual first-order (e.g., Concerta) and parallel zero-order and first-order (e.g., Metadate CD). The PD model described placebo-adjusted SKAMP response based on simulated plasma concentrations. Simulations were conducted by varying the fast absorption rate constant (ka) to assess how changes in early exposure metrics affect AUEC of the SKAMP response. The results indicated that pAUC generally showed greater sensitivity to SKAMP response than C and C. Although C exhibited high sensitivity in products with dual first-order absorption, its responsiveness remained inferior to pAUC. These findings support the use of pAUC as the primary early exposure metric for therapeutic equivalence assessment and suggest that C may not provide further discriminatory value beyond that of pAUC
Dacarbazine-loaded Bilayer Dissolving Microneedle Array Patch for Localized Delivery in Cutaneous Melanoma.
Gowda BHJ, Yalcin TE, Pandya AK … +5 more , Gade S, Ahmed MG, Thakur RRS, Donnelly RF, Vora LK
AAPS J · 2025 Oct · PMID 41148445 · Publisher ↗
Melanoma is a highly aggressive skin cancer that accounts for only ~ 1% of all skin cancer cases but is responsible for most skin cancer-related deaths. Despite advances in systemic therapies, localized treatment options...
Melanoma is a highly aggressive skin cancer that accounts for only ~ 1% of all skin cancer cases but is responsible for most skin cancer-related deaths. Despite advances in systemic therapies, localized treatment options remain limited. Dacarbazine (DCB), the only FDA-approved chemotherapeutic agent for melanoma, is administered intravenously and is associated with systemic toxicity, poor patient compliance, and nonspecific drug distribution. This study presents a bilayer dissolving microneedle array patch (dMAP) for localized, minimally invasive delivery of DCB to the skin, offering a potential alternative for treating cutaneous melanoma. The tip-casting gel formulation was optimized to ensure sharp, defect-free MAP tips with uniform drug distribution. The optimized bilayer dMAP exhibited strong mechanical properties (< 10% needle deformation) and effective insertion capability, reaching approximately 390 µm in depth within the Parafilm® M model. Ex vivo evaluations using full-thickness neonatal porcine skin demonstrated the complete dissolution of bilayer dMAP tips within 60 min and effective pore formation, as confirmed by methylene blue staining. In ex vivo setup, the bilayer dMAP formulation demonstrated 3.93-fold increase in permeability and a 3.02-fold increase in DCB deposition compared with those of the suspension. Furthermore, bilayer dMAP maintained complete drug stability over 8 days at room temperature under light-protected conditions, whereas free DCB showed approximately 7.5% degradation in aqueous media over the same duration. Therefore, bilayer dMAP provides a stable, minimally invasive, and efficient platform for localized drug delivery to the skin, highlighting its potential as a promising alternative to conventional topical formulations for the treatment of cutaneous melanoma.
Mechanistic Modeling of Intramuscular Administration of a Long-acting Injectable Accounting for Tissue Response At the Depot Site.
Silva DA, Le Merdy M, Mullin J … +7 more , Malavia N, Alam K, Tsakalozou E, Al Shoyaib A, Wang Y, Burgess D, Lukacova V
AAPS J · 2025 Oct · PMID 41136823 · Full text
The tissue response to long-acting injectables (LAIs) suspension injection may impact the product in vivo performance. One such response is the formation of an inflammatory cell layer (ICL) resulting in an envelope aroun...
The tissue response to long-acting injectables (LAIs) suspension injection may impact the product in vivo performance. One such response is the formation of an inflammatory cell layer (ICL) resulting in an envelope around the injected particles. This study aims to use a mechanistic model to describe the clinical in vivo exposure and performance of an intramuscular LAI suspension and evaluate impact of ICL physiological response at the injection site in humans. Aripiprazole lauroxil (AR-L) was used as the model drug. A baseline pharmacokinetics model was built and validated for aripiprazole. The impact of inflammation on the LAI in vivo performance was assessed by including an ICL model. The developed pharmacokinetic model adequately described the observed plasma profiles of AR following intravenous and oral administration in humans. The initial intramuscular predictions assumed that the absorption rate is dependent on the dissolution and partitioning of AR-L into the systemic circulation from the intramuscular (IM) depot. The simulation resulted in a shape mismatch between the simulated and observed data and an earlier predicted T The inclusion of an ICL in the model resulted in adequate predictions (fold errors less than 25%) of the exposure and shape of the plasma concentration-time profiles. Utilizing a time-dependent change in ICL thickness resulted in reasonable predictions of AR pharmacokinetic profiles following IM administration of multiple strengths of the AR-L suspension. This shows the utility of physiologically based pharmacokinetic (PBPK) model in mechanistically describing the in vivo performance of LAIs.
Calibration Transfer Across Instrument Vendors for Bioprocess Raman Monitoring.
Myers NM, Gao B, Amchin D … +2 more , Masucci EM, Balss KM
AAPS J · 2025 Oct · PMID 41136795 · Publisher ↗
Raman spectroscopy is a proven Process Analytical Technology (PAT) for monitoring mammalian cell culture processes in biopharmaceutical manufacturing. In-line Raman probes provide real-time chemical fingerprints of metab...
Raman spectroscopy is a proven Process Analytical Technology (PAT) for monitoring mammalian cell culture processes in biopharmaceutical manufacturing. In-line Raman probes provide real-time chemical fingerprints of metabolites and cell culture health analyzed via chemometric modeling. However, Raman hardware (e.g. cables, detectors, optics, probes, and lasers) and software - performing calibration, noise reduction, and cosmic ray removal - impart vendor specific spectral signatures, rendering Raman chemometric models specific to the vendors. This vendor specificity complicates method validation and transfer between manufacturing sites deploying different vendor equipment and impedes upgrades, maintenance, and replacement of obsolete Raman equipment. In this work, we compared two calibration transfer methods to address vendor-to-vendor variation. Piecewise Direct Standardization (PDS) and Spectral Subspace Transformation (SST) methods successfully reduced spectral response variation between previous (Parent) and new (Child) Raman systems. We tested calibration transfer results with offline samples and an established validation approach utilizing paired spectra from Parent and Child Raman systems. Finally, we explored the influence of calibration transfer parameters including training set size, preprocessing position, and window size (number of components) for PDS and SST. Through this investigation we demonstrate the feasibility of this proposed vendor-to-vendor calibration transfer approach as a promising and effective chemometric model transfer between Raman vendors without significant method re-development or re-validation. This approach improves agility within the deployment strategy of chemometric models across supply chain networks and bolsters Raman spectroscopy as a versatile PAT tool for advanced manufacturing within the biopharmaceutical industry.
Matching in Organ Impairment Studies: A Systematic Review of Accepted Methodologies.
Dubich T, Arold G, Smith KL … +2 more , van Iersel T, van Hoogdalem EJ
AAPS J · 2025 Oct · PMID 41136722 · Publisher ↗
Although the use of demographic matching in organ impairment studies is recommended to exclude the confounding effect of demographics on the pharmacokinetic (PK) study results, very little guidance exists on the practica...
Although the use of demographic matching in organ impairment studies is recommended to exclude the confounding effect of demographics on the pharmacokinetic (PK) study results, very little guidance exists on the practical implementation of this approach. Individual matching (IM) as well as several strategies for group matching (GM) have been described in literature. We conducted a systematic review, including 170 renal (RI) and 173 hepatic impairment (HI) studies completed in the last 25 years and characterized used matching methodologies and selected matching criteria. In RI, GM appears more common (70%), while in HI IM was preferred (55%). Age, body weight or body mass index (BMI), and sex were the most commonly used matching criteria, with the most common acceptance margins of ± 10 years for age, ± 10-20% for body weight, and ± 15-20% for BMI, irrespective of matching method used. While IM required notably more subjects in the control group, we did not find a significant effect of various matching strategies on study duration or recruitment between different matching strategies. No matching was used in most of the studies conducted in the target patient population with organ impairment, as opposed to the studies conducted in general organ impairment population without the target indication. Based on the results of this review, we proposed a framework for selection of matching strategy, with IM being a recommended matching method in most cases and GM being suitable for compounds that have well-characterized impact of demographic characteristics on PK and a low between-subject variability.
Net Influx Rather Than Directional Rates: Re-evaluating Transporter Characterization In Vivo and In Vitro for Renal and Hepatic Clearance.
Benet LZ, Sodhi JK
AAPS J · 2025 Oct · PMID 41131222 · Publisher ↗
Here we challenge the assumption that hepatic uptake can be rate-limited solely by transporter-mediated influx clearance, as commonly concluded in interpretations based on the Extended Clearance Concept (ECC). We initial...
Here we challenge the assumption that hepatic uptake can be rate-limited solely by transporter-mediated influx clearance, as commonly concluded in interpretations based on the Extended Clearance Concept (ECC). We initially review the derivation of renal and hepatic clearance independent of differential equations based on adaptation of Kirchhoff's Laws from physics, incorporating clinically relevant aspects such as transporter activity, organ blood flow, and clearance from the site of drug delivery into systemic circulation. In doing so, we highlight the limitations of the ECC framework, which does not adequately capture all aspects of these mechanistic elements and note that no experimental data or PBPK analyses definitively support its validity. In contrast, we show that all hepatic clearance data can be adequately explained based on our derivations, which provide a more robust and mechanistically consistent framework for interpreting renal and hepatic clearance. The derived equations define the net difference between influx and efflux clearances as the key determinant of transporter involvement in hepatic drug disposition, rather than considering influx alone as in the ECC. This approach is analogous to the treatment of secretion and reabsorption clearances as opposing processes in renal clearance, where their difference determines the net transport. We also question the mechanistic accuracy of determining hepatic influx and efflux clearances in vitro using initial rates of membrane passage, as is typically done for passive processes. Such measurements inherently reflect the net intramembrane difference between influx and efflux clearances, and do not allow for independent quantification of directional transport, due to the inability to measure drug concentrations within the membrane. Finally, while we acknowledge the utility of ECC and PBPK analyses for predicting changes in pharmacokinetic exposure due to DDIs (or other variables such as disease state, pharmacogenomics, etc.), we caution that model-based data fitting, however useful, does not constitute mechanistic validation.
Association of Immunogenicity and Drug Exposure and the Importance of Target Engagement in ADA Development: A Clinical Case Study of Anti-SARS-CoV-2 Biotherapeutics.
Irvin SC, Ganguly S, Wang Z … +20 more , He ZW, Alejandro M, Donohue K, Elango C, Gallo C, Guttmann S, Kalicharan S, Kameron K, Laird J, Laurino K, Trotter H, Rodriguez J, Santiago K, Speaks E, Sumner G, Andisik MD, Yan H, Turner KC, Davis JD, Partridge MA
AAPS J · 2025 Oct · PMID 41131208 · Publisher ↗
The administration of therapeutic proteins, such as monoclonal antibodies (mAbs) may result in the formation of anti-drug antibodies (ADA), but there is limited publicly available data for biotherapeutics with exogenous...
The administration of therapeutic proteins, such as monoclonal antibodies (mAbs) may result in the formation of anti-drug antibodies (ADA), but there is limited publicly available data for biotherapeutics with exogenous targets or with targets in low abundance systemically. ADAs can impact a biotherapeutic's safety, efficacy, and pharmacokinetics, so evaluation of immunogenicity is required for all therapeutic proteins. This analysis sought to evaluate the immunogenicity of two mAbs against COVID-19, casirivimab (CAS) and imdevimab (IMD) administered as a cocktail (CAS + IMD), in multiple clinical trials across different participant populations to add knowledge about the immunogenicity risk of protein therapeutics against exogenous targets and the association between immunogenicity and drug exposure. Overall, the incidence of treatment-boosted and treatment-emergent ADAs and neutralizing antibodies in both disease treatment and prophylaxis settings were low (i.e., < 11%). Participants in these studies were followed for up to 225 days post-last dose. Over time, the incidence of treatment-emergent and treatment-boosted immunogenicity for each mAb increased, but the rates and titers remained low overall; when it developed, patients usually developed ADA to both mAbs. Frequency of administration, dose, and route of administration did not appear to impact rates of immunogenicity. Concentrations of CAS and IMD were similar between participants of different immunogenicity status, indicating immunogenicity of CAS and IMD had no impact on pharmacokinetics of these mAbs; there was also no observed impact on safety or efficacy. The data presented here may provide supportive information for assessing the immunogenicity risk of protein therapeutics with exogenous targets.
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