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Jane Weitzel, , Gregory M. Banik, Amy R. Barker, Elizabeth Bladen, Narendra Chirmule, Joseph DeFeo, Jennifer Devine, Steven Emrick, Taha Kass Hout, et al.
Published: 15 October 2021
The AAPS Journal, Volume 23, pp 1-8; https://doi.org/10.1208/s12248-021-00634-5

Abstract:
Recent changes in the pharmaceutical industry have led to significant paradigm shifts in the pharmaceutical quality environment. Globalization of the pharmaceutical industry, increasingly rapid development of novel therapies, and adoption of new manufacturing techniques have presented numerous challenges for the established regulatory framework and quality environment and are impacting the approaches utilized to ensure the quality of pharmaceutical products. Regulators, industry, and standards-setting organizations have begun to recognize the need to rely more on integrated risk-based approaches and to create more nimble and flexible standards to complement these efforts. They also increasingly have recognized that quality needs to be built into systems and processes throughout the lifecycle of the product. Moreover, the recent COVID-19 crisis has emphasized the need to adopt practices that better promote global supply chain resilience. In this paper, the USP Quality Advisory Group explores the various paradigm shifts currently impacting pharmaceutical quality and the approaches that are being taken to adapt to this new environment. Broad adoption of the Analytical Procedure Lifecycle approach, improved data management, and utilization of digital technologies are identified as potential solutions that can help meet the challenges of these quality paradigm shifts. Further discussion and collaboration among stakeholders are needed to pursue these and other solutions that can ensure a continued focus on quality while facilitating pharmaceutical innovation and development.
Elizabeth S. Levy, Jesse Yu, Alberto Estevez, Jialin Mao, Liling Liu, Elizabeth Torres, ,
Published: 14 October 2021
The AAPS Journal, Volume 23, pp 1-12; https://doi.org/10.1208/s12248-021-00651-4

The publisher has not yet granted permission to display this abstract.
, Vladimir Villanueva-Lopez, Shashank Venkat Muddu, Gregory D. Doddridge, Dana Alhasson, Michael C. Dennis
Published: 14 October 2021
AAPS PharmSciTech, Volume 22, pp 1-12; https://doi.org/10.1208/s12249-021-02148-x

The publisher has not yet granted permission to display this abstract.
Sara Fathollahi, Julia Kruisz, Stephan Sacher, Jakob Rehrl, M. Sebastian Escotet-Espinoza, James DiNunzio, Benjamin J. Glasser,
Published: 12 October 2021
AAPS PharmSciTech, Volume 22, pp 1-14; https://doi.org/10.1208/s12249-021-02104-9

Abstract:
This paper proposes a feed rate control strategy for a novel volumetric micro-feeder, which can accomplish low-dose feeding of pharmaceutical raw materials with significantly different powder properties. The developed feed-forward control strategy enables a constant feed rate with a minimum deviation from the set-point, even for materials that are typically difficult to accurately feed (e.g., due to high cohesion or low density) using conventional continuous feeders. Density variations observed during the feeding process were characterized via a displacement feed factor profile for each powder. The characterized effective displacement density profile was applied in the micro-feeder system to proactively control the feed rate by manipulating the powder displacement rate (i.e., computing the feed rate from the powder displacement rate). Based on the displacement feed factor profile, the feed rate can be predicted during the feeding process and at any feed rate set-point. Three pharmaceutically relevant materials were used for the micro-feeder evaluation: di-calcium phosphate (large-particle system, high density), croscarmellose sodium (small-particle system, medium density), and barium sulfate (very small-particle <10 μm, high density). A significant improvement in the feeding performance was achieved for all investigated materials. The feed rate deviation from the set-point and its relative standard deviation were minimal compared to operations without the control strategy.
Jin Niu, Van Anh Nguyen, Mohammad Ghasemi, Ting Chen,
Published: 7 October 2021
The AAPS Journal, Volume 23, pp 1-15; https://doi.org/10.1208/s12248-021-00640-7

The publisher has not yet granted permission to display this abstract.
Manal A. Elsheikh, Samar A. Rizk, , Ossama Y. Abdallah
Published: 6 October 2021
AAPS PharmSciTech, Volume 22, pp 1-12; https://doi.org/10.1208/s12249-021-02112-9

The publisher has not yet granted permission to display this abstract.
, Pan Gao, Zhujun Jiang, Qiao Luo, Chengqiao Mu, Mengsuo Cui
Published: 5 October 2021
AAPS PharmSciTech, Volume 22, pp 1-12; https://doi.org/10.1208/s12249-021-02085-9

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Rahil Dalal, , Bapi Gorain, Hira Choudhury, Shery Jacob, Tejal A. Mehta, Hiral Shah, Anroop B. Nair
Published: 4 October 2021
AAPS PharmSciTech, Volume 22, pp 1-20; https://doi.org/10.1208/s12249-021-02132-5

The publisher has not yet granted permission to display this abstract.
Andrew F. Dengler, Rachel Weiss, Tiffany Truong, Susan C. Irvin, Nidhi Gadhia, Mohamed Hassanein, Camille Georgaros, Jessica-Ann Taylor, Anne Paccaly, Giane Sumner, et al.
Published: 4 October 2021
The AAPS Journal, Volume 23, pp 1-10; https://doi.org/10.1208/s12248-021-00643-4

Abstract:
Monoclonal antibodies (mAbs) are a leading class of biotherapeutics. In oncology, patients often fail on early lines of biologic therapy to a specific target. Some patients may then enroll in a new clinical trial with a mAb specific for the same target. Therefore, immunoassays designed to quantify the current mAb therapy or assess immunogenicity to the drug may be susceptible to cross-reactivity or interference with residual prior biologics. The impact of two approved anti-PD-1 mAbs, pembrolizumab and nivolumab, was tested in several immunoassays for cemiplimab, another approved anti-PD-1 mAb. The methods included a target-capture drug concentration assay, a bridging anti-drug antibody (ADA) assay and a competitive ligand-binding neutralizing antibody (NAb) assay. We also tested bioanalytical strategies to mitigate cross-reactivity or interference in these assays from other anti-PD-1 biologics. Both pembrolizumab and nivolumab cross-reacted in the cemiplimab drug concentration assay. This was mitigated by addition of antibodies specific to pembrolizumab or nivolumab. ADA specific for pembrolizumab and nivolumab did not interfere in the cemiplimab ADA assay. However, pembrolizumab and nivolumab generated a false-positive response in a target-capture NAb assay. Our results demonstrate that similar exogenous pre-existing anti-PD-1 mAbs (biotherapeutics) such as pembrolizumab and nivolumab are detected and accurately quantified in the cemiplimab drug concentration assay. However, once steady state is achieved for the new therapy, prior biologics would likely not be detected. Cross-reactivity and interference in immunoassays from previous treatment with class-specific biotherapeutic(s) pose significant bioanalytical challenges, especially in immuno-oncology. Graphical abstract
Mumuni Sumaila, Thashree Marimuthu, Pradeep Kumar,
Published: 30 September 2021
AAPS PharmSciTech, Volume 22, pp 1-25; https://doi.org/10.1208/s12249-021-02124-5

The publisher has not yet granted permission to display this abstract.
Gayathri Ramachandran,
Published: 30 September 2021
AAPS PharmSciTech, Volume 22, pp 1-15; https://doi.org/10.1208/s12249-021-02125-4

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Shuang Li, Jueshuo Guo, Zonghua Tian, Jing Chen, Guojing Gou, Yang Niu, ,
Published: 29 September 2021
AAPS PharmSciTech, Volume 22, pp 1-17; https://doi.org/10.1208/s12249-021-02123-6

The publisher has not yet granted permission to display this abstract.
, Suthep Saengsod, Sontaya Limmatvapirat
Published: 29 September 2021
AAPS PharmSciTech, Volume 22, pp 1-9; https://doi.org/10.1208/s12249-021-02127-2

The publisher has not yet granted permission to display this abstract.
Kai-Wei Wu, Corinne Sweeney, Narendar Dudhipala, Prit Lakhani, Narayan D. Chaurasiya, Babu L. Tekwani,
Published: 29 September 2021
AAPS PharmSciTech, Volume 22, pp 1-12; https://doi.org/10.1208/s12249-021-02108-5

The publisher has not yet granted permission to display this abstract.
Sudeep Sudesh Pukale, Anupama Mittal,
Published: 24 September 2021
AAPS PharmSciTech, Volume 22, pp 1-17; https://doi.org/10.1208/s12249-021-02116-5

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, Mitra Azadeh, George Buchlis, Travis Harrison, Mike Havert, Vibha Jawa, Brian Long, Jim McNally, Mark Milton, Robert Nelson, et al.
Published: 16 September 2021
The AAPS Journal, Volume 23, pp 1-17; https://doi.org/10.1208/s12248-021-00628-3

The publisher has not yet granted permission to display this abstract.
, Alexander Abbott, Yelizaveta Babayan, Jenny Carhart, Chi-Wan Chen, Elke Debie, Mingkun Fu, Cherokee Hoaglund-Hyzer, Andrew Lennard, Hanlin Li, et al.
Published: 16 September 2021
The AAPS Journal, Volume 23, pp 1-9; https://doi.org/10.1208/s12248-021-00641-6

The publisher has not yet granted permission to display this abstract.
Ruchika Bajaj, Lisa B Chong, Ling Zou, Eleftheria Tsakalozou, Zhanglin Ni, Kathleen M Giacomini,
Published: 15 September 2021
The AAPS Journal, Volume 23, pp 1-12; https://doi.org/10.1208/s12248-021-00631-8

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Zhicheng Wang,
Published: 10 September 2021
The AAPS Journal, Volume 23, pp 1-8; https://doi.org/10.1208/s12248-021-00630-9

The publisher has not yet granted permission to display this abstract.
C. Lagan, , J. M. Katz, B. Khorsand, D. Daurio, G. P. Andrews, J. Chung, F. Alvarez-Nunez
Published: 8 September 2021
AAPS PharmSciTech, Volume 22, pp 1-9; https://doi.org/10.1208/s12249-021-02122-7

The publisher has not yet granted permission to display this abstract.
Aman Gour, , Narendra Kumar Jain
Published: 2 September 2021
AAPS PharmSciTech, Volume 22, pp 1-8; https://doi.org/10.1208/s12249-021-02103-w

The publisher has not yet granted permission to display this abstract.
, Maitham Naqvi, Dillan Pattni, Aderonke Ayinke Adepoju-Bello
Published: 31 August 2021
AAPS PharmSciTech, Volume 22, pp 1-18; https://doi.org/10.1208/s12249-021-02105-8

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Karim S. Shalaby, Muhammad I. Ismail,
Published: 31 August 2021
AAPS PharmSciTech, Volume 22, pp 1-9; https://doi.org/10.1208/s12249-021-02040-8

Abstract:
Cyclodextrin (CD) complexes are frequently used for enhancing the solubility or absorption of poorly water-soluble drugs. On the contrary, little is known about their complex formation with water-soluble drugs. Here, we have studied the interaction between 2-hydroxypropyl β-CD (HPβCD) and three water-soluble drugs, namely naloxone (NX), oxycodone (OC), and tramadol (TR), by isothermal titration calorimetry (ITC) combined with molecular modeling in view of the potential impact on drug release. The results showed that the complex formation of HPβCD with all three drugs occurs spontaneously. The complexes formed with NX and OC were found to be 2NX:1HPβCD and 3OC:2HPβCD, respectively. TR was found to form 2 complexes with HPβCD; of 1:2 and 1:1 complexation ratios. The binding of HPβCD to NX was greater than to OC due to the higher hydrophobicity of the structure of the former. Moreover, the binding affinity of HPβCD to TR was higher than to OC, which indicated the effect of the higher flexibility of the guest in increasing the binding affinity. In vitro drug release experiments from the various complexes revealed a significant impact of the stoichiometry of the complex on the release profiles. Accordingly, the co-administration of cyclodextrins with water-soluble drugs should be closely monitored, as it may result in unintentional complex formation that can potentially impact the drugs’ gastrointestinal absorption.
Asha J Kapetas, , Michael J Sorich, Ross A McKinnon, A David Rodrigues, Andrew Rowland, Ashley M Hopkins
Published: 31 August 2021
The AAPS Journal, Volume 23, pp 1-8; https://doi.org/10.1208/s12248-021-00632-7

The publisher has not yet granted permission to display this abstract.
, David T. Vodak, Philip J. Kuehl, David Revelli, Yue Zhou, Amanda M. Pluntze, Molly S. Adam, Julia C. Oddo, Lauren Switala, Jonathan L. Cape, et al.
Published: 31 August 2021
AAPS PharmSciTech, Volume 22, pp 1-11; https://doi.org/10.1208/s12249-021-02095-7

Abstract:
Local delivery of biotherapeutics to the lung holds great promise for treatment of lung diseases, but development of physically stable, biologically active dry powder formulations of large molecules for inhalation has remained a challenge. Here, spray drying was used to manufacture a dry powder pulmonary formulation of bevacizumab, a monoclonal antibody approved to treat non-small cell lung cancer (NSCLC) by intravenous infusion. By reformulating bevacizumab for local delivery, reduced side effects, lower doses, and improved patient compliance are possible. The formulation had aerosol properties suitable for delivery to the deep lung, as well as good physical stability at ambient temperature for at least 6 months. Bevacizumab’s anti-VEGF bioactivity was not impacted by the manufacturing process. The formulation was efficacious in an in vivo rat model for NSCLC at a 10-fold decrease in dose relative to the intravenous control.
, Nabil K. Alruwaili, Syed Sarim Imam, Omar Awad Alsaidan, Khalid Saad Alharbi, Mohd Yasir, Mohammed Elmowafy, Elshaer F. Mohammed, Ziad H. Al-Oanzi
Published: 31 August 2021
AAPS PharmSciTech, Volume 22, pp 1-16; https://doi.org/10.1208/s12249-021-02098-4

The publisher has not yet granted permission to display this abstract.
, Michael Pourdehnad, Soraya Carrancio, Daniel W. Pierce, Shailaja Kasibhatla, Mark McConnell, Matthew W. B. Trotter, Remco Loos, ,
Published: 27 August 2021
The AAPS Journal, Volume 23, pp 1-13; https://doi.org/10.1208/s12248-021-00623-8

Abstract:
Avadomide is a cereblon E3 ligase modulator and a potent antitumor and immunomodulatory agent. Avadomide trials are challenged by neutropenia as a major adverse event and a dose-limiting toxicity. Intermittent dosing schedules supported by preclinical data provide a strategy to reduce frequency and severity of neutropenia; however, the identification of optimal dosing schedules remains a clinical challenge. Quantitative systems pharmacology (QSP) modeling offers opportunities for virtual screening of efficacy and toxicity levels produced by alternative dose and schedule regimens, thereby supporting decision-making in translational drug development. We formulated a QSP model to capture the mechanism of avadomide-induced neutropenia, which involves cereblon-mediated degradation of transcription factor Ikaros, resulting in a maturation block of the neutrophil lineage. The neutropenia model was integrated with avadomide-specific pharmacokinetic and pharmacodynamic models to capture dose-dependent effects. Additionally, we generated a disease-specific virtual patient population to represent the variability in patient characteristics and response to treatment observed for a diffuse large B-cell lymphoma trial cohort. Model utility was demonstrated by simulating the avadomide effect in the virtual population for various dosing schedules and determining the incidence of high-grade neutropenia, its duration, and the probability of recovery to low-grade neutropenia.
, Susan Bogdanowich-Knipp, Daniel Smith, Matthias Zeller, Stephen Byrn, Pamela Smith, Dale K. Purcell, Kari Clase
Published: 25 August 2021
AAPS PharmSciTech, Volume 22, pp 1-16; https://doi.org/10.1208/s12249-021-02106-7

Abstract:
Bedaquiline is used to treat multi-resistant tuberculosis in adults. The fumarate salt is commercially available and used in the product Sirturo. To provide open access to bedaquiline molecule once the patent on the chemical substance expires, new salts were screened. This work offers additional information on the bedaquiline system, as new salts may present better pharmacokinetic properties. The current studies focus on the attempted isolation of the acetate, benzoate, benzenesulfonate, hydrobromide, succinate, hydrochloride, tartrate, lactate, maleate, malate, and mesylate salts of bedaquiline. Potential salts were screened using a unique combination of conventional screening, and small-scale experiments supplemented by crystallographic analysis and infrared microspectroscopy. Salts were prepared on a larger scale by dissolving 1:1 ratios of the individual salt formers and bedaquiline base (30 mg, 0.055 mmol) in different solvents and allowing the solutions to evaporate or crystallize. X-ray diffraction (XRD) techniques and spectroscopic and thermal analyses were employed to characterize the salts. The benzoate and maleate salts were selected as lead candidates after reviewing preliminary characterization data. To determine the most stable forms for the leads, a polymorph screen was conducted using solvents of various polarities. These salt screens successfully generated five new salts of bedaquiline, namely, benzoate, maleate, hydrochloride, besylate, and mesylate. The existence of these salts was confirmed by powder XRD, proton NMR, and IR spectroscopies. TGA and DSC thermal analysis along with hot-stage optical microscopy were further used to characterize the salts. The polymorph screen conducted on the salts suggested the absence of additional polymorphs at 1 g scale.
, Keita Teruya, Yasuhiro Abe, Takayuki Furuishi, Kaori Fukuzawa, Etsuo Yonemochi, Ken-Ichi Izutsu
Published: 24 August 2021
AAPS PharmSciTech, Volume 22, pp 1-11; https://doi.org/10.1208/s12249-021-02117-4

The publisher has not yet granted permission to display this abstract.
Tingting Qin, Libiao Yan, Xin Wang, Siqi Lin,
Published: 23 August 2021
AAPS PharmSciTech, Volume 22, pp 1-13; https://doi.org/10.1208/s12249-021-02088-6

The publisher has not yet granted permission to display this abstract.
, Kevin J. Carroll, J. David Christopher, Beth Morgan, Scott Haughie, Alessandro Cavecchi, Christopher Wiggenhorn, Hayden Beresford, Helen Strickland, Svetlana Lyapustina
Published: 19 August 2021
AAPS PharmSciTech, Volume 22, pp 1-11; https://doi.org/10.1208/s12249-021-02063-1

Abstract:
Batch-to-batch pharmacokinetic (PK) variability of orally inhaled drug products has been documented and can render single-batch PK bioequivalence (BE) studies unreliable; results from one batch may not be consistent with a repeated study using a different batch, yet the goal of PK BE is to deliver a product comparison that is interpretable beyond the specific batches used in the study. We characterized four multiple-batch PK BE approaches to improve outcome reliability without increasing the number of clinical study participants. Three approaches include multiple batches directly in the PK BE study with batch identity either excluded from the statistical model (“Superbatch”) or included as a fixed or random effect (“Fixed Batch Effect,” “Random Batch Effect”). A fourth approach uses a bio-predictive in vitro test to screen candidate batches, bringing the median batch of each product into the PK BE study (“Targeted Batch”). Three of these approaches (Fixed Batch Effect, Superbatch, Targeted Batch) continue the single-batch PK BE convention in which uncertainty in the Test/Reference ratio estimate due to batch sampling is omitted from the Test/Reference confidence interval. All three of these approaches provided higher power to correctly identify true bioequivalence than the standard single-batch approach with no increase in clinical burden. False equivalence (type I) error was inflated above the expected 5% level, but multiple batches controlled type I error better than a single batch. The Random Batch Effect approach restored 5% type I error, but had low power for small (e.g., <8) batch sample sizes using standard [0.8000, 1.2500] bioequivalence limits.
, Kevin J. Carroll, Johanna Mielke, Byron Jones, Leslie Z. Benet
Published: 19 August 2021
AAPS PharmSciTech, Volume 22, pp 1-8; https://doi.org/10.1208/s12249-021-02064-0

The publisher has not yet granted permission to display this abstract.
Feroz Jameel, Alina Alexeenko, Akhilesh Bhambhani, Gregory Sacha, Tong Zhu, Serguei Tchessalov, Lokesh Kumar, Puneet Sharma, Ehab Moussa, Lavanya Iyer, et al.
Published: 18 August 2021
AAPS PharmSciTech, Volume 22, pp 1-18; https://doi.org/10.1208/s12249-021-02086-8

Abstract:
This work describes lyophilization process validation and consists of two parts. Part I focuses on the process design and is described in the current paper, while part II is devoted to process qualification and continued process verification. The intent of these articles is to provide readers with recent updates on lyophilization validation in the light of community-based combined opinion on the process and reflect the industrial prospective. In this paper, the design space approach for process design is described in details, and examples from practice are provided. The approach shows the relationship between the process inputs; it is based on first principles and gives a thorough scientific understanding of process and product. The lyophilization process modeling and scale-up are also presented showing the impact of facility, equipment, and vial heat transfer coefficient. The case studies demonstrating the effect of batch sizes, fill volume, and dose strength to show the importance of modeling as well as the effect of controlled nucleation on product resistance are discussed.
Jinyan Wan, Yu Long, Songyu Liu, Yulu Zhang, Yan Xiang, Dan Li, Ai Shi, Yu Shuang, Ying Li, Yanan He, et al.
Published: 18 August 2021
AAPS PharmSciTech, Volume 22, pp 1-12; https://doi.org/10.1208/s12249-021-02093-9

The publisher has not yet granted permission to display this abstract.
Osamah Malallah, Zara Rashid, Chee Lok Li, Abdulmalik Alqurshi, Mohamed A. Alhanan, Ben Forbes,
Published: 16 August 2021
AAPS PharmSciTech, Volume 22, pp 1-13; https://doi.org/10.1208/s12249-021-02080-0

Abstract:
Measuring tablet disintegration is essential for quality control purposes; however, no established method adequately accounts for the timeframe or small volumes of the medium associated with the dissipation process for fast disintegrating tablets (FDTs) in the mouth. We hypothesised that digital imaging to measure disintegration in a low volume of the medium might discriminate between different types of FTD formulation. A digital image disintegration analysis (DIDA) was designed to measure tablet disintegration in 0.05–0.7 mL of medium. A temperature-controlled black vessel was 3D-printed to match the dimensions of each tablet under investigation. An overhead camera recorded the mean grey value of the tablet as a measure of the percentage of the formulation which remained intact as a function of time. Imodium Instants, Nurofen Meltlets and a developmental freeze-dried pilocarpine formulation were investigated. The imaging approach proved effective in discriminating the disintegration of different tablets (p < 0.05). For example, 10 s after 0.7 mL of a saliva simulant was applied, 2.0 ± 0.3% of the new pilocarpine tablet remained, whereas at the same time point, 22 ± 9% of the Imodium Instants had not undergone disintegration (temperature within the vessel was 37 ± 0.5°C). Nurofen Meltlets were observed to swell and showed a percentage recovery of 120.7 ± 2.4% and 135.0 ± 6.1% when 0.05 mL and 0.7 mL volumes were used, respectively. Thus, the new digital image disintegration analysis, DIDA, reported here effectively evaluated fast disintegrating tablets and has the potential as a quality control method for such formulations.
Lauren E. Waggoner, Marianne I. Madias, Alan A. Hurtado,
Published: 16 August 2021
The AAPS Journal, Volume 23, pp 1-12; https://doi.org/10.1208/s12248-021-00626-5

Abstract:
Peptides are used to control the pharmacokinetic profiles of nanoparticles due to their ability to influence tissue accumulation and cellular interactions. However, beyond the study of specific peptides, there is a lack of understanding of how peptide physicochemical properties affect nanoparticle pharmacokinetics, particularly in the context of traumatic brain injury (TBI). We engineered nanoparticle surfaces with peptides that possess a range of physicochemical properties and evaluated their distribution after two routes of administration: direct injection into a healthy mouse brain and systemic delivery in a mouse model of TBI. In both administration routes, we found that peptide-modified nanoparticle pharmacokinetics were influenced by the charge characteristics of the peptide. When peptide-modified nanoparticles are delivered directly into the brain, nanoparticles modified with positively charged peptides displayed restricted distribution from the injection site compared to nanoparticles modified with neutral, zwitterionic, or negatively charged peptides. After intravenous administration in a TBI mouse model, positively charged peptide-modified nanoparticles accumulated more in off-target organs, including the heart, lung, and kidneys, than zwitterionic, neutral, or negatively charged peptide-modified nanoparticles. The increase in off-target organ accumulation of positively charged peptide-modified nanoparticles was concomitant with a relative decrease in accumulation in the injured brain compared to zwitterionic, neutral, or negatively charged peptide-modified nanoparticles. Understanding how nanoparticle pharmacokinetics are influenced by the physicochemical properties of peptides presented on the nanoparticle surface is relevant to the development of nanoparticle-based TBI therapeutics and broadly applicable to nanotherapeutic design, including synthetic nanoparticles and viruses. Graphical abstract
, Uday Arvind Deokate, Sachidanand Shankar Angadi
Published: 13 August 2021
AAPS PharmSciTech, Volume 22, pp 1-14; https://doi.org/10.1208/s12249-021-02100-z

The publisher has not yet granted permission to display this abstract.
Shibani Mitra-Kaushik, Anita Mehta-Damani, Jennifer J. Stewart, Cherie Green, Virginia Litwin,
Published: 13 August 2021
The AAPS Journal, Volume 23, pp 1-15; https://doi.org/10.1208/s12248-021-00633-6

The publisher has not yet granted permission to display this abstract.
, Roland F. Staack
Published: 13 August 2021
The AAPS Journal, Volume 23, pp 1-6; https://doi.org/10.1208/s12248-021-00625-6

Abstract:
The testing of protein drug candidates for inducing the generation of anti-drug antibodies (ADA) plays a fundamental role in drug development. The basis of the testing strategy includes a screening assay followed by a confirmatory test. Screening assay cut points (CP) are calculated mainly based on two approaches, either non-parametric, when the data set does not appear normally distributed, or parametric, in the case of a normal distribution. A normal distribution of data is preferred and may be achieved after outlier exclusion and, if necessary, transformation of the data. The authors present a Weibull transformation and a comparison with a decision tree-based approach that was tested on 10 data sets (healthy human volunteer matrix, different projects). Emphasis is placed on a transformation calculation that can be easily reproduced to make it accessible to non-mathematicians. The cut point value and the effect on the false positive rate as well as the number of excluded samples of both methods are compared.
Emileigh Greuber, Kip Vought, Kalpana Patel, Hiroaki Suzuki, Kazuhiro Usuda, Akira Shiramizu, Luana Pesco Koplowitz, Barry Koplowitz, Howard I. Maibach,
Published: 12 August 2021
AAPS PharmSciTech, Volume 22, pp 1-10; https://doi.org/10.1208/s12249-021-02101-y

Abstract:
Recently, lidocaine topical systems utilizing nonaqueous matrices have been developed and provide efficient lidocaine delivery through the skin, such that lower concentrations of drug provide equivalent or greater drug delivery than drug-in-matrix hydrogel lidocaine patches. This study characterizes drug delivery from a nonaqueous lidocaine topical system with increasing drug load both in vitro and in vivo. Topical systems formulated with either 1.8% or 5.4% lidocaine were applied to healthy volunteers’ backs (n = 15) for 12 h in a single-center, open-label, four-treatment, four-period crossover pharmacokinetic study. Subjects were dosed with either three 1.8% systems or one, two, or three 5.4% systems in each period. Blood was collected for up to 48 h, and plasma lidocaine levels were measured with a validated HPLC method. In parallel, human and mouse skin models characterized the in vitro skin permeation profile. The pharmacokinetic profile was linear between one, two, and three lidocaine 5.4% applications. Application of three lidocaine 1.8% systems (108 mg lidocaine) was bioequivalent to one lidocaine 5.4% system (108 mg lidocaine). Both topical systems remained well adhered to the skin and irritation was mild. The 5.4% system had approximately threefold higher skin permeability than the 1.8% system in the mouse and human skin models. The results indicate increasing the drug load by three times results in triple the drug delivery both in vivo and in vitro. The relationship between the in vitro permeation and in vivo absorption correlates and is nonlinear.
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