Pharmaceutics

Oral microemulsions are one drug delivery system often implemented to improve intestinal permeability and oral bioavailability of poorly-water soluble drugs. They also present several practical advantages including high patient compliance and simplified manufacturing methods which contribute to their promise as marketable drug products. Despite these advantages, however, the microemulsion formulation development process is extremely time consuming and resource intensive, typically involving extensive screening of components and excessive preliminary trials in order to achieve stable formulations. As a result, MEs are often suboptimal in their therapeutic performance, and there is an unmet need for improved methods to streamline microemulsion formulation design. In this work, a batch Bayesian Optimization strategy was used to design a subset of unique in-specification microemulsions with highly optimized physicochemical properties in five iterations containing batches of five experiments. A two-phase modeling approach was developed to achieve this goal and allowed for navigating a complex experimental design space, including multiple oils, surfactants, cosurfactants, and processing parameters with a training dataset consisting of 22 experiments. As a result of this study, five high-performing blank microemulsions were identified, and four of them exhibited physical stability upon storage for up to 30 days. Further, when loaded with two different model drug candidates, three of the microemulsions achieved high drug loading, acceptable stability and improved in-vitro permeability, highlighting their promise for potential translation to later stages of development.

This work develops and characterises a hierachichal oral drug delivery system based on the microencpasulation of drug-loaded amphiphilic nanogels within a mucoadhesive alginate/chitosan shell. Results show a more controlled release and a statistically significant oral half-life with respect to the free drug.

Treatment of neurological disorders such as Alzheimers disease remains a challenge due to ineffective drug delivery to the brain. In recent years, intranasal administration has emerged as a promising non-invasive approach for nose-to-brain delivery. Compared to other routes of administration, nose-to-brain delivery provides a possibility of bypassing both the blood-brain-barrier and the first-pass metabolism in the liver, allowing for a decrease in the delivered dose and thereby a reduced risk of systemic side-effects. While the most common nasal devices, spray pumps, ensure a wide distribution in the nasal cavity and a fast onset of action, a slower release and increased retention time is desired for treatment of many neurological disorders. In this study, we tested the feasibility of a novel nasal insert, NosaPlugs, for prolonged release and delivery of memantine. Using an in vitro anatomically realistic nasal model, we demonstrated cumulative release of memantine from the nasal inserts up to eight hours. Additionally, the therapeutic substance was distributed to all parts of the nasal cavity, with higher amounts accumulating in the middle part. In vivo, an acute dose of memantine in the gas phase released from the nasal device reached pharmacologically relevant levels in both plasma and the brains of the mice. Future research should investigate the release and delivery of alternative substances interesting for brain diseases, and larger animal models are required to determine the efficacy of nose-to-brain delivery using NosaPlugs nasal inserts. Importantly, our study provides the first proof-of-concept that NosaPlugs can serve as an effective intranasal device for targeted drug delivery to the brain.

APOSECTM, a complex mixture of secreted proteins, lipids, and extracellular vesicles from stressed peripheral blood monocytes, is currently in clinical trials for the treatment of chronic, poorly healing wounds. When applied to open wounds, 1 mL reconstituted APOSECTM lyophilisate is syringe-mixed with 3 g sterile hydrogel prior to administration. This study investigates the pharmaceutical performance of this novel administration system. A gel formulation (APOgel) was developed for terminal sterilisation in pre-filled syringes with post-sterilisation viscosity ([~]325-350{square}Pa*s at 1{square}s-1) comparable to a commercial benchmark gel. Syringe mixing of APOgel with a liquid APOSECTM surrogate (3:1) reduced viscosity by [~]67% but was highly reproducible across different operators (CV < 6%). Administration of three sequential dose units of the mixture from the syringe revealed an [~]20% higher content of active ingredients in the first and final dispensed compared to the middle unit, indicating non-uniform mixing in the closed syringe system. In vitro release studies over 72{square}h showed a 32% and 48% higher release of a small molecule marker and total proteins from the sterile APOgel compared to the benchmark gel as well as more pronounced gel swelling. However, efficacy studies in a murine wound healing model showed no significant difference between APOgel and the benchmark. These findings indicate that terminal sterilisation of gels for topical applications may provide benefits for more rapid release of active agents but syringe mixing of gels and a liquid requires optimisation to ensure uniform drug distribution. HighlightsO_LIAn autoclavable hydrogel for APOSECTM delivery was developed C_LIO_LIA novel syringe-mixing system for combining a gel with a liquid with subsequent dispensing of different volume units showed non-homogenous active ingredient distribution C_LIO_LIFinal optimised APOSECTM-APOgel formulation maintains functional wound-healing efficacy C_LI

Background/ObjectivesThe quality and characteristics of approved medicines can vary substantially depending on manufacturing processes and standards within a given country. The aim of the study was to compare the available marketed brands of ademetionine tablets derived from various countries in order to identify potential differences between the different formulations. MethodsWe performed comprehensive analyses of the physical, chemical, and dissolution characteristics of different formulations of ademetionine tablets marketed in China, India, Russia, Ukraine, and Uzbekistan, using the originator formulation of Heptral(R) as the reference standard. The formulations were evaluated at initial analysis and after 3 months at 40{degrees}C/75% relative humidity. Clinical parameters such as ademetionine content, degradation products, S,S-isomer, and water content were assessed using HPLC, and a dissolution profile analysis performed in 2 hours of acid solution followed by 90 minutes in a buffer solution. ResultsThe Nusam (India) and Ximeixin (China) products were the two products most comparable to the Heptral products. Adenomak (Ukraine), the only food-grade product and only one with the tosylate salt showed the most significant quality variations compared to Heptral including dissolution failure as well as considerable variability between batches. ConclusionsThe study highlights the importance of using pharmaceutical-grade ademetionine products to maintain clinical efficacy and ensuring standards are maintained across global markets.

PurposeDespite advances in oral and injectable HIV prevention options and oral prophylaxis for sexually transmitted infections (STIs) of bacterial origin, there remains a critical need for effective on-demand topical (vaginal/rectal) products for pre- and post-exposure prophylaxis (PrEP and PEP). To fill this gap, we have developed single and first-in-kind multi-active topical inserts for bacterial STIs and HIV/STIs prevention. MethodsWe have formulated two different inserts, one containing doxycycline (DOX) at 10, 50, and 100mg doses for bacterial STI prevention, and a multipurpose prevention product (TED insert) that combines DOX (10mg) with the antiretrovirals tenofovir alafenamide (TAF; 20mg) and elvitegravir (EVG; 16mg) to target both bacterial STIs and HIV. ResultsInserts were manufactured through a simple, cost-effective process. Drug loading was within 95-105% of the labeled amount, confirming a robust manufacturing process. In vitro, they disintegrated within 10min with >95% drug release within 60min. The dissolution behavior of DOX inserts showed surface erosion but was affected by medium volume and drug amount. The inserts met key physicochemical targets: hardness (5-8kg), friability (<1%), moisture content (<2%), and osmolality (<550mOsm/kg). Based on 6-month storage stability, DOX inserts maintained their physicochemical properties, suggesting a shelf life of >2years. Preliminary 1-month stability of TED inserts under accelerated conditions showed preservation of their physicochemical properties. ConclusionThis study represents the first formulation development report on topical inserts containing DOX alone or in combination with antiretrovirals. Both inserts offer a novel, on-demand topical STI prevention option that supports flexible PrEP/PEP use by both women and men.

Biotherapeutics are required to achieve high remission rates in patients with severe ulcerative colitis (UC); however, adverse effects, complex dosing regimens, administration routes, and low patient compliance may limit their widespread clinical use. Given the localized nature of UC, this study aimed to develop and evaluate a localized delivery strategy for infliximab (IFX), an anti-tumor necrosis factor- (TNF-) monoclonal antibody (mAb) recommended by the European Crohns and Colitis Organization (ECCO) and the American Crohns & Colitis Foundation for moderately-to-severely active UC. Exploiting the intrinsic biocompatibility, mucoadhesivity, and protein-entrapment capacity of lipid mesophases (LMPs), IFX was encapsulated within the gel matrix, providing protection against enzymatic and environmental degradation. IFX-loaded LMPs were designed for targeted delivery to inflamed colonic tissues via rectal or oral administration, with patient-centric oral dosage forms manufactured using a 3D printing approach. A comprehensive physicochemical characterization was performed to elucidate mesophase self-assembly and its relationship with IFX release profiles in biorelevant fluids. Therapeutic efficacy was evaluated in vivo using a dextran sulfate sodium (DSS)-induced colitis rat model, which demonstrated rectal gel retention for at least 8 h and colonic targeting of the oral formulation within 6 h. Under severe inflammatory conditions, LMP-based formulations reduced disease activity, inflammatory biomarkers (TNF- and fecal lactoferrin), and colon shortening to values comparable to those of healthy controls, outperforming the therapeutic efficacy of subcutaneous IFX. Overall, this study establishes a biocompatible delivery platform that enables targeted colonic IFX release and suppresses systemic absorption, representing a promising advancement in the biotherapeutic treatment of UC.

In siRNA-based applications, cellular delivery remains one of the main hurdles. Many formulations are tested for the same and peptides came up as one of the optimal options. The latter have various advantages like natural biological presence, high specificity, and natural metabolism etc. siRNA in conjugation with peptides have exhibited enhanced mRNA silencing. Peptides aid siRNAs in condensation to smaller volumes, enhance nuclease protection, increase half-life, promote cell specific binding as well as endosomal escape and release in cytosol. Despite its prime importance, no resource is available for the peptide-based delivery of siRNAs, therefore to fill the gap we developed PEPsRNA web server. It includes 2266 entries of 270 different kinds of peptides, 106 different types of siRNAs and shRNAs along with more than 80 conjugate molecules targeting 55 different genes, experimentally tested for the delivery of the siRNAs. To provide the detailed insights of the procedure, we have incorporated analysis of the peptides (e.g. secondary structure, amino acid composition, polarity, hydrophobicity etc.), siRNAs (e.g. secondary structures with minimum free energies etc.) and associated conjugate molecules (e.g. structure, SMILES, Inchl). We have derived these values using various other tools and resources to make the web server comprehensive. We further compared various physicochemical properties with the efficacy of the peptide based on the target gene silencing, but these properties do not shown any distinct conclusive relationship. The data is available for browsing, searching and downloading freely on the web server with URL: http://bioinfo.imtech.res.in/manojk/pepsirna. Highlights PEPsRNA is the first database of experimentally tested peptides for siRNA delivery It comprised of 2266 entries with 270 peptides and about 80 conjugate molecules Analysis of peptides, siRNAs and details of conjugate molecules are provided Browse, search and various tools are incorporated for data retrieval and usage

BackgroundExtracellular vesicles (EVs) are nano and macro-sized, lipid-bound particles, involved in cellular communication. Interestingly, cancer-derived EVs show a heterologous and cross-species tumour tropism which makes them a potential tool for efficient delivery of therapeutic small interfering RNA (siRNA) to the tumour cells. MethodsEVs derived from glioblastoma cells (U373P and U373vIII) were loaded with EGFRvIII siRNA to develop a targeted therapeutic strategy against glioblastoma. EV biodistribution was evaluated using fluorescent indocyanine green (ICG) staining followed by ex vivo imaging. Different loading strategies, including passive loading, sonication, saponin-mediated membrane permeabilization, electroporation, and transfection were assessed for their efficiency in loading siRNA into EVs. The efficiency of each method was evaluated by nano flowcytometry, in vitro uptake assay followed by immunoblot (western blot) analysis. Eventually, the most effective formulation was tested for the systemic siRNA administration and selective tumour delivery in vivo, followed by evaluation of tumour size and EGFRvIII expression. ResultsHere, we showed that siRNA transfection into EVs was the most effective loading strategy, as confirmed by nano-flow cytometry, uptake assays, and western blot analysis, achieving over 90% knockdown efficiency in vitro for EVs carrying EGFRvIII siRNA. In vivo, EGFRvIII siRNA-loaded EVs homed to the tumour site and downregulated EGFRvIII expression compared with the PBS-siRNA control group; however, no significant tumour shrinkage was observed. ConclusionEGFRvIII-targeting, glioblastoma cell-derived EVs can be used as siRNA delivery carriers for targeted gene therapy in glioblastoma. However, further optimization of siRNA delivery and treatment duration is required.

Chemically modified peptides, including cyclic peptides, have emerged as promising candidates for oral delivery yet they face the challenge of low membrane permeability. In this study, the datasets were sourced from CycPeptMPDB, a database for membrane permeability of peptides obtained from different assays. Our quantitative analysis showed a clear discordance between permeability measured using PAMPA and cell-based assays (Caco-2, MDCK, and, RRCK), thereby explaining its limits as surrogate for cell-based assays. Therefore, we developed assay-specific predictive models to more accurately capture permeability determinants in each system. We systematically compute diverse features of modified peptides using open-source software and used fine-tuned peptide embeddings generated using pretrained chemical language models. Baseline models were developed using the generated multi-hierarchical molecular features. We also developed a stacked ensemble architecture, which utilizes multi-hierarchical features in models as base learners. The ensemble model achieved the best PAMPA test set performance with an MSE of 0.200, R2 of 0.685, and PCC of 0.830; and a R2 of 0.783 on Caco-2 test set. Model trained on 2D Mordred descriptors attained the highest performance on the Caco-2 test-set with MSE of 0.129, R2 of 0.793, and PCC of 0.892, surpassing state-of-the-art approaches such as CPMP. To support widespread adoption, we developed an open-access web-server (https://webs.iiitd.edu.in/raghava/pcppred/) for users to design modified peptides using human comprehensible MAP (Modifications and Annotations of Proteins) format, converting MAP to SMILES format, and predict permeability across assays with result visualization. To ensure widespread adoption, and reproducibility, we also provided a standalone on GitHub (https://github.com/raghavagps/pcppred).

The current investigation introduces single-cell physiologically-based pharmacokinetic (scPBPK) models to gain insight into drug disposition at the cellular scale. The transition from standard PBPK (sPBPK) models to scPBPK models required depiction of expression-dependent (ED) processes, such as drug metabolism or membrane transport. ED processes utilize weighting functions - a defined or data-driven distribution -that yield heterogeneity in individual cell kinetics. Two scPBPK model examples are provided, one involving a drug (AZD1775) subject to 3 ED blood-brain barrier transport processes, and another drug (midazolam) with a single ED process of metabolism by hepatocytes. For both examples, the weighting function for each ED process was defined by a negative binomial distribution that is often used in scRNAseq analytics. The AZD1775 model simulations indicated a large degree of single cell drug concentration heterogeneity, whereas those for midazolam did not, due to high membrane transport relative to metabolism. scPBPK models offer a means to probe cellular pharmacokinetics compatible with modern omic technologies and may be extended to pharmacodynamic models. TeaserThe modeling framework to predict drug concentrations in single cells is presented.

The hollow fiber infection model (HFIM) is a translational in vitro model that links time-varying human pharmacokinetic profiles to the associated viral dynamic responses, from which pharmacokinetic/pharmacodynamic (PK/PD) targets can be derived. Establishing such targets is essential for antiviral dose selection and optimization. This is particularly important for cytomegalovirus (CMV) infection treatment, which primarily affects vulnerable patient populations. PK/PD targets for ganciclovir, the first-line drug for treatment, are not yet defined. The lack of an undefined PK/PD target makes dose optimization challenging and may result in suboptimal exposure, prolonged toxicity, and the emergence of resistance. For the first time, we have demonstrated the use of a low-cost hemodialyzer hollow fiber cartridge with application for CMV infection using ganciclovir. We have established a system that 1) supports CMV culture for PD analysis, 2) reproduces a clinically relevant ganciclovir PK profile, and 3) maintains consistent drug exposure in the infected cells, allowing reliable PK/PD analysis. Quantitative methods such as tissue culture infectious dose 50% (TCID50) and quantitative PCR were used to assess both active virus replication and genome copies production. Ganciclovir PK was measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS). This validation study serves as a fundamental step that can allow further PK/PD studies for ganciclovir and other antiviral agents that is still largely understudied. Consequently, this model could provide an affordable and practical platform for establishing clinically relevant PK/PD targets and guide treatment optimization.

Voluntary ingestion is a refined method for substance administration that can replace oral gavage in rats and mice. It requires no physical restraint and has no associated risks of adverse effects, resulting in improved welfare and reduced distress for both animals and research staff. This method has been shown to be effective for a variety of compounds but is still not widely used due to concerns about accuracy and reliability. One potential issue is aversion to the taste of the compound being administered, including a common issue of bitter taste. In this study we tested compounds used in oral preparations for human medicines to mask bitter tasting drugs, including a commercial formulation designed for this purpose, Bitter Drug Powder (BDP). The masking agents were given in combination with a palatable vehicle (10% condensed milk) and the amount consumed and time to consume recorded. Animals were first habituated to the vehicle with reliable ingestion achieved within a few days. In the first studies, only BDP was fully effective at masking the bitter taste of quinine and preventing the progressive reduction in reliability of intake of the antidepressant, venlafaxine in mice and rats. We were able to replicate these effects using a combination of two different artificial sweeteners, saccharine and acesulfame K, and a thickening agent xanthan gum. These studies demonstrate that using a masking agent can improve the reliability of voluntary oral dosing in mice and rats and provide evidence to support a formulation which is readily available for researchers.

AbstractInflammation and oxidative stress are key drivers in the pathogenesis of chronic lung diseases, including asthma, pulmonary fibrosis, and chronic obstructive pulmonary disease. Extracellular vesicles derived from the marine microalga Tetraselmis chuii, referred to as nanoalgosomes, have recently gained attention as natural nanocarriers that possess inherent antioxidant and anti-inflammatory properties. In this study, we investigated the biocompatibility and protective effects of aerosolized nanoalgosomes in a bronchial epithelial-macrophage co-culture model at the air-liquid interface. Co-cultures of CALU-3 epithelial cells and differentiated THP-1 macrophages were primed with aerosolised nanoalgosomes and subsequently exposed to either oxidative stress (tert-butyl hydroperoxide) or an inflammatory stimulus (lipopolysaccharide; LPS). Epithelial barrier integrity and cytotoxicity were evaluated using transepithelial electrical resistance and lactate dehydrogenase release assays, respectively, while intracellular reactive oxygen species levels and cytokine secretion were measured to assess antioxidant and immunomodulatory responses. Nanoalgosomes were non-cytotoxic, preserved epithelial barrier integrity, and significantly reduced oxidative stress. In addition, nanoalgosomes priming attenuated LPS-induced secretion of pro-inflammatory cytokines (IL-1{beta}, IL-6, IL-8, IL-18, TNF-) as well as the anti-inflammatory cytokine IL-10, suggesting a balanced immunomodulatory response. Overall, aerosolized nanoalgosomes maintained epithelial homeostasis and mitigated both oxidative and inflammatory stress, underscoring their potential as a safe, sustainable, and effective therapeutic strategy for chronic inflammatory lung diseases. Given their natural origin, excellent biocompatibility, and suitability for aerosol delivery, nanoalgosomes represent a promising class of inhalable biotherapeutics.

Anthracycline induced cardiotoxicity is a significant problem for oncologists and cancer patients. The leading cause of non-cancer death in cancer patients and survivors is heart failure, which is frequently attributed to the exposure to chemotherapeutics like anthracyclines. The most notorious of these chemotherapies is doxorubicin, which causes cardiac contractile dysfunction that in some cases is irreversible. In this study, we report the development of NanoDMX, a phosphatidylserine-containing liposomal formulation of DMX5804, a small molecule inhibitor of MAP4K4, and demonstrate that its administration prevents doxorubicin-induced left ventricular dysfunction in mice. Additionally, we demonstrate that DMX-5804 protects cardiomyocytes in vitro through a combination of mechanisms outside of the expected route of suppressing the JNK pathway. Overall, we demonstrate that the use of NanoDMX, a novel liposomal system using both DMX-5804 and phosphatidylserine, can prevent the damage induced by doxorubicin over the course of a single high dose in vivo model.

mRNA-lipid nanoparticles (LNP) have proven their potential as a rapidly adaptable vaccine platform and promise to revolutionize numerous therapeutic areas. A major hurdle towards the widespread adoption of mRNA-LNP vaccines and therapeutics is their limited liquid shelf-life compared to more established modalities currently necessitating an ultralow temperature cold-chain to enable their distribution and storage. While ongoing efforts aim to improve liquid stability through chemical modification of mRNA and lipid components, complementary strategies that are broadly applicable across chemistries may further accelerate translation. Here, we present an approach to improve the liquid shelf-life of mRNA-LNPs that does not rely on modifications to the mRNA or LNP chemistry. In particular, we show that bleb formation induced by high ionic strength acidic citrate buffers during LNP formation reduces mRNA degradation and retains in vitro activity during extended liquid storage. We observed an increase in the in vitro activity storage half-life from 2.8 to 18.9 days at 25{degrees}C when prepared using high ionic strength buffers translating into a [~]7-fold improvement in the liquid shelf-life of MC3-LNPs. This enhanced stability of LNPs with large amount of bleb formation was mainly attributed to reduced rates of lipid-mRNA adduct formation and mRNA fragmentation. Furthermore, the acidic buffer dependent stabilization was observed across different ionizable lipids with the extent dependent on the ionizable lipid head group. We envision that the induction of bleb formation via selection of appropriate acidic mixing buffers may represent a universal approach to enhance mRNA-LNPs stability and enable extended long-term refrigerated storage.

Target-mediated drug disposition (TMDD) models have been widely used to describe nonlinear pharmacokinetic profiles driven by high-affinity, low-capacity drug-target binding. A pTMDD model, derived by applying the Pade approximation of the quasi-steady-state (QSS) model (qTMDD) was previously proposed. Although pTMDD model showed a comparable estimation accuracy while maintaining computational efficiency, further validation in realistic clinical scenarios and comprehensive performance evaluations have been needed to assess its practical applicability. Here, we evaluated the pTMDD model using five clinical datasets and extended the previous study that focused on simulations. Using the full TMDD as a reference, the approximation models were compared in terms of the parameter estimation results (parameter estimates, relative standard error values and model diagnostics) and computational efficiency (estimation and bootstrap runtimes). The pTMDD model, previously validated in simulation settings, also preserved the estimation accuracy while reducing the computation time of the clinical data. Both pTMDD and qTMDD remained close to the full TMDD model, whereas Michaelis-Menten TMDD (mTMDD) model showed substantial discrepancies especially at low doses, including biased estimates for key TMDD-related parameters (e.g., kdeg, kint, krec, and kup) and higher objective function values. Moreover, pTMDD was faster than qTMDD in four of the five cases compared to the full TMDD. The time savings were particularly pronounced for larger datasets, supporting the computational efficiency of pTMDD. Q2PCONV, an R Shiny application that converts NONMEM code from qTMDD to pTMDD, was also developed, thereby making this new approximation more accessible to researchers. The findings support pTMDD as a practical alternative to existing TMDD approximation models. Author SummaryTarget-mediated drug disposition (TMDD) models describe a high-affinity, low-capacity binding between drug and its target. To avoid overparameterization, approximation models have been used. The two primary models are Michaelis-Menten model (mTMDD), which is accurate only at high doses, and Quasi-steady-state (qTMDD), which is accurate in wider ranges but requires longer runtime. We have proposed a new approximation model named pTMDD. Here, we evaluated pTMDD using five real clinical trial datasets to assess its practical usefulness. pTMDD produced parameter estimates closer to those from the full TMDD model and showed lower uncertainty than both the full TMDD and mTMDD models. In terms of computational efficiency, pTMDD reduced estimation time by an average of 11% and bootstrap time by an average of 6% relative to qTMDD across cases. In addition, we also developed an R shiny application to help researchers apply pTMDD in practice. Our work supports pTMDD as a practical and efficient tool for TMDD modeling in drug development.

Messenger RNA (mRNA) vaccines using lipid nanoparticles (LNPs) are well-established and globally approved with acceptable safety profiles for preventing respiratory disease. Other mRNA-LNP product concepts are also emerging as novel treatments for broader clinical use. Here, we describe mRNA-LNP vaccine tissue distribution and kinetics after intramuscular dosing using three products formulated with same LNP matrix: mRNA-1273 (Spikevax), mRNA-1647 (a candidate cytomegalovirus [CMV] vaccine), and a reporter mRNA (nascent peptide-luciferase) drug product. Consistent biodistribution patterns were observed across studies: tissues with highest exposures were the injection site, draining lymph nodes, and spleen, with minimal distribution to non-lymphoid tissues. Vaccine components cleared rapidly from circulation and tissues, with complete elimination simulated to occur by [~]2 weeks. Following mRNA-1273 vaccination, Spike protein levels were transiently observed (elimination <5 days) and did not accumulate with repeated dosing. The ionizable lipid in the LNP matrix, Lipid H, underwent biotransformation and was excreted renally and hepatically, with no human-specific metabolites. Collectively, these results indicate that the LNP composition, not mRNA cargo, governs biodistribution. Furthermore, in a SARS-CoV-2 infection-free model, there was no evidence of Spike protein persistence. Overall, the data establish a framework that justifies leveraging biodistribution data across products and supports eliminating redundant animal studies.

Topiramate (TPM) is approved for seizures and migraine prophylaxis and is used off-label for several neuropsychiatric conditions. The available dosage forms, including tablets and sprinkle capsules, are unsuitable for patients who may be unable to take medicine orally. The resulting potential treatment interruptions could have untoward consequences and underscores the importance of developing a parenteral formulation. In this study, we developed a population pharmacokinetic model of a novel, intravenous TPM formulation using data from a study in patients with epilepsy or migraine receiving a single intravenous dose of stable-labeled TPM. In total, 246 TPM concentrations from 20 adult patients were included for model development. A three-compartment pharmacokinetic model with linear elimination fit the concentration-time data best. Simulations for various loading and maintenance regimens for patients with and without enzyme-inducing comedications were performed. The final estimates(95% confidence interval (CI)) for CL (L/h), V1 (L), and the peripheral volumes, V2 and V3 for a 70 kg person were 1.31(1.01 - 1.53), 9.84 (8.49 - 11.0), 39.1 (36.5 - 41.8)L, and 9.01 (6.41 - 44.3) respectively. The use of enzyme-inducing co-medication was the only significant covariate, associated with a 63% increase in clearance .Goodness-of-fit plots and visual predictive checks indicate satisfactory model performance and prediction. The simulation results indicate that adjusting doses for patients receiving IV TPM can mitigate the changes in plasma TPM concentrations resulting from enzyme induction. This population pharmacokinetic model for intravenous topiramate can inform dosing decisions for patients with epilepsy when used as either initiation or bridging therapy.

BackgroundCompounded versions of tirzepatide are widely available in the U.S. in the form of fixed-dose combinations of tirzepatide and various analogs of vitamin B12. These combinations are mass marketed in the U.S. and other countries as comparable to FDA-approved tirzepatide products even though they undergo no evaluation of their potency or impurity profiles. Research Design and MethodsSamples of compounded tirzepatide combined with B12 obtained from various sources in the U.S. market were tested using various analytical methods. Samples were assessed for unacceptable levels of peptide-related impurities. ResultsOur testing identified a widespread and previously unidentified impurity in compounded tirzepatide-B12 products resulting from a chemical reaction between tirzepatide and certain analogs of B12. ConclusionDespite the presence of this impurity, these products continue to be mass marketed as "personalized" treatments. Our findings underscore the importance of testing and FDA approval before new drugs are marketed and highlights potential risks for patients associated with untested combinations. A novel impurity, present at substantial levels in compounded tirzepatide/B12 products, highlights risks inherent in marketing complex therapies outside the drug-approval framework. Although clinical effects of this impurity are unknown, the identification of a widespread impurity adds to the existing quality concerns presented by compounded tirzepatide.