Xenobiotica最新文献

The advanced in silico simulation tools, such as physiologically based biopharmaceutics models (PBBM) or physiologically based pharmacokinetic models (PBPK), play critical role in model informed formulation development. This approach has been successfully implemented in the present case for development of novel omeprazole delayed-release orally disintegrating tablets (ODT) formulation, aimed to enhance patient compliance.PBBM was developed using physicochemical, biopharmaceutical, and dissolution data. The dissolution studies for pilot formulations were conducted in biopredictive media in fasting (0.1 N HCl followed by pH 6.8) and fed (pH 5 followed by pH 6.8) conditions. The model was extensively validated in three stages: pilot fasted, pilot fed virtual bioequivalence and food effect assessments. Impressively, the model was able to predict both passed and failed batches appropriately.Based on insights from the pilot study, a higher scale pivotal formulation was optimised. Prospective predictions were made for pivotal formulations using validated model and bio results were found to be in line with model predictions in fasting condition.Overall, a rationale and patient compliant formulation was developed using innovative modelling approach and filed to regulatory agency. The novel omeprazole formulation enhanced patient compliance through ease of administration thereby circumventing challenges of conventional formulation.

LD14b is an amyloid-β (Aβ) 17β-hydroxysteroid dehydrogenase type 10 (Aβ-17β-HSD10) protein-protein interaction modulator that shows promising in vitro and ex vivo activity to rescue Aβ-induced mitochondrial dysfunction, Aβ-induced toxicity, and Aβ-mediated inhibition of estradiol synthesis.The current study investigated in vitro human S9 fractions metabolic stability, apparent permeability, human and mouse plasma protein binding, in vivo pharmacokinetics, and tissue distribution in Balb/cJ mice. A fast (8-min), sensitive, reliable, and reproducible LC-MS/MS method was developed and validated over the dynamic range of 1-1000 ng/mL for the quantification of LD14b in different biological matrices (plasma, liver, kidney, brain, lungs, heart).LD14b was metabolically stable in human liver S9 fractions with 70% remaining after 90 minutes of incubation, showed intermediate apparent permeability of 3.55 × 10^-06 cm/s and 6.16 × 10^-06 cm/s for apical-to-basolateral (A-to-B) and basolateral-to-apical (B-to-A), respectively across the Caco-2 monolayer, and was medium/highly bound to human plasma proteins (84.1%), mouse plasma proteins (85.7%), and mouse brain homogenate (95.4%).LD14b showed an in vivo predicted % absorption of 52% in Balb/cJ mice and was well-distributed to the peripheral tissues (liver, kidney, lungs, and heart) including the brain.

Increasing complexity of mAbs in development creates challenges in predicting human pharmacokinetic (PK) parameters from preclinical data. The aim of this analysis was to identify optimal allometric scaling exponents.Data were extracted from literature to create a central database (currently the largest available published database) of two-compartment model parameters for mAbs (n = 59) in cynomolgus monkey (CM) and human.Global allometric exponents were calculated and drug-dependent factors were investigated as potential variables in determining the optimal scaling factor.The global exponents for scaling CM mAb PK data were 0.74 (CL), 0.80 (CL with Fc-modified mAbs excluded), 0.44 (CL with Fc-modified mAbs only), 0.71 (Q), 1.12 (V1), and 0.99 (V2). These values are in line with previously published literature values.

Workplace exposure to diisocyanates like 4,4'-methylene diphenyl diisocyanate can cause occupational asthma (MDI-OA), and the underlying biological pathways are still being researched.Although uncertainty remains, evidence supports the hypothesis that dermal exposure to MDI plays an important role in the development of MDI-OA.Gene expression, proteomics, and informatics tools were utilised to characterise changes in expression of RNA and protein in cultured human HEKa keratinocyte cells following exposure to conjugates of MDI with glutathione (MDI-GSH).RT-qPCR analysis using a panel of 39 candidate primers demonstrated 9 candidate genes upregulated and 30 unchanged.HPLC-MS/MS analysis of HEKa cell lysate identified 18 540 proteins across all samples 60 proteins demonstrate statistically significant differential expression in exposed cells, some of which suggest activation of immune and inflammatory pathways.The results support the hypothesis that dermal exposures have the potential to play an important role in the development of MDI-OA. Furthermore, proteomic and gene expression data suggest multiple immune (adaptive and innate) and inflammatory pathways may be involved in the development of MDI-OA.

Aficamten, a small molecule selective inhibitor of cardiac myosin, was characterised in preclinical in vitro and in vivo studies.Protein binding in human plasma was 10.4% unbound and ranged from 1.6% to 24.9% unbound across species. Blood-to-plasma ratios ranged from 0.69 to 1.14 across species. Aficamten hepatic clearance in human was predicted to be low from observed high metabolic stability in vitro in human liver microsomes. Aficamten demonstrated high permeability in Caco-2 cell monolayers.Aficamten in vivo clearance was low across species at 8.8, 2.1, 3.3, and 11 mL/min/kg in mouse, rat, dog, and monkey, respectively. The volume of distribution was low-to-high ranging from 0.53 in rat to 11 L/kg in dog. Oral bioavailability ranged from 41% in monkey to 98% in mouse.Aficamten was metabolised in vitro to eight metabolites with hydroxylated metabolites M1a and M1b predominating. CYP phenotyping indicated multiple CYPs (2C8, 2C9, 2D6, and 3A4) contributing to the metabolism of aficamten.Human clearance (1.1 mL/min/kg) and volume of distribution (6.5 L/kg) were predicted using 4-species allometry employing 'rule-of-exponents'. A predicted 69 hour half-life is consistent with observed half-life in human Phase-1.No CYP-based drug-drug interaction liability as a precipitant was predicted for aficamten.

1. Antibody-drug conjugates (ADCs) have demonstrated impressive clinical usefulness in treating several types of cancer, with the notion of widening of the therapeutic index of the cytotoxic payload through the minimisation of the systemic toxicity. Therefore, choosing the most appropriate payload molecule is a particularly important part of the early design phase of ADC development, especially given the highly competitive environment ADCs find themselves in today.2. The focus of the current review is to describe critical attributes/considerations needed in the discovery and ultimately development of cytotoxic payloads in support of ADC design. In addition to potency, several key dispositional characteristics including solubility, permeability and bystander effect, pharmacokinetics, metabolism, and drug-drug interactions, are described as being an integral part of the integrated activities required in the design of clinically safe and useful ADC therapeutic agents.

Background: Monomethyl auristatin E (MMAE) has been used as a payload for several Food and Drug Administration (FDA) approved antibody-drug conjugates (ADCs). It is known that MMAE is released from the ADC following binding, internalisation and proteolytic degradation in target tissues. A striking discrepancy in systemic MMAE levels has been observed across species with 50-fold higher MMAE levels in human than that in rodents when normalised by ADC dose with unknown mechanism.Hypothesis and purpose: Multiple factors could affect systemic MMAE levels such as production and elimination of unconjugated MMAE following ADC dosing. In this study, we have explored whether MMAE displays differential red blood cell (RBC) partitioning across species that may contribute to the different MMAE levels seen between human and animals.Experiments: To determine MMAE RBC partitioning, tritium labelled MMAE ([³H]-MMAE) was incubated in whole blood from mice, rats, monkeys and humans in vitro, then RBC partitioning was determined and compared across species. To test whether MMAE released from the ADC would show any difference in RBC partitioning, pinatuzumab vedotin or polatuzumab vedotin was administered to mice, rats, and monkeys. MMAE levels were measured in both blood and plasma, and the ratios of MMAE levels were calculated as blood-to-plasma ratio (in vivo RBC partitioning).Results: Our in vitro data showed that unconjugated MMAE has a species-dependent RBC partitioning with strong RBC partitioning in mouse, rat, followed by monkey blood, whereas minimal RBC partitioning was seen in human blood. Incubation of 2 nM of MMAE in mouse blood resulted in a blood-to-plasma ratio of 11.8 ± 0.291, followed by rat, monkey, and human at 2.36 ± 0.0825, 1.57 ± 0.0250, and 0.976 ± 0.0620, respectively. MMAE RBC partitioning is also concentration-dependent, with an inverse relationship between RBC partitioning and MMAE concentration (higher RBC partitioning at lower concentration). In vivo dosing of pinatuzumab vedotin in mouse displayed systemic MMAE at about a 5-fold higher blood concentration compared to plasma concentration once MMAE reached a pseudo-equilibrium, while systemic MMAE from blood and plasma concentration showed a 1.65-fold difference in rat.Implication and conclusion: These data demonstrated that MMAE has a distinct RBC partitioning across different species, which may contribute to, at least in part, to the differential in the systemic MMAE levels observed in vivo between preclinical and clinical studies. These findings highlight the importance of fully characterising the ADME properties of both the ADC and its payload, to enable better translation from animals to human for ADC development.

Antibody drug conjugates are an exciting therapeutic modality that combines the targeting specificity of antibodies with potent cytotoxins to selectively kill cancer cells. The targeting component improves efficacy and protects non-target cells from the harmful effects of the payload. To date 15 ADCs have been approved by regulatory agencies for commercial use and shown to be valuable tools in the treatment of cancer.The assembly of an ADC requires the chemical ligation of a linker-payload to an antibody. Conventional conjugation methods targeting accessible lysines and cysteines have produced all the ADCs currently on the market. While successful, technologies aiming to improve the homogeneity and stability of ADCs are being developed and tested.Here we provide a review of developing methods for ADC construction. These include enzymatic methods, oligosaccharide remodelling, and technologies using genetic code expansion techniques. The virtues and limitations of each technology are discussed.Emerging conjugation technologies are being applied to produce new formats of ADCs with enhanced functionality including bispecific ADCs, dual-payload ADCs, and nanoparticles for targeted drug delivery. The benefits of these novel formats are highlighted.

ADCs represent a transformative class of medicine that combines the specificity of monoclonal antibodies with the potency of highly cytotoxic agents through linkers, aiming to enhance the therapeutic index of cytotoxic drugs. Given the complex molecular structures of ADCs, combining the molecular characteristics of small-molecule drugs and those of large-molecule biotherapeutics, there are several unique considerations when designing nonclinical-to-clinical PK/PD translation strategies.This complexity also demands a thorough understanding of the ADC's components - antibody, linker, and payload - to the overall toxicological, PK/PD, and efficacy profile. ADC development is a multidisciplinary endeavour requiring a strategic integration of nonclinical safety, pharmacology, and PK/PD modelling to translate from bench to bedside successfully.The ADC development underscores the necessity for a robust scientific foundation, leveraging advanced analytical and modelling tools to predict human responses and optimise therapeutic outcomes.This review aims to provide an ADC translational PK/PD framework by discussing unique aspects of ADC nonclinical to clinical PK translation, starting dose determination, and leveraging PK/PD modelling for human efficacious dose prediction and potential safety mitigation.

1. Antibody-drug conjugates (ADCs) are an important class of cancer therapies. They are complex molecules, comprising an antibody, a cytotoxic payload, and a linker. ADCs intend to confer high specificity by targeting a unique antigen expressed predominately on the surface of the tumour cells than on the normal cells and by releasing the potent cytotoxic drug inside the tumour causing cytotoxic cell death. Despite high specificity to tumour antigens, many ADCs are associated with off-target and on-target off-tumour toxicities, often leading to safety concerns before achieving the desirable clinical efficacy. Therefore, it is crucial to improve the therapeutic index (TI) of ADCs to enable the full potential of this important therapeutic modality. 2. The review summarises current approaches to improve the translation of safety, pharmacokinetics, and TI of ADCs. Common safety findings of ADCs resulting from off-target and on-target toxicities and nonclinical approaches to de-risk ADC safety will be discussed; multiple approaches of using preclinical and clinical dose and exposure data to calculate TI to guide clinical dosing will be elaborated; different approaches to improve TI of ADCs, including selecting the right target, right payload-linker and patients, optimising physicochemical properties, and using fractionation dosing, will also be discussed.