Parameterization of Physiologically Based Biopharmaceutics Models: Workshop Summary Report.

This Article shares the proceedings from the August 29th, 2023 (day 1) workshop "Physiologically Based Biopharmaceutics Modeling (PBBM) Best Practices for Drug Product Quality: Regulatory and Industry Perspectives". The focus of the day was on model parametrization; regulatory authorities from Canada, the USA, Sweden, Belgium, and Norway presented their views on PBBM case studies submitted by industry members of the IQ consortium. The presentations shared key questions raised by regulators during the mock exercise, regarding the PBBM input parameters and their justification. These presentations also shed light on the regulatory assessment processes, content, and format requirements for future PBBM regulatory submissions. In addition, the day 1 breakout presentations and discussions gave the opportunity to share best practices around key questions faced by scientists when parametrizing PBBMs. Key questions included measurement and integration of drug substance solubility for crystalline vs amorphous drugs; impact of excipients on apparent drug solubility/supersaturation; modeling of acid-base reactions at the surface of the dissolving drug; choice of dissolution methods according to the formulation and drug properties with a view to predict the in vivo performance; mechanistic modeling of in vitro product dissolution data to predict in vivo dissolution for various patient populations/species; best practices for characterization of drug precipitation from simple or complex formulations and integration of the data in PBBM; incorporation of drug permeability into PBBM for various routes of uptake and prediction of permeability along the GI tract.

Structural Determination of an Unusual CuI -Porphyrin-π-Bond in a Hetero-Pacman Cu-Zn-Complex.

The synthesis and characterization of a hetero-dinuclear compound is presented, in which a copper(I) trishistidine type coordination unit is positioned directly above a zinc porphyrin unit. The close distance between the two coordination fragments is secured by a rigid xanthene backbone, and a unique (intramolecular) copper porphyrin-π-bond was determined for the first time in the molecular structure. This structural motif was further analyzed by temperature-dependent NMR studies: In solution at room temperature the coordinative bond fluctuates, while it can be frozen at low temperatures. Preliminary reactivity studies revealed a reduced reactivity of the copper(I) moiety towards dioxygen. The results adumbrate why nature is avoiding metal porphyrin-π-bonds by fixing reactive metal centers in a predetermined distance to each other within multimetallic enzymatic reaction centers.

Fluoride Chemistry in Tin Halide Perovskites.

Tin is the frontrunner for substituting toxic lead in perovskite solar cells. However, tin suffers the detrimental oxidation of SnII to SnIV . Most of reported strategies employ SnF2 in the perovskite precursor solution to prevent SnIV formation. Nevertheless, the working mechanism of this additive remains debated. To further elucidate it, we investigate the fluoride chemistry in tin halide perovskites by complementary analytical tools. NMR analysis of the precursor solution discloses a strong preferential affinity of fluoride anions for SnIV over SnII , selectively complexing it as SnF4 . Hard X-ray photoelectron spectroscopy on films shows the lower tendency of SnF4 than SnI4 to get included in the perovskite structure, hence preventing the inclusion of SnIV in the film. Finally, small-angle X-ray scattering reveals the strong influence of fluoride on the colloidal chemistry of precursor dispersions, directly affecting perovskite crystallization.

Integration of physiological changes during the postpartum period into a PBPK framework and prediction of amoxicillin disposition before and shortly after delivery.

The objective of this study was to develop a physiologically based pharmacokinetic (PBPK) model for amoxicillin for non-pregnant, pregnant and postpartum populations by compiling a database incorporating reported changes in the anatomy and physiology throughout the postpartum period. A systematic literature search was conducted to collect data on anatomical and physiological changes in postpartum women. Empirical functions were generated describing the observed changes providing the basis for a generic PBPK framework. The fraction unbound ([Formula: see text]) of predominantly albumin-bound drugs was predicted in postpartum women and compared with experimentally observed values. Finally, a specific amoxicillin PBPK model was newly developed, verified for non-pregnant populations and translated into the third trimester of pregnancy (29.4-36.9 gestational weeks) and early postpartum period (drug administration 1.5-3.8 h after delivery). Pharmacokinetic predictions were evaluated using published clinical data. The literature search yielded 105 studies with 1092 anatomical and physiological data values on 3742 postpartum women which were used to generate various functions describing the observed trends. The [Formula: see text] could be adequately scaled to postpartum women. The pregnancy PBPK model predicted amoxicillin disposition adequately as did the postpartum PBPK model, although clearance was somewhat underestimated. While more research is needed to establish fully verified postpartum PBPK models, this study provides a repository of anatomical and physiological changes in postpartum women that can be applied to future modeling efforts. Ultimately, structural refinement of the developed postpartum PBPK model could be used to investigate drug transfer to the neonate via breast-feeding in silico.

Anatomical and physiological alterations of pregnancy.

The extensive metabolic demands of pregnancy require specific physiological and anatomical changes. These changes affect almost all organ systems, including the cardiovascular, respiratory, renal, gastrointestinal, and hematologic system. The placenta adds another layer of complexity. These changes make it challenging for clinicians to understand presenting signs and symptoms, or to interpret laboratory and radiological tests. Furthermore, these physiological alterations can affect the pharmacokinetics and pharmacodynamics of drugs. Drug safety in lactation is only supported by limited evidence. In addition, the teratogenic effects of medications are often extrapolated from animals, which further adds uncertainties. Unfortunately, pregnant women are only rarely included in clinical drug trials, while doses, regimens, and side effects are often extrapolated from studies conducted in non-pregnant populations. In this comprehensive review, we present the changes occurring in each system with its effects on the pharmacokinetic variables. Understanding these physiological changes throughout normal pregnancy helps clinicians to optimize the health of pregnant women and their fetuses. Furthermore, the information on pregnancy-related physiology is also critical to guide study design in this vulnerable 'orphan' population, and provides a framework to explore pregnancy-related pathophysiology such as pre-eclampsia.

Mercaptothiacalixarenes Steer 24 Copper(I) Centers to form a Hollow-Sphere Structure Featuring Cu2 S2 Motifs with Exceptionally Short Cu⋠⋠⋠Cu Distances.

Tetramercaptotetrathiacalix[4]arene (LH4 ) can be used as a coordination platform to bind four CuI ions at the thiolate and thioether S atoms. Donor ligands such as phosphanes can stabilize the resulting [LCu4 ] units, which then remain monomeric ([(Ph3 PCu)4 L]). In the absence of donor ligands, they aggregate, providing a hexamer ([LCu4 ]6 ) in high yields, with a hollow-sphere structure formed by an unprecedented Cu24 S48 cage that is surrounded by the organic framework of the calixarene chalices. Preliminary NMR experiments with regard to the host-guest chemistry in solution showed that the compound represents a polytopic host for acetonitrile and methane.

Highly Cooperative Photoswitching in Dihydropyrene Dimers.

We present a strategy to achieve highly cooperative photoswitching, where the initial switching event greatly facilitates subsequent switching of the neighboring unit. By linking donor/acceptor substituted dihydropyrenes via suitable π-conjugated bridges, the quantum yield of the second photochemical ring-opening process could be enhanced by more than two orders of magnitude as compared to the first ring-opening. As a result, the intermediate mixed switching state is not detected during photoisomerization although it is formed during the thermal back reaction. Comparing the switching behavior of various dimers, both experimentally and computationally, helped to unravel the crucial role of the bridging moiety connecting both photochromic units. The presented dihydropyrene dimer serves as model system for longer cooperative switching chains, which, in principle, should enable efficient and directional transfer of information along a molecularly defined path. Moreover, our concept allows to enhance the photosensitivity in oligomeric and polymeric systems and materials thereof.

Specific Decoration of a Discrete Bismuth Oxido Cluster by Selected Peptides towards the Design of Metal Tags.

Metal tags find application in a multitude of biomedical systems and the combination with laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) offers an opportunity for multiplexing. To lay the foundation for an increase of the signal intensities in such processes, we herein present a general approach for efficient functionalization of a well-defined metal oxido cluster [Bi6 O4 (OH)4 (SO3 CF3 )6 (CH3 CN)6 ]⋅2 CH3 CN (1), which can be realized by selecting 7mer peptide sequences via combinatorial means from large one-bead one-compound peptide libraries. Selective cluster-binding peptide sequences (CBS) for 1 were discriminated from non-binders by treatment with H2 S gas to form the reduction product Bi2 S3 , clearly visible to the naked eye. Interactions were further confirmed by NMR experiments. Extension of a binding peptide with a maleimide linker (Mal) introduces the possibility to covalently attach thiol-bearing moieties such as biological probes and for their analysis the presence of the cluster instead of mononuclear entities should lead to an increase of signal intensities in LA-ICP-MS measurements. To prove this, CBS-Mal was covalently bound onto thiol-presenting glass substrates, which then captured 1 effectively, so that LA-ICP-MS measurements demonstrated drastic signal amplification compared to single lanthanide tags.

A Silylene-Borane Lewis Pair as a Tool for Trapping a Water Molecule: Silanol Formation and Dehydrogenation.

The Lewis acid B(C6 F5 )3 and the cyclic silane (ArN 2 Si)3 (1) (ArN =o-(CH3 )2 NCH2 C6 H4 ) are useful precursors to access the silylene(II)-borane adduct ArN 2 Si-B(C6 F5 )3 (2). Treatment of 2 with water led to coordination and gave the Lewis pair (ArN 2 H2 O)Si-B(C6 F5 )3 (3) that exhibits a hydrogen-bond-stabilized silanol unit. It can be converted into the siloxane [(HArN )2 SiOB(C6 F5 )3 ]2 O (6) by dehydrogenation in the presence of a base. Heteronuclear NMR spectroscopic data to characterize the compounds were supported by quantum-chemical calculations.

Features of Auxiliaries That Enable Native Chemical Ligation beyond Glycine and Cleavage via Radical Fragmentation.

Native chemical ligation (NCL) is an invaluable tool in the total chemical synthesis of proteins. Ligation auxiliaries overcome the requirement for cysteine. However, the reported auxiliaries remained limited to glycine-containing ligation sites and the acidic conditions applied for cleavage of the typically applied N-benzyl-type linkages promote side reactions. With the aim to improve upon both ligation and cleavage, we systematically investigated alternative ligation scaffolds that challenge the N-benzyl dogma. The study revealed that auxiliary-mediated peptide couplings are fastest when the ligation proceeds via 5-membered rather than 6-membered rings. Substituents in α-position of the amine shall be avoided. We observed, perhaps surprisingly, that additional ß-substituents accelerated the ligation conferred by the ß-mercaptoethyl scaffold. We also describe a potentially general means to remove ligation auxiliaries by treatment with an aqueous solution of triscarboxyethylphosphine (TCEP) and morpholine at pH 8.5. NMR analysis of a 13 C-labeled auxiliary showed that cleavage most likely proceeds through a radical-triggered oxidative fragmentation. High ligation rates provided by ß-substituted 2-mercaptoethyl scaffolds, their facile introduction as well as the mildness of the cleavage reaction are attractive features for protein synthesis beyond cysteine and glycine ligation sites.

Advancing Drug Formulation Additives toward Precision Additives with Release Mediating Peptide Interlayer.

Amphiphilic drug formulation additives based on palmitic acid-modified poly(ethylene glycol) (Pal-PEG) are combined with a tailored drug binding peptide that is positioned at the hydrophobic-hydrophilic interface. The peptide originates from combinatorial selection and enables precise modulation of the drug release profiles. While Pal provides a cost-effective reservoir for drug storage, the PEG realizes solubility and shielding. The precision additives reach high payloads close to 1:1, rendering a photosensitizer water-soluble and providing adjustable drug activation kinetics by fine-tuning the peptide interface layer.

Site-Specific Isotope-Labeling of Inosine Phosphoramidites and NMR Analysis of an Inosine-Containing RNA Duplex.

Structural features and internal dynamics of inosine-containing RNAs are poorly understood. NMR studies of such RNAs require 13 C,15 N-labeling, which cannot be achieved using in vitro transcription as inosine and guanosine are not distinguished by RNA polymerase. Herein, we report the synthesis of an inosine phosphoramidite with selective 13 C8 and 15 N7-isotope incorporation in the base and uniform 13 C-labeling of the ribose. Chemical synthesis of an RNA duplex containing four consecutive IU base pairs with this optimized isotope-labeling scheme greatly simplifies NMR spectra and resolves signal overlap. The absence of detectable NMR signals of imino protons and unusual inter-residue NOE correlations in this RNA indicate deviations from standard A-form geometry, consistent with reduced stability of this duplex seen in UV melting studies compared to its nonedited RNA counterparts. These studies indicate that the introduction of IU base pairs distorts and destabilizes RNA helices significantly compared to the also noncanonical GU base-pairs. Our optimized isotope-labeling scheme enables high-resolution NMR studies of inosine-edited RNAs.

Control of Imine Exchange Kinetics with Photoswitches to Modulate Self-Healing in Polysiloxane Networks by Light Illumination.

Various aldehyde-containing photoswitches have been developed whose reactivity toward amines can be controlled externally. A thermally stable bifunctional diarylethene, which in its ring-closed form exhibits imine formation accelerated by one order of magnitude, was used as a photoswitchable crosslinker and mixed with a commercially available amino-functionalized polysiloxane to yield a rubbery material with viscoelastic and self-healing properties that can be reversibly tuned by irradiation.

Physiologically Based Pharmacokinetic Modeling in Pregnancy, during Lactation and in Neonates: Achievements, Challenges and Future Directions.

Obstetric subjects represent a special population in pharmacology [...].

Physiologically Based Pharmacokinetic Modeling of Nilotinib for Drug-Drug Interactions, Pediatric Patients, and Pregnancy and Lactation.

Nilotinib is a second-generation BCR-ABL tyrosine kinase inhibitor for the treatment of Philadelphia chromosome-positive chronic myeloid leukemia in both adult and pediatric patients. The pharmacokinetics (PK) of nilotinib in specific populations such as pregnant and lactating people remain poorly understood. Therefore, the objectives of the current study were to develop a physiologically based pharmacokinetic (PBPK) model to predict nilotinib PK in virtual drug-drug interaction (DDI) studies, as well as in pediatric, pregnant, and lactating populations. The nilotinib PBPK model was built in PK-Sim, which is part of the free and open-source software Open Systems Pharmacology. The observed clinical data for the validation of the nilotinib models were obtained from the literature. The model reasonably predicted nilotinib concentrations in the adult population; the DDIs between nilotinib and rifampin or ketoconazole in the adult population; and the PK in the pediatric, pregnant, and lactating populations, although in the latter 2 populations plasma concentrations were slightly underestimated. The ratio of predicted versus observed PK parameters for the adult model ranged from 0.71 to 1.11 for area under the concentration-time curve and 0.55 to 0.95 for maximum concentration. For the DDI, the predicted area under the concentration-time curve ratio and maximum concentration ratio fell within the Guest criterion. The current study demonstrated the utility of using PBPK modeling to understand the mechanistic basis of PK differences between adults and specific populations, such as pediatrics, and pregnant and lactating individuals, indicating that this technology can potentially inform or optimize dosing conditions in specific populations.

In-Depth Analysis of the Selection of PBPK Modeling Tools: Bibliometric and Social Network Analysis of the Open Systems Pharmacology Community.

Since the Open Source Initiative laid the foundation for the open source software environment in 1998, the popularity of free and open source software has been steadily increasing. Model-informed drug discovery and development (MID3), a key component of pharmaceutical research and development, heavily makes use of computational models which can be developed using various software including the Open Systems Pharmacology (OSP) software (PK-Sim/MoBi), a free and open source software tool for physiologically based pharmacokinetic (PBPK) modeling. In this study, we aimed to investigate the impact, application areas, and reach of the OSP software as well as the relationships and collaboration patterns between organizations having published OSP-related articles between 2017 and 2023. Therefore, we conducted a bibliometric analysis of OSP-related publications and a social network analysis of the organizations with which authors of OSP-related publications were affiliated. On several levels, we found evidence for a significant growth in the size of the OSP community as well as its visibility in the MID3 community since OSP's establishment in 2017. Specifically, the annual publication rate of PubMed-indexed PBPK-related articles using the OSP software outpaced that of PBPK-related articles using any software. Our bibliometric analysis and network analysis demonstrated that the expansion of the OSP community was predominantly driven by new authors and organizations without prior connections to the community involving the generation of research clusters de novo and an overall diversification of the network. These findings suggest an ongoing evolution of the OSP community toward a more segmented, diverse, and inclusive network.

Appropriation of group II metals: synthesis and characterisation of the first alkaline earth metal supported transition metal carbonite complexes.

Nickel carbonite complexes supported by alkaline earth metals have been accessed via salt-metathesis of the corresponding alkali metal precursors. The new complexes undergo Schlenk-like exchange reactions in solution which have been investigated by NMR spectroscopy. Also their reactivity towards epoxides and carbon monoxide was studied.

Development of a Generic Fetal Physiologically Based Pharmacokinetic Model and Prediction of Human Maternal and Fetal Organ Concentrations of Cefuroxime.

BACKGROUND AND OBJECTIVE: Physiologically based pharmacokinetic (PBPK) models for pregnant women have recently been successfully used to predict maternal and umbilical cord pharmacokinetics (PK). Because there is very limited opportunity for conducting clinical and PK investigations for fetal drug exposure, PBPK models may provide further insights. The objectives of this study were to extend a whole-body pregnancy PBPK model by multiple compartments representing fetal organs, and to predict the PK of cefuroxime in the maternal and fetal plasma, the amniotic fluid, and several fetal organs. METHODS: To this end, a previously developed pregnancy PBPK model for cefuroxime was updated using the open-source software Open Systems Pharmacology (PK-Sim®/MoBi®). Multiple compartments were implemented to represent fetal organs including brain, heart, liver, lungs, kidneys, the gastrointestinal tract (GI), muscles, and fat tissue, as well as another compartment lumping organs and tissues not explicitly represented. RESULTS: This novel PBPK model successfully predicted cefuroxime concentrations in maternal blood, umbilical cord, amniotic fluid, and several fetal organs including heart, liver, and lungs. Further model validation with additional clinical PK data is needed to build confidence in the model. CONCLUSIONS: Being developed with an open-source software, the presented generic model can be freely re-used and tailored to address specific questions at hand, e.g., to assist the design of clinical studies in the context of drug research or to predict fetal organ concentrations of chemicals in the context of fetal health risk assessment.

Applied physiologically-based pharmacokinetic modeling to assess uridine diphosphate-glucuronosyltransferase-mediated drug-drug interactions for Vericiguat.

Vericiguat (Verquvo; US: Merck, other countries: Bayer) is a novel drug for the treatment of chronic heart failure. Preclinical studies have demonstrated that the primary route of metabolism for vericiguat is glucuronidation, mainly catalyzed by uridine diphosphate-glucuronosyltransferase (UGT)1A9 and to a lesser extent UGT1A1. Whereas a drug-drug interaction (DDI) study of the UGT1A9 inhibitor mefenamic acid showed a 20% exposure increase, the effect of UGT1A1 inhibitors has not been assessed clinically. This modeling study describes a physiologically-based pharmacokinetic (PBPK) approach to complement the clinical DDI liability assessment and support prescription labeling. A PBPK model of vericiguat was developed based on in vitro and clinical data, verified against data from the mefenamic acid DDI study, and applied to assess the UGT1A1 DDI liability by running an in silico DDI study with the UGT1A1 inhibitor atazanavir. A minor effect with an area under the plasma concentration-time curve (AUC) ratio of 1.12 and a peak plasma concentration ratio of 1.04 was predicted, which indicates that there is no clinically relevant DDI interaction anticipated. Additionally, the effect of potential genetic polymorphisms of UGT1A1 and UGT1A9 was evaluated, which showed that an average modest increase of up to 1.7-fold in AUC may be expected in the case of concomitantly reduced UGT1A1 and UGT1A9 activity for subpopulations expressing non-wild-type variants for both isoforms. This study is a first cornerstone to qualify the PK-Sim platform for use of UGT-mediated DDI predictions, including PBPK models of perpetrators, such as mefenamic acid and atazanavir, and sensitive UGT substrates, such as dapagliflozin and raltegravir.