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Questionnaire study to investigate the preference of children, parents, and healthcare professionals for different formulations of oral medicinal products
No full textSince acceptability of a drug might have a relevant impact on therapeutic outcome, this study aimed to determine and compare the preferences of children, parents, and healthcare profes-sionals for the most often used pediatric formulations for oral medicines (syrup, mini-tablets, oblong tablets, round tablets) addressing all pediatric age groups from 0-<18 years (y).
This survey study employed sex-, age- and participant group-adapted questionnaires for 8 co-horts of participants, i.e. children 6-<12 y, adolescents 12-<18 y, parents of children in 4 age groups (0-<2 y, 2-<6 y, 6-<12 y, 12-<18 y), nurses, and pediatricians. Descriptive statistics were used for data analysis.
In the age groups 0-<2 y and 2-<6 y, mini-tablets were preferred over syrup by all participants. In the age group 6-12 y, also solid dosage forms were preferred over syrup by all participants. In the age group 12-<18 y, healthcare professionals preferred solid dosage forms over syrup. Parents preferred higher amounts of mini-tablets and syrup compared to round and oblong tablets while adolescents’ preferences did not differentiate between these formulations.
Based on the study results and in contrast with current practice, it is suggested to consider solid dosage forms for future age-appropriate medicinal products already for younger age groups
Predicting the Intravenous Pharmacokinetics of Covalent Drugs in Animals and Humans.
No full text30 covalent drugs were used to assess clearance (CL) prediction reliability in animals and humans. In animals, marked CL underprediction was observed using cryopreserved hepatocytes or liver microsomes (LMs) supplemented for cytochrome P450 activity. Improved quantitative performance was observed by combining metabolic stability data from LMs and liver S9 fractions, the latter supplemented with reduced glutathione for glutathione transferase activity. While human LMs provided reliable human CL predictions, prediction statistics were improved further by incorporating S9 stability data. CL predictions with allometric scaling were less robust compared to in vitro drug metabolism methods; the best results were obtained using the fu-corrected intercept model. Human volume of distribution (Vd) was well predicted using allometric scaling of animal pharmacokinetic data; the most reliable results were achieved using simple allometric scaling of unbound Vd values. These results provide a quantitative framework to guide appropriate method selection for human PK prediction with covalent drugs
Recommendations on the Use of Multiple Labels in Human Mass Balance Studies.
No full textThe administration of radiolabeled drug candidates is considered the gold standard in absorption, distribution, metabolism, and excretion studies for small-molecule drugs since it allows facile and accurate quantification of parent drug, metabolites, and total drug-related material independent of the compound structure. The choice of the position of the radiolabel, typically 14C or 3H, is critical to obtain relevant information. Sometimes, a biotransformation reaction may lead to cleavage of a part of the molecule. As a result, only the radiolabeled portion can be followed, and information on the fate of the nonlabeled metabolite may be lost. Synthesis and administration of two or more radiolabeled versions of the parent drug as a mixture or in separate studies may resolve this issue but comes with additional challenges. In this paper, we address the questions that may be considered to help make the right choice whether to use a single or multiple radiolabel approach and discuss the pros and cons of different multiple-labeling strategies that can be taken as well as alternative methods that allow the nonlabeled part of the molecule to be followed. SIGNIFICANCE STATEMENT: Radiolabeled studies are the gold standard in drug metabolism research, but molecules can undergo cleavage with loss of the label. This often results in discussions around potential use of multiple labels, which seem to be occurring with increased frequency since an increasing proportion of the small-molecule drugs are tending towards larger molecular weights. This review provides insight and decision criteria in considering a multiple-label approach as well as pros and cons of different strategies that can be followed
Beyond the classical type I error: Bayesian metrics for Bayesian designs using informative priors
No full textThere is growing interest in Bayesian clinical trial designs with informative prior distributions, e.g. for extrapolation of adult data to pediatrics, or use of external controls. While the classical type I error is commonly used to evaluate such designs, it cannot be strictly controlled and it is acknowledged that other metrics may be more appropriate. We focus on two common situations – borrowing control data or information on the treatment contrast – and discuss several fully probabilistic metrics to evaluate the risk of false positive conclusions. Each metric requires specification of a design prior, which can differ from the analysis prior and permits understanding of the behaviour of a Bayesian design under scenarios where the analysis prior differs from the true data generation process. The metrics include the average type I error and the pre-posterior probability of a false positive result. We show that, when borrowing control data, the average type I error is asymptotically
(in certain cases strictly) controlled when the analysis and design prior coincide. We illustrate use of these Bayesian metrics with real applications, and discuss how they could facilitate discussions between sponsors, regulators and other stakeholders about the appropriateness of Bayesian borrowing designs for pivotal studies
People of TM: Video of Michelle Krishnan
No full textThe video will be used for an external social media engagement campaign on platforms like linked-in, facebook etc. featruing stories of people in TM. No IP related content
Improving In Vitro-In Vivo Extrapolation of Clearance Using Rat Liver Microsomes for Highly Plasma Protein-Bound Molecules.
No full textIt is common practice in drug discovery and development to predict in vivo hepatic clearance from in vitro incubations with liver microsomes or hepatocytes using the well-stirred model (WSM). When applying the WSM to a set of approximately 3000 Novartis research compounds, 73% of neutral and basic compounds (extended clearance classification system [ECCS] class 2) were well-predicted within 3-fold. In contrast, only 44% (ECCS class 1A) or 34% (ECCS class 1B) of acids were predicted within 3-fold. To explore the hypothesis whether the higher degree of plasma protein binding for acids contributes to the in vitro-in vivo correlation (IVIVC) disconnect, 68 proprietary compounds were incubated with rat liver microsomes in the presence and absence of 5% plasma. A minor impact of plasma on clearance IVIVC was found for moderately bound compounds (fraction unbound in plasma [fup] ≥1%). However, addition of plasma significantly improved the IVIVC for highly bound compounds (fup <1%) as indicated by an increase of the average fold error from 0.10 to 0.36. Correlating fup with the scaled unbound intrinsic clearance ratio in the presence or absence of plasma allowed the establishment of an empirical, nonlinear correction equation that depends on fup Taken together, estimation of the metabolic clearance of highly bound compounds was enhanced by the addition of plasma to microsomal incubations. For standard incubations in buffer only, application of an empirical correction provided improved clearance predictions. SIGNIFICANCE STATEMENT: Application of the well-stirred liver model for clearance in vitro-in vivo extrapolation (IVIVE) in rat generally underpredicts the clearance of acids and the strong protein binding of acids is suspected to be one responsible factor. Unbound intrinsic in vitro clearance (CLint,u) determinations using rat liver microsomes supplemented with 5% plasma resulted in an improved IVIVE. An empirical equation was derived that can be applied to correct CLint,u-values in dependance of fraction unbound in plasma (fup) and measured CLint in buffer
Hydrogen bond formation may enhance RDC-based discrimination of enantiomers
No full textThe distinction of enantiomers based on residual anisotropic parameters obtained by alignment in chiral poly--benzyl-L-glutamate (PBLG) is among the strongest in high resolution NMR spectroscopy. However, large variations in enantiodifferentiation among different solutes are frequently observed. One hypothesis is that the formation of hydrogen bonds between solute and PBLG is important for the distinction of enantiomers. With a small set of three almost spherical enantiomeric pairs we address this issue in a systematic way: borneol contains a single functional group that can act as a hydrogen bond donor, camphor a single group that may act as a hydrogen bond acceptor, and quinuclidinol can act as both hydrogen bond donor and acceptor. The results are unambiguous: while camphor shows low enantiodifferentiation with PBLG and alignment that can be predicted well by the purely steric TRAMITE approach, the distinction of enantiomers for the other enantiomeric pairs is significantly higher with alignment properties that must involve a specific interaction in addition to steric alignment
Principles for defining estimands in clinical trials – a proposal
No full textThe ICH E9(R1) guideline outlines the estimand framework to align planning, design, conduct, analysis, and interpretation of a clinical trial. The benefits and value of using this framework in clinical trials have been outlined in the literature and guidance has been provided on how to choose the estimand and define the estimand attributes. Although progress has been made in the implementation of estimands in clinical trials, to the best of our knowledge, there is no published discussion on the basic principles that estimands in clinical trials should fulfil to be well-defined and consistent with the ideas presented in the ICH E9(R1) guideline. Therefore, in this Viewpoint article, we propose five key principles for defining an estimand. These principles form a basis for well-defined treatment effects reflecting the estimand thinking process. We hope that this Viewpoint will stimulate a discussion on which fundamental properties an estimand in a clinical trial should have and that such discussions will eventually lead to an improved clarity and precision for defining estimands in clinical trials
Serum proteomics reveal APOE-ε4-dependent and APOE-ε4-independent protein signatures in Alzheimer’s disease
No full textA deeper understanding of the molecular processes underlying late-onset Alzheimer’s disease (LOAD) could aid in biomarker and drug target discovery. Using high-throughput serum proteomics in the prospective population-based Age, Gene/Environment Susceptibility–Reykjavik Study (AGES) cohort of 5,127 older Icelandic adults (mean age, 76.6 ± 5.6 years), we identified 303 proteins associated with incident LOAD over a median follow-up of 12.8 years. Over 40% of these proteins were associated with LOAD independently of APOE-ε4 carrier status, were implicated in neuronal processes and overlapped with LOAD protein signatures in brain and cerebrospinal fluid. We identified 17 proteins whose associations with LOAD were strongly dependent on APOE-ε4 carrier status, with mostly consistent associations in cerebrospinal fluid. Remarkably, four of these proteins (TBCA, ARL2, S100A13 and IRF6) were downregulated by APOE-ε4 yet upregulated due to LOAD, a finding replicated in external cohorts and possibly reflecting a response to disease onset. These findings highlight dysregulated pathways at the preclinical stages of LOAD, including those both independent of and dependent on APOE-ε4 status
ADENOSINE-MEDIATED IMMUNE RESPONSES IN INFLAMMATORY BOWEL DISEASE
No full textExtracellular ATP and its derivates mediate a signaling pathway that might be pharmacologically targeted to treat inflammatory conditions. Extracellular adenosine, the product of ATP hydrolysis by ectonucleotidase enzymes, plays a key role in halting inflammation while promoting immune tolerance. The rate-limiting ectoenzyme ENTPD1/CD39 and the ecto-5′-nucleotidase/CD73 are the prototype members of the ectonucleotidase family, being responsible for ATP degradation into immunosuppressive adenosine. The biological effects of adenosine are mediated via adenosine receptors, a family of G protein-coupled receptors largely expressed on immune cells where they modulate innate and adaptive immune responses.
Inflammatory bowel disease (IBD) is a serious inflammatory condition of the gastrointestinal tract, associated with substantial morbidity and often refractory to currently available medications. IBD is linked to altered interactions between the gut microbiota and the immune system in genetically predisposed individuals. A wealth of studies conducted in patients and animal models highlighted the role of various adenosine receptors in the modulation of chronic inflammatory diseases like IBD.
In this review, we will discuss the most recent findings on adenosine-mediated immune responses in different cell types, with a focus on IBD and its most common manifestations, Crohn's disease (CD) and ulcerative colitis (UC)