Patient groups prone to polypharmacy and special subpopulations are susceptible to suboptimal treatment. Refined dosing in special populations is imperative to improve therapeutic response and/or ...lowering the risk of toxicity. Model‐informed precision dosing (MIPD) may improve treatment outcomes by achieving the optimal dose for an individual patient. There is, however, relatively little published evidence of large‐scale utility and impact of MIPD, where it is often implemented as local collaborative efforts between academia and healthcare. This article highlights some successful applications of bringing MIPD to clinical care and proposes strategies for wider integration in healthcare. Considerations are brought up herein that will need addressing to see MIPD become “widespread clinical practice,” among those, wider interdisciplinary collaborations and the necessity for further evidence‐based efficacy and cost–benefit analysis of MIPD in healthcare. The implications of MIPD on regulatory policies and pharmaceutical development are also discussed as part of the roadmap.
The aim of this work was to develop a joint population pharmacokinetic model for simvastatin (SV) and its active metabolite, simvastatin acid (SVA), that incorporates the effects of multiple genetic ...polymorphisms and clinical/demographic characteristics. SV/SVA plasma concentrations, demographic/clinical data, and genotypes for 18 genetic variants were collected from 74 individuals (three clinical trials) and analyzed using a nonlinear mixed‐effects modeling approach. The structural model that best described the data included a two‐ and a one‐compartment disposition model for SV and SVA, respectively. Age, weight, Japanese ethnicity, and seven genetic polymorphisms—rs4149056 (SLCO1B1), rs776746 (CYP3A5), rs12422149 (SLCO2B1), rs2231142 (ABCG2), rs4148162 (ABCG2), rs4253728 (PPARA), and rs35599367 (CYP3A4)—were identified as significantly affecting model parameters. The developed model was used to assess combinations of these covariates, highlighting specific risk factors associated with altered SV/SVA pharmacokinetics, and consequently myopathy cases that cannot be solely attributed to the rs4149056 CC genotype.
Clinical Pharmacology & Therapeutics (2014); 96 1, 90–100. doi:10.1038/clpt.2014.55
In this article, we present an enhanced version of Cutler's deconvolution method to address the limitations of the original algorithm in estimating realistic input and output parameters. Cutler's ...method, based on orthogonal polynomials, suffers from unconstrained solutions, leading to the lack of realism in the deconvolved signals in some applications. Our proposed approach incorporates constraints using a ridge factor and Lagrangian multipliers in an iterative fashion, maintaining Cutler's iterative projection-based nature. This extension avoids the need for external optimization solvers, making it particularly suitable for applications requiring constraints on inputs and outputs. We demonstrate the effectiveness of the proposed method through two practical applications: the estimation of COVID-19 curves and the study of mavoglurant, an experimental drug. Our results show that the extended method presents a sum of squared residuals in the same order of magnitude of that of the original Cutler's method and other widely known unconstrained deconvolution techniques, but obtains instead physically plausible solutions, correcting the errors introduced by the alternative methods considered, as illustrated in our case studies.
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OrBiTo is a new European project within the IMI programme in the area of oral biopharmaceutics tools that includes world leading scientists from nine European universities, one ...regulatory agency, one non-profit research organization, four SMEs together with scientists from twelve pharmaceutical companies. The OrBiTo project will address key gaps in our knowledge of gastrointestinal (GI) drug absorption and deliver a framework for rational application of predictive biopharmaceutics tools for oral drug delivery. This will be achieved through novel prospective investigations to define new methodologies as well as refinement of existing tools. Extensive validation of novel and existing biopharmaceutics tools will be performed using active pharmaceutical ingredient (API), formulations and supporting datasets from industry partners. A combination of high quality in vitro or in silico characterizations of API and formulations will be integrated into physiologically based in silico biopharmaceutics models capturing the full complexity of GI drug absorption. This approach gives an unparalleled opportunity to initiate a transformational change in industrial research and development to achieve model-based pharmaceutical product development in accordance with the Quality by Design concept. Benefits include an accelerated and more efficient drug candidate selection, formulation development process, particularly for challenging projects such as low solubility molecules (BCS II and IV), enhanced and modified-release formulations, as well as allowing optimization of clinical product performance for patient benefit. In addition, the tools emerging from OrBiTo are expected to significantly reduce demand for animal experiments in the future as well as reducing the number of human bioequivalence studies required to bridge formulations after manufacturing or composition changes.
Background and Purpose
Whole body physiologically based pharmacokinetic (PBPK) models have been increasingly applied in drug development to describe kinetic events of therapeutic agents in animals ...and humans. The advantage of such modelling is the ability to incorporate vast amounts of physiological information, such as organ blood flow and volume, to ensure that the model is as close to reality as possible.
Experimental Approach
Previous PBPK model development of enantiomers of a series of seven racemic β‐blockers, namely, acebutolol, betaxolol, bisoprolol, metoprolol, oxprenolol, pindolol and propranolol, together with S‐timolol in rat was based on tissue and blood concentration data at steady state. Compounds were administered in several cassettes with the composition mix and blood and tissue sampling times determined using a D‐optimal design.
Key Results
Closed‐loop PBPK models were developed initially based on the application of open loop forcing function models to individual tissues and compounds. For the majority of compounds and tissues, distribution kinetics was adequately characterized by perfusion rate‐limited models. For some compounds in the testes and gut, a permeability rate‐limited distribution model was required to best fit the data. Parameter estimates of the tissue‐to‐blood partition coefficient through fitting of individual enantiomers and of racemic pair were generally in agreement and also concur with those from previous steady‐state experiments.
Conclusions and Implications
PBPK modelling is a very powerful tool to aid drug discovery and development of therapeutic agents in animals and humans. However, careful consideration of the assumptions made during the modelling exercise is essential.
Summary
Objective Corticosteroid‐binding globulin (CBG) is the principal carrier for cortisol in the circulation. Variations in CBG‐binding capacity are predicted to alter total serum cortisol ...disposition, but free serum cortisol is believed to be unaffected. Unbound cortisol pharmacokinetics (PK) have not been studied in the context of CBG changes. We aimed to assess the regulation of cortisol PK by CBG.
Design and subjects Women on oestrogens oral contraceptive pill, (OCP), patients homozygous for a nonfunctioning CBG variant (CBG null) and healthy controls (HV) were studied before and after IV and oral administration of hydrocortisone 20 mg.
Measurements PK parameters were studied for total serum cortisol (SerF), free serum cortisol (FreeF) and cortisone (FreeE), and salivary cortisol (SalF) and cortisone (SalE): area under the curve (AUC), clearance (CL), half‐life and volume of distribution (Vd).
Results Following IV hydrocortisone, AUC and half‐life of SerF were significantly higher in the OCP group and lower in the CBG null. SerF CL and Vd were significantly lower in the OCP group and increased in the CBG null, compared to HV. PK parameters for FreeF and the salivary biomarkers were not different between the CBG null and HV, although OCP patients still had higher AUC compared to HV and prolonged half‐life. These findings were confirmed following oral hydrocortisone, but concentration–time profiles were highly heterogeneous and SalF interpretation was problematic because of oral contamination.
Conclusions We have demonstrated that CBG has a distinct effect on cortisol PK. When CBG binding is disrupted, FreeF retains normal PK characteristics, although CBG null patients lack a CBG‐bound pool of readily releasable cortisol. Women on oestrogens may have altered free serum cortisol kinetics and thus may be potentially overexposed to glucocorticoids.
The aim was to characterize ropivacaine and 2′,6′-pipecoloxylidide (PPX) pharmacokinetics and factors affecting them in paediatric anaesthesia.
Population pharmacokinetics of ropivacaine and its ...active metabolite PPX were estimated after single and continuous ropivacaine blocks in 192 patients aged 0–12 yr from six pooled published studies. Unbound and total ropivacaine and PPX plasma concentration and PPX urinary excretion data were used for non-linear mixed-effects modelling by NONMEM. Covariates included age, body weight, gender, ethnic origin, ASA, site and method of administration, and total dose.
One-compartment first-order pharmacokinetic models incorporating linear binding of ropivacaine and PPX to α1-acid glycoprotein were used. After accounting for the effect of body weight, clearance of unbound ropivacaine and PPX reached 41% and 89% of their mature values, respectively, at the age of 6 months. Ropivacaine half-life decreased with age from 13 h in the newborn to 3 h beyond 1 yr. PPX half-life differed from 19 h in the newborn to 8–11 h between 1 and 12 months to 17 h after 1 yr. Simulations indicate that for a single caudal block, the recommended dose could be increased by a factor of 2.9 (0–1 month group) and 6.3 (1–12 yr group) before the unbound plasma concentrations would cross the threshold for systemic toxicity. Corresponding factors for continuous epidural infusion are 1.8 and 4.9.
Ropivacaine and PPX unbound clearance depends on body weight and age. The results support approved dose recommendations of ropivacaine for the paediatric population.
An algorithm for automatic order reduction of models defined by large systems of differential equations is presented. The algorithm was developed with systems biology models in mind and the ...motivation behind it is to develop mechanistic pharmacokinetic/pharmacodynamic models from already available systems biology models. The approach used for model reduction is proper lumping of the system's states and is based on a search through the possible combinations of lumps. To avoid combinatorial explosion, a heuristic, greedy search strategy is employed and comparison with the full exhaustive search provides evidence that it performs well. The method takes advantage of an apparent property of this kind of systems that lumps remain consistent over different levels of order reduction. Advantages of the method presented include: the variables and parameters of the reduced model retain a specific physiological meaning; the algorithm is automatic and easy to use; it can be used for nonlinear models and can handle parameter uncertainty and constraints. The algorithm was applied to a model of NF-B signalling pathways in order to demonstrate its use and performance. Significant reduction was achieved for the example model, while agreement with the original model was proportional to the size of the reduced model, as expected. The results of the model reduction were compared with a published, intuitively reduced model of NF-B signalling pathways and were found to be in agreement, in terms of the identified key species for the system's kinetic behaviour. The method may provide useful insights which are complementary to the intuitive reduction approach, especially in large systems.
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