Target Site Delivery and Residence of Nanomedicines: Application of Quantitative Systems Pharmacology.

Quantitative systems pharmacology (QSP), an emerging field that entails using modeling and computation to interpret, interrogate, and integrate drug effects spanning from the molecule to the whole organism to forecast treatment outcomes, is expected to enhance the efficiency of drug development. Since late 2017, the U.S. Food and Drug Administration has advocated the use of an analogous approach of model-informed drug development. This review focuses on issues pertaining to nanosized medicines (NP) and the potential utility of QSP to determine NP delivery and residence at extracellular or intracellular targets in vivo. The kinetic processes governing NP disposition and transport, interactions with biologic matrix components, binding and internalization in cells, and intracellular trafficking are determined, sometimes jointly, by NP properties (e.g., dimension, materials, surface charge and modifications, shape, and geometry) and target tissue properties (e.g., perfusion status, vessel pore size and wall thickness, vessel and cell density, composition of extracellular matrix, and void volume fraction). These various determinants, together with the heterogeneous tissue structures and microenvironment factors in solid tumors, lead to environment-, spatial-, and time-dependent changes in NP concentrations that are difficult to predict. Adding to the complexity is the recent discovery that NP surface-coating protein corona, whose composition depends on NP properties and which undergoes continuous evolution with time and local protein environments, is yet another unpredictable variable. Examples are provided to demonstrate the potential utility of QSP-based multiscale modeling to capture the physicochemical and biologic processes in equations to enable computational studies of the key kinetic processes in cancer treatments.

A physiologically based model for tramadol pharmacokinetics in horses.

This work proposes an application of a minimal complexity physiologically based pharmacokinetic model to predict tramadol concentration vs time profiles in horses. Tramadol is an opioid analgesic also used for veterinary treatments. Researchers and medical doctors can profit from the application of mathematical models as supporting tools to optimize the pharmacological treatment of animal species. The proposed model is based on physiology but adopts the minimal compartmental architecture necessary to describe the experimental data. The model features a system of ordinary differential equations, where most of the model parameters are either assigned or individualized for a given horse, using literature data and correlations. Conversely, residual parameters, whose value is unknown, are regressed exploiting experimental data. The model proved capable of simulating pharmacokinetic profiles with accuracy. In addition, it provides further insights on un-observable tramadol data, as for instance tramadol concentration in the liver or hepatic metabolism and renal excretion extent.

Is It Time to Use Modeling of Cellular Transporter Homeostasis to Inform Drug-Drug Interaction Studies: Theoretical Considerations.

Mathematical modeling has been an important tool in pharmaceutical research for 50 + years and there is increased emphasis over the last decade on using modeling to improve the efficiency and effectiveness of drug development. In an earlier commentary, we applied a multiscale model linking 6 scales (whole body, tumor, vasculature, cell, spatial location, time), together with literature data on nanoparticle and tumor properties, to demonstrate the effects of nanoparticle particles on systemic disposition. The current commentary used a 4-scale model (cell membrane, intracellular organelles, spatial location, time) together with literature data on the intracellular processing of membrane receptors and transporters to demonstrate disruption of transporter homeostasis can lead to drug-drug interaction (DDI) between victim drug (VD) and perpetrator drug (PD), including changes in the area-under-concentration-time-curve of VD in cells that are considered significant by the US Food and Drug Administration (FDA). The model comprised 3 computational components: (a) intracellular transporter homeostasis, (b) pharmacokinetics of extracellular and intracellular VD/PD concentrations, and (c) pharmacodynamics of PD-induced stimulation or inhibition of an intracellular kinetic process. Model-based simulations showed that (a) among the five major endocytic processes, perturbation of transporter internalization or recycling led to the highest incidence and most extensive DDI, with minor DDI for perturbing transporter synthesis and early-to-late endosome and no DDI for perturbing transporter degradation and (b) three experimental conditions (spatial transporter distribution in cells, VD/PD co-incubation time, extracellular PD concentrations) were determinants of DDI detection. We propose modeling is a useful tool for hypothesis generation and for designing experiments to identify potential DDI; its application further aligns with the model-informed drug development paradigm advocated by FDA.

Quantitative Systems Pharmacology Modeling of Avadomide-Induced Neutropenia Enables Virtual Clinical Dose and Schedule Finding Studies.

Avadomide is a cereblon E3 ligase modulator and a potent antitumor and immunomodulatory agent. Avadomide trials are challenged by neutropenia as a major adverse event and a dose-limiting toxicity. Intermittent dosing schedules supported by preclinical data provide a strategy to reduce frequency and severity of neutropenia; however, the identification of optimal dosing schedules remains a clinical challenge. Quantitative systems pharmacology (QSP) modeling offers opportunities for virtual screening of efficacy and toxicity levels produced by alternative dose and schedule regimens, thereby supporting decision-making in translational drug development. We formulated a QSP model to capture the mechanism of avadomide-induced neutropenia, which involves cereblon-mediated degradation of transcription factor Ikaros, resulting in a maturation block of the neutrophil lineage. The neutropenia model was integrated with avadomide-specific pharmacokinetic and pharmacodynamic models to capture dose-dependent effects. Additionally, we generated a disease-specific virtual patient population to represent the variability in patient characteristics and response to treatment observed for a diffuse large B-cell lymphoma trial cohort. Model utility was demonstrated by simulating the avadomide effect in the virtual population for various dosing schedules and determining the incidence of high-grade neutropenia, its duration, and the probability of recovery to low-grade neutropenia.

Clinical trial on the efficacy of a new symbiotic formulation, Flortec, in patients with acute diarrhea: a multicenter, randomized study in primary care.

OBJECTIVES: Few randomized studies have been carried out on adult patients affected by acute diarrhea especially in primary care, which is the natural context for this kind of disorder. Lactobacillus paracasei B 21060 is a novel strain of lactobacillus, which has been shown to be effective in relieving symptoms associated with diarrhea of irritable bowel syndrome subtype and in shortening diarrhea duration. In this study, we compared the therapeutic efficacy, safety, and tolerability of a new symbiotic formulation, Flortec, containing L. paracasei B-21060, with lactobacillus GG (FlorVis GG) in the treatment of acute presumed infectious diarrhea. METHODS: Fourteen general practitioners working in the Perugia health authority district carried out a randomized controlled, parallel-group, open trial in 174 adult patients suffering from acute diarrhea (87 enrolled in the Flortec group and 87 in the FlorVis group). Both the products were administered according to their standard recommended dosage. The main efficacy criterion was the duration of diarrhea after beginning treatment. Treatment duration was 10 days. Enrolled patients kept a careful track of their symptoms noting them in a personal diary for 12 days. RESULTS: The 2 groups resulted to be homogeneous at baseline with regard to prognostic variables. The mean duration of diarrhea from the start of treatment in the Flortec group was 4.24 (2.73 SD) days versus 5.09 (3.72 SD) days in the FlorVis group (P=0.09).Clinical success rates in terms of absence of abdominal pain and absence of diarrhea (defined as <2 bowel movements of watery or loose stool consistency) recorded at different time-points were statistically superior in the Flortec group (Kaplan-Meyer P=0.05 for both the symptoms). The physician judged that overall efficacy was good or very good in 91.8% of the patients in the Flortec group. The corresponding value in the FlorVis group was 83.7% (P=0.003). The 2 treatments showed a very good tolerability profile, with negligible and similar adverse event rates and similar concomitant medication usage rates. CONCLUSIONS: Oral therapy with Flortec proved to be more effective than FlorVis GG in the treatment of acute diarrhea in adults treated at a primary care setting.

Systemic Bioequivalence Is Unlikely to Equal Target Site Bioequivalence for Nanotechnology Oncologic Products.

Approval of generic drugs by the US Food and Drug Administration (FDA) requires the product to be pharmaceutically equivalent to the reference listed drug (RLD) and demonstrate bioequivalence (BE) in effectiveness when administered to patients under the conditions in the RLD product labeling. Effectiveness is determined by drug exposure at the target sites. However, since such measurement is usually unavailable, systemic exposure is assumed to equal target site exposure and systemic BE to equal target site BE. This assumption, while it often applies to small molecule drug products that are readily dissolved in biological fluids and systemically absorbed, is unlikely to apply to nanotechnology products (NP) that exist as heterogeneous systems and are subjected to dimension- and material-dependent changes. This commentary provides an overview of the intersecting and spatial-dependent processes and variables governing the delivery and residence of oncologic NP in solid tumors. In order to provide a quantitative perspective of the collective effects of these processes, we used quantitative systems pharmacology (QSP) multi-scale modeling to capture the physicochemical and biological events on several scales (whole-body, organ/suborgan, cell/subcellular, spatial locations, time). QSP is an emerging field that entails using modeling and computation to facilitate drug development; an analogous approach (i.e., model-informed drug development) is advocated by to FDA. The QSP model-based simulations illustrated that small changes in NP attributes (e.g., size variations during manufacturing, interactions with proteins in biological milieu) could lead to disproportionately large differences in target site exposure, rending systemic BE unlikely to equal target site BE.

Clinical trial on the efficacy of a new symbiotic formulation, Flortec, in patients with irritable bowel syndrome: a multicenter, randomized study.

OBJECTIVES: Efficacy of symbiotics in patients with irritable bowel syndrome (IBS) remains unknown. METHODS: Patients were randomized to a prebiotic (n=135), or a symbiotic formulation containing Lactobacillus paracasei B21060 (Flortec, n=132). Primary efficacy was the responder rate for pain and global relief of symptoms in the overall population and in patients with predominant diarrhea (n=47). Post hoc time-trend analyses for changes within each treatment were carried out. RESULTS: Patients with absent/mild pain amounted to 54.7% in the symbiotic group and to 57.4% in the prebiotic group at treatment week 4, and to 53.9% and 53.4% at the end of treatment. Patients with amelioration of well-being were, respectively, 60.7% versus 61.7% at treatment week 4, and 63.3% versus 60.9% at the end of treatment. Within each treatment group, patients with absent/mild pain increased in the Flortec and the prebiotic group, but time trend analyses were significant only for Flortec (P=0.019). In IBS-predominant diarrhea, Flortec significantly reduced bowel movements, pain, and IBS scores. CONCLUSIONS: To improve pain and well-being, Flortec is encouraging in patients with diarrhea predominant IBS. To establish its efficacy for the majority of IBS patients, Flortec has to be compared with an inert placebo in future work.

A physiologically-based model to predict individual pharmacokinetics and pharmacodynamics of remifentanil.

Remifentanil based anesthesia is nowadays spread worldwide. This drug is characterized by a rapid onset of the analgesic effects, but also by a rapid onset of the side effects. For this reason, the knowledge of the remifentanil concentration in the human body is a key topic in anesthesiology. The aims of this work are to propose and validate a physiologically based pharmacokinetic model capable to predict both the pharmacokinetics and pharmacodynamics of remifentanil, and to take into account the inter-individual differences among the patients (such as height and body mass). The blood concentration of remifentanil has been successfully simulated and compared with experimental literature data. The pharmacodynamics, in terms of effect of remifentanil on minute ventilation and electroencephalogram, has been implemented in this model. Moreover, the remifentanil concentration in various organs and tissues is predicted, which is a significant improvement with respect to the traditional compartmental models. The availability of the model makes possible the prediction of the effects of remifentanil administration, also accounting for individual parameters.

Innovations and Improvements in Pharmacokinetic Models Based on Physiology.

BACKGROUND: Accompanied by significant improvements of modeling techniques and computational methods in medical sciences, the last thirty years saw the flourishing of pharmacokinetic models for applications in the pharmacometric field. In particular, physiologically based pharmacokinetic (PBPK) models, grounded on a mechanistic foundation, have been applied to explore a multiplicity of aspects with possible applications in patient care and new drugs development, as in the case of siRNA therapies. METHOD: This article summarizes the features we recently introduced in PBPK modeling within a threeyear research project funded by Italian Research Ministry. Four major points are detailed: (i) the mathematical formulation of the model, which allows modulating its complexity as a function of the administration route and active principle; (ii) a dedicated parameter of the PBPK model quantifies the drugprotein binding, which affects the active principle distribution; (iii) the gall bladder compartment and the bile enterohepatic circulation process; (iv) the coupling of the pharmacokinetic and pharmacodynamic models to produce an overall understanding of the drug effects on mammalian body. RESULTS: The proposed model is applied to two separate endovenous (remifentanil) and oral (sorafenib) drug administrations. The resulting PBPK simulations are consistent with the literature experimental data. Blood concentration predictability is confirmed in multiple reference subjects. Furthermore, in case of sorafenib administration in mice, it is possible to evaluate the drug concentration in the liver and reproduce the effects of the enterohepatic circulation. Finally, a preliminary application of the coupling of the pharmacokinetic/pharmacodynamic models is presented and discussed.

Engineering approaches in siRNA delivery.

siRNAs are very potent drug molecules, able to silence genes involved in pathologies development. siRNAs have virtually an unlimited therapeutic potential, particularly for the treatment of inflammatory diseases. However, their use in clinical practice is limited because of their unfavorable properties to interact and not to degrade in physiological environments. In particular they are large macromolecules, negatively charged, which undergo rapid degradation by plasmatic enzymes, are subject to fast renal clearance/hepatic sequestration, and can hardly cross cellular membranes. These aspects seriously impair siRNAs as therapeutics. As in all the other fields of science, siRNAs management can be advantaged by physical-mathematical descriptions (modeling) in order to clarify the involved phenomena from the preparative step of dosage systems to the description of drug-body interactions, which allows improving the design of delivery systems/processes/therapies. This review analyzes a few mathematical modeling approaches currently adopted to describe the siRNAs delivery, the main procedures in siRNAs vectors' production processes and siRNAs vectors' release from hydrogels, and the modeling of pharmacokinetics of siRNAs vectors. Furthermore, the use of physical models to study the siRNAs vectors' fate in blood stream and in the tissues is presented. The general view depicts a framework maybe not yet usable in therapeutics, but with promising possibilities for forthcoming applications.

Chemical Engineering in the "BIO" World.

Modern Chemical Engineering was born around the end of the 19th century in Great Britain, Germany, and the USA, the most industrialized countries at that time. Milton C. Whitaker, in 1914, affirmed that the difference between Chemistry and Chemical Engineering lies in the capability of chemical engineers to transfer laboratory findings to the industrial level. Since then, Chemical Engineering underwent huge transformations determining the detachment from the original Chemistry nest. The beginning of the sixties of the 20th century saw the development of a new branch of Chemical Engineering baptized Biomedical Engineering by Peppas and Langer and that now we can name Biological Engineering. Interestingly, although Biological Engineering focused on completely different topics from Chemical Engineering ones, it resorted to the same theoretical tools such as, for instance, mass, energy and momentum balances. Thus, the birth of Biological Engineering may be considered as a Darwinian evolution of Chemical Engineering similar to that experienced by mammals which, returning to water, used legs and arms to swim. From 1960 on, Biological Engineering underwent a considerable evolution as witnessed by the great variety of topics covered such as hemodialysis, release of synthetic drugs, artificial organs and, more recently, delivery of small interfering RNAs (siRNA). This review, based on the activities developed in the frame of our PRIN 2010-11 (20109PLMH2) project, tries to recount origins and evolution of Chemical Engineering illustrating several examples of recent and successful applications in the biological field. This, in turn, may stimulate the discussion about the Chemical Engineering students curriculum studiorum update.

Nutritional supplementation with branched-chain amino acids in advanced cirrhosis: a double-blind, randomized trial.

BACKGROUND & AIMS: The role of oral supplementation with branched-chain amino acids (BCAA) in advanced cirrhosis is far from settled. A nutritional approach might prevent progressive liver failure and improve nutritional parameters and quality of life. METHODS: A multicenter, randomized study comparing 1-year nutritional supplementation with BCAA against lactoalbumin or maltodextrins was performed in 174 patients with advanced cirrhosis. Primary outcomes were the prevention of a combined end point (death and deterioration to exclusion criteria), the need for hospital admission, and the duration of hospital stay. Secondary outcomes were nutritional parameters, laboratory data and Child-Pugh score, anorexia, health-related quality of life, and need for therapy. RESULTS: Treatment with BCAA significantly reduced the combined event rates compared with lactoalbumin (odds ratio, 0.43; 95% confidence interval, 0.19-0.96; P = 0.039) and nonsignificantly compared with maltodextrins (odds ratio, 0.51; 95% confidence interval, 0.23-1.17; P = 0.108). The average hospital admission rate was lower in the BCAA arm compared with control treatments (P = 0.006 and P = 0.003, respectively). In patients who remained in the study, nutritional parameters and liver function tests were, on average, stable or improved during treatment with BCAA and the Child-Pugh score decreased (P = 0.013). Also, anorexia and health-related quality of life (SF-36 questionnaire) improved. Long-term compliance with BCAA was poor. CONCLUSIONS: In advanced cirrhosis, long-term nutritional supplementation with oral BCAA is useful to prevent progressive hepatic failure and to improve surrogate markers and perceived health status. New formulas are needed to increase compliance.