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Quantitative translation of information on drug absorption, disposition, receptor engagement and drug-drug interactions from bench to bedside requires models informed by physiological parameters that link in vitro studies to in vivo outcomes. To predict in vivo outcomes, biochemical data from experimental systems are routinely scaled using protein quantity in these systems and relevant tissues. Although several laboratories have generated useful quantitative proteomic data using state-of-the-art mass spectrometry, no harmonized guidelines exit for sample analysis and data integration to in vivo translation practices. To address this gap, a workshop was held on September 27(th) and 28(th), 2018, in Cambridge, MA, with 100 experts attending from academia, the pharmaceutical industry and regulators. Various aspects of quantitative proteomics and its applications in translational pharmacology were debated. A summary of discussions and best practices identified by this expert panel are presented in this ‘White Paper’ alongside unresolved issues which were outlined for future debates.

Developmental pharmacology describes the impact of maturation on drug disposition (pharmacokinetics, PK) and drug effects (pharmacodynamics, PD) throughout the paediatric age range. This paper, written by a multidisciplinary group of experts, summarizes current knowledge, and provides suggestions to pharmaceutical companies, regulatory agencies and academicians on how to incorporate the latest knowledge regarding developmental pharmacology and innovative techniques into neonatal and paediatric drug development. Biological aspects of drug absorption, distribution, metabolism and excretion throughout development are summarized. Although this area made enormous progress during the last two decades, remaining knowledge gaps were identified. Minimal risk and burden designs allow for optimally informative but minimally invasive PK sampling, while concomitant profiling of drug metabolites may provide additional insight in the unique PK behaviour in children. Furthermore, developmental PD needs to be considered during drug development, which is illustrated by disease- and/or target organ-specific examples. Identifying and testing PD targets and effects in special populations, and application of age- and/or population-specific assessment tools are discussed. Drug development plans also need to incorporate innovative techniques such as preclinical models to study therapeutic strategies, and shift from sequential enrolment of subgroups, to more rational designs. To stimulate appropriate research plans, illustrations of specific PK/PD-related as well as drug safety-related challenges during drug development are provided. The suggestions made in this joint paper of the Innovative Medicines Initiative conect4children Expert group on Developmental Pharmacology and the European Society for Developmental, Perinatal and Paediatric Pharmacology, should facilitate all those involved in drug development. ispartof: BRITISH JOURNAL OF CLINICAL PHARMACOLOGY vol:88 issue:12 pages:4965-4984 ispartof: location:England status: published

Paper spray high-resolution accurate mass spectrometry is a fast and versatile analysis method. This ambient ionization technique enables the quantitation of xenobiotics in complex biological matrices without chromatography or conventional sample extraction. The simplicity, rapidity, and affordability of the paper spray mass spectrometry (PS-MS) method make the technique especially attractive for clinical investigations where fast and affordable sample analysis is crucial. A new PS-MS method for the quantitation of voriconazole in equine tears was developed and validated. For a concentration range of 10 to 1000 ng/mL, good linearity (R2 > 0.99), inter- and intra-run precision (coefficient of variation (CV) max. 11.9%), accuracy (bias of the nominal concentration ± 13.9%), and selectivity (signal areas of the double blanks represent 0.13 ± 0.05% of the lower limit of quantitation (LLOQ) signal in equine tears) were observed. The quantitation of voriconazole was based on three product ions and calculated relative to the isotope-labeled internal standard, voriconazole-d3, which had a final concentration of 250 ng/mL in the standards and samples. The matrix effect of the method showed an ionization suppression by reduction of the voriconazole response to 63.6%, 70.2%, and 81.9% for 30 ng/mL, 450 ng/mL, and 900 ng/mL in equine tears compared with voriconazole in solvent (methanol:water, 50:50, v:v). The method was used to analyze 126 study samples collected for a pharmacokinetic study investigating a novel approach for treatment of fungal keratitis in horses. Therefore, the integrity of the sample dilution (n = 6, CV 6.90%, and bias of nominal concentration + 8.40%) and the carryover effect (increase from 0.33 ± 0.21% to 1.33 ± 0.89% of the signal of the LLOQ) was further investigated. To our knowledge, this method is the first application of PS-MS for quantitation of drug concentrations in tears from any species.

The coronavirus disease 2019 (COVID-19) pandemic poses an enormous challenge to healthcare systems in affected communities. Older patients and those with pre-existing medical conditions have been identified as populations at risk of a severe disease course. It remains unclear at this point to what extent chronic liver diseases should be considered as risk factors, due to a shortage of appropriate studies. However, patients with advanced liver disease and those after liver transplantation represent vulnerable patient cohorts with an increased risk of infection and/or a severe course of COVID-19. In addition, the current pandemic requires unusual allocation of healthcare resources which may negatively impact the care of patients with chronic liver disease that continue to require medical attention. Thus, the challenge hepatologists are facing is to promote telemedicine in the outpatient setting, prioritise outpatient contacts, avoid nosocomial dissemination of the virus to patients and healthcare providers, and at the same time maintain standard care for patients who require immediate medical attention.

The 2017 11th Workshop on Recent Issues in Bioanalysis took place in Los Angeles/Universal City, California, on 3–7 April 2017 with participation of close to 750 professionals from pharmaceutical/biopharmaceutical companies, biotechnology companies, contract research organizations and regulatory agencies worldwide. WRIB was once again a 5-day, week-long event – a full immersion week of bioanalysis, biomarkers and immunogenicity. As usual, it was specifically designed to facilitate sharing, reviewing, discussing and agreeing on approaches to address the most current issues of interest including both small- and large-molecule analysis involving LC–MS, hybrid ligand-binding assay (LBA)/LC–MS and LBA approaches. This 2017 White Paper encompasses recommendations emerging from the extensive discussions held during the workshop, and is aimed to provide the bioanalytical community with key information and practical solutions on topics and issues addressed, in an effort to enable advances in scientific excellence, improved quality and better regulatory compliance. Due to its length, the 2017 edition of this comprehensive White Paper has been divided into three parts for editorial reasons. This publication (Part 3) covers the recommendations for large-molecule bioanalysis, biomarkers and immunogenicity using LBA. Part 1 (LC–MS for small molecules, peptides and small molecule biomarkers) and Part 2 (hybrid LBA/LC–MS for biotherapeutics and regulatory agencies’ inputs) are published in volume 9 of Bioanalysis, issues 22 and 23 (2017), respectively.

PURPOSE In critically ill patients, changes in the pharmacokinetics (PK) of β-lactams can lead to significant variations in serum concentrations, with possibly detrimental effects on outcomes. The utilization of individually calculated doses, extended infusion regimens, and therapeutic drug monitoring (TDM)-guided dose adjustments can mitigate the PK changes and help to achieve and attain an individual PK target. METHODS We reviewed relevant literature from 2004-2021 using four search engines (PubMed, Web of Science, Scopus, and Google Scholar). Unpublished clinical data were also examined. RESULTS TDM-guided, individualized dosing strategies facilitated PK target attainment and improved patient outcomes. TDM-guided therapy is a core concept of individualized dosing that increases PK target attainment and monitors possible toxic β-lactam concentrations. CONCLUSION Individualized dosing and TDM facilitate the rational use of β-lactams and are integral for antibiotic stewardship interventions in critical care, affording both the optimal exposure of pathogen and drugs, along with enhanced treatment efficacy and reduced emergence of antimicrobial resistance.

The Global Bioanalysis Consortium (GBC) set up an international team to explore the impact of immunogenicity on pharmacokinetic (PK) assessments. The intent of this paper is to define the field and propose best practices when developing PK assays for biotherapeutics. We focus on the impact of anti-drug antibodies (ADA) on the performance of PK assay leading to the impact on the reported drug concentration and exposure. The manuscript describes strategies to assess whether the observed change in the drug concentration is due to the ADA impact on drug clearance rates or is a consequence of ADA interference in the bioanalytical method applied to measure drug concentration. This paper provides the bioanalytical scientist guidance for developing ADA-tolerant PK methods. It is essential that the data generated in the PK, ADA, pharmacodynamic and efficacy/toxicity evaluations are viewed together. Therefore, the extent for the investigation of the PK sensitivity to the presence of ADA should be driven by the project needs and risk based.

The new oral anticoagulants (NOACs) have radically changed the approach to the treatment and prevention of thromboembolic pulmonary embolism. The authors of this position paper face, in succession, issues concerning NOACs, including (i) their mechanism of action, pharmacodynamics, and pharmacokinetics; (ii) the use in the acute phase with the ‘double drug single dose’ approach or with ‘single drug double dose’; (iii) the use in the extended phase with demonstrated efficacy and with low incidence of bleeding events; (iv) the encouraging use of NOACs in particular subgroups of patients such as those with cancer, the ones under- or overweight, with renal insufficiency (creatinine clearance > 30 mL/min), the elderly (>75 years); (v) they propose a possible laboratory clinical pathway for follow-up; and (vi) carry out an examination on the main drug interactions, their potential bleeding risk, and the way to deal with some bleeding complications. The authors conclude that the use of NOACs both in the acute phase and in the extended phase is equally effective to conventional therapy and associated with fewer major bleeding events, which make their use in patients at higher risk of recurrences safer.

Contains fulltext : 200052.pdf (Publisher’s version ) (Closed access) Drug transporters are critically important for the absorption, distribution, metabolism, and excretion (ADME) of many drugs and endogenous compounds. Therefore, disruption of these pathways by inhibition, induction, genetic polymorphisms, or disease can have profound effects on overall physiology, drug pharmacokinetics, drug efficacy, and toxicity. This white paper provides a review of changes in transporter function associated with acute and chronic disease states, describes regulatory pathways affecting transporter expression, and identifies opportunities to advance the field.

A simple, low-cost, sensitive and selective LC method was developed for the determination of enrofloxacin and ciprofloxacin in chicken blood. The method was applied to whole blood from a chicken using dried blood spots on filter paper disks. The detection limits of enrofloxacin and ciprofloxacin (100 μl of whole blood on a disk) were 0.005 and 0.01 μg/ml, respectively. The whole procedure was verified in intra-laboratory studies (recoveries of both compounds were above 90%), and its applicability was tested with blood from the chicken receiving enrofloxacin in a single oral dose at a level of 10 mg/kg body mass. The method permits the use of a small volume of blood from a chicken and should be useful for pharmacokinetic studies.

Field studies of androgen pharmacology are complicated by the necessity to collect, process, and store blood samples in a central facility. We have assessed the feasibility of using capillary blood spots collected by fingerprick and dried on filter paper for pharmacokinetics and pharmacodynamic measurements with nandrolone and testosterone RIAs modified for extracts from capillary blood spots. Assays on punched spots of 7.9-mm diameter (14.9 μL of dried blood) permitted accurate quantification of testosterone down to 0.4 nmol/L from a single spot and nandrolone down to 0.9 nmol/L from two spots. Stability of the steroids in dried blood spots to adverse environmental conditions, notably increased temperatures, was investigated both in the laboratory and in field studies of dried spots sent through the postal system. Storage or postal transport under moderate conditions appeared to have no deleterious effects on apparent androgen concentrations. However, under extreme conditions of storage at 50 °C for a week or more, or transport to a very hot tropical location, a rise in the final concentration of nandrolone, and, to a lesser extent, testosterone when corrected for tracer recovery, was noticed. These effects were largely due to apparent susceptibility of tritiated tracer, but not unlabeled androgens, to thermal degradation. In a pilot pharmacological study involving intramuscular injection of 100 mg of nandrolone decanoate in 1 mL of arachis oil, nandrolone concentrations in concurrently collected plasma as well as venous and capillary blood spots showed good agreement. Testosterone concentrations in contemporaneously collected plasma and venous blood spots also showed very good agreement. We propose that these methods may allow patients and experimental subjects to self-collect samples at remote or field locations for convenient mailing to a central laboratory for androgen assay. Applications of this methodology are now under way.

Pharmacogenomic (PGx) research on the absorption, distribution, metabolism, and excretion (ADME) properties of drugs has begun to have impact for both drug development and utilization. To provide a cross-industry perspective on the utility of ADME PGx, the Pharmaceutical Research and Manufacturers of America (PhRMA) conducted a survey of major pharmaceutical companies on their PGx practices and applications during 2003-2005. This white paper summarizes and interprets the results of the survey, highlights the contributions and applications of PGx by industrial scientists as reflected by original research publications, and discusses changes in drug labels that improve drug utilization by inclusion of PGx information. In addition, the paper includes a brief review on the clinically relevant genetic variants of drug-metabolizing enzymes and transporters most relevant to the pharmaceutical industry.

It has been recognized for several decades in the pharmaceutical industry that the safety evaluation of pharmacological agents must include pharmacokinetic (PK) studies, which are designed to determine the rate of absorption, distribution, metabolism, and excretion (ADME). In recent years the importance of such ADME studies in toxicology has also become increasingly apparent to the chemical industry. This increased focus has led to testing strategies that can produce ADME/PK data with greater applicability to toxicity testing and risk assessment. An example of such a strategy is the concept of a tiered approach to the conduct of ADME/PK studies (Wilson, A. G. E., Frantz, S. W., and Keifer, L. C. (1994). Environ. Health Perspect., in press). However, in practice, PK data are often viewed as being of limited usefulness and of only ancillary importance to the determination of chemical toxicity. As a consequence, the close integration of PK studies with toxicity-testing protocols is not always practiced within the chemical industry and is thus frequently scheduled independently from toxicity testing. This lack of integration has resulted in the design of subchronic (13-week) and chronic (2-year) toxicity studies without the benefit of PK information to establish the appropriate dose levels to be used, often because of inappropriate timing. The result is that much of the PK data which have been generated is without a clear consideration of its application to toxicity testing and risk assessment. This position paper is intended to provide recommendations for the appropriate design and interpretation of a PK study, as well as when and how to use PK data in the interpretation of toxicology data. Additional issues discussed in the paper include the design of PK studies to evaluate tissue time-course relationships and chemical persistence, the overall usefulness of PK data to toxicology testing, and the utility of PK as a useful interpretive and predictive tool in toxicology and risk assessment.

Many decisions in drug development and medical practice are based on measuring blood concentrations of endogenous and exogenous molecules. Yet most biochemical and pharmacological events take place in the tissues. Also, most drugs with few notable exceptions exert their effects not within the bloodstream, but in defined target tissues into which drugs have to distribute from the central compartment. Assessing tissue drug chemistry has, thus, for long been viewed as a more rational way to provide clinically meaningful data rather than gaining information from blood samples. More specifically, it is often the extracellular (interstitial) tissue space that is most closely related to the site of action (biophase) of the drug. Currently microdialysis (mu D) is the only tool available that explicitly provides data on the extracellular space. Although mu D as a preclinical and clinical tool has been available for two decades, there is still uncertainty about the use of mu D in drug research and development, both from a methodological and a regulatory point of view. In an attempt to reduce this uncertainty and to provide an overview of the principles and applications of mu D in preclinical and clinical settings, an AAPS-FDA workshop took place in November 2005 in Nashville, TN, USA. Stakeholders from academia, industry and regulatory agencies presented their views on mu D as a tool in drug research and development.

Developmental physiological changes occur throughout childhood, with important changes observed within the first few weeks and months from birth, potentially affecting drug pharmacokinetics. The impact of confounding factors in relation to the availability of clinically relevant and adequate drug formulations and administration devices is underestimated. Hence, it is important to highlight presently the relevance of formulation issues. Since 2007, the EU Paediatric Regulation enforces paediatric investigation plans in which the applicant has to justify the clinical relevance of each dosage form proposed in relation to age subsets involved and the suitability of administration modalities. Therefore, pediatric drug development has become more relevant, and the importance of using age-appropriate drug formulations has been acknowledged by investigators and other stakeholders. Palatability and acceptability assessment is considered to be important by the regulatory bodies as well as excipient safety and tolerability, as it can be an issue particularly in very young children. However, there remains a lack of research into pediatric biopharmaceutics (methodological input regarding in vitro tools and bridging studies). Clinical pharmacologists with expertise ranging from pharmacodynamics, pharmacokinetics, adverse drug effects, and toxicology should actively contribute in advancing drug formulation issues in children.

Literature data relevant to the decision to allow a waiver of in vivo bioequi- valence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing ethambutol dihydrochloride as the only active pharmaceutical ingredient (API) are reviewed. Ethambutol dihydrochloride is a Biopharmaceutics Classification System (BCS) Class III drug with permeability properties approaching the border between BCS Class I and III. BE problems of ethambutol formulations containing different excipients and different dosages forms have not been reported and hence the risk of bioinequivalence caused by excipients is low. Ethambutol has a narrow therapeutic index related to ocular toxicity. However, as long as the prescribers' information of the test product stipulates the need for regular monitoring of ocular toxicity, the additional patient risk is deemed acceptable. It is concluded that a biowaiver can be recommended for IR solid oral dosage forms provided that the test product (a) contains only excipients present in ethambutol IR solid oral drug products approved in ICH or associated countries, for instance as presented in this paper, (b) complies with the criteria for ''very rapidly dissolving'' and (c) has a prescribers' information indicating theneed for testing thepatient's visionprior toinitiating ethambutol therapy and regularly during therapy. 2007 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 97:1350-1360, 2008

Abstract 3479 Poster Board III-416 Introduction ELISA assays have been proposed as a complement to the Bethesda assay for detection and follow-up of factor VIII (FVIII) antibodies in subjects with hemophilia. The Bethesda assay has several drawbacks. Most importantly, the Bethesda assay would not detect non-inhibitory antibodies, even though these could be responsible for low in vivo recovery of FVIII and /or a pharmacokinetic pattern suggestive of rapid clearance of FVIII. ELISA assays for detecting antibodies to FVIII are not routinely performed in most hospital laboratories and as such, specimens need to be transported to specialized laboratories for processing. Transportation of plasma specimens frozen on dry ice, however, is both costly and cumbersome. Room temperature storage of whole blood and serum specimens adsorbed and dried onto filter paper has been shown to be a convenient and reliable alternative to frozen whole blood and serum samples for various analyses. This study was undertaken to assess whether FVIII antibodies from haemophilic plasma would display similar stability when stored adsorbed onto filter paper at room temperature for 1 month or on plasma specimens stored frozen. Stability was assessed by comparing results of ELISA assays. Methods two hundred and thirteen frozen (at -80°C) plasma samples from patients with or without known FVIII inhibitors were tested. Samples came from 97 congenital haemophilic subjects and 5 subjects with acquired haemophilia. The samples were tested with a previously reported ELISA assay (Haemophilia 2009; 15: 374-6) with minor modifications. The coating antigens were two therapeutic preparations of recombinant FVIII: the full length FVIII preparation Helixate® FS, and the B-domain deleted FVIII Xyntha®. Five dilutions of plasma from a subject with congenital severe hemophilia A known to have a high Bethesda titer was put on all plates as positive control. Six normal plasmas were used on all plates as negative controls. Mean and standard deviation of optical densities were calculated for negative controls. Mean was subtracted from optical density of each test plasma. The resulting value was divided by the value of one standard deviation of negative controls to generate the number of standard deviations for test plasmas. All plasmas were assayed in duplicate. The numbers of standard deviations were compared between frozen samples and samples dried on filter papers. Results The correlation between the numbers of standard deviations obtained with frozen specimens and with specimens dried on filter paper was excellent for both therapeutic preparations of recombinant FVIII, going from R= 0.91 to R= 0.99. Conclusion FVIII antibodies tested by ELISA using plasma dried on filter paper for one month at room temperature or plasma stored at -80°C give comparable results. Disclosures: No relevant conflicts of interest to declare.

Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing cimetidine are reviewed. According to the current Biopharmaceutics Classification System (BCS), cimetidine would be assigned to Class III. Cimetidine's therapeutic use and therapeutic index, its pharmacokinetic properties, data related to the possibility of excipient interactions, and reported BE/bioavailability (BA) problems were also taken into consideration. On the basis of the overall evidence, a biowaiver can be recommended for cimetidine IR products, provided that the test product contains only those excipients reported in this paper in their usual amounts, and that the test and the comparator drug products both are “rapidly dissolving” as per BCS.

Literature data are reviewed on the properties of ibuprofen related to the biopharmaceutics classification system (BCS). Ibuprofen was assessed to be a BCS class II drug. Differences in composition and/or manufacturing procedures were reported to have an effect on the rate, but not the extent of absorption; such differences are likely to be detectable by comparative in vitro dissolution tests. Also in view of its therapeutic use, its wide therapeutic index and uncomplicated pharmacokinetic properties, a biowaiver for immediate release (IR) ibuprofen solid oral drug products is scientifically justified, provided that the test product contains only those excipients reported in this paper in their usual amounts, the dosage form is rapidly dissolving (85% in 30 min or less) in buffer pH 6.8 and the test product also exhibits similar dissolution profiles to the reference product in buffer pH 1.2, 4.5, and 6.8.

Although no randomized studies have demonstrated a positive impact of therapeutic drug monitoring (TDM) on clinical outcome in epilepsy, evidence from nonrandomized studies and everyday clinical experience does indicate that measuring serum concentrations of old and new generation antiepileptic drugs (AEDs) can have a valuable role in guiding patient management provided that concentrations are measured with a clear indication and are interpreted critically, taking into account the whole clinical context. Situations in which AED measurements are most likely to be of benefit include (1) when a person has attained the desired clinical outcome, to establish an individual therapeutic concentration which can be used at subsequent times to assess potential causes for a change in drug response; (2) as an aid in the diagnosis of clinical toxicity; (3) to assess compliance, particularly in patients with uncontrolled seizures or breakthrough seizures; (4) to guide dosage adjustment in situations associated with increased pharmacokinetic variability (e.g., children, the elderly, patients with associated diseases, drug formulation changes); (5) when a potentially important pharmacokinetic change is anticipated (e.g., in pregnancy, or when an interacting drug is added or removed); (6) to guide dose adjustments for AEDs with dose-dependent pharmacokinetics, particularly phenytoin.

Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing amitriptyline hydrochloride are reviewed. Its therapeutic uses, its pharmacokinetic properties, the possibility of excipient interactions and reported BE/bioavailability (BA) problems are also taken into consideration. Literature data indicates that amitriptyline hydrochloride is a highly permeable active pharmaceutical ingredient (API). Data on the solubility according to the current Biopharmaceutics Classification System (BCS) were not fully available and consequently amitriptyline hydrochloride could not be definitively assigned to either BCS Class I or BCS Class II. But all evidence taken together, a biowaiver can currently be recommended provided that IR tablets are formulated with excipients used in existing approved products and that the dissolution meets the criteria defined in the Guidances.