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Keywords: Pharmacogenomics; ADME; PhRMA; drug-metabolizing enzymes; genotyping 849 PharmacogenomicsPhRMA White Paper on ADME Pharmacogenomics SAGE Publications, Inc.200810.1177/0091270008319329 J. AndrewWilliams PhD Pfizer Global Research and Development, San Diego, California, james.williams2@pfizer.com TommyAndersson [...]

Keywords: Microdialysis; regulatory aspects; tissue pharmacokinetics BACKGROUND AND RATIONALE Many decisions in drug development and medical practice are based on measuring blood concentrations of endogenous and exogenous molecules. Yet most [...]

Per the well‐known resistance of hepatitis B virus to nucleoside/nucleotide analogs, alternative treatment options with higher resistance barriers have been approved for use in both treatment‐naïve and lamivudine‐resistant hepatitis B virus infections. This phase I study was conducted in adults with normal and impaired renal function to evaluate the effect of renal impairment on the pharmacokinetics of besifovir, a prodrug of an acyclic nucleotide phosphonate, that is mainly cleared via renal excretion. An open‐label, single‐dose parallel‐group clinical study was conducted in subjects with normal renal function and mild, moderate, and severe renal impairment. Subjects received a single oral dose of besifovir dipivoxil 150 mg, and serial blood and urine samples were collected for up to 72 hours after dosing to assess the pharmacokinetic characteristics of besifovir. The extent of plasma exposure of besifovir, detected as its major and active metabolites, LB80331 and LB80317, respectively, increased with worsening renal function. Compared to the subjects with normal renal function, the mean areas under the concentration‐time curves of LB80331 increased by 1.5‐, 2.5‐, and 4.5‐fold in subjects with mild, moderate, and severe impairment, respectively. LB80317 showed a 1.8‐, 3.2‐, and 6.2‐fold increase in subjects with mild, moderate, and severe renal impairment compared to those with normal function. The ratios of LB80331 renal clearance and the average estimated glomerular filtration rate of each renal impairment group with respect to the normal group were similar. The increase in plasma exposure and decrease in renal clearance suggest the need to adjust dosage regimens in patients with moderate to severe renal impairment. [ABSTRACT FROM AUTHOR]

This document is a position paper from the American College of Clinical Pharmacology (ACCP) discussing the use of GLP-1 receptor agonists for chronic weight management therapy. The paper emphasizes the need for healthcare professionals to ensure that these medications are appropriately prescribed, supplied, and filled per approved labels. It also encourages comprehensive treatment plans that include coaching for positive lifestyle changes and health literacy. The paper highlights potential risks and calls for regulatory agencies to prevent the manufacturing and importation of unapproved GLP-1 receptor agonists. The paper includes conflicts of interest disclosures and funding information. [Extracted from the article]

Patients admitted to the intensive care unit (ICU) are frequently exposed to potential drug‐drug interactions (pDDIs). However, reported frequencies of pDDIs in the ICU vary widely between studies. This can be partly explained by significant variation in their methodological approach. Insight into methodological choices affecting pDDI frequency would allow for improved comparison and synthesis of reported pDDI frequencies. This study aimed to evaluate the association between methodological choices and pDDI frequency and formulate reporting recommendations for pDDI frequency studies in the ICU. The MEDLINE database was searched to identify papers reporting pDDI frequency in ICU patients. For each paper, the pDDI frequency and methodological choices such as pDDI definition and pDDI knowledge base were extracted, and the risk of bias was assessed. Each paper was categorized as reporting a low, medium, or high pDDI frequency. We sought associations between methodological choices and pDDI frequency group. Based on this comparison, reporting recommendations were formulated. Analysis of methodological choices showed significant heterogeneity between studies, and 65% of the studies had a medium to high risk of bias. High risk of bias, small sample size, and use of drug prescriptions instead of administrations were related to a higher pDDI frequency. The findings of this review may support researchers in designing a reliable methodology assessing pDDI frequency in ICU patients. The reporting recommendations may contribute to standardization, comparison, and synthesis of pDDI frequency studies, ultimately improving knowledge about pDDIs in and outside the ICU setting. [ABSTRACT FROM AUTHOR]

Combination therapies have become increasingly researched and used in the treatment and management of complex diseases due to their ability to increase the chances for better efficacy and decreased toxicity. To evaluate drug combinations in drug development, pharmacokinetic and pharmacodynamic interactions between drugs in combination can be quantified using mathematical models; however, it can be difficult to deduce which models to use and how to use them to aid in clinical trial simulations to simulate the effect of a drug combination. This review paper aims to provide an overview of the various methods used to evaluate combination drug interaction for use in clinical trial development and a practical guideline on how combination modeling can be used in the settings of clinical trials. [ABSTRACT FROM AUTHOR]

Idiopathic pulmonary fibrosis (IPF) is a continuous, progressive, and lethal age-related respiratory disease. It is characterized by condensed and rigid lung tissue, which leads to a decline in the normal functioning of the lungs. The pathophysiology of IPF has still not been completely elucidated, so current strategies are lagging behind with respect to improving the condition of patients with IPF and increasing their survival rate. The desire for a better understanding of the pathobiology of IPF and its early detection has led to the identification of various biomarkers associated with IPF. The use of drugs such as pirfenidone and nintedanib as a safe and effective treatment alternative have marked a new chapter in the treatment of IPF. However, nonpharmacological therapies, involving long-term oxygen therapy, transplantation of the lungs, pulmonary rehabilitation, ventilation, and palliative care for cough and dyspnea, are still considered to be beneficial as supplementary methods for IPF therapy. A major risk factor for IPF is aging, with associated hallmarks such as telomere attrition, senescence, epigenetic drift, stem cell exhaustion, loss of proteostasis, and mitochondrial dysfunction. These are promising earmarks for the development of potential therapy for the disease. In this review, we have discussed current and emerging novel therapeutic strategies for IPF, especially for targets associated with age-related mechanisms., (© 2024, The American College of Clinical Pharmacology.)

To define and evaluate the attention devoted to drug use in children rather than just review existing reviews, the present attempt is to seek out the primary sources of information in the hope that this effort would not only yield more reliable data, but would also provide an opportunity for reconsidering methodological problems which are possibly even more important. An English-language literature search for drug use in children from 1988 was conducted on two databases and a manual search was made of the literature, with a check of references quoted in main original articles, reviews and textbooks. The review was then organized in two main sections: an overall evaluation of the recent literature concerning drug use in children; the epidemiological profile of drug exposure as described cumulatively by the drug-utilization studies. A substantial lack of systematic attention to this area of drug epidemiology was found: drug use in the children is a 'hidden' reality in the literature; the wealth of methodologic developments that have taken place in the general field of drug use monitoring has scantly reached children. Children can be considered still 'methodologic orphans' with respect to the transferable knowledge on the benefit/risk profile of therapies they receive. A network has to be developed to monitor clinical problems, including drug use, as part of an 'audit' of the overall management of children. [ABSTRACT FROM AUTHOR]

This study investigated the differences in the pharmacokinetics (PK) of dextromethorphan and desipramine in healthy African volunteers to understand the effect of allelic variants of the human cytochrome P450 2D6 (CYP2D6) enzyme, namely the diplotypes of CYP2D6*1/*2 (*1*1, *1*2, *2*2) and the genotypes of CYP2D6*17*17 and CYP2D6*29*29. Overall, 28 adults were included and split into 3 cohorts after genotype screening: CYP2D6*1/*2 (n = 12), CYP2D6*17*17 (n = 12), and CYP2D6*29*29 (n = 4). Each subject received a single oral dose of dextromethorphan 30 mg syrup on day 1 and desipramine 50 mg tablet on day 8. The PK parameters of area under the plasma concentration-time curve from time of dosing to time of last quantifiable concentration (AUC last ), and extrapolated to infinity (AUC inf ), and the maximum plasma concentration (C max ) were determined. For both dextromethorphan and desipramine, AUC inf and C max were higher in subjects of the CYP2D6*29*29 and CYP2D6*17*17 cohorts, as compared with subjects in the CYP2D6*1/*2 diplotype cohort and with normal metabolizers from the literature. All PK parameters, including AUC inf , C max , and the elimination half-life, followed a similar trend: CYP2D6*17*17 > CYP2D6*29*29 > CYP2D6*1/*2. The plasma and urinary drug/metabolite exposure ratios of both drugs were higher in subjects of the CYP2D6*17*17 and CYP2D6*29*29 cohorts, when compared with subjects in the CYP2D6*1/*2 diplotype cohort. All adverse events were mild, except in 1 subject with CYP2D6*17*17 who had moderately severe headache with desipramine. These results indicate that subjects with CYP2D6*17*17 and CYP2D6*29*29 genotypes were 5-10 times slower metabolizers than those with CYP2D6*1/*2 diplotypes. These findings suggest that dose optimization may be required when administering CYP2D6 substrate drugs in African patients. Larger studies can further validate these findings., (© 2023, The American College of Clinical Pharmacology.)

The aim of this study was to compare the degree of taste disturbance by losartan, an angiotensin II receptor blocker, with that of perindopril, an angiotensin-converting enzyme inhibitor. Perindopril erbumine (2 mg), losartan potassium (25 mg), or vehicle was given to Japanese volunteers (n = 7) for 14 days in a randomized, placebo-controlled, 3-way crossover design with a 14-day washout period. Gustometry by filter-paper test and electrogustometry were performed before and at the end of each trial. Plasma renin activity (PRA) and serum and salivary zinc concentrations were measured. One subject dropped out because of a perindopril-induced dry cough, but no one claimed a taste disturbance. Detection thresholds of 4 basic tastes (sweet, salty, sour, and bitter) by the paper-disc test and electrogustometry were significantly worsened, and plasma renin activity was elevated by the drugs, whereas the deteriorating effects of 2 drugs did not significantly differ. These drugs did not affect zinc concentrations in plasma and saliva. It was concluded that losartan and perindopril similarly alter taste sensitivity during repeated dosing of the drugs. [ABSTRACT FROM PUBLISHER]

The immunogenicity of cemiplimab, a fully human immunoglobulin G4 monoclonal antibody directed against programmed cell death 1, was assessed in patients across multiple tumor types. The development of antidrug antibodies (ADAs) against cemiplimab was monitored using a validated bridging immunoassay. To identify ADA-positive samples in the assay, statistically determined cut points were established by analyzing baseline clinical study samples from a mixed population of different tumor types, and this validation cut point was used to assess immunogenicity in all subsequent studies. Regulatory guidance requires that ADA assay cut points be verified for appropriateness in different patient populations. Thus, for the cemiplimab ADA assay, we evaluated whether each new oncology population was comparable with the validation population used to set the cut point. Assay responses from 2393 individual serum samples from 8 different tumor types were compared with the validation population, using established statistical methods for cut-point determination and comparison, with no significant differences observed. Across tumor types, the immunogenicity of cemiplimab was low, with an overall treatment-emergent ADA incidence rate of 1.9% and 2.5% at intravenous dose regimens of 3 mg/kg every 2 weeks and 350 mg every 3 weeks, respectively. Moreover, no neutralizing antibodies to cemiplimab were detected in patients with ADA-positive samples, and there was no observed impact of cemiplimab ADAs on pharmacokinetics. Study-specific cut points may be required in some diseases, such as immune and inflammatory diseases; however, based on this analysis, in-study cut points are not required for each new oncology disease indication for cemiplimab., (© 2023 The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

This paper describes the pharmacokinetics (PK), mass balance, metabolic profiling, and safety of talazoparib after a single oral dose of 14C‐talazoparib in 6 patients with advanced solid tumors. Patients were aged ≥18 years, with a histologically confirmed advanced solid tumor at screening. A single 1‐mg dose of talazoparib oral solution supplemented with 100 µCi of 14C‐labeled talazoparib was administered. Blood, urine, and feces samples were collected at various time points and analyzed for talazoparib and 14C radioactivity. Metabolic profiling and identification were also carried out. Mean recovery of 14C radioactivity was 68.7% in urine and 19.7% in feces. Talazoparib was minimally metabolized. Renal excretion of unchanged talazoparib was a major route of elimination, with mean recovery of 54.6% of the administered dose, whereas fecal excretion of talazoparib was limited, with mean recovery of 13.6% of the administered dose. No major metabolites of talazoparib were identified in plasma, and no metabolites that individually represented more than 10% of the administered dose were recovered in urine or feces. The concentration‐time profiles of unchanged talazoparib, total 14C radioactivity in plasma, and total 14C radioactivity in whole blood were similar, with a median time at peak concentrations of 30 minutes and mean half‐life of 89.8, 96.2, and 77.6 hours, respectively. Talazoparib was minimally metabolized, and renal excretion of unchanged talazoparib was the major route of elimination. [ABSTRACT FROM AUTHOR]

Intravaginal rings (IVRs) are an established option for continuous administration of drugs in women. The combination of anastrozole (ATZ) and levonorgestrel (LNG) in an IVR with an intended 4‐week wearing period has been considered for long‐term treatment of endometriosis‐associated pelvic pain. A randomized, parallel‐group, multicenter phase 2b study to assess the efficacy and safety of different dose combinations in women with symptomatic endometriosis has recently been performed. This paper will focus on the investigation of pharmacokinetic (PK) effects of ATZ on LNG using data collected from this study. Two hundred sixteen patients were randomized to the treatment group with IVRs releasing LNG 40 μg/day alone or in combination with ATZ 300 μg/day, 600 μg/day, or 1050 μg/day for 12 weeks. PK blood samples were taken before dosing and before IVR replacement or removal (days 28, 56, and 84). The primary PK parameter was the plasma concentration in apparent steady state of ATZ and LNG at the end of each IVR wearing period. Results of PK analysis demonstrate that ATZ concentrations increased proportionally with increasing dose (geometric mean values of 7.85, 15.48, and 22.61 μg/L at 300, 600, and 1050 μg/day nominal release, respectively). All point estimates for LNG concentration in apparent steady state ratios between the mono and combination IVR groups were close to 1, and the 90% confidence interval limits were in the 0.80 to 1.25 range (1.01 [0.85‐1.19], 1.03 [0.88‐1.20], 0.94 [0.80‐1.10]). In conclusion, our data indicate there is no evidence of drug‐drug interaction of ATZ on LNG. [ABSTRACT FROM AUTHOR]

Since 2015, concentration-QTc (C-QTc) analysis has been used to exclude the possibility that a drug has a concerning effect on the QTc interval. This has enabled the replacement of the designated thorough QT (TQT) study with serial electrocardiograms (ECGs) in routine clinical pharmacology studies, such as the first-in-human (FIH) study. The E14 revision has led to an increased proportion of FIH studies with the added objective of QT evaluation, with the intention of replacing the TQT study. With the more recent revision of the S7B/E14 Q&A document in February 2022, nonclinical assays/studies can be brought into the process of regulatory decisions at the time of marketing application. If the hERG (human ether-a-go-go-related gene) and the non-rodent in vivo study are conducted according to the described best practices and are negative, the previous requirement that a QTc effect of >10 milliseconds must be excluded in healthy subjects at plasma concentrations 2-fold above what can be seen in patients can be reduced to covering the concentrations seen in patients. For drugs that cannot be safely given in high doses to healthy subjects, ECG evaluation is often performed at the therapeutic dose in patients. If a QTc effect of >10 milliseconds can be excluded, an argument can be made that the drug should be considered as having a low likelihood of proarrhythmic effects due to delayedrepolarization, if supported by negative best practices hERG and in vivo studies. In this article, we describe what clinicians involved in early clinical development need to understand in terms of the hERG and in vivo studies to determine whether these meet best practices and therefore can be used in an integrated clinical/nonclinical QT/QTc risk assessment., (© 2023 The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

Abstract: In recent years, health care has been increasingly delivered by interprofessional teams in the inpatient, outpatient, and transition‐of‐care arenas. For many reasons, effective communication between patient‐centered care teams and patients is critically important in order to optimize care, ensure patient safety, and prevent medical and medication misadventures. In rapid‐paced, high‐stress medical environments, it is especially important to carefully evaluate the causes of all misadventures in a manner that avoids assigning blame and identifies the root causes and, through team activity, leads to development of remedies that reduce the likelihood of future misadventures. Using a series of illustrative cases, this paper seeks to bring attention to these issues and provide insights regarding some tools developed to assist in improving patient safety and effective team communication. [ABSTRACT FROM AUTHOR]

The main objective of this paper is to propose a quantitative model to describe the absorption process for monoclonal antibody (mAb) following subcutaneous (SC) or intramuscular (IM) administration. A hybrid model was established by coupling the physiologically based absorption process with a conventional pharmacokinetic-pharmacodynamic (PK-PD) or PK model associated with intravenous infusion. Key physiological parameters evaluated include the volume distribution before systemic absorption, mAb drug clearance during lymphatic transport, the neonatal Fc receptor (FcRn) capacity, the intrinsic drug clearance via lysosomal proteolytic process, and the lymphatic flow rate. Sensitivity analyses were performed to identify those physiological parameters significantly impacting time to peak concentration (Tmax) or drug bioavailability. Simulation results showed that lymphatic flow rate is the only influential factor to Tmax. Lymphatic transit time and drug clearance during lymphatic transport are most influential to bioavailability but not identifiable in their effects. Bioavailability is positively related to the lymphatic flow only at its low range (i.e., at <0.5-fold of the selected value of 0.043 mL/min). The rest of physiological parameters only have marginal effects on either drug bioavailability or Tmax. Finally, simulation results confirmed lymphatic transport as the major route of mAb delivery. [ABSTRACT FROM AUTHOR]

Motion sickness symptoms affect approximately 50% of the crew during space travel and are commonly treated with intramuscular injections of promethazine. The purpose of this paper is to compare the effectiveness of three treatments for motion sickness: intramuscular injections (IM) of promethazine, a physiological training method (autogenic feedback training exercise [AFTE]), and a no-treatment control. An earlier study tested the effects of promethazine on cognitive and psychomotor performance and motion sickness tolerance in a rotating chair. For the present paper, motion sickness tolerance, symptom reports, and physiological responses of these subjects were compared to matched subjects selected from an existing database who received either AFTE or no treatment. Three groups of 11 men, between the ages of 33 and 40 years, were matched on the number of rotations tolerated during their initial rotating-chair motion sickness test. The motion sickness test procedures and the 7-day interval between tests were the same for all subjects. The drug group was tested under four treatment conditions: baseline (no injections), a 25 mg dose of promethazine, a 50 mg dose of promethazine, and a placebo of sterile saline. AFTE subjects were given four 30-minute AFTE sessions before their second, third, and fourth motion sickness tests (6 hours total). The notreatment control subjects were only given the four rotating chair tests. Motion sickness tolerance was significantly increased after 4 hours of AFTE when compared to either 25 mg (p < 0.00003) or 50 mg (p < 0.00001) of promethazine. The control and promethazine groups did not differ. AFTE subjects reported fewer or no symptoms at higher rotational velocities than subjects in the control or promethazine groups. The primary physiological effect of promethazine was an inhibition of skin conductance level. The AFTE group showed significantly less heart rate and skin conductance variability during motion sickness tests administered after training [ABSTRACT FROM PUBLISHER]

Despite the increasing awareness and guidance to support drug research and development in the pregnant population, there is still a high unmet medical need and off-label use in the pregnant population for mainstream, acute, chronic, rare disease, and vaccination/prophylactic use. There are many obstacles to enrolling the pregnant population in a study, ranging from ethical considerations, the complexity of the pregnancy stages, postpartum, fetus-mother interaction, and drug transfer to breast milk during lactation and impacts on neonates. This review will outline the common challenges of incorporating physiological differences in the pregnant population and historical but noninformative practice in a past clinical trial in pregnant women that led to labeling difficulties. The recommendations of different modeling approaches, such as a population pharmacokinetic model, physiologically based pharmacokinetic modeling, model-based meta-analysis, and quantitative system pharmacology modeling, are presented with some examples. Finally, we outline the gaps in the medical need for the pregnant population by classifying various types of diseases and some considerations that exist to support the use of medicines in this area. Ideas on the potential framework to support clinical trials and collaboration examples are also presented that could also accelerate understanding of drug research and medicine/prophylactics/vaccines in the pregnant population., (© 2023, The American College of Clinical Pharmacology.)

This review paper summarizes the epidemiology of hepatitis C virus (HCV) and chronic HCV infection, including HCV virology and treatment regimens. Specifically, we focus on the evolution of past, current, and future HCV treatment options, the reasons for treatment failure, and the impact of resistance-associated variants on treatment success. [ABSTRACT FROM AUTHOR]

The contents of this paper have been written to be used in a teaching program specifically designed for medical postgraduate education of resident physicians and fellows in training interested in the clinical pharmacology of antiepileptic drugs and their role in the treatment of epilepsy and/or in the prevention of sudden unexpected death associated with this disease. With some modifications, such as a specific lecture to provide an overview of the numerous concepts presented in the text, the article could be used when teaching fourth-year medical students. The format of the paper is a combination of didactic review and eight case reports in a self-learning format. A quiz for self-assessment is included at the end of the article (see Appendix). This material was covered in part in the 1992 Board Review Course for Clinical Pharmacology sponsored by the American College of Clinical Pharmacology. The format or setting of instruction for this material could include small learning groups composed of 10 to 15 students. When used in combination with other topics prepared in similar formats, this could become a take home course for those preparing to take the Boards in Clinical Pharmacology. Each instructor could select specific publications from the reference list for assigned readings depending upon the material emphasized by the instructor. The questions included at the end of the text could be used as either a closed or an open book quiz to assess student learning. [ABSTRACT FROM AUTHOR]

This paper presents a detailed critical review of the knowledge accumulated in the last three decades concerning research on sleep, work-rest schedules, and circadian rhythms in space. The focus of the paper is preceded by a brief review of the basic principles of the human circadian system and the physiology of the sleep-wake cycle, relevant to understanding the problem of astronaut work-rest scheduling. Much of what is known is based on anecdotal reports, mission log books, and debriefing of astronauts after flights. The broad literature reviewed, which includes studies from American and Soviet space missions, as well as some studies conducted under simulated weightlessness, offers just a handful of objective studies on the physiology of sleep and circadian rhythms in space. Nevertheless, the data are remarkably consistent, and indicate that sleep can be of reasonably good quality in space. The risk of sleep loss and associated performance degradation appears to be a manageable one. However, one clear conclusion arises from this review: whatever the type of mission or flight plan, its success will depend on whether the principles of circadian and sleep-wake regulation have been taken into account during the planning phase of work-rest schedules. That is, satisfactory sleep and alertness is more likely to occur if crews maintain a reasonable (i.e., constant) relation with their normal terrestrial rhythm. This is not as easy a task as it may appear; indeed, unexpected, high-intensity operational demands have been the major cause of acute problems of sleep loss and performance degradation in space. Moreover, the growing complexity of space missions indicate that emergencies will never disappear. Therefore, one of the most important research challenges for future space missions is the development of strategies that could permit astronauts to function closest to maximal efficiency during intensive and prolonged work. Countermeasures for optimizing astronaut performance, as well as other factors affecting sleep and performance in space, are reviewed and discussed in detail in this paper. [ABSTRACT FROM AUTHOR]

This paper focuses on (1) stable isotope labeling of drugs, in combination with mass spectrometry (MS)-based methods, to facilitate the recognition and identification of metabolites and (2) the employment of stable isotope-labeled derivatization reagents (e.g., bis-trimethylsilylacetamide-d18) in the structure elucidation of metabolites from unlabeled drugs via gas-liquid chromatography-MS techniques. In both cases, it is the so-called isotope peak shift that permits generation of data useful for metabolite identification. Furthermore, judicious labeling of a drug permits characterization of drug-related species (metabolites) by MS-based recognition of isotope cluster signatures. Studies using stable isotope-labeled drugs are exemplified by work on aminopyrine and isopropylantipyrine metabolism; examples of the derivatization peak shift approach include those from studies of timolol and cyproheptadine. [ABSTRACT FROM AUTHOR]

Accounting for subject nonadherence and eliminating inappropriate subjects in clinical trials are critical elements of a successful study. Nonadherence can increase variance, lower study power, and reduce the magnitude of treatment effects. Inappropriate subjects (including those who do not have the illness under study, fail to report exclusionary conditions, falsely report medication adherence, or participate in concurrent trials) confound safety and efficacy signals. This paper, a product of the International Society for CNS Clinical Trial Methodology (ISCTM) Working Group on Nonadherence in Clinical Trials, explores and models nonadherence in clinical trials and puts forth specific recommendations to identify and mitigate its negative effects. These include statistical analyses of nonadherence data, novel protocol design, and the use of biomarkers, subject registries, and/or medication adherence technologies. [ABSTRACT FROM AUTHOR]

There is continued emphasis from the various worldwide regulatory agencies to ensure that the pharmaceutical industry fully understands the products they are developing. This emphasis is seen via development of quality-by-design (QbD) publications and guidelines generated by the International Committee on Harmonization. The challenge to meet these expectations is primarily associated with the generation of in vivo data (eg, pharmacokinetic data) that is resource intensive. A technique reducing the resources needed to generate this in vivo data permits a more extensive application of QbD principles. This paper presents the application of stable isotopes in pharmacokinetic studies. The data show that the use of stable isotopes can significantly reduce the number of subjects required for a study. This reduction in subjects thus translates into a significant reduction in resources and time needed to generate the required in vivo data to support QbD. [ABSTRACT FROM AUTHOR]

An introduction is presented in which the editor discusses various articles within the issue on topics including contemporary antibiotic drug therapy; probiotics and their use in fostering/supporting good health; and the state of individual vaccines.

As the temporal, financial, and ethical cost of randomized clinical trials (RCTs) continues to rise, researchers and regulators in drug discovery and development face increasing pressure to make better use of existing data sources. This pressure is especially high in rare disease, where traditionally designed RCTs are often infeasible due to the inability to recruit enough patients or the unwillingness of patients or trial leaders to randomly assign anyone to placebo. Bayesian statistical methods have recently been recommended in such settings for their ability to combine disparate data sources, increasing overall study power. The use of these methods has received a boost in the United States thanks to a new willingness by regulators at the Food and Drug Administration to consider complex innovative trial designs. These designs allow trialists to change the nature of the trial (eg, stop early for success or futility, drop an underperforming trial arm, incorporate data on historical controls, etc) while it is still running. In this article, we review a broad collection of Bayesian techniques useful in rare disease research, indicating the benefits and risks associated with each. We begin with relatively innocuous methods for combining information from RCTs and proceed on through increasingly innovative approaches that borrow strength from increasingly heterogeneous and less carefully curated data sources. We also offer 2 examples from the very recent literature illustrating how clinical pharmacology principles can make important contributions to such designs, confirming the interdisciplinary nature of this work., (© 2022, The American College of Clinical Pharmacology.)

Several studies have demonstrated that using a template for recording general and diagnostic information in the medical record (MR) improves the completeness of MR documentation, communication between doctors, and performance of doctors. However, little is known about how therapeutic information should be structured in the MR. The aim of this study was to investigate which specific therapeutic information registrars and consultants in internal medicine consider essential to record in the MR. Therefore, we carried out a 2-round Internet Delphi study. Fifty-nine items were assessed on a 5-pointscale; an item was considered important if ≥80% of the respondents awarded it a score of 4 or 5. In total, 26 registrars and 30 consultants in internal medicine completed both rounds of the study. Overall, they considered it essential to include information about 11 items in the MR. Subgroup analyses revealed that the registrars considered 8 additional items essential, whereas the consultants considered 1 additional item essential to record. Study findings can be used as a starting point to develop a structured section of the MR for therapeutic information for both paper and electronic MRs. This section should contain at least 11 items considered essential by registrars and clinical consultants in internal medicine. [ABSTRACT FROM AUTHOR]

Over the last 3 decades, there has been little change in the paradigm to derive dosing recommendations for specific populations (e.g., renal failure, elderly, or obese patients) despite better understanding of clearance pathways in these groups and availability of modeling and simulation tools. Dosing recommendations for specific populations are often incomplete or unavailable at the time of drug approval. Currently, there is no regulatory framework to incorporate model-based dosing recommendations for specific populations. This paper proposes a scientific framework for using modeling and simulation to support specific population dosing recommendations. This framework creates a knowledgebase of drug and population attributes where model-based approaches can be developed to inform dosing recommendations. The framework may benefit patients by having reliable dosing information at the time of drug approval. Patients with conditions where studies are difficult to perform would benefit from dosing based on state-of-the-art knowledge. Industry and regulators would benefit from a scientific and efficient approach to improve specific population prediction. A research approach to determine specific population dose prediction is discussed along with challenges and risks. We hope to initiate a dialogue to explore the role of modeling based on data for drugs with similar clearance mechanisms to predict drug dosing. [ABSTRACT FROM AUTHOR]

This study is to compare the effectiveness of combinational use of bupivacaine with fentanyl (BUPI-FEN) and sufentanil (BUPI-SUF) in epidural/intrathecal analgesia for labor. Electronic databases were searched for relevant research papers published between 1985 and 2014. Meta-analyses of mean differences or odds ratios were performed and statistical heterogeneity between the studies tested by I2 index. Ten studies recruiting a total of 728 women in labor were selected. Concentrations of the anesthetics used as mean ± sd were bupivacaine 0.115 ± 0.056%, fentanyl 0.0007 ± 0.001%, and sufentanil 0.00017 ± 0.00022%. Duration of analgesia was not significantly different between BUPI-SUF and BUPI-FEN administered mothers (mean difference [95%CI] of −33.55 [−74.94, 7.83] minutes; P = .11) under random effects. The onset of analgesia was also not significantly different between both groups (mean difference [95%CI] of −0.61 [−1.38, 0.16] minutes; P = .12). The number of neonates with Apgar score < 7 was significantly lower in BUPI-FEN group (odd ratio [95%CI] of 0.31 [0.10, 0.95]; P < .05). Pruritus incidence was similar. In conclusion, BUPI-FEN combination exhibits significantly better tolerability at an approximate ratio of 6 FEN:1 SUF, albeit, both fentanyl and sufentanil in combination with bupivacaine provide similar analgesic properties via the epidural or intrathecal routes for labor pain relief. [ABSTRACT FROM AUTHOR]

Registration of innovative biologics in Emerging Markets (EMs) poses many opportunities and challenges. The BRIC-MT countries (Brazil, Russia, India, China, Mexico, and Turkey) that are the fastest growing markets and regulators in these countries have imposed certain requirements, including the need for local clinical studies, for registration of biologics. The regulatory landscape in these countries is rapidly evolving, which necessitates an up-to-date understanding of such requirements. There is growing evidence which suggests that race, after accounting for body weight differences, may not influence the pharmacokinetics of biologics to the same extent that it does for small molecules. Thus, the requirements for clinical pharmacology trials in EMs are driven mainly by regulatory needs set forth by local Ministry of Health. In addition to the clinical Phase I to III studies done in the global program that supports registration in large geographies, countries such as China require local single and multiple dose Phase I studies. Participating in global studies with clinical sites within their country may be sufficient for some markets, while other regulators may be satisfied with a Certificate of Pharmaceutical Product. This paper discusses the current requirements for registration of innovative biologics in key EMs. [ABSTRACT FROM AUTHOR]

Chronic kidney disease (CKD) has been shown to alter the pharmacokinetics of drugs that are eliminated not only via the renal pathway but also by nonrenal clearance and transport. Dosing recommendations in subjects with CKD have historically come from small pharmacokinetic (PK) studies, which have been insulated from the broader clinical development strategy. Opportunities for prospective strategic integration of both preclinical and clinical data on drug clearance mechanisms, model-based approaches, and clinical knowledge of therapeutic index are therefore often missed in designing and analyzing the results of PK studies in subjects with CKD, and eventually providing dosing recommendations. These considerations are valuable in designing informative PK studies in subjects with CKD, as well as for guiding kidney function-related inclusion/ exclusion criteria in the broader clinical program and ultimately defining dosing guidelines that optimize benefit-risk balance for these special patient populations based on all available data. This paper offers points to consider for drug developers to increase adoption of a contemporary multidisciplinary approach, which includes key considerations on study design and conduct, methodologies for analysis (population PK and physiologically based PK modeling), and a roadmap to interpret the effect of kidney function on the overall benefit-risk profile of drugs in development. [ABSTRACT FROM AUTHOR]

The author presents a paper that discusses the lack of pharmacology education in medical and nursing schools in the U.S. He states that he conducted an informal poll of 50 medical school departments of pharmacology in the U.S. on whether formal training in pharmacology for medical students has decreased in past some years, and 35 of the 39 respondents agreed. He also mentions of a white paper published by the British Pharmacological Society on value of clinical pharmacology and therapeutics. [ABSTRACT FROM AUTHOR]

Recent articles and advertisements suggest that drug design is within the reach of any chemically oriented scientist who obtains the latest three-dimensional computer graphics programs for his personal computer. This sort of 'rational' drug design has however had limited success. When it has been successful, it has required the rigorous application of computational chemistry. Bowen et al. in their accompanying paper provide a summary of a number of approaches and the assumptions involved. The papers by McDonnell et al. and Hendry describe two different approaches: utilizing molecular genetics to test the effective interaction in vitro of ligands with their receptors and utilizing the model structure of DNA as a blueprint for the structure of the intracellular targets of drugs. [ABSTRACT FROM AUTHOR]