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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.

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.

We have read the paper by Wang and Zhang[1]. We are pleased to see that other authors further illustrate and also find nice properties for an evaluation tool that we first used more than ten years ago[2], presented at PAGE in 20003 and published extensively first in 2006[4]. However we disagree with some of the conclusions made by the authors, and we feel that an important reference should have been included in their manuscript. As Wang and Zhang point out themselves, what they call SVPC is nothing other than the prediction discrepancies (pd) named that way, after being called pseudo-residuals by Mentre and Escolano in 2006[4]. It is therefore misleading to present SVPC as something novel when in fact it goes back on something that our group has published and presented in conferences. Plots of SVPC versus time in the paper by Wang and Zhang[1] are very similar to plots of pd versus time in Mentre and Escolano[4], therefore we disagree with the statement on page 2 that “Neither pd nor npde was intended/recommended for evaluation of model predictions over a time course”. pd and npde were developed for their improved statistical properties over linearisation-based residuals but are used as visual diagnostic tools in a similar way. Also the paper is not complete when it comes to the current state of literature. Wang and Zang[1] missed one important reference, in which we have compared pd, npde, VPC, as well as tests based on prediction intervals with or without decorrelation[5]. We have also proposed tests for covariate models illustrating how npde can be used to evaluate covariate models. Their paper is rather inaccurate when comparing the properties of the pd to those of the npde. The idea behind the npde, as recalled in the paper, is to decorrelate observations within individuals. In Mentre and Escolano[4], it had been shown that the type I error of the test based on pd was inflated when subjects contribute several observations, because of the within-subject correlation between observations, and it was anticipated that the decorrelation would improve this feature. Indeed, in Brendel et al.[5] we have shown that the type I error of the npde is close to the expected 5% while the type I error for the pd or the test based on prediction intervals of the VPC was larger. In that paper, we performed a full simulation study, i.e. with several replications of the simulated data set, while in the manuscript of Wang and Zhang only one simulated dataset is given, from which it is very hard to draw meaningful conclusions. It is quite possible that for one simulated dataset the pd detects something that the npde does not, indeed, our simulations have shown that on a large number of simulated datasets, the tests with npde maintain type I error while the tests with pd have an increased type I error and hence a higher power. A discussion of the power to detect model misspecification should therefore take into account the increase in type I error under the null hypothesis. Also in their table V, there was a significant departure from 0 of the mean npde for the wrong model (p=0.03 with a Wilcoxon test). We would also like to take this opportunity to mention that more informative VPC graphs have been proposed by Wilkins[6] et al in 2006, which use prediction intervals around the simulated percentiles, and that we have adapted these graphs to pd and npde[7]. In that paper, we made a case of using pd instead of npde to plot diagnostic graphs because the decorrelation tends to blur the relationship with time when used for visual diagnostics. Finally, we join Wang and Zhang to stress the nice properties of simulation-based model evaluation tools such as pd (SVPC) over VPC and to encourage readers to use them.

This paper presents the population pharmacokinetic (PopPK) analysis and exposure/response analyses for the primary efficacy endpoint-acute graft-versus-host disease (aGVHD) Day 28 response-and select safety measures (incidence of thrombocytopenia, hypertriglyceridemia, and cytomegalovirus infection) from a phase 3 randomized, double-blind study comparing itacitinib plus corticosteroids versus placebo plus corticosteroids for the treatment of aGVHD. The PopPK dataset contained sparse data from aGVHD patients and select enriched data from healthy volunteers. The structural model was a 2-compartment model with first-order elimination and dose-dependent nonlinear absorption with dual first-order absorption pathways with lag times. Strong cytochrome P450 3A (CYP3A) inhibitor coadministration, moderate renal impairment, and participant population (healthy volunteers vs aGVHD patients) were covariates on apparent clearance. Participant population was also a covariate on apparent intercompartmental clearance and lag time of the secondary absorption compartment. Apparent clearance decreased 42% with coadministration of strong CYP3A inhibitors. Simulations supported the following dose reductions with concomitant use of a strong CYP3A inhibitor: 300 mg once daily (QD) to 200 mg QD, 400 mg QD to 300 mg QD, and 600 mg QD to 400 mg QD. No dose adjustment is recommended for any other covariate based on the magnitude of impact when they were retained in the model. The exposure/response relationship was characterized between itacitinib exposure and probability of aGVHD Day 28 response using a linear logistic regression model. Both itacitinib exposure and aGVHD risk status were significant predictors of response. There was no relationship between itacitinib exposure and thrombocytopenia, hypertriglyceridemia, or cytomegalovirus infection. This article is protected by copyright. All rights reserved.

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.

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 (i.m.) 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 no-treatment 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 (p0.00003) or 50 mg (p0.00001) 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.

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 of 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.

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.

Challenges in pediatric drug development include small patient numbers, limited outcomes research, ethical barriers, and sparse biosamples. Increasingly pediatric drug development is focusing on extrapolation: leveraging knowledge about adult disease and drug responses to inform projections of drug and clinical trial performance in pediatric subpopulations. Pharmacokinetic-pharmacodynamic (PK-PD) modeling and extrapolation aim to reduce the number of patients and data points needed to establish efficacy. Planning for PK-PD and biomarker studies should begin early in the adult drug development program. Extrapolation relies upon the assumption that both the underlying disease as well as the mechanism of action of the drug used to treat that disease, are similar between adults and pediatric subpopulations. Clearly, developmental changes in PK and PD need to be considered to enhance the quality of PK-PD modeling and, therefore, increase the success of extrapolation. This paper focuses on the influence of differences in PD between adults and pediatric subpopulations that are highly relevant for the use of extrapolation.

This paper describes the pharmacokinetics (PK), mass balance, metabolic profiling, and safety of talazoparib after a single oral dose of

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.

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.

Therapeutics in all subspecialties of medicine has become more complex in recent years for a variety of reasons. Newer pharmaceuticals with greater and potentially serious toxicities are commonly used today for a large number of serious illnesses. Such drugs often interact adversely with food and with many so-called “natural” medicines such as Saint. John’s wort. They may also interact with other drugs, such as those used to treat comorbidities that are outside of the realm of expertise of the physician treating the patient’s most serious problem. Many newer agents need to be given in precise doses based on the patient’s weight or body surface area, and somemust be taken in specific relationship to food intake. Drug dosing in many instances must take into account dietary components, administration of other drugs, and patient genetics. Consequently, correct prescribing of medicines today requires a complete knowledge of the pharmacokinetics, pharmacodynamics, drug–drug interactions, and other aspects of the agent to be prescribed. Unfortunately, there is abundant evidence in the form of prescription errors (paper and electronic) and increasing numbers of hospital admissions for drug toxicity in this country and many others that prescribers are not always sufficiently educated to properly administer and monitor present-day therapeutics. For physicians, nurses, and physician assistants, the lack of sufficient clinical pharmacologic training can often be traced all the way back to undergraduate school.

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.

Clinical pharmacologists, neurologists, internists, and all health care givers must consider the efficacy, safety, and side effect profile of a given antiepileptic drug (AED) when determining which drug is best for a given patient. The first purpose of this paper is to address whether the "new" AEDs have advantages over the "old" drugs. The second purpose is to teach those interested in clinical pharmacology about the use of Web-based information access to answer a neurology/clinical pharmacology problem: to compare the efficacy and side effects of topiramate versus lamotrigine versus phenobarbital using odds ratios. Cost of all three AEDs was also compared. A number of new AEDs, including topiramate and lamotrigine, have been developed for chronic focal and secondarily generalized epileptic seizures. Efficacy of these drugs as anticonvulsants does not seem to be superior to that of traditional anticonvulsants such as phenobarbital. However, the advantage of the new drugs is a different spectrum of possible adverse events. Newer AEDs may or may not induce sedation and may minimize noncompliance by reducing side effects of lethargy and cognitive impairment. The difficulty in achieving therapeutic dosage because of side effects makes one consider whether these agents are "better" than the oldest and most side effect-prone AED, phenobarbital. The new AEDs have less frequent interactions, leading to improved tolerability with comedication. This exercise compares two "new" AEDs, topiramate and lamotrigine, with phenobarbital by evaluating efficacies and side effects using relative odds ratios, a method commonly used in drug development research. Development of new algorithms and/or new knowledge will bring beneficial tools to all clinical pharmacologists.

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-point scale; 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.

A vast and continuously growing amount of material on drugs exists in the literature to read and evaluate. Frequently, the papers and their recommendations are conflicting and contradictory. Readers are faced with the dilemma of deciding what to believe. The need for evidence-based medicine as a foundation for optimal clinical research and patient care requires application of the best scientific methods. Various methods are discussed. Generally, the most powerful method to test a clinical hypothesis is the randomized, controlled clinical trial. By contrast, epidemiology/observation studies have certain inherent weaknesses that can lead to erroneous conclusions. The examples of estrogen therapy in postmenopausal women and of vitamin E therapy to reduce cardiovascular risk are discussed extensively to provide historical perspective and to demonstrate erroneous conclusions reached using epidemiology/observation studies. The sociology of journal publication is briefly described, and an attempt is made to assess who benefits and who is harmed when leading medical journals publish erroneous results. Types of bias and confounding issues leading to errors are discussed, and the need is emphasized for publication of rigorous studies after careful evaluation by editors to avoid repetition of past mistakes and to ensure publication of correct medical information.

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.

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 I(2) 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

Recent research has established that many children and adult diagnosed with autism experience gastrointestinal symptoms. Furthermore, research has demonstrated that gastrointestinal symptoms can impact drug availability and absorption. In this paper we explore the presence of gastrointestinal symptoms in autism and put forth a call for a formal evaluation of the potential relationship between gastrointestinal symptoms and psychotropic medication effectiveness in individuals with autism.

Assessment of pharmacokinetic (PK) based drug-drug interactions (DDI) is essential for ensuring patient safety and drug efficacy. With the substantial increase in therapeutic proteins (TP) entering the market and drug development, evaluation of TP-drug interaction (TPDI) has become increasingly important. Unlike for small molecule (e.g., chemical-based) drugs, conducting TPDI studies often presents logistical challenges, while the population PK (PPK) modeling may be a viable approach dealing with the issues. A working group was formed with members from the pharmaceutical industry and the FDA to assess the utility of PPK-based TPDI assessment including study designs, data analysis methods, and implementation strategy. This paper summarizes key issues for consideration as well as a proposed strategy with focuses on (1) PPK approach for exploratory assessment; (2) PPK approach for confirmatory assessment; (3) importance of data quality; (4) implementation strategy; and (5) potential regulatory implications. Advantages and limitations of the approach are also discussed.

Predicting late phase outcomes from early-phase findings can help inform decisions in drug development. If the measurements in early-phase differ from those in late phase, forecasting is more challenging. In this paper, we present a model-based approach for predicting glycosylated hemoglobin (HbA1c) in late phase using glucose and insulin concentrations from an early-phase study, investigating an anti-diabetic treatment. Two previously published models were used; an integrated glucose and insulin (IGI) model for meal tolerance tests and an integrated glucose-red blood cell-HbA1c (IGRH) model predicting the formation of HbA1c from the average glucose concentration (Cg,av ). Output from the IGI model was used as input to the IGRH model. Parameters of the IGI model and drug effects were estimated using data from a phase1 study in 59 diabetic patients receiving various doses of a glucokinase activator. Cg,av values were simulated according to a Phase 2 study design and used in the IGRH model for predictions of HbA1c. The performance of the model-based approach was assessed by comparing the predicted to the actual outcome of the Phase 2 study. We have shown that this approach well predicts the longitudinal HbA1c response in a 12-week study using only information from a 1-week study where glucose and insulin concentrations were measured.

Use of the immunomodulators thiopurines and methotrexate (MTX) in the treatment of inflammatory bowel disease (IBD), i.e., Crohn's disease and ulcerative colitis (UC), is considered to be good clinical practice. However, despite being administered to a considerable number of IBD patients over the years, questions remain about the most rational treatment regimens of azathioprine (AZA), 6-mercaptopurine (6-MP), and MTX, and results from a range of recent studies necessitate increased attention to how to optimize the use of these immunomodulators. First and foremost, it is of utmost importance to define the subgroup of IBD patients in need of immunomodulators, including those in need of combination therapy with biologic agents, especially because some side effects may be rather severe. Second, colorectal cancer is observed more often in IBD patients than in the background population. However, a recent nationwide Dutch study pointed to a preventive effect of thiopurines. Finally, the need for an appropriate approach to the discontinuation of immunomodulators is emphasized. Since controversy continues regarding the most appropriate use of immunomodulators, this paper is focusing on pharmacokinetics, pharmacogenetics, and therapeutic blood testing, as well as the occurrence of adverse events, when using AZA, 6-MP, and MTX in an attempt to determine a more up-to-date and rational treatment regimen in IBD.

To optimize drug dosing, it is critical to understand how various intrinsic and extrinsic factors affect systemic exposure of the drug and the response. Chronic kidney disease (or renal impairment) can affect pharmacokinetic characteristics of a therapeutic drug and its metabolites and therefore is one of the most important intrinsic factors that can affect a patient's response to drugs. During drug development, it is critical to understand how renal impairment can affect a drug's pharmacokinetics so that appropriate dosing recommendations can be included in the label. The US Food and Drug Administration (FDA) has published various guidance documents and opinion papers to address scientific and regulatory issues in the study design, data analysis, and labeling recommendations related to dosing in patients with impaired renal function. The 2010 FDA draft guidance on renal impairment provides several updated recommendations that include criteria or principles for evaluating the pharmacokinetics of drugs that are either principally renally cleared or nonrenally cleared in subjects with renal impairment and for categorizing renal function by equations estimating glomerular filtration rate using the Modification of Diet in Renal Disease equations or creatinine clearance using the Cockcroft-Gault equation. The objective of this article is to discuss the FDA's current recommendations and provide examples that illustrate the importance of and challenges in studying effect of renal impairment during drug development.

Following the thalidomide disaster of 1961–21, systematic study of adverse drug reactions began. Prior to this time, specific drug-induced diseases such as aplastic anemia and halothane hepatitis were studied but adverse drug reactions, as a topic, was not a subject for medical research. Thalidomide changed that, and epidemiologic techniques developed for infectious disease research were transferred to the study of drug effects. In 1966, Smith, Seidl, and Cluff reported on adverse events in hospitalized patients and found that people with blood urea nitrogen (BUN) greater than 40 mg/dl (14.3mmlo/L) had 2.5 times the number of adverse drug reactions as those whose BUN values were below 20 mg/dl (7.1mmol/L). Other investigators in the 1960’s also found that patients with poor kidney function were predisposed to various adverse drug reactions (see the introduction in ref 3). Those observations stimulated research on why people with impaired renal function were predisposed to adverse drug reactions. It was known at that time that drugs that were excreted unchanged were cleared more slowly in people with poor renal function than in those with normal renal function. Kunin was the first, in 1967, to publish a table of data of antibiotic kinetics in patients including dosage recommendations for patients with renal disease 4. Periodically, this table was updated with additional classes of drugs included and published in the Annals of Internal Medicine 5,6. Now, dosage recommendations are considered in the official labeling of all new drugs. In 1970, Dettli, Spring, and Habersang presented their rigorous paper on calculating drug doses in renal failure 7. Their contribution was that by knowing the drug elimination rate in normal subjects and uremic patients, one can extrapolate to find the elimination rates for patients with renal function between these extreme values. They used creatinine clearance as their valid measure of renal function and showed how the kinetics of the drug in normal subjects including the fraction eliminated by non-renal mechanisms, and the creatinine clearance of the patient, could be used to calculate the dose. This approach was a big advance over not knowing how to calculate a dose for a drug with both renal and non-renal clearance. Despite, or perhaps because of, the mathematical rigor of Dettli’s analyses, his approach did not achieve wide spread use in clinical medicine. When the Cockcroft and Gault method of calculating creatinine clearance was reported 8, determining dosage for individual patients was further simplified. A problem in understanding the information from the epidemiological studies of adverse reactions in the 1960’s was that studies showing increased rates of adverse reactions in uremic patients were done in major university hospitals. One could assume that the doctors knew to give low doses of excreted drugs but conventional wisdom was to give full doses of metabolized drugs to azotemic patients if they did not have concurrent liver disease. At that time, little was known about drug metabolism in uremia or whether nonrenal clearance was altered in azotemic patients. To study drug metabolism systematically, one had to classify drugs by their pathways of metabolism and not by their therapeutic use. Then, one could select drugs to probe specific pathways of drug metabolism with the results potentially generalizable to all drugs metabolized by the pathway studied. My first study of drug metabolism in renal failure in 1968 used sulfisoxazole as the test drug since its pathways of elimination, several drug conjugations, were known and it was safe to give to volunteers. Its metabolism was slowed in azotemic patients9. Research in 1960’s (reviewed in ref 3, chapter 3) found that people who metabolized some drugs slowly metabolized some other drugs slowly as well. I then classified drugs by their pathways of metabolism in 1971 and presented in a table what was known about how renal failure effects drug metabolic pathways in 19743, 10. At that time the metabolic pathways were classified as oxidation, reduction, syntheses, and hydrolyses. Subsequent research by many investigators expanded the list of drugs studied and subcategorized the metabolic pathways in each of these major groups. Observations that azotemic patients developed toxicity from the usual loading dose of digoxin led to the finding by Aronson and Grahame-Smith that the volume of distribution of digoxin was reduced in renal failure11. This study showed that pharmacokinetic processes in addition to drug elimination could be affected by renal failure. An epileptic patient with cessation of seizures with phenytoin concentrations well below the therapeutic range (10–20 mg/L) had impaired drug plasma protein binding of phenytoin. This determination led to a systematic study of drug- protein binding in renal failure 10 concluding that protein binding is impaired for drugs that are anionic in renal failure but not for cationic drugs11. A nomogram showing the value for the appropriate therapeutic level of phenytoin for varying degrees of azotemia presented in 197312 remains in use today. Studies of laboratory animals in the 1950’s found that azotemia increased sensitivity to barbiturates and bromide, presumable due to an impaired blood-brain barrier. Altered sensitivity to some drugs in azotemia was first shown in humans in 1954 by Dundee and Richards who found in patients having prostatectomy that those with azotimia received less thiopental than those with normal kidney function to achieve the same level of sedation (chapter 4 of ref 3). A study of the dose-response to atropine found a diminished response to atropine in azotemic subjects13. Thus drug sensitivity as well as drug disposition is altered in renal failure.

Clinical pharmacologists, neurologists, internists, and all health care givers must consider the efficacy, safety, and side effect profile of a given antiepileptic drug (AED) when determining which drug is best for a given patient. The first purpose of this paper is to address whether the "new" AEDs have advantages over the "old" drugs. The second purpose is to teach those interested in clinical pharmacology about the use of Web-based information access to answer a neurology/clinical pharmacology problem: to compare the efficacy and side effects of topiramate versus lamotrigine versus phenobarbital using odds ratios. Cost of all three AEDs was also compared. A number of new AEDs, including topiramate and lamotrigine, have been developed for chronic focal and secondarily generalized epileptic seizures. Efficacy of these drugs as anticonvulsants does not seem to be superior to that of traditional anticonvulsants such as phenobarbital. However, the advantage of the new drugs is a different spectrum of possible adverse events. Newer AEDs may or may not induce sedation and may minimize noncompliance by reducing side effects of lethargy and cognitive impairment. The difficulty in achieving therapeutic dosage because of side effects makes one consider whether these agents are "better" than the oldest and most side effect-prone AED, phenobarbital. The new AEDs have less frequent interactions, leading to improved tolerability with comedication. This exercise compares two "new" AEDs, topiramate and lamotrigine, with phenobarbital by evaluating efficacies and side effects using relative odds ratios, a method commonly used in drug development research. Development of new algorithms and/or new knowledge will bring beneficial tools to all clinical pharmacologists.

Bioequivalence testing for locally acting gastrointestinal products is a challenging issue for both the pharmaceutical industry and the global regulatory authorities. It is widely accepted that for medicinal products not intended to be delivered into the systemic circulation, pharmacokinetic bioavailability cannot be used. However, it is becoming increasingly accepted that local availability may be assessed, where appropriate, by approaches that qualitatively reflect the presence of the active substance at the site of action. These methods must be specifically chosen for that combination of active substance and route of drug delivery. This paper argues for the use of gamma scintigraphy as a validated measure of local availability and bioequivalence for topically acting products administered to the gastrointestinal tract by the oral and rectal route.

Because there is a possibility that cannabis or cannabis-like molecules might be used as treatments for certain conditions in the future, it becomes important to consider the possible adverse effects of these compounds. In this paper, the authors review the evidence for persisting effects of nonacute cannabis use on the central nervous system, as reflected by alteration in neuropsychological performance. From the 40 articles that met criteria for inclusion in this review, the authors could not detect consistent evidence for persisting neuropsychological deficits in cannabis users; however, 22 of the 40 studies reported at least some subtle impairments. The inability to reach a firm conclusion results largely from methodological limitations inherent in most studies. These are considered in detail to inform future studies on (nonacute) consequences of cannabis consumption on cognitive abilities.

A vast and continuously growing amount of material on drugs exists in the literature to read and evaluate. Frequently, the papers and their recommendations are conflicting and contradictory. Readers are faced with the dilemma of deciding what to believe. The need for evidence-based medicine as a foundation for optimal clinical research and patient care requires application of the best scientific methods. Various methods are discussed. Generally, the most powerful method to test a clinical hypothesis is the randomized, controlled clinical trial. By contrast, epidemiology/observation studies have certain inherent weaknesses that can lead to erroneous conclusions. The examples of estrogen therapy in postmenopausal women and of vitamin E therapy to reduce cardiovascular risk are discussed extensively to provide historical perspective and to demonstrate erroneous conclusions reached using epidemiology/observation studies. The sociology of journal publication is briefly described, and an attempt is made to assess who benefits and who is harmed when leading medical journals publish erroneous results. Types of bias and confounding issues leading to errors are discussed, and the need is emphasized for publication of rigorous studies after careful evaluation by editors to avoid repetition of past mistakes and to ensure publication of correct medical information.

The two domains in clinical pharmacology dealing with optimizing dosing recommendations are pharmacokinetics and pharmacodynamics. However, the usefulness of these disciplines is limited if viewed in isolation. Pharmacokinetic/pharmacodynamic (PK/PD) relationships and modeling builds the bridge between these two classical disciplines of clinical pharmacology. It links the concentration-time profile as assessed by pharmacokinetics to the intensity of observed response as quantified by pharmacodynamics. Thus, the resulting so-called integrated PK/PD-models allow the description of the complete time course of the desired and/or undesired effects in response to a drug therapy. PK/PD-modeling can elucidate the causative relationship between drug exposure and response and provide a better understanding of the sequence of events that result in the observed drug effect. This information can then be used to streamline the drug development process and dose optimization. This consensus paper presents an update on the current state of PK/PD-modeling from an academic, industrial and regulatory perspective.

Exposure to weightlessness induces physiologic changes that may lead to pharmacokinetic and pharmacodynamic alterations of drugs administered to crew members in flight. Preliminary data from flight and ground-based studies indicate that pharmacologically significant changes occur in the kinetics of medications given in weightlessness and in simulated microgravity (head-down bed rest). Conducting flight studies on all available medications to identify the changes in their pharmacokinetic behavior in weightlessness is not feasible. An alternative approach for obtaining such information is to use computer simulations employing physiologically based pharmacokinetic (PBPK) models. Information thus obtained would be helpful in predicting the therapeutic effectiveness of medications in space, and also in developing plans for flight studies. This paper presents a brief review of relevant physiologic factors and pharmacokinetic implications of space flight, and includes a preliminary PBPK model for estimating plasma concentration-time profiles of acetaminophen under different experimental conditions.

This paper summarizes the lower body negative pressure experiments performed in space, beginning with the experiments conducted on Skylab, because this program provided the most cardiovascular physiology data for United States space flight. Data obtained during studies of lower body negative pressure for use as a countermeasure after months of Russian space flight are also presented. Lower body negative pressure experiments conducted aboard Space Shuttle flights provide data about the deadaptation response of the cardiovascular system to orthostatic stress occurring during periods of zero gravity, and about protection against postflight orthostatic intolerance. Data obtained using Russian and American lower body negative pressure devices indicate that, when a crew member stands, as opposed to being supported by a seat or saddle as in the American device, there may be a slight detrimental effect in terms of the cardiovascular response to this orthostatic stress. Comparison of heart rate and blood pressure response to entry and landing of the Shuttle indicate that, although lower body negative pressure is a different stress and is applied in a different manner, the maximum heart rates during lower body negative pressure are reached at approximately the same point that the maximum heart rates are reached during entry and landing. Thus, the use of a lower body negative pressure stress in flight is a fairly good predictor of the cardiovascular response to the actual entry and landing of the Shuttle.

This paper reviews the cardiovascular responses of six healthy male subjects to 6 hours in a 5 degrees head-down bed rest model of weightlessness, and compares these responses to those obtained when subjects were positioned in head-up tilts of 10 degrees, 20 degrees, and 42 degrees, simulating 1/6, 1/3, and 2/3 G, respectively. Thoracic fluid index, cardiac output, stroke volume, and peak flow were measured using impedance cardiography. Cardiac dimensions and volumes were determined from two-dimensional guided M-mode echocardiograms in the left lateral decubitus position at 0, 2, 4, and 6 hours. Cardiovascular response to a stand test were compared before and after bed rest. The impedance values were related to tilt angle for the first 2 hours of tilt; however, after 3 hours, at all four angles, values began to converge, indicating that cardiovascular homeostatic mechanisms seek a common adapted state, regardless of effective gravity level (tilt angle) up to 2/3 G. Echocardiography revealed that left ventricular end-diastolic and end-systolic volume, stroke volume, ejection fraction, heart rate, and cardiac output had returned to control values by hour 6 for all tilt angles. The lack of a significant immediate change in left ventricular end-diastolic volume, despite decrements in stroke volume (P < .05) and heart rate (not significant), indicates that multiple factors may play a role in the adaptation to simulated hypogravity. The echocardiography data indicated that no angle of tilt, whether head-down or head-up for 4 to 6 hours, mimicked exactly the changes in cardiovascular function recorded after 4 to 6 hours of space flight. Changes in left ventricular end-diastolic volume during space flight and tilt may be similar, but follow a different time course. Nevertheless, head-down tilt at 5 degrees for 6 hours mimics some (stroke volume, systolic and diastolic blood pressure, mean arterial blood pressure, and total resistance), but not all, of the changes occurring in an equivalent time of space flight. The magnitude of the change in the mean heart rate response to standing was greater after six hours of tilt at -5 degrees or 10 degrees. Thus, results from the stand test after 6 hours of bed rest at -5 degrees and 10 degrees, but not at 20 degrees or 42 degrees, are similar to those obtained after space flight.

In the past, the only kind of medicines used for symptomatic treatment of space motion sickness (SMS) in space had been oral, transdermal, or suppositories. This paper describes the effect of the first intramuscular (IM) administration of Phenergan (50-mg in single dose) on SMS in one subject who exhibited grade-3 symptoms and signs which persisted unabated throughout the first and the second flight days aboard the Space Shuttle. Thirty minutes after the injection, the subject had completely recovered. His symptoms were gone, his appetite was back, and he had no recurrences for the remainder of the flight. Since that experiment, intramuscular injections have been given nine more times on subsequent flights, with similar results.

The rubidium and lithium ions are known to have opposite effects on a wide range of biochemical and behavioral parameters in experimental animals. Based on the proven effectiveness of lithium as an antimanic agent, several trials have been conducted with rubidium in the acute treatment of the depressive phase of bipolar illness. The results to date are promising. However, the 30- to 60-day biologic half-life of rubidium has mandated careful studies of potential toxicity before engaging in long-term administration of this ion to depressive subjects. One area of potential concern is the possibility of renal toxicity, which could be expressed as unexpectedly increased retention of rubidium. The data in this paper show that after 15 days of rubidium administration, there are no changes beyond the normal range in a variety of kidney function tests, including in four enzymes which are specific markers of tubule cell function.

The role of the clinical pharmacist in the institutional setting has been expanding at an ever increasing rate. His role as a clinical consultant with the rounding team has become firmly established. This is supplemented with rational product selection utilizing a hospital formulary. Both clinical pharmacokinetics and nutrition are services that benefit the patient directly in his inpatient environment. Toxicology and drug information provided directly to the consumer has also become accepted. Services provided to institution-wide committees allow a comprehensive understanding of the selection, delivery, and follow-up of medication administration to the patient. Many of these services described have become reimbursable by third-party carriers and other appropriate agencies. As other services are reimbursed, the role of the clinical pharmacist will expand beyond the limited scopes discussed in this paper.

This paper underscores the need for true sample selection before statistical inference of any value can be made. Its findings suggest that the sample selection strategy of symptomatic volunteers can produce samples of anxious subjects with remarkable demographic similarity across the country. Anxiety as a constitutional rather than pathognomonic symptom is illustrated by the heterogeneity of its psychometric evaluation in our volunteers. Expecting a drug to safely relieve the anxiety of all anxious symptomatic volunteers is akin to expecting a drug to safely relieve the headaches of all headache sufferers. We feel that careful psychodiagnosis remains the best sample selection strategy.

Using the twin crossover, balanced incomplete block design described in the previous paper, a double-blind determination of the relative analgesic potency of graded intramuscular doses of Win 20,836 (8-methoxycyclazocine) and morphine was carried out in patients with postoperative pain. Although no preliminary data at all on the human analgesic activity of Win 20,836 were available, the sequential decision-making process designed to choose the doses of the test medication most closely equianalgesic with the standard functioned efficiently to establish doses of Win 20,836 that had analgesic activity. Unfortunately, the occurrence of psychotomimetic side effects prevented the administration of doses of Win 20,836 equieffective with the morphine standard, and this necessitated substantal extrapolation of the dose-response curve of the test drug to arrive at a relative potency estimate. However, our relative potency estimate, which indicated that Win 20,836 is three to six times as potent as morphine, was dependable enough to predict with reasonable certainty that doses of Win 20,836 equieffective to the usual doses of morphine would produce an unacceptable level of psychotomimetic side effects. Clinical investigation of the drug was therefore terminated.

The subject of this symposium is naproxen, a new drug that resulted from an investigation to find a superior anti-inflammatory agent. It was synthesized by Harrison et al. in 1970 at the Syntex Institute of Organic Chemistry and Biological Sciences. How can we chart the evolution of this or any other drug? Three steps are necessary: first, chemical studies (synthesis, analysis); second, animal pharmacology; third, human pharmacology. The last step can additionally be divided into four phases: metabolism and toxicology of the drug in normal volunteers; dose titration and initial clinical trials with sick subjects (pharmacometry); confirmatory clinical trials when the drug is accepted on the market and revaluation (familiarization trials). To discover the truth about naproxen, we must all participate actively with a critical mind, following the principles of scientific methodology. We shall find that the papers to be presented today all deal with the third step in the evaluation process--clinical pharmacology. It is quite evident that the final and most decisive test must be aimed at the most valuable target: the human being. The end product of this day's work for each of us should be the formation of an opinion based on solid scientific proofs. And let us hope that we will all enjoy fulfilling the symposium in its entire etymological meaning this evening. In vino veritas.