Personalized medicine: elusive dream or imminent reality?

The market for molecular diagnostic tests is predicted to grow at extraordinary rates over the next 10 years, fueled by pharmacogenetics and the elusive dream of personalized medicine. The challenge is managing the expectations of the medical community and the public at large that have already been set by speculation, promises, and the repeated exposure to headlines about genetic discoveries. Personalized medicine is a paradigm that exists more in conceptual terms than in reality, with only a few marketed drug-test companion products and not very many actual clinical practices set up to personalize medicine in the way that supporters have intended. Nevertheless, the reality of personalized medicine has become more imminent because of the increased awareness of the shortcomings in the delivery of drugs with adequate benefit/risk to patients, a better molecular understanding of how to optimize drug selection and dosing, and an increased demand for integrating more clinically relevant genetic information into the drug development process to improve both innovation and productivity. This paper focuses on personalized medicine by (1) looking at some converging changes taking place in the health-care landscape that are creating a scientific and social infrastructure to enable personalized medicine, (2) considering challenges that need to be addressed with regard to clinical evidence standards for validating genotype-phenotype associations, and (3) considering how clinical pharmacology can help construct a rational personalized medicine framework. As therapeutic experts, clinical pharmacologists can work to assure that "good therapeutics follows good diagnostics". They are well equipped to provide timely genetic education to others and to interpret genetic data so that actionable decisions, especially about drug dosing in individual patients, can be implemented in clinical practice.

Paving the critical path: how can clinical pharmacology help achieve the vision?

It has been almost 3 years since the launch of the FDA critical path initiative following the publication of the paper "Innovation or Stagnation: Challenges and Opportunities on the Critical Path of New Medical Product Development." The initiative was intended to create an urgency with the drug development enterprise to address the so-called "productivity problem" in modern drug development. Clinical pharmacologists are strategically aligned with solutions designed to reduce late phase clinical trial failures to show adequate efficacy and/or safety. This article reviews some of the ways that clinical pharmacologists can lead and implement change in the drug development process. It includes a discussion of model-based, semi-mechanistic drug development, drug/disease models that facilitate informed clinical trial designs and optimal dosing, the qualification process and criteria for new biomarkers and surrogate endpoints, approaches to streamlining clinical trials and new types of interaction between industry and FDA such as the end-of-phase 2A and voluntary genomic data submission meetings respectively.

Drug interaction studies: study design, data analysis, and implications for dosing and labeling.

One of the most effective ways in which regulatory agencies communicate with sponsors and guide drug development is through the issuance of guidances or guidelines. These can be issued domestically in a given region such as the United States by the Food and Drug Administration (FDA) or internationally through the International Conference on Harmonization. Currently, there are over 400 final or draft guidances that can be found through the FDA website. The development of guidances proceeds through a process known as Good Guidance Practices, which is intended to assure that there is an appropriate level of meaningful public participation in the development of guidance. In the past 10 years, clinical pharmacology guidances covering important areas have been issued, including pharmacokinetic data in patients with renal and hepatic impairment, dose-response studies, and drug-drug interactions.

Impact of pharmacometric reviews on new drug approval and labeling decisions--a survey of 31 new drug applications submitted between 2005 and 2006.

Exploratory analyses of data pertaining to pharmacokinetic, pharmacodynamic, and disease progression are often referred to as the pharmacometrics (PM) analyses. The objective of the current report is to assess the role of PM, at the Food and Drug Administration (FDA), in drug approval and labeling decisions. We surveyed the impact of PM analyses on New Drug Applications (NDAs) reviewed over 15 months in 2005-2006. The survey focused on both the approval and labeling decisions through four perspectives: clinical pharmacology primary reviewer, their team leader, the clinical team member, and the PM reviewer. A total of 31 NDAs included a PM review component. Review of NDAs involved independent quantitative evaluation by FDA pharmacometricians. PM analyses were ranked as important in regulatory decision making in over 85% of the 31 NDAs. Case studies are presented to demonstrate the applications of PM analysis.

Identifying clinically relevant sources of variability: The clopidogrel challenge.

High interindividual variability in clinical outcomes following clopidogrel's standard dosing regimen continues to be a challenge even two decades after its approval. CYP2C19 polymorphisms, obesity, older age, diabetes, and drug-drug interactions have been identified as risk factors for adverse events and treatment failure. We conducted a mechanism-based pharmacokinetic/pharmacodynamic analysis, where we integrated knowledge on in vitro enzyme kinetic, physiological, genetic, and demographic information to characterize changes in platelet reactivity from baseline following clopidogrel antiplatelet therapy. When considering the combined impact of these covariates, our analysis results indicate that higher maintenance doses are required for CYP2C19 intermediate metabolizers and poor metabolizers compared to extensive metabolizers and that respective maintenance doses have to be further increased for obese subjects for each of these CYP2C19 phenotypes. In addition, interindividual differences in the fraction absorbed and the CES1 activity were identified as sources of interindividual differences in clopidogrel's active metabolite concentrations and, thus, platelet reactivity.

Why has model-informed precision dosing not yet become common clinical reality? lessons from the past and a roadmap for the future.

Patient groups prone to polypharmacy and special subpopulations are susceptible to suboptimal treatment. Refined dosing in special populations is imperative to improve therapeutic response and/or lowering the risk of toxicity. Model-informed precision dosing (MIPD) may improve treatment outcomes by achieving the optimal dose for an individual patient. There is, however, relatively little published evidence of large-scale utility and impact of MIPD, where it is often implemented as local collaborative efforts between academia and healthcare. This article highlights some successful applications of bringing MIPD to clinical care and proposes strategies for wider integration in healthcare. Considerations are brought up herein that will need addressing to see MIPD become "widespread clinical practice," among those, wider interdisciplinary collaborations and the necessity for further evidence-based efficacy and cost-benefit analysis of MIPD in healthcare. The implications of MIPD on regulatory policies and pharmaceutical development are also discussed as part of the roadmap.

Effect of cholesterol content on antitumor activity and toxicity of liposome-encapsulated 1-beta-D-arabinofuranosylcytosine in vivo.

1-beta-D-Arabinofuranosylcytosine (ara-C) was encapsulated in anionic multilamellar liposomes prepared with different lecithin: cholesterol (L:C) ratios. The chemotherapeutic activity of encapsulated ara-C was compared with comparable doses of ara-C in 0.85% saline solution (single- and multiple-dose schedules) in mice bearing L1210 (i.p.) leukemia. Maximum survival was obtained in animals given injections of ara-C (40 mg/kg) encapsulated in liposomes with a L:C ratio of 1:1. The effect of L:C ratio on survival was not pronounced in multiple-dose schedules. Multiple doses (every 4.5 hr for 3 separate injections) of 40 mg/kg with L:C ratios of 1:1 and 1:0.5 were toxic, resulting in 83 and 50% mortality, respectively, of mice by Day 7. This study shows that drug efflux and in vivo antitumor activity and toxicity of encapsulated ara-C is influenced by the cholesterol content of the liposomal lipid bilayer.

Anticoagulants: What is new and what is the standard?

This commentary focuses on the status of oral anticoagulants, namely, warfarin and the novel oral anticoagulants (NOACs) such as dabigatran, rivaroxaban, apixaban, and edoxaban.

Quantitative Systems Pharmacology Model to Predict the Effects of Commonly Used Anticoagulants on the Human Coagulation Network.

Warfarin is the anticoagulant of choice for venous thromboembolism (VTE) treatment, although its suppression of the endogenous clot-dissolution complex APC:PS may ultimately lead to longer time-to-clot dissolution profiles, resulting in increased risk of re-thrombosis. This detrimental effect might not occur during VTE treatment using other anticoagulants, such as rivaroxaban or enoxaparin, given their different mechanisms of action within the coagulation network. A quantitative systems pharmacology model was developed describing the coagulation network to monitor clotting factor levels under warfarin, enoxaparin, and rivaroxaban treatment. The model allowed for estimation of all factor rate constants and production rates. Predictions of individual coagulation factor time courses under steady-state warfarin, enoxaparin, and rivaroxaban treatment reflected the suppression of protein C and protein S under warfarin compared to rivaroxaban and enoxaparin. The model may be used as a tool during clinical practice to predict effects of anticoagulants on individual clotting factor time courses and optimize antithrombotic therapy.

Hormone action at the membrane level. IV. Epinephrine binding to rat liver plasma membranes and rat epididymal fat cells.

[3-H]Epinephrine binding to isolated purified rat liver plasma membranes is a reversible process. An initial peak in binding occurs at about 15 min and a plateau occurs by 50 min. Optimal binding occurred at a membrane protein concentration of 125mug. Rat liver plasma membranes stored at-70 degrees C up to 4 weeks showed no difference in epinephrine binding capacity as compared to control fresh membranes. Epinephrine binding to liver plasma membranes was decreased by 79% by phospholipase A2 (phosphatide acylhydrolase EC 3.1.1.4), 81% by phospholipase C (phosphatidylcholine choline phosphohydrolase EC 3.1.4.3) and 59% by phospholipase D (phosphatidylcholine phosphatidohydrolase EC 3.1.4.4). Trypsin and pronase digestion of the membrane decreased epinephrine binding by 97 and 47% respectively. In the presence of 10-3M Mg-2+ ions, increasing concentrations of QTP decreased epinephrine binding to liver plasma membranes. A maximal effect was demonstrated with 10-5M GTP, representing an inhibition of 52% of the control. In a Mg-2+ -free system, epinephrine binding was unaffected by GTP. However, in a Mg-2+ -free system, increasing concentrations of ATP cause increasing inhibition of hormone binding. ATP at 10-3 M reduced epinephrine binding to 28% of the control. GRP (10-5 M) was shown to inhibit epinephrine uptake rather than epinephrine release from the membrane. [3-H]Epinephrine binding to isolated rat epididymal fat cells shows an initial peak within 5 min followed by a gradual rise which plateaus after 60 min. Epinephrine binding increased nearly linearly with increasing fat cell protein concentration (40-200 mug protein). GTP (10-5 M) and ATP (10-4 M) decreased epinephrine binding to rat epididymal fat cells by 41%. Nearly complete inhibition of binding was demonstrated with 10-2-10-3M ATP. Epinephrine analogs that contain two hydroxyl groups in the 3 and 4 position on the benzene ring act as inhibitors of [3-H]epinephrine binding to rat adipocytes. Alteration of the epinephrine side chain has relatively little influence on binding. Analogs in which one of the ring hydroxyl groups is missing or methylated are poor inhibitors of [3-H]epinephrine binding. Alpha-(phentolamine and phenoxybenzamine) and beta-(propranolol and dichorisoproterenol) adrenergic blocking agents were tested with respect to their ability to influence [3-H]epinephrine binding and their influence on epinephrine-stimulated lipolysis. Only dichloroisoproterenol significantly inhibited epinephrine binding (by 25%). The two beta-adrenergic blocking agents caused an inhibition of epinephrine-stimulated glycerol release, with propranolol being most effective. Phentolamine and phenoxybenzamine had no significant effect on the epinephrine stimulation of glycerol release by fat cells.

Physiologically Based Pharmacokinetics Is Impacting Drug Development and Regulatory Decision Making.

It is no coincidence that the reports of two meetings, one organized by the US Food and Drug Administration (FDA), in March 2014, and the other by the UK Medicines and Healthcare Products Regulatory (MHRA), in collaboration with ABPI (the Association of British Pharmaceutical Industry), in June 2014, have been published in tandem in CPT-PSP.12 Both reports deal with the same topic, namely, the impact of physiologically based pharmacokinetics (PBPK) in clinical drug development and the best practices for such applications. This reflects the transition of PBPK from academic curiosity to industrial norm, manifested by the regulatory agencies encouraging its use and receiving an increasing number of submissions containing PBPK models. The goal of both meetings was to help determine the need and facilitate the development of regulatory guidances on this subject within the conceptual framework of model informed drug development and regulatory decision-making. A further reflection of this intent is the publication by the European Medicines Agency of a Concept Paper on PBPK.3 One is reminded of a similar train of events surrounding the introduction of population PK/PD and nonlinear mixed effects modeling in the early-late 1990s, again with encouragement and receptivity of regulatory agencies leading to FDA guidance on the topic.4 Indeed, the intention of PBPK modeling and simulation is to complement other approaches, such as compartmental modeling, or, in some cases, replace them with a more mechanistic approach. PBPK models represent an important class of models that characterize absorption, distribution, metabolism, excretion (ADME) processes and their underlying biological and physiological drivers. An increased understanding of these drivers and their unique interactions with drug substance and formulation factors provides critical insights into how drugs will behave in healthy volunteers and patients with disease.

Sobol Sensitivity Analysis: A Tool to Guide the Development and Evaluation of Systems Pharmacology Models.

A systems pharmacology model typically integrates pharmacokinetic, biochemical network, and systems biology concepts into a unifying approach. It typically consists of a large number of parameters and reaction species that are interlinked based upon the underlying (patho)physiology and the mechanism of drug action. The more complex these models are, the greater the challenge of reliably identifying and estimating respective model parameters. Global sensitivity analysis provides an innovative tool that can meet this challenge. CPT Pharmacometrics Syst. Pharmacol. (2015) 4, 69-79; doi:10.1002/psp4.6; published online 25 February 2015.

Cutaneous papillomatous hyperplasia in cyclosporine-A treated beagles.

All twelve Beagle dogs undergoing long-term therapy (26 weeks) with the immunosuppressive drug cyclosporine-A (30 mg/kg), developed cutaneous papillomatous hyperplasia. By week 7 all dogs developed generalized lesions distributed over the entire body. These occurred as irregular, oval, sessile, unpigmented, firm masses. The incidence and severity of the skin lesions varied among dogs and anatomic site, with no correlation to the blood level of cyclosporine. Microscopic analysis revealed that the epidermis formed short papillary folds on broad fibrovascular stalks and was hyperkeratotic and acanthotic. Mild hyperplasia of hair follicles and sebaceous glands was also evident. A mild diffuse infiltrate of lymphocytes and plasma cells was present in the papillary dermis. No histopathologic changes typical of papillomavirus infection were identified, nor were papillomavirus group-specific antigens or viral DNA detected. Other cutaneous side effects included hyperkeratosis of footpads, increased growth of hair and nails, and hyperkeratinization of the haired skin of the prepuce. All cutaneous lesions regressed spontaneously within 8 weeks following termination of cyclosporine administration. The hyperplastic lesions may have resulted from the action of cyclosporine via the T-lymphocyte system. Conversely a direct action of this drug on epithelial cells may have stimulated proliferation and keratinization.

Theophylline serum protein binding in obstructive airways disease.

The percentage of theophylline bound to protein in sera obtained from patients with obstructive airways disease was determined by ultrafiltration. The bound theophylline fraction in 71 serum specimens collected from 51 patients was 60.7 +/- 10.0% (mean +/- SD) and from 30.8% to 83.2%. The correlation between unbound serum theophylline concentration and total concentration (range 0.8 to 90 mg/l) was linear (r = 0.97, p less than 0.001). Theophylline binding correlated poorly with serum albumin (r = 0.39) and total serum protein (r = 0.35), although the correlations were statistically significant (p less than 0.05), Theophylline binding in women did not differ from that in men. The extent of theophylline binding in younger patients was greater than in patients over 55 yr (64.3 +/- 8.5% and 57.0 +/- 10.4%, p less than 0.005). Variation in theophylline binding in 12 patients from whom two or more serum samples were collected was relatively small. Analysis of variance showed interpatient variation in theophylline binding (p less than 0.01) but not between sampling occasions in the same patient. The demonstrated variability in serum protein binding of theophylline should influence theophylline distribution and elimination kinetics and may be another determinant of clinical response. Patients with lower binding levels should have higher plasma levels of unbound drug after a loading dose and will need more frequent dosing.

Vancomycin disposition: the importance of age.

We examined the influence of age on vancomycin kinetics in 12 normal healthy men (six young and six elderly) after an intravenous infusion of 6 mg/kg. Serial blood and urine samples were collected for up to 2 days after dosing and were assayed for unchanged drug by a specific radioimmunoassay. Serum concentrations of vancomycin after infusion declined in a multiphasic manner. Both serum and urinary excretion data were simultaneously fit by a three-compartment model with SAAM-27 computer programs. Estimates of mean t1/2 obtained from the terminal phase of the drug disposition profile showed the t1/2 to be longer in the elderly than in the young subjects (12.1 and 7.2 hr). Although there was no change in the initial distribution volume of the central compartment, total systemic and renal clearances were reduced in the elderly and did not correlate with renal function. The increase in the vancomycin volume of distribution at steady state was ascribed to enhanced tissue binding of drug in the elderly, since the mean fraction of vancomycin bound in systemic pool of the young and elderly did not differ (0.53 and 0.56). In-depth analysis of excretion data tends to support suggestions of vancomycin excretion solely by glomerular filtration. Our data strongly suggest the need for adjustment or modification of recommended vancomycin dosing schedules in the elderly.

In vitro metabolic interaction studies: experience of the Food and Drug Administration.

A total of 194 new molecular entities approved by the Food and Drug Administration between 1992 and 1997 were surveyed to determine the role of in vitro metabolic interactions in the conduct of drug-drug interaction studies and to examine the methods used in these studies. Approximately 30% of the submissions were found to have in vitro metabolism-based interaction studies, most of which were inhibitory in nature. Chemical inhibition was the most commonly used approach in studying drug interactions in vitro. In this article, an attempt to assess the quality of the chemical inhibition approach was made. Four areas were found to be often overlooked: (1) incubation time and concentrations of the drug, (2) the difference between inhibition constant (k(i)) and 50% inhibitory concentration (IC50) values, (3) the substrate-dependent inhibition potential, and (4) the metabolic genotype or phenotype of the liver donor. We discuss the pitfalls in estimating drug interactions when these four areas are overlooked.

The effects of St John's wort (Hypericum perforatum) on human cytochrome P450 activity.

BACKGROUND: St John's wort (Hypericum perforatum) is a popular over-the-counter dietary supplement and herbal remedy that has been implicated in drug interactions with substrates of several cytochrome P450 (CYP) isozymes. The effect of St John's wort on CYP activity in vivo was examined with a probe drug cocktail. METHODS: Twelve healthy subjects (5 female, 7 male) completed this 3-period, open-label, fixed schedule study. Tolbutamide (CYP2C9), caffeine (CYP1A2), dextromethorphan (CYP2D6), oral midazolam (intestinal wall and hepatic CYP3A), and intravenous midazolam (hepatic CYP3A) were administered before, with short-term St John's wort dosing (900 mg), and after 2 weeks of intake (300 mg 3 times a day) to determine CYP activities. RESULTS: Short-term administration of St John's wort had no effect on CYP activities. Long-term St John's wort administration caused a significant (P <.05) increase in oral clearance of midazolam from 121.8 +/- 70.7 to 254.5 +/- 127.8 and a corresponding significant decline in oral bioavailability from 0.28 +/- 0.15 to 0.17 +/- 0.06. In contrast to the >50% decrease in the area under the plasma concentration-time curve (AUC) when midazolam was administered orally, long-term St John's wort administration caused a 20% decrease in AUC when midazolam was given intravenously. There was no change in CYP1A2, CYP2C9, or CYP2D6 activities as a result of St John's wort administration. CONCLUSION: Long-term St John's wort administration resulted in a significant and selective induction of CYP3A activity in the intestinal wall. St John's wort did not alter the CYP2C9, CYP1A2, or CYP2D6 activities. Reduced therapeutic efficacy of drugs metabolized by CYP3A should be anticipated during long-term administration of St John's wort.

In vivo drug-drug interaction studies--a survey of all new molecular entities approved from 1987 to 1997.

Ninety-eight new molecular entities applications approved between 1987 to 1991 (period I) and 193 applications for new molecular entities between 1992 to 1997 (period II) were surveyed for drug-drug interaction studies. In period I (used as a comparator), 32 applications contained drug-drug interaction studies for a total of 117 studies. In period II, 106 applications reported drug-drug interaction studies, and the number of studies per new molecular entity ranged from 0 to 15. Most studies (77%) were performed in healthy subjects, with 44% using crossover designs, 7% using parallel designs, and the remaining using fixed sequence designs. The most common dosing scheme for new molecular entities/interacting drug was multiple dose (47%), whereas single dose/multiple dose was used in 31% of studies, and single dose/single dose was used in 18% of studies. Of the 540 drug-drug interaction studies submitted in period II, 80 (15%) resulted in clinically significant labeling statements. Submissions for new molecular entities to the Center for Drug Evaluation and Research divisions most likely to include drug-drug interaction studies were neuropharmacology, cardiorenal, antiviral, and antiinfective drugs. Some drug classes such as oncology drug products and radioimaging products were least likely to include drug-drug interaction studies in their submissions. We conclude that the use of drug-drug interaction studies in the drug development process has increased between the two periods.

Development of in vivo bioequivalence methodology for dermatologic corticosteroids based on pharmacodynamic modeling.

BACKGROUND: Dermatologic corticosteroid products produce skin blanching that is related to clinical potency and dose. (For application of the vasoconstrictor assay to bioavailability and bioequivalence assessment, dose is defined in terms of duration of treatment exposure [dose duration], so the terms dose and dose duration have been used interchangeably). The vasoconstrictor assay is the method of choice to assess dermatologic corticosteroid products bioequivalence if dose-response is validated. This article examines dose-response validation to meet objectives of US Food and Drug Administration (FDA) bioequivalence guidance for dermatologic corticosteroid products. METHODS: An exploratory dose-response study was conducted to determine applicability of the empirical maximum effect (Emax) model to the individual subject and population dose-response relationships of six dermatologic corticosteroid product creams that varied from the most to the least potent classes. Products were applied to the skin of 10 healthy subjects in each of two dosing periods for dose durations of 0.5, 1, 2, and 6 hours. Skin blanching was measured by reflectance colorimeter through 24 hours after application. Area under the effect curve (AUEC) was determined for each dose duration. An Emax model was fitted to the AUEC versus dose duration data. A similar analysis was conducted for a bioequivalence study on two formulations of a dermatologic corticosteroid product in 40 healthy subjects. RESULTS: In the exploratory study, the number of individual subject data sets for which the Emax model provided an acceptable fit generally increased with the potency of the dermatologic corticosteroid product. On the basis of population modeling, dose-response data of all products, except the lowest potency cream, were adequately described by the Emax model. Values for population ED50 (the dose duration required to achieve 50% of the fitted AUECmax value) decreased with increase in dermatologic corticosteroid product potency. CONCLUSIONS: Acceptable model fits to all individual subject dose-response data were not achieved for any dermatologic corticosteroid product. However, population dose-responses were adequately described by the Emax model. On the basis of these data, the optimal dose duration used for comparison of multisource dermatologic corticosteroid products is recommended to be equal to the ED50 based on population modeling of pilot dose-response study data.

Pharmacokinetic analysis of bioequivalence trials: implications for sex-related issues in clinical pharmacology and biopharmaceutics.

OBJECTIVES: To address the questions of whether women should be included in bioequivalence trials and whether dosage adjustment may be needed in women relative to men. METHODS: Sex-related analysis was conducted for 26 bioequivalence studies involving both sexes. A total of 94 data sets [47 each for the areas under the plasma concentration-time curve (AUC) and maximum concentration (Cmax)] were used. ANOVA was performed. Three statistical models were used to estimate population means and intrasubject variability between sexes, as well as sex-by-formulation interactions. Comparisons were made by use of confidence intervals, magnitude of observed differences, and statistical significance (alpha = .05). RESULTS: With some exceptions, intrasubject variabilities were similar for men and women. In about 10% of the data sets (AUC or Cmax), women had significantly higher variability. Although fewer, there were examples with higher variability in men. With a 20 percentage point difference used in the test-over-reference mean ratios between sexes as a signal of sex-by-formulation interaction, the frequency of this interaction (AUC or Cmax) is approximately 13% and approximately 35%, counting by data sets and studies, respectively. Mean sex-related differences of > or = 20% in the pharmacokinetic parameters for the reference product were observed in 39% of the data sets (AUC or Cmax). In approximately 28% of the data sets, these differences were statistically significant. The frequency was approximately 15% after body weight correction. CONCLUSIONS: In general, men and women have similar intrasubject variability. Where variability differs between sexes, there is a suggestion that higher variability in women may be more frequent. The data also suggest that a sex-based subject-by-formulation interaction can occur, although the frequency may be low. Sex-related differences in pharmacokinetics are apparent in many drugs studied. Dosage adjustment with body weight may be warranted for drugs that exhibit a steep dose-response curve. Although exploratory, the results of this study support recommendations of the 1993 Food and Drug Administration gender guideline that women not be excluded from bioequivalence trials.