Pharmacodynamic Information Research Articles

Simulated Drug Administration: An Emerging Tool for Teaching Clinical Pharmacology During Anesthesiology Training

A thorough understanding of the dose-response relationship is required for optimizing the efficacy of anesthetics while minimizing adverse drug effects. Nowadays, except for the inhaled anesthetics (for which end-tidal concentrations can be measured online), most of the drugs used in clinical anesthesia are administered using standard dosing guidelines, without giving due consideration to their pharmacokinetics and dynamics in guiding their administration. Various studies have found that introducing pharmacokinetics and pharmacodynamics as part of the inputs in clinical anesthesiology could lead to better patient care. With this in mind, it is extremely important that clinicians understand and apply the principles of clinical pharmacology that determine the time course of a drug's disposition and effect. Clinical pharmacology is one of the most challenging topics to teach in anesthesiology. The development of simulators to illustrate the time course of a drug's disposition and effect provides online visualization of pharmacokinetic-pharmacodynamic information during the clinical use of anesthetics. The aim of this review is to discuss the importance of simulation as a clinical pharmacology teaching tool for trainees in anesthesiology.

Pharmacokinetic Studies in Microdosing and Phase 0 Trials

Pharmacokinetic Studies in Microdosing and Phase 0 Trials

The pharmacokinetics of meloxicam in vultures

Vulture populations across the Asian subcontinent have declined dramatically in the last 15 years and are now on the verge of extinction. Although the cause of the population decline was initially unknown, the decrease has recently been conclusively linked to the use of the nonsteroidal anti-inflammatory drug diclofenac in cattle that inadvertently ended up in the vulture food chain. With the vulture numbers continuing to decline by up to 48% a year, the Indian, Nepali and Pakistan governments have recently banned the manufacture and importation of veterinary diclofenac. They have also suggested meloxicam as an alternate anti-inflammatory for use in cattle. This recommendation was based on extensive acute safety studies in the African White-backed vulture (Gyps africanus), which evaluated worst case scenarios of maximum intake based on a once in three day feeding pattern. However, the possible cumulative pharmacokinetic and pharmacodynamic effects in vultures receiving multiple daily doses of meloxicam over time were not assessed. At present very little pharmacokinetic or pharmacodynamic information is available to add further support for the safety of meloxicam in this animal species. This article discusses the oral and intramuscular pharmacokinetics of meloxicam in Cape Griffon vultures (Gyps coprotheres). Therapeutic drug monitoring was also undertaken in White-backed, Egyptian (Neophron pernopterus) and one Lappet Faced vulture (Torgos tracheliotos). In all these species, meloxicam was characterized by a short half-life of elimination. The rapid metabolism of meloxicam in combination with a short duration of effect in the studied species Gyps vultures shown in this study makes it unlikely that the drug could accumulate. This confirms the safety of repeated exposure to meloxicam in vultures of this genus.

Has Molecular and Cellular Imaging Enhanced Drug Discovery and Drug Development?

A great many efforts have been made to accelerate the drug discovery and development process, which is extremely time and money consuming. Recently developed molecular imaging has many significant advantages over conventional methods for examining molecular pathways and obtaining pharmacokinetic, pharmacodynamic and mechanistic information. This review briefly summarizes various molecular and cellular imaging techniques and discusses several important applications of molecular and cellular imaging in drug discovery and development, which include: (i) measurement of pharmacodynamic endpoints by imaging metabolism and proliferation, imaging angiogenic parameters, and imaging a particular pathway or downstream target; (ii) evaluation of pharmacokinetics; and (iii) imaging therapeutic gene expression with relevance to gene therapy. Molecular imaging is becoming more widely used as a non-invasive tool for drug discovery and drug screening. Further refinements in imaging techniques, optimization of imaging probes and collaborative efforts will be needed to fully realise the vast potential of molecular imaging techniques in discovering and developing new drugs.

Pharmacokinetics of Acyclovir after Intravenous Infusion of Acyclovir and after Oral Administration of Acyclovir and Its Prodrug Valacyclovir in Healthy Adult Horses

The purpose of this study was twofold. The first aim was to evaluate the oral bioavailability and pharmacokinetics (PKs) of acyclovir in horses after intravenous (i.v.) administration and after oral administration of acyclovir and its prodrug, valacyclovir. Second, we aimed to combine these PK data with pharmacodynamic (PD) information, i.e., 50% effective concentrations (EC(50) values) from in vitro studies, to design an optimal dosage schedule. Three treatments were administered to healthy adult horses: 10 mg of acyclovir/kg of body weight delivered as an i.v. infusion over 1 h, 20 mg of acyclovir/kg administered as tablets by nasogastric intubation, and 20 mg of valacyclovir/kg administered as tablets by nasogastric intubation. Total plasma concentrations were measured by a high-performance liquid chromatography method combined with fluorescence detection, while unbound plasma concentrations were determined by liquid chromatography-tandem mass spectrometry. The peak concentration of i.v. acyclovir was approximately 10 mug/ml for both the total and the unbound plasma concentrations. The mean half-life of elimination was between 5.05 h (total concentration) and 11.9 h (unbound concentration). Oral administration of acyclovir resulted in low maximum concentration in plasma (C(max)) and poor bioavailability. A 10-times-higher C(max) and an 8-times-higher bioavailability were achieved with oral administration of valacyclovir. The i.v. administration of 10 mg/kg acyclovir and the oral administration of 20 mg/kg valacyclovir achieved concentrations within the sensitivity range of equine herpesvirus type 1 (EHV-1). The higher bioavailability of valacyclovir makes it an attractive candidate for the prophylactic and/or therapeutic treatment of horses infected with EHV-1. The results from the PK/PD modeling showed that a dosage of 40 mg/kg valacyclovir, administered three times daily, would be sufficient to reach plasma concentrations above the EC(50) values.

Development of a pharmacodynamic model of murine malaria and antimalarial treatment with dihydroartemisinin

Antimalarial treatment strategies based on in vitro studies are limited by the paucity of pharmacodynamic information for dosage regimen design. We postulated that a murine model could be used for pre-clinical stages of drug development, especially in dose–response studies and evaluation of combination therapies. Swiss mice infected with Plasmodium berghei parasites (2–5% starting parasitaemia) were given dihydroartemisinin (0–100 mg/kg single dose). Parasite density was regularly determined from thin blood films. A parasite population growth model comprising parasite multiplication, decline in erythrocyte count with increasing parasitaemia and parasite clearance after drug administration was developed. This model described the rise in parasitaemia following inoculation, the nadir following dihydroartemisinin administration, and the subsequent resurgence of parasitaemia (analogous to ‘recrudescence’). At doses of 10, 30 and 100 mg/kg dihydroartemisinin, there was a graded response with 2.5 ± 1, 5 ± 1 and 12 ± 4-fold decreases in parasitaemia, respectively. The nadir parasitaemia (at 21–27 h) was also dose-dependent. This study demonstrates that a murine malaria pharmacodynamic model is a valuable tool for understanding how single drugs and their dosing schedules alter the time course and level of infection.

Pharmacodynamics and safety of intravenous pegaspargase during remission induction in adults aged 55 years or younger with newly diagnosed acute lymphoblastic leukemia

AbstractIn contrast to that in children, pharmacokinetic, pharmacodynamic, and safety information on pegaspargase in adults is very limited. We administered a single intravenous dose of pegaspargase (2000 IU/m2) as part of a standard frontline induction regimen to 25 adults with newly diagnosed acute lymphoblastic leukemia (ALL), and obtained serum samples on several time points. The population mean peak serum concentration of asparaginase enzymatic activity was 1 IU/mL, the elimination half-life was 7 days, and the volume of distribution was 2.43 L/m2. After the single dose, asparagine deamination was complete in all patients after 2 hours, and in 100%, 81%, and 44% on days 14, 21, and 28, respectively. A pharmocodynamic correlation model showed minimal enzymatic activity of 0.2 IU/mL for optimal asparagine depletion. The kinetic posthoc analyses demonstrated enzymatic activity for 3 weeks or more. One patient developed neutralizing antiasparaginase antibodies on day 22 after administration. Pegaspargase was well tolerated, with few grade 3/4 side effects. No allergic reactions or pancreatitis were observed. In adults aged 55 years or younger, pegaspargase produces a long duration of asparagine depletion and can be given intravenously, with a safety profile that is similar to equivalent multiple doses of intramuscular Escherichia coli asparaginase.

CYP2C8 and antimalaria drug efficacy.

Malaria is a major infectious disease. In the last 10 years it has killed more than 20 million people, mainly small children in Africa. The highly efficacious artemisinine combination therapy is being launched globally, constituting the main hope for fighting the disease. Amodiaquine is a main partner in these combinations. Amodiaquine is almost entirely metabolized by the polymorphic cytochrome P450 (CYP) isoform 2C8 to the pharmacologically active desethylamodiaquine. The question remains whether the efficacy of amodiaquine is affected by the gene polymorphism. Genotype-inferred low metabolizers are found in 1–4% of African populations, which corresponds to millions of expected exposures to the drug. In vivo pharmacokinetic data on amodiaquine is limited. By combining it with published in vitro pharmacodynamic and drug metabolism information, we review and predict the possible relevance, or lack of, of CYP2C8 polymorphisms in the present and future efficacy of amodiaquine. Chloroquine and dapsone, both substrates of CYP2C8, are also discussed in the same context.

Clinical Pharmacokinetics and Pharmacodynamics of Mycophenolate in Solid Organ Transplant Recipients

This review aims to provide an extensive overview of the literature on the clinical pharmacokinetics of mycophenolate in solid organ transplantation and a briefer summary of current pharmacodynamic information. Strategies are suggested for further optimisation of mycophenolate therapy and areas where additional research is warranted are highlighted. Mycophenolate has gained widespread acceptance as the antimetabolite immunosuppressant of choice in organ transplant regimens. Mycophenolic acid (MPA) is the active drug moiety. Currently, two mycophenolate compounds are available, mycophenolate mofetil and enteric-coated (EC) mycophenolate sodium. MPA is a potent, selective and reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH), leading to eventual arrest of T- and B-lymphocyte proliferation. Mycophenolate mofetil and EC-mycophenolate sodium are essentially completely hydrolysed to MPA by esterases in the gut wall, blood, liver and tissue. Oral bioavailability of MPA, subsequent to mycophenolate mofetil administration, ranges from 80.7% to 94%. EC-mycophenolate sodium has an absolute bioavailability of MPA of approximately 72%. MPA binds 97-99% to serum albumin in patients with normal renal and liver function. It is metabolised in the liver, gastrointestinal tract and kidney by uridine diphosphate gluconosyltransferases (UGTs). 7-O-MPA-glucuronide (MPAG) is the major metabolite of MPA. MPAG is usually present in the plasma at 20- to 100-fold higher concentrations than MPA, but it is not pharmacologically active. At least three minor metabolites are also formed, of which an acyl-glucuronide has pharmacological potency comparable to MPA. MPAG is excreted into the urine via active tubular secretion and into the bile by multi-drug resistance protein 2 (MRP-2). MPAG is de-conjugated back to MPA by gut bacteria and then reabsorbed in the colon. Mycophenolate mofetil and EC-mycophenolate sodium display linear pharmacokinetics. Following mycophenolate mofetil administration, MPA maximum concentration usually occurs in 1-2 hours. EC-mycophenolate sodium exhibits a median lag time in absorption of MPA from 0.25 to 1.25 hours. A secondary peak in the concentration-time profile of MPA, due to enterohepatic recirculation, often appears 6-12 hours after dosing. This contributes approximately 40% to the area under the plasma concentration-time curve (AUC). The mean elimination half-life of MPA ranges from 9 to 17 hours. MPA displays large between- and within-subject pharmacokinetic variability. Dose-normalised MPA AUC can vary more than 10-fold. Total MPA concentrations should be interpreted with caution in patients with severe renal impairment, liver disease and hypoalbuminaemia. In such individuals, MPA and MPAG plasma protein binding may be altered, changing the fraction of free MPA available. Apparent oral clearance (CL/F) of total MPA appears to increase in proportion to the increased free fraction, with a reduction in total MPA AUC. However, there may be little change in the MPA free concentration. Ciclosporin inhibits biliary excretion of MPAG by MRP-2, reducing enterohepatic recirculation of MPA. Exposure to MPA when mycophenolate mofetil is given in combination with ciclosporin is approximately 30-40% lower than when given alone or with tacrolimus or sirolimus. High dosages of corticosteroids may induce expression of UGT, reducing exposure to MPA. Other co-medications can interfere with the absorption, enterohepatic recycling and metabolism of mycophenolate. Most pharmacokinetic investigations of MPA have involved mycophenolate mofetil rather than EC-mycophenolate sodium therapy. In population pharmacokinetic studies, MPA CL/F in adults ranges from 14.1 to 34.9 L/h (ciclosporin co-therapy) and from 11.9 to 25.4 L/h (tacrolimus co-therapy). Patient bodyweight, serum albumin concentration and immunosuppressant co-therapy have a significant influence on CL/F. The majority of pharmacodynamic data on MPA have been obtained in patients receiving mycophenolate mofetil therapy in the first year after kidney transplantation. Low MPA AUC is associated with increased incidence of biopsy-proven acute rejection. Gastrointestinal adverse events may be dose related. Leukopenia and anaemia have been associated with high MPA AUC, trough concentration and metabolite concentrations in some, but not all, studies. High free MPA exposure has been identified as a risk factor for leukopenia in some investigations. Targeting a total MPA AUC from 0 to 12 hours (AUC12) of 30-60 mg.hr/L is likely to minimise the risk of acute rejection and may reduce toxicity. IMPDH monitoring is in the early experimental stage. Individualisation of mycophenolate therapy should lead to improved patient outcomes. MPA AUC12 appears to be the most useful exposure measure for such individualisation. Limited sampling strategies and Bayesian forecasting are practical means of estimating MPA AUC12 without full concentration-time profiling. Target concentration intervention may be particularly useful in the first few months post-transplant and prior to major changes in anti-rejection therapy. In patients with impaired renal or hepatic function or hypoalbuminaemia, free drug measurement could be valuable in further interpretation of MPA exposure.

An Overview of TCI and TIVA.

An Overview of TCI and TIVA.

Drug treatment of depression in the 2000s: an overview of achievements in the last 10 years and future possibilities

During the past 10 years our knowledge about the pharmacotherapy of depression has been consolidated, and a variety of very interesting new compounds launched onto the market. The pipeline of the pharmaceutical industry is still filled with an assortment of new developments and very promising new approaches towards the pharmacotherapy of depressive disorders. Future pharmacological treatments of depression will not only enhance serotonergic and noradrenergic neurotransmission: other systems, such as the melatonergic receptor system and the hypothalamus–pituitary–adrenal axis, are also the targets of newly developed and upcoming substances with putative antidepressant effects. The main advantages of the currently available newer pharmacotherapeutic options are the broadening of the spectrum of possible antidepressant treatments, which is of particular importance for the growing number of patients suffering from difficult-to-treat depression, and a far better tolerability profile in comparison to older compounds such as tricyclic antidepressants. Unresolved issues are the unacceptably high rate of non-responsiveness during antidepressant treatment, a latency of sometimes several weeks until clinical improvement and remission can be achieved, and a variety of possible side effects also present during treatment with modern compounds. This review mainly presents the development of antidepressant pharmacotherapies during the past 10 years, together with pharmacokinetic and pharmacodynamic information and a comparison of different pharmacological treatment principles evaluated in randomized controlled clinical trials. In addition, new pharmacological strategies that are not yet available on the market and strategies currently under development are reviewed in detail. The study of new treatment options is of major importance to provide better strategies for the clinical management of depression in the future, and is thus also of great socio-economic importance.

Simulating chemotherapeutic schemes in the individualized treatment context: The paradigm of glioblastoma multiforme treated by temozolomide in vivo

A novel patient individualized, spatiotemporal Monte Carlo simulation model of tumor response to chemotherapeutic schemes in vivo is presented. Treatment of glioblastoma multiforme by temozolomide is considered as a paradigm. The model is based on the patient's imaging, histopathologic and genetic data. A discretization mesh is superimposed upon the anatomical region of interest and within each geometrical cell of the mesh the most prominent biological “laws” (cell cycling, apoptosis, etc.) in conjunction with pharmacokinetics and pharmacodynamics information are applied. A good qualitative agreement of the model's predictions with clinical experience supports the applicability of the approach to chemotherapy optimization.

The effect of AMG 706, a novel multi-kinase inhibitor, on vascular permeability and blood flow as assessed by dynamic contrast enhanced magnetic resonance imaging in an in vivo preclinical tumor model

3134 Background: AMG 706 is a potent, oral, multi-kinase inhibitor with anti-angiogenic and anti-tumor activity achieved by selectively targeting all known VEGF, PDGF, Kit and Ret receptors. In previous experiments, AMG 706 treatment resulted in regression of large, established A431 epidermoid carcinoma tumors within seven days of the initiation of treatment. The present experiments were carried out to relate the therapeutic effect to changes in vascular permeability and blood flow, with the intent of identifying a pharmacodynamic marker for use in clinical trials. Methods: After an initial dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) baseline scan, mice bearing A431 xenografts (300 mm3) were dosed with either vehicle or AMG 706 at dose levels ranging between 10 and 75 mg/kg. DCE-MRI was repeated after 24, 48 or 96 hrs of treatment. All MRI studies were performed at 4.7 Tesla (Bruker Biospin, Billerica, MA). During the DCE-MRI scans, 0.2 mmol/kg gadopentetate dimeglumine was injected intravenously via a tail vein catheter. Results: DCE-MRI analysis identified a statistically significant (p = 0.0235) decrease in contrast agent uptake (AUC relative to baseline), occurring in a dose dependent fashion in the interior region of the tumor after only 24 hrs of treatment with AMG 706. The effect seen at 24 hrs is consistent with the previous observation that tumor endothelial cell apoptosis occurs within 12 hrs of initiation of treatment, and indicates a statistically significant treatment related reduction in tumor blood flow and vascular permeability in the A431 tumor model. Conclusions: Oral administration of AMG 706 produced a statistically significant reduction in vascular blood flow and/or permeability in the A431 human tumor xenograft model as early as 24 hrs of treatment. These results are consistent with previous observations indicating the destruction of tumor blood vessels as the mechanism of action of AMG 706, and support the use of DCE-MRI to obtain pharmacodynamic information in clinical trials of AMG 706. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Amgen Amgen Amgen

Microdialysis

Microdialysis is a probe-based sampling method, which, if linked to analytical devices, allows for the measurement of drug concentration profiles in selected tissues. During the last two decades, microdialysis has become increasingly popular for preclinical and clinical pharmacokinetic studies. The advantage of in vivo microdialysis over traditional methods relates to its ability to continuously sample the unbound drug fraction in the interstitial space fluid (ISF). This is of particular importance because the ISF may be regarded as the actual target compartment for many drugs, e.g. antimicrobial agents or other drugs mediating their action through surface receptors. In contrast, plasma concentrations are increasingly recognised as inadequately predicting tissue drug concentrations and therapeutic success in many patient populations. Thus, the minimally invasive microdialysis technique has evolved into an important tool for the direct assessment of drug concentrations at the site of drug delivery in virtually all tissues. In particular, concentrations of transdermally applied drugs, neurotransmitters, antibacterials, cytotoxic agents, hormones, large molecules such as cytokines and proteins, and many other compounds were described by means of microdialysis. The combined use of microdialysis with non-invasive imaging methods such as positron emission tomography and single photon emission tomography opened the window to exactly explore and describe the fate and pharmacokinetics of a drug in the body. Linking pharmacokinetic data from the ISF to pharmacodynamic information appears to be a straightforward approach to predicting drug action and therapeutic success, and may be used for decision making for adequate drug administration and dosing regimens. Hence, microdialysis is nowadays used in clinical studies to test new drug candidates that are in the pharmaceutical industry drug development pipeline.

Toxicity classification and evaluation of four pharmaceuticals classes: antibiotics, antineoplastics, cardiovascular, and sex hormones.

Four different classes of environmental concern are quantitatively and qualitatively assessed for environmental hazards; antibiotics (n = 226), antineoplastics (n = 81), cardiovascular (n = 272), and sex hormones (n = 92). These along with an ECOSAR scan of all pharmaceuticals (n = 2848) were then classified according to the OECD aquatic toxicity classification system. The predicted species susceptibility is: daphnid > fish > algae, and the predicted rank order of relative toxicity: sex hormones > cardiovascular = antibiotics > antineoplastics (Table 1). Generally, a relatively large proportion (1/3) of all pharmaceuticals are potentially very toxic to aquatic organisms (Table 2). The qualitative risk assessment ranking relative to probability and potential severity for human and environmental health effects is: antibiotics > sex hormones > cardiovascular > antineoplastics. (Q)SARs and pharmacodynamic information should be used to prioritize and steer experimental risk assessments of pharmaceuticals, and potentially, also be used in new drug discovery optimizing efficacy and in minimising environmental hazards of new products. Nuclear receptors are relatively well conserved in evolution. Currently, antibacterial resistance represents the most significant human health hazard, and potentially the largest non-target organism hazard is sex hormones acting as endocrine modulators in wildlife. Data for the individual compounds are accessible via.

Issues in pharmacokinetics and pharmacodynamics of anti-infective agents: kill curves versus MIC.

The success of antimicrobial therapy is determined by complex interactions between an administered drug, a host, and an infecting agent. In a clinical situation, the complexity of these interactions is usually reflected by a high variability in the dose-response relationship. Therefore, to minimize the dose-response variability, key characteristics of the drug, the infecting agent and the host have to be taken into account for selecting an appropriate antibiotic and an appropriate dose. Failure to do so may result in either therapeutic failure or emergence of resistant strains. To date, dose and drug selection is mostly based on a static in vitro parameter, the MIC and on the drug′s serum concentration as a pharmacokinetic parameter. In practice, however, a pharmacodynamic effect in vivo is rather the result of a dynamic exposure of the infective agent to the unbound antibiotic drug fraction at the relevant effect site. Thus, static conditions in an in vitro setting hardly reflect a dynamic situation in a target organ under in vivo conditions. Furthermore, serum concentrations do not reflect the unbound concentrations at the target site. In recent years substantial efforts were devoted to systematically elucidate the dynamic relationship between pharmacokinetic and pharmacodynamic variables. The main concept of this pharmacokinetic-pharmacodynamic approach is to use the concentration-effect relationship of the drug of interest in dosage adjustment and product development in a logical way and minimize trial-and-error approaches (29, 80). This approach can potentially result in substantial savings of time and expenses and may help to avoid unnecessary and, hence, unethical clinical studies (97). Thus, dosages and dosing intervals of antimicrobial agents should be designed with reference to dynamic pharmacokinetic and pharmacodynamic parameters. Accordingly, several efficacy indices or surrogate markers that take into account both pharmacokinetic and pharmacodynamic information have been defined and used by different authors to describe the antibacterial activity of various classes of antimicrobial agents (100, 106, 59). Currently there are two main trends for antibiotic pharmacokinetic-pharmacodynamic models; those based on the MIC and those based on a kill-curve approach, both of which will be described in detail in the following.

Preliminary susceptibility testing guidelines for AZD2563, a long-acting oxazolidinone

Rapid expansion of antimicrobial resistance has led to the development of new antimicrobial agents. AZD2563 is a novel oxazolidinone that has activity similar to linezolid and the potential for extended dosing intervals. Recent Gram-positive clinical organisms (1572 strains) were tested including four oxazolidinone-resistant enterococci. Strains processed were: 313 Staphylococcus aureus, 299 coagulase-negative staphylococci, 305 enterococci, 305 Streptococcus pneumoniae, 300 other streptococci (β-haemolytic and viridans group) and 50 other rarely isolated Gram-positive species. The methods (agar and broth dilution, disk diffusion) of the National Committee for Clinical Laboratory Standards (NCCLS; M7-A6, M2-A8) were followed and linezolid was used as a control agent. A tentative MIC breakpoint (≤2 mg/l) for AZD2563 was based on the manufacturer’s recommendation, preliminary pharmacodynamic information and similarity to the current linezolid interpretive criteria. Correlation between AZD2563 MIC values and zone diameters around 30 μg AZD2563 disks indicated a 99.9% categorical agreement and all intermethod errors were minor. Comparison of agar dilution to broth microdilution MIC results for AZD2563 showed 100.0% agreement ± one log 2 dilution step (89.2% of MIC results were identical). Scattergrams suggest that all Gram-positive organisms could be accurately tested using the same interpretive criteria: susceptible at ≤2 mg/l (≥20 mm), intermediate at 4 mg/l (17–19 mm) and resistant at ≥8 mg/l (≤16 mm). These tentative AZD2563 interpretive guidelines should facilitate in vitro susceptibility testing during clinical trials and detect all oxazolidinone-resistant isolates.

An automated blood sampler for simultaneous sampling of systemic blood and brain microdialysates for drug absorption, distribution, metabolism, and elimination studies

Introduction: A major problem in preclinical drug development where blood sampling from small animals is a routine practice is the time and labor involved in the serial sampling of small blood volumes from small animals such as rats for the duration of pharmacokinetic/pharmacodynamic (PK/PD) studies. The traditional method of manually drawing blood from the animal requires the animal to be anesthetized or restrained with some device, both of which cause stress to the animal. Methods: An automated blood sampler (ABS) was developed to simultaneously collect blood and brain microdialysate samples at preprogrammed time points from awake and freely moving animals. The samples are delivered to fraction collectors and stored at 4 °C until use. The lost blood volume during collection is replaced with sterile saline to prevent fluid loss from the animal. In addition, the system is capable of collecting urine and feces for metabolism studies and monitoring the animal activity for behavioral studies. In the present study, blood samples were collected for 24 h after dosing rats orally with a 5 mg/kg dose of olanzapine (OLAN). Brain dialysates were collected for the same duration from a microdialysis probe implanted in the striatum. Results: The pharmacokinetic parameters, obtained after an oral dose, are in good agreement with reported values in literature. The pharmacodynamic information obtained from brain dialysates data show that OLAN elevates the concentration of dopamine (DA) in the brain and remains in the brain even after it is cleared from the plasma. Discussion: The ABS described here is a very useful tool in drug development to accelerate the pace of preclinical in vivo studies and to simultaneously provide pharmacodynamic and physiological information.

Big physics, small doses: the use of AMS and PET in human microdosing of development drugs.

The process of early clinical drug development has changed little over the past 20 years despite an up to 40% failure rate associated with inappropriate drug metabolism and pharmacokinetics of candidate molecules. A new method of obtaining human metabolism data known as microdosing has been developed which will permit smarter candidate selection by taking investigational drugs into humans earlier. Microdosing depends on the availability of two ultrasensitive 'big-physics' techniques: positron emission tomography (PET) can provide pharmacodynamic information, whereas accelerator mass spectrometry (AMS) provides pharmacokinetic information. Microdosing allows safer human studies as well as reducing the use of animals in preclinical toxicology.

How Differences in Enzyme Expression Can Translate into Pharmacokinetic Variance and Susceptibility to Toxicity

Advances in risk assessment methodologies invite the consideration of more pharmacokinetic, pharmacodynamic, and biochemical information than ever before. When toxicity data are adequate, the identification of enzymes responsible for detoxication or bioactivation motivate their consideration in risk assessment. Consideration should be given not only to the ontogeny of enzyme expression, but to other biochemical factors such as tissue lipid content and changes in relative organ size and blood flow during development. Dogma that enzyme alterations result in alterations of risk requires reexamination. Sometimes these do not alter risk, even though the enzymes form toxicologically active metabolites. Knowledge that a given enzyme is responsible for metabolism of an environmental contaminant often stimulates the search for and use of information on its variance in expression and/or activity. Separate data on enzyme expression (content) and enzymatic activity can be useful in human health risk assessment, but r...