April Barbour
University of Florida
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Current Opinion in Pharmacology | 2008
Stephan Schmidt; April Barbour; Martina Sahre; Kenneth H. Rand; Hartmut Derendorf
The path of new compounds from discovery to bedside is long and costly and a large majority of compounds never make it to the market. To improve drug development, better tools are needed to assess efficacy and safety early in the process. One approach that has been suggested by the FDA to help streamlining the drug development process is pharmacokinetic/pharmacodynamic (PK/PD) modeling and simulation. In this approach, a model-based link between PK profiles and corresponding PD is established. Once a suitable model is identified and validated, predictions about efficacy and safety of different dosing regimens can be made. The goal of this review is to examine the current state of PK, PD, and PK/PD in antibiotic and antiviral research and development.
International Journal of Antimicrobial Agents | 2009
April Barbour; Stephan Schmidt; W. Robert Rout; Kfir Ben-David; Olaf Burkhardt; Hartmut Derendorf
Antibiotic prophylaxis is intended to prevent postoperative wound infections, a major source of morbidity and mortality in surgical patients. Cefuroxime is a well-established second-generation cephalosporin that is given preoperatively in surgery units at a standard dose of 1.5 g. It is therefore important to determine whether cefuroxime distributes to the interstitial space fluid (ISF) of subcutaneous (s.c.) soft tissues, especially in obese patients who are at a higher risk of surgical site infections. In a single centre, prospective, open-label study, six morbidly obese patients [body mass index (BMI)> or =40] undergoing abdominal surgery received a single intravenous dose of 1.5 g cefuroxime within 1h of incision. Blood and microdialysis samples from the ISF of skeletal muscle and s.c. adipose tissue were collected before, throughout and after surgery for up to 6h post-dosing. Cefuroxime concentrations were determined by high-performance liquid chromatography-ultraviolet (HPLC-UV). Total peak concentrations in plasma (C(max)) (66.8+/-18.9 microg/mL) were higher than free C(max) levels in the ISF of muscle (60.1+/-15.2 microg/mL) and s.c. adipose tissue (39.2+/-26.4 microg/mL). Mean area under the free concentration-time curve ratios of muscle/total plasma (1.0+/-0.2) or s.c. adipose tissue/total plasma (0.6+/-0.5) indicate that cefuroxime distributes into the ISF of these tissues. In conclusion, the findings of this pilot study indicate that cefuroxime distributes into the ISF of muscle and s.c. adipose tissue of morbidly obese patients undergoing abdominal surgery. Concentrations in the ISF of soft tissues following a single 1.5 g dose may be high enough to prevent infections with Gram-positive organisms but may be insufficient to prevent infections with Gram-negative organisms.
International Journal of Antimicrobial Agents | 2010
April Barbour; Francesco Scaglione; Hartmut Derendorf
The pharmacokinetic/pharmacodynamic (PK/PD) indices useful for predicting antimicrobial clinical efficacy are well established. The most common indices include the time free drug concentration in plasma is above the minimum inhibitory concentration (MIC) (fT(>MIC)) expressed as a percent of the dosing interval, the ratio of maximum concentration to MIC (C(max)/MIC), and the ratio of the area under the 24-h concentration-time curve to MIC (AUC(0-24)/MIC). A single PK/PD index may correlate well with an entire antimicrobial class. For example, the beta-lactams correlate well with the fT(>MIC). However, other classes may be more complex and a single index cannot be generalised to the class, e.g. the macrolides. The rationale behind which PK/PD index best correlates with efficacy depends on several factors, including the mechanism of action, the microbial kill kinetics, the degree of protein binding and the degree of tissue distribution. Studies have traditionally emphasised the first two factors, whilst the significance of protein binding and tissue distribution is increasingly appreciated. In fact, the latter two factors may partially elucidate why the magnitude of reported target indices are not always as expected. For example, tigecycline and telithromycin are clinically efficacious with average serum concentrations below their MICs over a 24-h period. Therefore, to understand more fully the PK/PD relationship of antibiotics and to better predict the clinical efficacy of antibiotic dosing regimens, assessment of free drug concentrations at the site of action is warranted.
Pediatric Blood & Cancer | 2011
Guy Young; Donald L. Yee; Sarah H. O'Brien; Rachna Khanna; April Barbour; Diane J. Nugent
The incidence of thromboembolic disease is increasing in children. New anticoagulants have been licensed in adults and need to be studied in children. This report describes the first prospective study of fondaparinux in children.
International Journal of Antimicrobial Agents | 2009
April Barbour; Stephan Schmidt; Kenneth H. Rand; Hartmut Derendorf
Ceftobiprole is a novel broad-spectrum cephalosporin with activity against a wide range of Gram-positive and Gram-negative bacteria, including several resistant species such as methicillin-resistant Staphylococcus aureus and penicillin-resistant Streptococcus pneumoniae. Ceftobiprole is administered intravenously as the prodrug ceftobiprole medocaril, which is almost immediately converted to the active form. It is currently under review by the US Food and Drug Administration (FDA) and is approved in Canada under the trade name Zeftera. The pharmacokinetics of ceftobiprole are non-complex as it displays a two-compartment model, dose proportionality, linear plasma protein binding and negligible accumulation. The volume of distribution is approximately equal to the extracellular fluid volume and it is cleared primarily by glomerular filtration, resulting in a half-life of approximately 3-4h. Ceftobiprole displays a low plasma protein binding of approximately 22%. The efficacy of ceftobiprole was demonstrated in two pivotal studies in patients with complicated skin and skin-structure infections (cSSSIs) that compared ceftobiprole with vancomycin in Gram-positive infections in one study and ceftobiprole with vancomycin plus ceftazidime in Gram-positive and Gram-negative infections in the other. The clinical cure rates were similar for ceftobiprole vs. comparator treatments: 93.3% vs. 93.5% with vancomycin only and 90.5% vs. 90.2% with vancomycin plus ceftazidime. The pharmacokinetic/pharmacodynamic profile supports the use of ceftobiprole to treat a wide range of cSSSIs.
Clinical Pharmacokinectics | 2009
April Barbour; Stephan Schmidt; Benjamin Ma; Lars Schiefelbein; Kenneth H. Rand; Olaf Burkhardt; Hartmut Derendorf
Rapid emergence of resistance against antibacterial s emphasizes the need for the development of novel and/or more potent antibacterials. Tigecycline is the first representative of a new drug class, the glycylcyclines, and was approved in 2005 by the US FDA for the treatment of complicated skin and skin structure infections, as well as complicated intra-abdominal infections. Tigecycline distributes extensively into the intracellular space of tissue and accumulates in cells, which may qualify it for the treatment of intracellular infections. The pharmacokinetics of tigecycline are complex with both linear and non-linear characteristics. The reason for this complexity is still not fully understood. Non-linearity can be found in the volume of distribution possibly due to extensive and variable tissue and/or plasma protein binding. In contrast, clearance and area under the plasma concentration-time curve are dose-independent. Tigecycline has a high incidence of mild adverse effects, mainly nausea and vomiting, but is otherwise well tolerated.
Antimicrobial Agents and Chemotherapy | 2009
April Barbour; Stephan Schmidt; Sreedharan Nair Sabarinath; Maria B. Grant; Christoph N. Seubert; Donna Skee; Bindu P. Murthy; Hartmut Derendorf
ABSTRACT Ceftobiprole is a promising new broad-spectrum cephalosporin with activity against several multidrug-resistant gram-positive and gram-negative species, including methicillin-resistant Staphylococcus aureus. In order to make efficacy predications against these resistant bacteria in soft-tissue infections, i.e., skin and skin structure infections, ceftobiproles ability to reach the site of action should be explored. Therefore, a microdialysis study was conducted in 12 healthy volunteers to determine the penetration of ceftobiprole into skeletal muscle and subcutaneous (s.c.) adipose tissue after a single intravenous dose of 500 mg. Plasma and tissue interstitial space fluid (ISF) drug concentrations were measured for 24 h from the start of the 2-h intravenous infusion. Pharmacokinetic parameters were determined using noncompartmental analysis. The penetration of ceftobiprole into the ISF of tissues was assessed by comparing the ratios between tissue and plasma of the free drug area under the concentration-time curve (fAUC). It was found that ceftobiprole distributes into the muscle (fAUCmuscle/fAUCplasma of 0.69 ± 0.13) and s.c. adipose tissue (fAUCs.c.adipose/fAUCplasma of 0.49 ± 0.28). The concentrations in both skeletal muscle and s.c. adipose tissue met the efficacy breakpoint (percentage of the time that free drug concentrations remained above the MIC) for at least 40% of the 8-h dosing interval for organisms with a MIC of 2 mg/liter. Therefore, ceftobiprole qualifies as a potential agent with drug penetration capabilities to treat complicated skin and skin structure infections due to both gram-negative and gram-positive pathogens with MICs equal to or below 2 mg/liter.
Antimicrobial Agents and Chemotherapy | 2009
Stephan Schmidt; Sreedharan Nair Sabarinath; April Barbour; Darren Abbanat; Prasarn Manitpisitkul; Sue Sha; Hartmut Derendorf
ABSTRACT Linezolid is the first FDA-approved oxazolidinone with activity against clinically important gram-positive pathogens, including methicillin (meticillin)-resistant Staphylococcus aureus (MRSA). RWJ-416457 is a new oxazolidinone with an antimicrobial spectrum similar to that of linezolid. The goal of the present study was to develop a general pharmacokinetic (PK)-pharmacodynamic (PD) model that allows the characterization and comparison of the in vitro activities of oxazolidinones, determined in time-kill curve experiments, against MRSA. The in vitro activities of RWJ-416457 and the first-in-class representative, linezolid, against MRSA OC2878 were determined in static and dynamic time-kill curve experiments over a wide range of concentrations: 0.125 to 8 μg/ml (MIC, 0.5 μg/ml) and 0.25 to 16 μg/ml (MIC, 1 μg/ml), respectively. After correction for drug degradation during the time-kill curve experiments, a two-subpopulation model was simultaneously fitted to all data in the NONMEM VI program. The robustness of the model and the precision of the parameter estimates were evaluated by internal model validation by nonparametric bootstrap analysis. A two-subpopulation model, consisting of a self-replicating, oxazolidinone-susceptible and a persistent, oxazolidinone-insusceptible pool of bacteria was appropriate for the characterization of the time-kill curve data. The PK-PD model identified was capable of accounting for saturation in growth, delays in the onsets of growth and drug-induced killing, as well as naturally occurring bacterial death. The simultaneous fit of the proposed indirect-response, maximum-effect model to the data resulted in concentrations that produced a half-maximum killing effect that were significantly (P < 0.05) lower for RWJ-416457 (0.41 μg/ml) than for linezolid (1.39 μg/ml). In combination with the appropriate PK data, the susceptibility-based two-subpopulation model identified may provide valuable guidance for the selection of oxazolidinone doses or dose regimens for use in clinical studies.
British Journal of Clinical Pharmacology | 2013
April Barbour; Lea Sarov-Blat; Gengqian Cai; Michael J. Fossler; Dennis L. Sprecher; Johann Graggaber; Adam T. McGeoch; Jo Maison; Joseph Cheriyan
AIMS The purpose of this study was to establish safety and tolerability of a single intravenous (IV) infusion of a p38 mitogen-activated protein kinase inhibitor, losmapimod, to obtain therapeutic levels rapidly for a potential acute coronary syndrome indication. Pharmacokinetics (PK) following IV dosing were characterized, and pharmacokinetic/pharmacodynamic (PK/PD) relationships between losmapimod and phosphorylated heat shock protein 27 (pHSP27) and high-sensitivity C-reactive protein were explored. METHODS Healthy volunteers received 1 mg losmapimod IV over 15 min (n = 4) or 3 mg IV over 15 min followed by a washout period and then 15 mg orally (PO; n = 12). Pharmacokinetic parameters were calculated by noncompartmental methods. The PK/PD relationships were explored using modelling and simulation. RESULTS There were no deaths, nonfatal serious adverse events or adverse events leading to withdrawal. Headache was the only adverse event reported more than once (n = 3 following oral dosing). Following 3 mg IV and 15 mg PO, Cmax was 59.4 and 45.9 μg l(-1) and AUC0-∞ was 171.1 and 528.0 μg h l(-1) , respectively. Absolute oral bioavailability was 0.62 [90% confidence interval (CI) 0.56, 0.68]. Following 3 mg IV and 15 mg PO, maximal reductions in pHSP27 were 44% (95% CI 38%, 50%) and 55% (95% CI 50%, 59%) occurring at 30 min and 4 h, respectively. There was a 17% decrease (95% CI 9%, 24%) in high-sensitivity C-reactive protein 24 h following oral dosing. A direct-link maximal inhibitory effect model related plasma concentrations to pHSP27 concentrations. CONCLUSIONS A single IV infusion of losmapimod in healthy volunteers was safe and well tolerated, and may potentially serve as an initial loading dose in acute coronary syndrome as rapid exposure is achieved.
International Journal of Antimicrobial Agents | 2014
April Barbour; Stephan Schmidt; Luning Zhuang; Kenneth H. Rand; Hartmut Derendorf
The purpose of this report was to compare two different methods for dose optimisation of antimicrobials. The probability of target attainment (PTA) was calculated using Monte Carlo simulation to predict the PK/PD target of fT>MIC or modelling and simulation of time-kill curve data. Ceftobiprole, the paradigm compound, activity against two MRSA strains was determined, ATCC 33591 (MIC=2mg/L) and a clinical isolate (MIC=1mg/L). A two-subpopulation model accounting for drug degradation during the experiment adequately fit the time-kill curve data (concentration range 0.25-16× MIC). The PTA was calculated for plasma, skeletal muscle and subcutaneous adipose tissue based on data from a microdialysis study in healthy volunteers. A two-compartment model with distribution factors to account for differences between free serum and tissue interstitial space fluid concentration appropriately fit the pharmacokinetic data. Pharmacodynamic endpoints of fT>MIC of 30% or 40% and 1- or 2-log kill were used. The PTA was >90% in all tissues based on the PK/PD endpoint of fT>MIC >40%. The PTAs based on a 1- or 2-log kill from the time-kill experiments were lower than those calculated based on fT>MIC. The PTA of a 1-log kill was >90% for both MRSA isolates for plasma and skeletal muscle but was slightly below 90% for subcutaneous adipose tissue (both isolates ca. 88%). The results support a dosing regimen of 500mg three times daily as a 2-h intravenous infusion. This dose should be confirmed as additional pharmacokinetic data from various patient populations become available.