American Cancer Society Colorectal Cancer Survivorship Care Guidelines.

Colorectal cancer (CRC) is the third most common cancer and third leading cause of cancer death in both men and women and second leading cause of cancer death when men and women are combined in the United States (US). Almost two-thirds of CRC survivors are living 5 years after diagnosis. Considering the recent decline in both incidence and mortality, the prevalence of CRC survivors is likely to increase dramatically over the coming decades with the increase in rates of CRC screening, further advances in early detection and treatment and the aging and growth of the US population. Survivors are at risk for a CRC recurrence, a new primary CRC, other cancers, as well as both short-term and long-term adverse effects of the CRC and the modalities used to treat it. CRC survivors may also have psychological, reproductive, genetic, social, and employment concerns after treatment. Communication and coordination of care between the treating oncologist and the primary care clinician is critical to effectively and efficiently manage the long-term care of CRC survivors. The guidelines in this article are intended to assist primary care clinicians in delivering risk-based health care for CRC survivors who have completed active therapy.

Retaining interest in caring for underserved patients among future medicine subspecialists: Underserved Medicine and Public Health (UMPH) program.

BACKGROUND: Accessing subspecialty care is hard for underserved patients in the U.S. Published curricula in underserved medicine for Internal Medicine residents target future-primary care physicians, with unknown impact on future medicine subspecialists. METHODS: The aim was to retain interest in caring for underserved patients among Internal Medicine residents who plan for subspecialist careers at an urban university hospital. The two-year Underserved Medicine and Public Health (UMPH) program features community-based clinics, evening seminars, reflection assignments and practicum projects for 3-7 Internal Medicine residents per year. All may apply regardless of anticipated career plans after residency. Seven years of graduates were surveyed. Data were analyzed using descriptive statistics. RESULTS: According to respondents, UMPH provided a meaningful forum to discuss important issues in underserved medicine, fostered interest in treating underserved populations and provided a sense of belonging to a community of providers committed to underserved medicine. After residency, 48% of UMPH graduates pursued subspecialty training and 34% practiced hospitalist medicine. 65% of respondents disagreed that "UMPH made me more likely to practice primary care" and 59% agreed "UMPH should target residents pursuing subpecialty careers." CONCLUSIONS: A curriculum in underserved medicine can retain interest in caring for underserved patients among future-medicine subspecialists. Lessons learned include [1] building relationships with local community health centers and community-practicing physicians was important for success and [2] thoughtful scheduling promoted high resident attendance at program events and avoided detracting from other activities required during residency for subspecialist career paths. We hope Internal Medicine residency programs consider training in underserved medicine for all trainees. Future work should investigate sustainability, whether training results in improved subspecialty access, and whether subspecialists face unique barriers caring for underserved patients. Future curricula should include advocacy skills to target systemic barriers.

Novel genetic predictors of venous thromboembolism risk in African Americans.

Venous thromboembolism (VTE) is the third most common life-threatening cardiovascular condition in the United States, with African Americans (AAs) having a 30% to 60% higher incidence compared with other ethnicities. The mechanisms underlying population differences in the risk of VTE are poorly understood. We conducted the first genome-wide association study in AAs, comprising 578 subjects, followed by replication of highly significant findings in an independent cohort of 159 AA subjects. Logistic regression was used to estimate the association between genetic variants and VTE risk. Through bioinformatics analysis of the top signals, we identified expression quantitative trait loci (eQTLs) in whole blood and investigated the messenger RNA expression differences in VTE cases and controls. We identified and replicated single-nucleotide polymorphisms on chromosome 20 (rs2144940, rs2567617, and rs1998081) that increased risk of VTE by 2.3-fold (P< 6 × 10(-7)). These risk variants were found in higher frequency among populations of African descent (>20%) compared with other ethnic groups (<10%). We demonstrate that SNPs on chromosome 20 are cis-eQTLs for thrombomodulin (THBD), and the expression of THBD is lower among VTE cases compared with controls (P= 9.87 × 10(-6)). We have identified novel polymorphisms associated with increased risk of VTE in AAs. These polymorphisms are predominantly found among populations of African descent and are associated with THBD gene expression. Our findings provide new molecular insight into a mechanism regulating VTE susceptibility and identify common genetic variants that increase the risk of VTE in AAs, a population disproportionately affected by this disease.

Single-dose euglycaemic clamp studies demonstrating pharmacokinetic and pharmacodynamic similarity between MK-1293 insulin glargine and originator insulin glargine (Lantus) in subjects with type 1 diabetes and healthy subjects.

AIMS: MK-1293 is an insulin glargine that has an amino acid sequence identical to that of Lantus, the originator insulin glargine. Two euglycaemic clamp studies, 1 in subjects with type 1 diabetes (T1D) and 1 in healthy subjects, were conducted to demonstrate pharmacokinetic (PK) and pharmacodynamic (PD) similarity between MK-1293 and Lantus commercially procured in both the European Union (EU-Lantus) and the USA (US-Lantus). MATERIALS AND METHODS: Both studies were single-dose, randomized, double-blind, single-centre, crossover studies with ≥7 days between dosing periods. A 2-treatment, 4-period replicate crossover study in T1D subjects (N = 76) compared the PK and PD of MK-1293 to EU-Lantus for 30 hours after dosing. A 3-period crossover study in healthy subjects (N = 109) compared the PK and PD of MK-1293, EU-Lantus and US-Lantus for 24 hours after dosing. In both studies, all subjects received single 0.4 units/kg subcutaneous doses of MK-1293 or Lantus in all dosing periods. Pharmacokinetic assessment was based on LC-MS/MS-based measurement of the major insulin glargine metabolite (M1) and PD was characterized using the euglycaemic clamp platform. RESULTS: In both studies, pre-specified similarity criteria were met between MK-1293 and Lantus for comparison of PK (AUC0-24 and Cmax of M1) and PD (GIR-AUC0-24 , GIR-AUC0-12 , GIR-AUC12-24 , and GIRmax ) primary endpoints. All treatments were well tolerated. CONCLUSION: Based on comparative assessment in both T1D and healthy subjects, it can be concluded that the PK and PD properties of MK-1293 are highly similar to those of Lantus. (ClinicalTrials.gov: NCT02059174).

Novel fusion of GLP-1 with a domain antibody to serum albumin prolongs protection against myocardial ischemia/reperfusion injury in the rat.

BACKGROUND: Glucagon-like peptide-1 (GLP-1) and its mimetics reduce infarct size in the setting of acute myocardial ischemia/reperfusion (I/R) injury. However, the short serum half-life of GLP-1 and its mimetics may limit their therapeutic use in acute myocardial ischemia. Domain antibodies to serum albumin (AlbudAbs) have been developed to extend the serum half-life of short lived therapeutic proteins, peptides and small molecules. In this study, we compared the effect of a long acting GLP-1 agonist, DPP-IV resistant GLP-1 (7-36, A8G) fused to an AlbudAb (GAlbudAb), with the effect of the GLP-1 mimetic, exendin-4 (short half-life GLP-1 agonist) on infarct size following acute myocardial I/R injury. METHODS: Male Sprague-Dawley rats (8-week-old) were treated with vehicle, GAlbudAb or exendin-4. Myocardial ischemia was induced 2 h following the final dose for GAlbudAb and 30 min post the final dose for exendin-4. In a subgroup of animals, the final dose of exendin-4 was administered (1 µg/kg, SC, bid for 2 days) 6 h prior to myocardial ischemia when plasma exendin-4 was at its minimum concentration (C(min)). Myocardial infarct size, area at risk and cardiac function were determined 24 h after myocardial I/R injury. RESULTS: GAlbudAb and exendin-4 significantly reduced myocardial infarct size by 28% and 23% respectively, compared to vehicle (both p < 0.01 vs. vehicle) after I/R injury. Moreover, both GAlbudAb and exendin-4 markedly improved post-ischemic cardiac contractile function. Body weight loss and reduced food intake consistent with the activation of GLP-1 receptors was observed in all treatment groups. However, exendin-4 failed to reduce infarct size when administered 6 h prior to myocardial ischemia, suggesting continuous activation of the GLP-1 receptors is needed for cardioprotection. CONCLUSIONS: Cardioprotection provided by GAlbudAb, a long acting GLP-1 mimetic, following myocardial I/R injury was comparable in magnitude, but more sustained in duration than that produced by short-acting exendin-4. Very low plasma concentrations of exendin-4 failed to protect the heart from myocardial I/R injury, suggesting that sustained GLP-1 receptor activation plays an important role in providing cardioprotection in the setting of acute myocardial I/R injury. Long-acting GLP-1 agonists such as GAlbudAb may warrant additional evaluation as novel therapeutic agents to reduce myocardial I/R injury during acute coronary syndrome.

Safety, tolerability, pharmacokinetics and pharmacodynamics of losmapimod following a single intravenous or oral dose in healthy volunteers.

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.

Efficacy and safety of itacitinib versus placebo in combination with corticosteroids for initial treatment of acute graft-versus-host disease (GRAVITAS-301): a randomised, multicentre, double-blind, phase 3 trial.

BACKGROUND: Acute graft-versus-host disease (GVHD) is a common and life-threatening complication of allogeneic haematopoietic stem cell transplantation (HSCT); there is an urgent unmet need for effective therapies. We aimed to evaluate the Janus kinase 1 inhibitor itacitinib versus placebo, both in combination with corticosteroids, for initial treatment of acute GVHD. METHODS: GRAVITAS-301 was an international, double-blind, adaptive (group sequential design) phase 3 study conducted at 129 hospitals and community practices in 19 countries. Eligible patients were aged 18 years or older, had previously received allogeneic HSCT for a haematological malignancy, developed grades II-IV acute GVHD, and received up to 2 days of systemic corticosteroids. Patients were stratified by clinical standard-risk or high-risk acute GVHD and randomly assigned (1:1), via a centralised interactive voice response system, to receive either oral itacitinib (200 mg) or placebo once daily, both in addition to corticosteroids. The primary endpoint was overall response rate (ORR) at day 28 (defined as the proportion of patients with complete response, very good partial response, or partial response 28 days after the start of treatment). For sample size determination, an absolute improvement in ORR at day 28 over standard therapy of 16% was considered clinically meaningful. Efficacy analyses were performed in the intention-to-treat population; safety analyses included patients who received at least one dose of study drug. GRAVITAS-301 is registered with ClinicalTrials.gov (NCT03139604) and is complete. FINDINGS: Between July 19, 2017, and Oct 3, 2019, 439 patients were randomly assigned to receive either itacitinib plus corticosteroids (n=219; itacitinib group) or placebo plus corticosteroids (n=220; placebo group). 173 (39%) patients were female and 390 (89%) were White. At baseline, 107 (24%) of 439 patients (itacitinib 51 [23%] of 219; placebo 56 [25%] of 220) had clinical high-risk acute GVHD. The ORR at day 28 was 74% (95% CI 67·6-79·7; 162 of 219; complete response 53% [116 of 219]) for itacitinib and 66% (59·7-72·6; 146 of 220; complete response, 40% [89 of 220]) for placebo (odds ratio for ORR 1·45, 95% CI 0·96-2·20; two-sided p=0·078). Grade 3 or worse adverse events occurred in 185 (86%) of 215 itacitinib recipients and 178 (82%) of 216 placebo recipients, and most commonly included thrombocytopenia or platelet count decreased (78 [36%] vs 68 [31%]), neutropenia or neutrophil count decreased (49 [23%] vs 45 [21%]), anaemia (42 [20%] vs 26 [12%]), and hyperglycaemia (26 [12%] vs 28 [13%]). Treatment-related deaths occurred in three of 215 patients (1%) in the itacitinib group and four of 216 (2%) in the placebo group. INTERPRETATION: The observed improvement in ORR at day 28 with the addition of itacitinib versus placebo to corticosteroids did not reach the prespecified significance level. Further studies might provide additional insight into the utility of selective JAK1 inhibition for the treatment of acute GVHD. FUNDING: Incyte.

FondaKIDS: a prospective pharmacokinetic and safety study of fondaparinux in children between 1 and 18 years of age.

BACKGROUND: 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. PROCEDURE: The purpose of the study was to determine the dosing, pharmacokinetics, and safety of fondaparinux in children with deep vein thrombosis (DVT) or heparin-induced thrombocytopenia (HIT). Hospitalized children between 1 and 18 years of age with DVT or HIT received fondaparinux 0.1 mg/kg once daily. Fondaparinux-based anti-factor Xa levels were assessed at 2, 4, 12, and 24 hr following the first dose, and peak levels were measured twice weekly thereafter. Detailed pharmacokinetic analyses were performed. RESULTS: Twenty four subjects in 3 age cohorts were enrolled and completed the study. Pharmacokinetic modeling demonstrated that a once-daily dose of fondaparinux at 0.1 mg/kg resulted in similar concentrations known to be efficacious in adults. Safety was demonstrated with only two bleeding events: one which may have pre-dated study drug administration and one which led only to temporary discontinuation of study drug. CONCLUSION: Dosing of fondaparinux at 0.1 mg/kg once daily in children resulted in PK profiles comparable to those in adults receiving standard dosing. Fondaparinux can be considered an attractive alternative to LMWH given its once-daily dosing, acceptable safety data, and other favorable properties.

Race and Drug Toxicity: A Study of Three Cardiovascular Drugs with Strong Pharmacogenetic Recommendations.

The Clinical Pharmacogenetics Implementation Consortium (CPIC®) establishes evidence-based guidelines for utilizing pharmacogenetic information for certain priority drugs. Warfarin, clopidogrel and simvastatin are cardiovascular drugs that carry strong prescribing guidance by CPIC. The respective pharmacogenes for each of these drugs exhibit considerable variability amongst different ethnic/ancestral/racial populations. Race and ethnicity are commonly employed as surrogate biomarkers in clinical practice and can be found in many prescribing guidelines. This is controversial due to the large variability that exists amongst different racial/ethnic groups, lack of detailed ethnic information and the broad geographic categorization of racial groups. Using a retrospective analysis of electronic health records (EHR), we sought to determine the degree to which self-reported race/ethnicity contributed to the probability of adverse drug reactions for these drugs. All models used individuals self-reporting as White as the comparison group. The majority of apparent associations between different racial groups and drug toxicity observed in the "race only" model failed to remain significant when we corrected for covariates. We did observe self-identified Asian race as a significant predictor (p = 0.016) for warfarin hemorrhagic events in all models. In addition, patients identifying as either Black/African-American (p = 0.001) or Other/Multiple race (p = 0.019) had a lower probability of reporting an adverse reaction than White individuals while on simvastatin even after correcting for other covariates. In both instances where race/ethnicity was predictive of drug toxicity (i.e., warfarin, simvastatin), the findings are consistent with the known global variability in the pharmacogenes described in the CPIC guidelines for these medications. These results confirm that the reliability of using self-identified race/ethnic information extracted from EHRs as a predictor of adverse drug reactions is likely limited to situations where the genes influencing drug toxicity display large, distinct ethnogeographic variability.

Effect of Hepatic Impairment on the Pharmacokinetics of Itacitinib.

Itacitinib is a potent, selective JAK-1 inhibitor currently in development for the treatment of chronic graft-vs-host-disease in combination with corticosteroids. Itacitinib is primarily eliminated via cytochrome P450 3A metabolism with minimal renal elimination. The purpose of this open-label study was to investigate the effect of hepatic impairment, as determined by Child-Pugh grade, on itacitinib pharmacokinetics. All participants received a single 300-mg dose of itacitinib orally in the fasted state. Blood samples were collected serially through 96 hours after dosing; 4 hours after dosing, an additional sample was collected for protein binding determination. Participants with moderate hepatic impairment (N = 8) had an approximate 2.5-fold increase in total exposure (area under the plasma concentration-time curve from time 0 to infinity [AUC0-∞ ]) and an approximate 2-fold increase in maximal exposure (Cmax ) compared to those with normal hepatic function (N = 8) (geometric mean ratio, 2.51 [90% confidence interval (CI), 1.54-4.08] for AUC0-∞ and 1.95 [90%CI, 1.14-3.35] for Cmax ). Participants with severe hepatic impairment (N = 6) had an approximate 4-fold increase in total exposure (AUC0-∞ ) and an approximate 3.5-fold increase in maximal exposure compared to participants with normal hepatic function (geometric mean ratio, 4.08 [90%CI, 2.41-6.89] for AUC0-∞ and 3.48 [90%CI, 1.94-6.23] for Cmax ). Protein binding was similar between participants with moderate or severe hepatic impairment and participants with normal hepatic function, with average unbound fractions (percent free) of 25.7%, 31.5%, and 25.6%, respectively. There were no serious or fatal treatment-related adverse events. The results of this study combined with exposure, efficacy, and safety data from the pivotal study in the relevant patient population will inform final dosing recommendations.

Differences in the Platelet mRNA Landscape Portend Racial Disparities in Platelet Function and Suggest Novel Therapeutic Targets.

The African American (AA) population displays a 1.6 to 3-fold higher incidence of thrombosis and stroke mortality compared with European Americans (EAs). Current antiplatelet therapies target the ADP-mediated signaling pathway, which displays significant pharmacogenetic variation for platelet reactivity. The focus of this study was to define underlying population differences in platelet function in an effort to identify novel molecular targets for future antiplatelet therapy. We performed deep coverage RNA-Seq to compare gene expression levels in platelets derived from a cohort of healthy volunteers defined by ancestry determination. We identified > 13,000 expressed platelet genes of which 480 were significantly differentially expressed genes (DEGs) between AAs and EAs. DEGs encoding proteins known or predicted to modulate platelet aggregation, morphology, or platelet count were upregulated in AA platelets. Numerous G-protein coupled receptors, ion channels, and pro-inflammatory cytokines not previously associated with platelet function were likewise differentially expressed. Many of the signaling proteins represent potential pharmacologic targets of intervention. Notably, we confirmed the differential expression of cytokines IL32 and PROK2 in an independent cohort by quantitative real-time polymerase chain reaction, and provide functional validation of the opposing actions of these two cytokines on collagen-induced AA platelet aggregation. Using Genotype-Tissue Expression whole blood data, we identified 516 expression quantitative trait locuses with Fst values > 0.25, suggesting that population-differentiated alleles may contribute to differences in gene expression. This study identifies gene expression differences at the population level that may affect platelet function and serve as potential biomarkers to identify cardiovascular disease risk. Additionally, our analysis uncovers candidate novel druggable targets for future antiplatelet therapies.

Evaluation of Clinical Cardiac Safety of Itacitinib, a JAK1 Inhibitor, in Healthy Participants.

Itacitinib is a JAK1-selective inhibitor in phase 3 development in graft-versus-host disease. A post hoc electrocardiogram (ECG) analysis and a plasma concentration-QTc (C-QTc) analysis were performed to assess cardiac safety using data from the first-in-human itacitinib study. The study included 2 cohorts of 12 healthy participants each in an interleaving dosing design with single doses of 10-300 mg or placebo; 500 and 1000 mg doses were subsequently added with 12 participants randomized to itacitinib or placebo. Continuous Holter recordings were collected from 1 hour predose to 8 hours postdose on each dosing day, and ECG intervals were blindly extracted to match timed pharmacokinetic samples. Data showed no hysteresis, and a prespecified linear mixed-effects C-QTc model was used with change-from-baseline QTcF (QT interval corrected for heart rate by Fridericia's method) as the dependent variable, plasma itacitinib concentrations and centered baseline QTcF as continuous covariates, treatment and time as categorical factors, and a random intercept per participant. The estimated slope of the C-QTc relationship was not significantly different from zero: 0.0002 milliseconds per nM (90%CI, -0.00019 to 0.00054 milliseconds). No clinically meaningful effects on cardiac conduction (PR and QRS intervals) or any categorical PR or QRS outliers were observed. A QTc effect exceeding the threshold of concern (10 milliseconds) can be excluded for itacitinib plasma concentrations up to ∼13 000 nM (∼7200 ng/mL), which is well above the maximum concentration expected with the highest proposed therapeutic dose of itacitinib either with concomitant use of cytochrome P450 3A4 inhibitors or in patients with impaired hepatic function.

The Effect of Renal Impairment on the Pharmacokinetics and Safety of Itacitinib.

Itacitinib is a novel, selective, Janus kinase 1 inhibitor in development for treatment of graft-versus-host disease. The objective of this study was to assess pharmacokinetics and safety of 300-mg itacitinib dosed in participants with normal renal function (n = 10), severe renal impairment (n = 8), and end-stage renal disease (ESRD) on hemodialysis (n = 8). Serial plasma and urine samples (urine from normal and severe groups only) were collected before dosing until 72 hours after dosing. In the ESRD group, itacitinib was evaluated in 2 periods, when dosed before (period 1) and after (period 2) a hemodialysis session. Geometric mean ratios (90% confidence interval) in participants with severe renal impairment, ESRD period 1 and ESRD period 2 relative to participants with normal renal function were 1.65 (1.13-2.39), 0.71 (0.49-1.03), and 0.83 (0.57-1.20) for maximum plasma drug concentration and 2.23 (1.56-3.18), 0.81 (0.57-1.16), and 0.95 (0.66-1.35) for area under the plasma concentration-time curve from time zero to infinity. Itacitinib was well tolerated, and 3 grade 1 treatment-emergent adverse events were reported over the course of the study. Given the magnitude of exposure changes in participants with severe renal impairment or ESRD and the historic risk-benefit profile, no dose adjustment is recommended for itacitinib in patients with impaired renal function, although the final dosage recommendation will be based on cumulative pharmacokinetics and safety from this study and from the pivotal graft-versus-host disease trial. Additionally, itacitinib may be administered to patients undergoing dialysis regardless of the time of dialysis.

Soft-tissue penetration of ceftobiprole in healthy volunteers determined by in vivo microdialysis.

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, ceftobiprole's 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 (fAUC(muscle)/fAUC(plasma) of 0.69 +/- 0.13) and s.c. adipose tissue (fAUC(s.c.adipose)/fAUC(plasma) 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.

Pharmacokinetic-pharmacodynamic modeling of the in vitro activities of oxazolidinone antimicrobial agents against methicillin-resistant Staphylococcus aureus.

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 microg/ml (MIC, 0.5 microg/ml) and 0.25 to 16 microg/ml (MIC, 1 microg/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 microg/ml) than for linezolid (1.39 microg/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.

PK/PD: new insights for antibacterial and antiviral applications.

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.

Effect of Itraconazole or Rifampin on Itacitinib Pharmacokinetics When Administered Orally in Healthy Subjects.

Itacitinib is a potent, selective JAK-1 inhibitor currently in phase 3 development for the treatment of acute and chronic graft-versus-host disease (GVHD) in combination with corticosteroids. Itacitinib is primarily eliminated via metabolism by cytochrome P-450 (CYP)3A4 with minimal renal elimination. A drug-drug interaction study was conducted to evaluate the impact of the strong CYP3A inhibitor itraconazole or the strong CYP3A4 inducer rifampin on the pharmacokinetics of itacitinib in healthy volunteers. In cohort 1, subjects received 200 mg sustained release (SR) tablets of itacitinib on days 1 and 6 and 200 mg itraconazole on days 2-7. In cohort 2, subjects received 200 mg SR itacitinib on days 1 and 9 and 600 mg rifampin on days 2-9. Thirty-six subjects were enrolled, 18 in each cohort with 17 completing itacitinib dosing in cohort 1 and 15 completing itacitinib dosing in cohort 2. Coadministration of itraconazole with itacitinib resulted in a nearly 5-fold increase in area under the concentration-time curve (AUC0-∞ ) (geometric mean ratio [GMR] 4.88, 90%Cl 4.17-5.72) and an ∼3-fold increase in peak concentration (Cmax ) (GMR 3.15, 90%Cl 2.58-3.54). Coadministration of rifampin with itacitinib resulted in a nearly 80% decrease in AUC0-∞ (GMR 0.208, 90%Cl 0.173, 0.249) and Cmax (GMR 0.231, 90%Cl 0.195, 0.274). Results of this study informed the study design of the phase 3 GVHD protocols with regard to coadministration of strong CYP3A inhibitors and CYP3A4 inducers. These data combined with phase 3 data will inform final dosing recommendations.

No Pharmacokinetic Interactions Between Elbasvir or Grazoprevir and Buprenorphine/Naloxone in Healthy Participants and Participants Receiving Stable Opioid Agonist Therapy.

The aims of these phase I trials were to evaluate the pharmacokinetic interaction between elbasvir (EBR) or grazoprevir (GZR) and buprenorphine/naloxone (BUP/NAL). Trial 1 was a single-dose trial in healthy participants. Trial 2 was a multiple-dose trial in participants on BUP/NAL maintenance therapy. Coadministration of EBR or GZR with BUP/NAL had minimal effect on the pharmacokinetics of BUP/NAL, EBR, and GZR. The geometric mean ratios (GMRs (90% CI)) for BUP, norbuprenorphine, and NAL AUC0-∞ were 0.98 (0.89-1.08), 0.97 (0.86-1.09), and 0.88 (0.78-1.00) in the presence/absence of EBR; 0.98 (0.81-1.19), 1.13 (0.97-1.32), and 1.10 (0.82-1.47) in the presence/absence of GZR. The GMRs (90% CI) for EBR and GZR AUC0-∞ in the absence/presence of BUP/NAL were 1.22 (0.98-1.52) and 0.86 (0.63-1.18). In conclusion, no dose adjustment for BUP/NAL, EBR, or GZR is required for patients with HCV infection receiving EBR/GZR and BUP/NAL maintenance therapy.

Ceftobiprole medocaril (BAL-5788) for the treatment of complicated skin infections.

INTRODUCTION: With resistance of S. aureus, the most prevalent identified pathogen in skin and soft tissue infections, on the rise, the need for safe, effective, and well-tolerated antibiotics is crucial. Ceftobiprole medocaril (BAL-5788), ceftobiprole's parenteral prodrug, is a bactericidal cephalosporin with broad Gram-positive and Gram-negative activity that has shown to be well-tolerated and noninferior to vancomycin and vancomycin plus ceftazidime in the treatment of MRSA complicated skin and skin structure infections (cSSSIs) in clinical trials. Areas Covered: This article overviews ceftobiprole medocaril's use for cSSSI, with specific focus on clinical efficacy and safety data in addition to summary information on its basic chemistry, microbiological profile, and pharmacokinetic/pharmacodynamic relationships supporting its use in cSSSIs. Information sources include peer-reviewed scientific literature, conference proceedings, publically available regulatory reports, as well as information from the drug sponsor's website. Expert Commentary: With increasing antibiotic resistance, safe, effective antibiotics agents are a welcome sight. There has been clinical evidence in support of using ceftobiprole for treatment of Gram-positive and -negative infections, including MRSA and susceptible P. aeruginosa. This broad antimicrobial activity might allow ceftobiprole to be an alternative to dual therapy combinations when potential drug toxicities, drug-drug or drug-disease interactions are concerns for other agents.

Effects of the Novel Long-Acting GLP-1 Agonist, Albiglutide, on Cardiac Function, Cardiac Metabolism, and Exercise Capacity in Patients With Chronic Heart Failure and Reduced Ejection Fraction.

OBJECTIVES: This study sought to determine if glucagon-like peptide (GLP)-1 ameliorates myocardial metabolic abnormalities in chronic heart failure. BACKGROUND: Albiglutide (GSK716155) is a GLP-1 agonist indicated for type 2 diabetes. METHODS: We performed a randomized, placebo-controlled study evaluating 12 weeks of albiglutide in New York Heart Association II or III subjects with ejection fraction <40%. Subjects received weekly placebo (n = 30) or albiglutide 3.75 mg (n = 12), 15 mg (n = 13), or 30 mg (n = 27). The primary comparison was between albiglutide 30 mg and placebo. Assessments included echocardiography, 6-minute-walk test, and peak oxygen consumption. In a subgroup of patients, myocardial glucose and oxygen use were assessed. Endpoints are reported as change from baseline ± SE. RESULTS: Albiglutide 30 mg compared with placebo did not improve change from baseline in left ventricular ejection fraction (2.4% [1.1%] vs. 4.4% [1.1%]; p = 0.22), 6-min walk test (18 [12] m vs. 9 [11] m; p = 0.58), myocardial glucose use (p = 0.59), or oxygen use (p = 0.25). In contrast, albiglutide 30 mg versus placebo improved change from baseline in peak oxygen consumption (0.9 [0.5] ml/kg/min vs. -0.6 [0.5] ml/kg/min; p = 0.02). Albiglutide was well tolerated. CONCLUSIONS: Although there was no detectable effect of albiglutide on cardiac function or myocardial glucose use, there was a modest increase in peak oxygen consumption, which could have been mediated by noncardiac effects. (A Multi-center, Placebo-controlled Study to Evaluate the Safety of GSK716155 and Its Effects on Myocardial Metabolism, Myocardial Function, and Exercise Capacity in Patients With NYHA Class II/III Congestive Heart Failure; NCT01357850).