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Background and objectives: A quantitative evaluation of the PK of meropenem, a broad-spectrum ��-lactam antibiotic, in plasma and interstitial space fluid (ISF) of subcutaneous adipose tissue of obese patients is lacking as of date. The objective of this study was the characterisation of meropenem population pharmacokinetics in plasma and ISF in obese and non-obese patients for identification of adequate dosing regimens via Monte-Carlo simulations. Methods: We obtained plasma and microdialysate concentrations after administration of meropenem 1000 mg to 15 obese and 15 non-obese surgery patients from a prospective clinical trial. After characterizing plasma- and microdialysis-derived ISF pharmacokinetics via population pharmacokinetic analysis, we simulated thrice-daily (TID) meropenem short-term (0.5 h), prolonged (3.0 h), and continuous infusions. Adequacy of therapy was assessed by the probability of pharmacokinetic/pharmacodynamic (PK/PD) target attainment (PTA) analysis based on time unbound concentrations exceeded minimum inhibitory concentrations (MIC) on treatment day 1 (%fT > MIC) and the sum of PTA weighted by relative frequency of MIC values for infections by pathogens commonly treated with meropenem. To avoid interstitial tissue fluid concentrations below MIC for the entire dosing interval during continuous infusions, a more conservative PK/PD index was selected (%fT > 4 �� MIC). Results: Adjusted body weight (ABW) and calculated creatinine clearance (CLCRCG_ABW) of all patients (body mass index [BMI] = 20.5-81.5 kg/m2) explained a considerable proportion of the between-patient pharmacokinetic variability (15.1-31.0% relative reduction). The ISF:plasma ratio of %fT > MIC was relatively similar for MIC ��� 2 mg/L but decreased for MIC = 8 mg/L over ABW = 60-120 kg (0.50-0.20). Steady-state concentrations were 2.68 times (95% confidence interval [CI] = 2.11-3.37) higher in plasma than in ISF, supporting PK/PD targets related to four times the MIC during continuous infusions to avoid suspected ISF concentrations constantly below the MIC. A 3000 mg/24 h continuous infusion was sufficient at MIC = 2 mg/L for patients with CLCRCG_ABW ��� 100 mL/min and ABW < 90 kg, whereas 2000 mg TID prolonged infusions were adequate for those with CLCRCG_ABW ��� 100 mL/min and ABW > 90 kg. For MIC = 2 mg/L and %fT> MIC = 95, PTA was adequate in patients over the entire investigated range of body mass and renal function using a 6000 mg continuous infusion. A prolonged infusion of meropenem 2000 mg TID was sufficient for MIC ��� 8 mg/L and all investigated ABW and CLCRCG_ABW when employing the PK/PD target %fT > MIC = 40. Short-term infusions of 1000 mg TID were sufficient for CLCRCG_ABW ��� 130 mL/min and distributions of MIC values for Escherichia coli, Citrobacter freundii, and Klebsiella pneumoniae but not for Pseudomonas aeruginosa. Conclusions: This analysis indicated a need for higher doses (��� 2000 mg) and prolonged infusions (��� 3 h) for obese and non-obese patients at MIC ��� 2 mg/L. Higher PTA was achieved with prolonged infusions in obese patients and with continuous infusions in non-obese patients.

The pharma industry designs increasingly less cytochrome P450 dependent and more metabolically stable drugs, and consequently UGT-metabolism becomes more frequently involved. This study compares 2 glucuronidation RAF-scaling approaches, product formation and substrate depletion, regarding their potential for prediction of in vivo DDI and the relative contribution of UGT-mediated phase II reactions in an industrial setting. RAFs were developed for UGT1A1, 1A3, 1A4, 1A6, 1A9, 2B7 and 2B15 recombinant UGT isoforms and a large 150-donor pooled human liver microsome batch. The RAF-values ranged from small values of 0.06 (UGT1A3), over 0.24 and 0.48 (UGT1A9 and UGT1A4), to values around 1 (1.11 for UGT2B7, 1.14 for UGT1A1), and high RAFs of 4.8 (UGT1A6) and 6.57 (UGT2B15). Both approaches identified the same primarily involved isoforms (≥75% relative contribution) of 5 clinical reference compounds (raloxifene, haloperidol, laropiprant, telmisartan and naloxone), in concordance with reported in vitro (R2 = 0.65) and clinical results for UGT1A1, 1A3, 1A4, 1A9, 2B7 and 2B15. This study is distinctive in that it is reporting the glucuronide formation in addition to substrate depletion. The product formation approach proved more sensitive and enables UGT phenotyping of slowly metabolized drugs, additionally it allows identification of structurally different glucuronides.

Aims: The most suitable method for predicting the glomerular filtration rate (GFR) in obesity is currently debated. Therefore, multiple GFR/creatinine clearance prediction methods were applied to (morbidly) obese and nonobese patients ranging from moderate renal impairment to glomerular hyperfiltration and their predictions were rated based on observed fosfomycin pharmacokinetics, as this model drug is exclusively eliminated via glomerular filtration. Methods: The GFR/creatinine clearance predictions via the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI), Modification of Diet in Renal Disease (MDRD; indexed and de-indexed by body surface area) and creatinine clearance via the Cockcroft–Gault formula (CLCRCG) using different body size descriptors were compared to the fosfomycin clearance (CLFOF) from 30 surgical patients (body mass index = 20.1–52.0 kg m−2), receiving 8000 mg as intravenous infusion. Results: The concordance between CLFOF and creatinine clearance predictions was highest for CLCRCG employing either ideal body weight or adjusted body weight (if body mass >1.3 ideal body weight; CLCRCG_ABW-Schwartz, concordance-correlation coefficient [95% confidence interval] = 0.474 [0.156; 0.703], CCC) and GFR predictions via the de-indexed MDRD equation (concordance-correlation coefficient = 0.452 [0.137; 0.685]). The proportion of predicted GFR values within ±30% of the observed CLFOF (P30 = 72.3–76.7%) was only marginally lower than the reported P30 in the original CKD-EPI and MDRD publications (P30 = 84.1–90.0%). Conclusion: This analysis represents a successful proof-of-concept for evaluating GFR/creatinine clearance prediction methods: Across all body mass index classes CLCRCG_ABW-Schwartz or the de-indexed MDRD were most suitable for predicting creatinine clearance/GFR also in (morbidly) obese, CKD stage

Aims To quantitatively compare pharmacokinetics (PK) and the exposure-response (ER) relationship of the sodium-glucose cotransporter-2 inhibitor, dapagliflozin, between adolescents/young adults and adults with type 1 diabetes mellitus (T1DM). Methods Data from 2 clinical studies for dapagliflozin were analysed using a non-linear mixed-effects approach. The PK and the relationship between dapagliflozin exposure and response (24-hour urinary glucose excretion) were characterized. PK was evaluated using a 2-compartment model with first-order absorption while the exposure response-relationship was analysed using a sigmoidal maximal-effect model. The 24-hour median blood glucose, estimated glomerular filtration rate (eGFR), sex, age and body weight were evaluated as covariates. Results A 2-compartment model with first order absorption provided a reasonable fit to the dapagliflozin PK data. Body weight was found to be a significant covariate on dapagliflozin exposure. The ER relationship was best described by a sigmoidal maximal effect model with 24-hour median blood glucose and eGFR as significant covariates on maximal effect. In accordance with the observed data, model-predicted urinary glucose excretion response following 10 mg dapagliflozin dose was higher in the study in adolescents/young adults (138.0 g/24 h) compared to adults (70.5 g/24 h) with T1DM. This is linked to higher eGFR and 24-hour median blood glucose in this trial. Conclusions Dapagliflozin PK and ER relationship were similar in the 2 analysed studies after accounting for covariate effects. These results suggest that no dose adjustment is required for adolescent patients with T1DM.

Precision dosing of piperacillin/tazobactam in obese patients is compromised by sparse information on target-site exposure. We aimed to evaluate the appropriateness of current and alternative piperacillin/tazobactam dosages in obese and nonobese patients. Based on a prospective, controlled clinical trial in 30 surgery patients (15 obese/15 nonobese, 0.5-h infusion of 4 g/0.5 g piperacillin/tazobactam), piperacillin pharmacokinetics were characterized in plasma and at target-site (interstitial fluid of subcutaneous adipose tissue) via population analysis. Thereafter, multiple 3–4-times daily piperacillin/tazobactam short-term/prolonged (recommended by EUCAST) and continuous infusions were evaluated by simulation. Adequacy of therapy was assessed by probability of pharmacokinetic/pharmacodynamic target-attainment (PTA ≥ 90%) based on time unbound piperacillin concentrations exceed the minimum inhibitory concentration (MIC) during 24 h (%fT&gt, MIC). Lower piperacillin target-site maximum concentrations in obese versus nonobese patients were explained by the impact of lean (approximately two thirds) and fat body mass (approximately one third) on volume of distribution. Simulated steady-state concentrations were 1.43-times, 95%CI = (1.27, 1.61), higher in plasma versus target-site, supporting targets of %fT&gt, 2×MIC instead of %fT&gt, 4×MIC during continuous infusion to avoid target-site concentrations constantly below MIC. In all obesity and renally impairment/hyperfiltration stages, at MIC = 16 mg/L, adequate PTA required prolonged (thrice-daily 4 g/0.5 g over 3.0 h at %fT&gt, MIC = 50) or continuous infusions (24 g/3 g over 24 h following loading dose at %fT&gt, MIC = 98) of piperacillin/tazobactam.

Background: This controlled clinical study aimed to investigate the impact of obesity on plasma and tissue pharmacokinetics of meropenem. Methods: Obese (body mass index (BMI) &ge, 35 kg/m2) and age-/sex-matched nonobese (18.5 kg/m2 &ge, BMI &le, 30 kg/m2) surgical patients received a short-term infusion of 1000-mg meropenem. Concentrations were determined via high performance liquid chromatography-ultraviolet (HPLC-UV) in the plasma and microdialysate from the interstitial fluid (ISF) of subcutaneous tissue up to eight h after dosing. An analysis was performed in the plasma and ISF by noncompartmental methods. Results: The maximum plasma concentrations in 15 obese (BMI 49 &plusmn, 11 kg/m2) and 15 nonobese (BMI 24 &plusmn, 2 kg/m2) patients were 54.0 vs. 63.9 mg/L (95% CI for difference: &minus, 18.3 to &minus, 3.5). The volume of distribution was 22.4 vs. 17.6 L, (2.6&ndash, 9.1), but the clearance was comparable (12.5 vs. 11.1 L/h, &minus, 1.4 to 3.1), leading to a longer half-life (1.52 vs. 1.31 h, 0.05&ndash, 0.37) and fairly similar area under the curve (AUC)8h (78.7 vs. 89.2 mg*h/L, &minus, 21.4 to 8.6). In the ISF, the maximum concentrations differed significantly (12.6 vs. 18.6 L, &minus, 16.8 to &minus, 0.8) but not the AUC8h (28.5 vs. 42.0 mg*h/L, &minus, 33.9 to 5.4). Time above the MIC (T &gt, MIC) in the plasma and ISF did not differ significantly for MICs of 0.25&ndash, 8 mg/L. Conclusions: In morbidly obese patients, meropenem has lower maximum concentrations and higher volumes of distribution. However, due to the slightly longer half-life, obesity has no influence on the T &gt, MIC, so dose adjustments for obesity seem unnecessary.

Purpose Systematic comparison of analysis methods of clinical microdialysis data for impact on target-site drug exposure and response. Methods 39 individuals received a 500 mg levofloxacin short-term infusion followed by 24-h dense sampling in plasma and microdialysate collection in interstitial space fluid (ISF). ISF concentrations were leveraged using non-compartmental (NCA) and compartmental analysis (CA) via (ii) relative recovery correction at midpoint of the collection interval (midpoint-NCA, midpoint-CA) and (ii) dialysate-based integrals of time (integral-CA). Exposure and adequacy of community-acquired pneumonia (CAP) therapy via pharmacokinetic/pharmacodynamic target-attainment (PTA) analysis were compared between approaches. Results Individual AUCISF estimates strongly varied for midpoint-NCA and midpoint-CA (≥52.3%CV) versus integral-CA (≤32.9%CV) owing to separation of variability in PK parameters (midpoint-CA = 46.5%–143%CVPK, integral-CA = 26.4%–72.6%CVPK) from recovery-related variability only in integral-CA (41.0%–50.3%CVrecovery). This also led to increased variability of AUCplasma for midpoint-CA (56.0%CV) versus midpoint-NCA and integral-CA (≤33.0%CV), and inaccuracy of predictive model performance of midpoint-CA in plasma (visual predictive check). PTA analysis translated into 33% of evaluated patient cases being at risk of incorrectly rejecting recommended dosing regimens at CAP-related epidemiological cut-off values. Conclusions Integral-CA proved most appropriate to characterise clinical pharmacokinetics- and microdialysis-related variability. Employing this knowledge will improve the understanding of drug target-site PK for therapeutic decision-making.

We theorized that sociocultural contexts characterized by a form of interdependence that emphasizes mutual obligations, emotional positivity, and readily accessible social support from family may maximize the benefits of social support. This form of interdependence characterizes Latino culture and is captured by the cultural value familism. Eighty-six Latino and non-Latino participants completed measures of familism and perceived social support before taking part in a standardized laboratory stress task that elicits cortisol reactivity. Cortisol reactivity is an indicator of bodily response to stress that is linked to vulnerability to the adverse effects that stress can have on future health. As predicted, results revealed a moderated mediation pattern. Conditional process analysis showed that familism was indirectly linked to cortisol reactivity through perceived social support, and this mediation effect was moderated by sociocultural context; stress buffering effects were only observed in the Latino sample. These novel findings highlight the role of culture and, specifically, familism in Latinos, for maximizing the benefits that social support can have for stress physiology implicated in long-term health outcomes.

Exposure to chronic discrimination is associated with increased morbidity and mortality. The study of biobehavioral pathways linking discrimination with health outcomes has mostly focused on the cardiovascular system, with fewer studies addressing the hypothalamus-pituitary-adrenal (HPA) axis. In this study we tested associations between Latino ethnicity, experiences of discrimination, and cortisol responses to an acute laboratory stressor. One hundred fifty eight individuals (92 female, 66 male) between the ages of 18 and 29 years participated in the study. Salivary cortisol was measured once before and eight times after administration of a laboratory stressor (the Trier Social Stress Test). Past experiences of discrimination were measured with the Experiences of Discrimination Scale. Findings from conditional process modeling suggest that Latino ethnicity predicted a) heightened cortisol reactivity and b) more pronounced cortisol recovery through discrimination experiences (mediator), and that this effect was further moderated by sex with a significant indirect effect only among males. The direct path from Latino ethnicity to cortisol reactivity or cortisol recovery was, however, not significant. In sum, findings suggest that Latino ethnicity and discrimination interact to predict cortisol dysregulation, which implies that an appropriate model for understanding minority health discrepancies must incorporate interactive processes and cannot simply rely on the effects of ethnicity or discrimination alone.

Numerous studies suggest that discrimination is associated with poor physical and mental health outcomes. Whereas the cardiovascular system has been extensively studied as a potential pathway linking discrimination with disease, the role of the hypothalamic-pituitary-adrenal (HPA) axis remains understudied. We conducted a systematic review of research on discrimination and related constructs as predictors and correlates of HPA axis activity. Twenty seven studies (10 experimental, 17 observational) met inclusion criteria. Studies suggest that discrimination is associated with alterations in HPA axis activity and that the direction of this association depends on the timing and chronicity of the discrimination experience. There is also evidence of important modulating variables (race, socioeconomic status) and contextual confounders (emotional, situational) that warrant further study. Accounting for the HPA axis in addition to the cardiovascular system will contribute to a more comprehensive understanding of the biobehavioral pathways contributing to physical and mental health inequities related to discrimination.

Objectives The aim was to characterize linezolid population pharmacokinetics in plasma and interstitial space fluid of subcutaneous adipose tissue (target site) of obese compared with non-obese patients and to determine dosing regimens enabling adequate therapy using Monte Carlo simulations. Methods In this prospective, parallel group, open-label, controlled, single-centre trial, 30 surgery patients (15 obese, 15 non-obese) received 600 mg of intravenous linezolid. A population pharmacokinetic analysis characterizing plasma and microdialysis-derived target site pharmacokinetics was followed by Monte Carlo simulations using twice/thrice daily 600–1200 mg short-term and extended infusions of linezolid. Adequacy of therapy was assessed by the probability of pharmacokinetic/pharmacodynamic target attainment for time and exposure-related indices. Results In the model, lean body weight and obesity status largely explained between-patient variability in linezolid PK parameters (12.0–44.9%). Both factors caused lower area under the concentration–time curve in typical obese patients in plasma (–20.4%, 95% CI –22.0% to –15.9%) and at target-site (–37.7%, 95% CI –47.1% to –24.2%) compared with non-obese patients. Probability of target attainment showed improvement with increasing linezolid doses. Depending on lean body weight, adequate therapy was partially attained for 900- and 1200-mg linezolid doses and minimum inhibitory concentrations (MICs) ≤2 mg/L (probability of target attainment 62.5–100%) but could not be reached for MIC = 4 mg/L (probability of target attainment ≤82.3%). Additionally, lower linezolid distribution into the target site in obese patients as described above might compromise the plasma-based probability of target attainment analysis. Discussion This analysis revealed risks of linezolid underdosing in empirical antibiotic therapy of most resistant bacteria for obese and non-obese patients. Doubling the standard dose is associated with adequate probability of target attainment throughout most body masses for MIC ≤2 mg/L. Further clinical studies with adjusted dosing regimens in for example intensive care patients are needed.

Objective Target-site concentrations obtained via the catheter-based minimally invasive microdialysis technique often exhibit high variability. Catheter calibration is commonly performed via retrodialysis, in which a transformation factor, termed relative recovery (RR), is determined. Leveraging RR values from a rich data set of a very large clinical microdialysis study, promised to contribute critical insight into the origin of the reportedly high target-site variability. The present work aimed (i) to quantify and explain variability in RR associated with the patient (including non-obese vs. obese) and the catheter, and (ii) to derive recommendations on the design of future clinical microdialysis studies. Methods A prospective, age- and sex-matched parallel group, single-centre trial in non-obese and obese patients (BMI=18.7-86.9 kg/m2) was performed. 1-3 RR values were obtained in the interstitial fluid of the subcutaneous fat tissue in one catheter per upper arm of 120 patients via the retrodialysis method (nRR=1008) for a panel of drugs (linezolid, meropenem, tigecycline, cefazolin, fosfomycin, piperacillin and acetaminophen). A linear mixed-effects model was developed to quantify the different types of variability in RR and to explore the association between RR and patient body size descriptors. Results Estimated RR was highest for acetaminophen (69.7%, 95%CI=65.0% to 74.3%) and lowest for piperacillin (40.4%, 95%CI=34.6% to 46.0%). The linear mixed-effects modelling analysis showed that variability associated with the patient (σ=15.9%) was the largest contributor (46.7%) to overall variability, whereas the contribution of variability linked to the catheter (σ=5.55%) was ~1/6 (16.8%). The relative contribution of residual unexplained variability (σ=12.0%, including intracatheter variability) was ~1/3 (36.4%). The limits of agreement of repeated RR determinations in a single catheter ranged from 0.694-1.64-fold (linezolid) to 0.510-3.02-fold (cefazolin). Calculated fat mass affected RR, explaining the observed lower RR in obese (ΔRRmean= -29.7% relative reduction) versus non-obese patients (p Conclusions Three recommendations for clinical microdialysis trial design were derived: 1) High interindividual variability underscored the necessity of measuring individual RR per patient. 2) The low relative contribution of intercatheter variability to overall variability indicated that measuring RR with a single catheter per patient is sufficient for reliable catheter calibration. 3) The wide limits of agreement from multiple RR in the same catheter implied an uncertainty of a factor of two in target-site drug concentration estimation necessitating to perform catheter calibration (retrodialysis sampling) multiple times per patient. To allow routine clinical use of microdialysis, research efforts should aim at further understanding and minimising the method-related variability. Optimised study designs in clinical trials will ultimately yield more informative microdialysis data and increase our understanding of this valuable sampling technique to derive target-site drug exposure.

Perinatal depression negatively impacts mother-infant health and well-being. Previous work has linked cortisol reactivity to perinatal depressive symptoms, but moderating effects including social support and neuroticism, have not been studied. Forty-nine pregnant women (9 – 30 weeks’ gestational age; GA) provided saliva samples in response to the Trier Social Stress Test (TSST) and to awakening (cortisol awakening response, CAR), and completed questionnaires on perceived social support, personality, and depressive symptoms. Two hierarchical logistic regressions, one including the TSST response and one including the CAR as predictor variables, suggest that cortisol reactivity, social support from the baby’s father, and neuroticism contribute to depressive symptoms, controlling for GA (both p < .01). Significant statistical interactions among predictors of pregnancy depressive symptoms were, however, only found in the model using the CAR. Findings highlight the importance of considering biopsychosocial interactions in studies predicting perinatal depressive symptoms.

Actuarial violence risk assessments, many of which include the construct of psychopathy, have been shown to be superior to clinical judgment in the prediction of long-term risk of community violence and recidivism. While these instruments initially appeared to provide similarly accurate judgments of risk of institutional aggression, recent research has indicated that such assessments may be less robust in this setting. One explanation may lie in the types of aggression most frequently observed in each setting. Impulsive (or reactive/affective) is the type of physical aggression most commonly exhibited in psychiatric facilities. This research examines the relationship between risk assessments and aggression in an inpatient forensic setting, with such aggression categorized as impulsive, predatory or psychotic aggression. Consistent with previous research, impulsive aggression was the most frequent type observed (58%). Anger (as measured by the Novaco Anger Scale) and clinical issues (as measured by the HCR-20) were most associated with impulsive aggression, with AUC values of .73 and .71 respectively. In contrast, anger and psychopathy (as measured by the PCL-R) were more associated with predatory aggression, with AUC values of .95 and .84 respectively. Psychotic symptoms were highly associated with psychotically motivated aggression (AUC=.90). These results suggest that traditional violence risk assessments may have limited utility in predicting aggression in an institutional setting and that psychiatric symptoms and heightened affect are more relevant. Language: en

Stress-reduction interventions have been linked with enhanced well-being and health. This study examined affect and cortisol in 111 individuals randomly assigned to a single 35-minute guided relaxation or a stress management lecture control group. Positive affect increased more in the relaxation compared to the control group ( F = 6.62, p = .01). Dispositional stress reactivity had a moderating influence ( R2 = .248, p

Neuroticism is the heritable and stable personality trait defined by the tendency to experience negative emotion, be easily stressed, and slow to soothe. Neuroticism poses a risk for poor social and health outcomes that has been identified as a major public health concern. To date, factors that attenuate neuroticism's costs have not been identified. The goal of this work was to test the hypothesis that the costs of neuroticism would be attenuated in sociocultural contexts that emphasize readily accessible social support, emotional positivity, and physical proximity in interdependent relationships. U.S. Latino culture fits these characteristics. Two studies, an online survey study (Study 1) and a laboratory study (Study 2), tested whether three key costs of high neuroticism-less support (Study 1), more distress (Study 2), and blunted cortisol reactivity (Study 2)-would be attenuated in U.S. Latinas relative to non-Latinas of European and East Asian cultural background. Consistent with previous research, neuroticism was associated with less perceived support, more distress, and blunted cortisol reactivity in non-Latina women of European and East Asian cultural background. For Latina women, however, these effects were attenuated. Latina women who were high in neuroticism continued to feel supported, were not as distressed, and their cortisol reactivity was less blunted. The role of sociocultural context for generating a better understanding of personality processes and the social malleability of neuroticism's costs are discussed. © 2014 American Psychological Association.