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Background: In vitro-in vivo extrapolation (IVIVE) of hepatic drug clearance (CL) involves the scaling of hepatic intrinsic clearance (CLint,uH) by functional liver size, which is approximated by total liver volume (LV) as per the convention. However, in most overweight and obese patients, LV includes abnormal liver fat, which is not thought to contribute to drug elimination, thus overestimating drug CL. Therefore, lean liver volume (LLV) might be a more appropriate scaler of CLint,uH. Objective: The objective of this work was to assess the application of LLV in CL extrapolation in overweight and obese patients (BMI>25 kg/m2) using a model drug antipyrine. Methods: Recently, a model to predict LLV from patient sex, weight, and height was developed and evaluated. In order to assess the LLV model’s use in IVIVE, a correlation-based analysis was conducted using antipyrine as an example drug. Results: In the overweight group (BMI >25 kg/m2), LLV could describe 36% of the variation in antipyrine CL (R2 = 0.36), which was >2-fold higher than that was explained by LV (R2 = 0.17). In the normal-weight group (BMI ≤25 kg/m2), the coefficients of determination were 58% (R2 = 0.58) and 43% (R2= 0.43) for LLV and LV, respectively. Conclusion: The analysis indicates that LLV is potentially a more appropriate descriptor of functional liver size than LV, particularly in overweight individuals. Therefore, LLV has a potential application in IVIVE of CL in obesity.

AIMS: The prevalence of vitamin D deficiency is high in children with chronic kidney disease (CKD). However, current dosing recommendations are based on limited pharmacokinetic (PK) data. This study aimed to develop a population PK model of colecalciferol that can be used to optimise colecalciferol dosing in this population.METHODS: Data from 83 children with CKD were used to develop a population PK model using a nonlinear mixed effects modelling approach. Serum creatinine and type of kidney disease (glomerular vs. nonglomerular disease) were investigated as covariates, and optimal dosing was determined based on achieving and maintaining 25-hydroxyvitamin D (25(OH)D) concentration of 30-48 ng/mL.RESULTS: The time course of 25(OH)D concentrations was best described by a 1-compartment model with the addition of a basal concentration parameter to reflect endogenous 25(OH)D production from diet and sun exposure. Colecalciferol showed wide between-subject variability in its PK, with total body weight scaled allometrically the only covariate included in the model. Model-based simulations showed that current dosing recommendations for colecalciferol can be optimised using a weight-based dosing strategy.CONCLUSION: This is the first study to describe the population PK of colecalciferol in children with CKD. PK model informed dosing is expected to improve the attainment of target 25(OH)D concentrations, while minimising the risk of overdosing.

Fat-free mass has gained wide acceptance as a scaler of the maintenance dose rate in obese patients. The choice of fat-free mass as a size scaler for the maintenance dose rate is based on its relationship with drug clearance, on the basis that only lean tissue is sufficiently metabolically active to provide capacity for elimination. For xenobiotics, the majority of biotransformation occurs in the liver and hence fat-free mass is implied to scale linearly with the component of liver that is metabolically active. The liver, like the body, can be assumed to comprise two components, lean mass and fat mass. We expect the lean liver mass (or volume) to be the component that most closely relates to drug clearance. The objective of this study was to investigate the relationship of lean liver volume and fat-free mass. Total liver volume and liver fat volume were measured in 100 Indian adults by computed tomography. Lean liver volume was derived as the difference between the two measurements (as liver volume − liver fat volume). Covariate modelling to describe lean liver volume, using NONMEM version 7.3, involved testing the influence of body weight, sex, body surface area and fat-free mass with or without allometric scaling (by estimating the exponent) and the influence of clinical chemistry variables. The final model did not exclude a linear relationship between lean liver volume and fat-free mass, while allometric scaling by body weight0.75 was also supported by the data. While scaling by fat-free mass, the coefficient of proportionality (i.e. lean liver volume per kg fat-free mass) was higher in female (31.25 mL) than male (25.81 mL) subjects. A model to predict lean liver volume from readily available patient data was developed and evaluated. Fat-free mass plus sex was found to be the best body descriptor to scale lean liver volume. The utility of this model in scaling drug clearance and dose requirements of hepatically cleared drugs needs further exploration.

Background: Emerging safety and efficacy data for rivaroxaban suggest traditional therapy and rivaroxaban are comparable in the morbidly obese. However, real-world data that indicate pharmacokinetic (PK) parameters are comparable at the extremes of body size are lacking. The International Society of Thrombosis and Haemostasis Scientific and Standardisation Committee (ISTH SSC) suggests avoiding the use of direct oral anticoagulants (DOACs) in patients weighing >120 kg or with a body mass index >40 kg/m 2 and gives no recommendation on the use of DOACs in those 120 kg, n = 74 BMI >40 kg/m 2, and n = 30

Schizophrenia is a common disease which is commonly managed using antipsychotic medications (APS). Inadequate response and lack of adherence often prevent optimal therapeutic effectiveness. Monitoring APS concentrations can be useful to help improve outcomes for the patient. The aim of this study was to develop “reference ranges” for oral aripiprazole, olanzapine, and quetiapine to allow clinicians to understand expected variability in patients treated with APS. The reference ranges were constructed to account for different oral doses, sampling times, and variability both between, and within, subjects. Population pharmacokinetic models were used to simulate plasma concentrations over time under different doses and population demographics. The references were validated against external data both numerically and graphically. Reference ranges for oral aripiprazole, olanzapine, and quetiapine were derived and successfully validated against the external data. The 80% reference range for aripiprazole following a 2-mg oral dose was 14.7–41.6 ng/mL 0–4 h post dose and 10.6–37.1 ng/mL 20–24 h post dose. These ranges increased to 221–624 ng/mL 0–4 h post dose following administration of a 30-mg dose, and 159–557 ng/mL 20–24 h post dose. The 80% reference range 0–4 h post dose was 22.5–67.1 ng/mL following a 15-mg dose once daily of oral olanzapine, and 179–768 ng/mL following a 150-mg dose once daily of oral quetiapine. Comparing individual patients’ APS levels with reference ranges, along with a full clinical assessment, could provide important insights to help a clinician optimize APS therapy.

Respiratory syncytial virus (RSV) causes acute lower respiratory tract infections, and is a major cause of hospital admissions and death in young children. Limited treatments currently exist that can prevent or minimise exacerbation of the disease. The aims of this work were: 1) to develop a population pharmacodynamic model to describe RSV kinetics (RSVK) in nasal lavage, 2) evaluate the impact of an investigational fusion inhibitor, JNJ-53718678, on RSVK, and 3) determine the relationship between RSVK and symptoms scores. The best model to fit the RSVK data was a target-cell limited viral kinetics model previously developed for influenza A infections (Baccam et al., 2006), which included a series of compartments for infected, non-producing and infected, and producing cell populations. The model was adapted to account for longer incubation times seen in RSV, by including 4 additional transit compartments, with the virus elimination rate constant and initial number of target cells fixed to literature values to ensure model parameter identifiability. Between-subject variability was included on the infection rate constant and virus production rate constant. The effect of JNJ-53718678 on RSVK was best described by a non-dose dependent transformation of the infectious virions into a non-infectious state, with a proportional odds model successfully describing symptoms scores, using individual model predicted viral loads as predictor.

EssentialsThe optimal dosing strategy of rivaroxaban for patients at the extremes of body weight is not known.A pharmacokinetic study was conducted based in real-world patients in a London teaching hospital.In the cohort of patients studied, weight on its own did not impact significantly on rivaroxaban pharmacokinetics.A larger study with patients in the weight categories of interest from the real-world population is required to further clarify the situation.BackgroundThere is concern amongst clinicians that the fixed dosing strategy of rivaroxaban for the treatment of venous thromboembolism (VTE) might not be optimal in those patients under or overweight.ObjectiveTo develop a pharmacokinetic model for rivaroxaban, based on real-world patients, specifically focusing on the impact of patients’ body weight on rivaroxaban pharmacokinetics.Patients/methodsOne hundred and one patients prescribed rivaroxaban prophylactic or treatment doses for the prevention or treatment of VTE were recruited at a London teaching hospital. Subjects had up to 3 rivaroxaban concentrations measured during a single dosing period (trough, 1 and 3 hours post dose). Population pharmacokinetic analyses was conducted to develop a rivaroxaban model, which was subsequently evaluated.ResultsA one-compartment model with between-subject variability on rivaroxaban clearance and volume of distribution, with a combined (additive and proportional) error model, best fitted the data. Following a full covariate analysis, creatinine clearance on rivaroxaban clearance was found to be the significant covariate impacting on the pharmacokinetic profile of rivaroxaban in the dataset.ConclusionsOur results suggest that the most important covariate impacting on rivaroxaban pharmacokinetics is creatinine clearance and the weight alone has little effect. These findings are in line with previous studies for rivaroxaban. Larger datasets, from real-world patients who are followed longitudinally, should be conducted to provide front-line clinicians with further reassurance when prescribing rivaroxaban for the acute management of VTE.

Schizophrenia is a common disease managed by a range of interventions, with the primary treatment being antipsychotic medications (APS). Inadequate response, lack of adherence, and/or adverse events often prevent optimal therapeutic effects or therapeutic efficiency. Monitoring APS plasma concentrations can be used together with a full clinical evaluation to help improve patient care or offer better treatment options for the patient. To enable interpretation of individual risperidone and paliperidone plasma concentrations, we developed "reference ranges," which consider the expected variability in plasma concentrations between subjects across the population, rather than representing a "therapeutic range" that relates to efficacy and/or safety outcomes. The reference ranges were derived from population pharmacokinetic models, which varied based upon administration route, dose, and time after dose. Good agreement between the proposed reference ranges and external data was obtained through graphical and numerical evaluations, indicating they could be reliably used in clinical practice.

In vitro-in vivo extrapolation (IVIVE) of hepatic drug clearance (The objective of this work was to assess the application ofRecently, a model to predictIn the overweight group (BMI25 kg/m2),The analysis indicates that

PIANO (NCT00665847) investigated etravirine pharmacokinetics, efficacy, and safety in children and adolescents. Treatment-experienced, HIV-1-infected patients (≥6 to

Etravirine is a non-nucleoside reverse transcriptase inhibitor indicated in combination with other antiretrovirals for treatment-experienced HIV patients ≥6 years of age. Etravirine is primarily metabolized by cytochrome P450 (CYP) 2C9, CYP2C19, and CYP3A. This analysis determined the impact of concomitant antiretrovirals and CYP2C9/CYP2C19 phenotype on the pharmacokinetics of etravirine. We used 4728 plasma concentrations from 817 adult subjects collected from four clinical studies to develop the population pharmacokinetic model. The presence of atazanavir/ritonavir, lopinavir/ritonavir, darunavir/ritonavir, tenofovir disoproxil fumarate, or enfuvirtide together with the CYP2C9 and CYP2C19 phenotype and other demographics were evaluated. A one-compartment model with first-order input and a lag-time best described the data. Estimates of apparent total clearance (CL/F), apparent central volume of distribution (V c/F), first-order absorption rate constant (k a), and absorption lag-time were 41.7 L/h, 972 L, 1.16 h, and 1.32 h, respectively. Estimates of between-subject variability on CL/F, V c/F, and relative bioavailability (F) were 39.4 %CV (percentage coefficient of variation), 35.9 %CV and 35.5 %CV, respectively. Between-occasion variability on F was estimated to be 30.0 %CV. CL/F increased non-linearly with body weight and creatinine clearance (CLCR), and also varied based on CYP2C9/CYP2C19 phenotype. In this analysis, body weight, CLCR, and CYP2C9/CYP2C19 phenotype were found to describe some of the variability in CL/F. It was not possible to show an impact of concomitant antiretrovirals on the pharmacokinetics of etravirine for adults predominantly taking coadministered boosted protease inhibitors as a background antiretroviral regimen.

Model based personalised dosing (MBPD) is a sophisticated form of individualised therapy, where a population pharmacokinetic (PK) or pharmacodynamic model is utilised to estimate the dose required to reach a target exposure or effect. The choice of which model to implement in MBPD is a subjective decision. By choosing one model, information from the remaining models is ignored, as well as the rest of the literature base. This manuscript describes a methodology to develop a 'hybrid' model for voriconazole that incorporated information from prior models in a biologically plausible manner. Voriconazole is a triazole antifungal with difficult to predict PK, although it does have a defined exposure-response relationship. Nine population PK models of voriconazole were identified from the literature. The models differed significantly in structural components. The hybrid model contained a two-compartment disposition model with mixed linear and nonlinear time-dependent clearance. The parameters for the hybrid model were determined using simulation techniques. Validation of the hybrid model was assessed via visual predictive checks, which indicated the majority of the variability in the literature models was captured by the hybrid model. The predictive performance was assessed using four different sampling strategies of limited concentrations from ten richly PK sampled subjects to predict future concentrations. Overall, the hybrid model predicted future concentrations with good precision. Further prospective and retrospective validation of the hybrid model is required before it could be used in clinical practice.

Schizophrenia is a common disease, characterized by progressive functional decline exacerbated by psychotic relapses that often result from a lack of full adherence to antipsychotic (APS) medication. Although atypical APS medications do not have clear therapeutic windows, as generally required for therapeutic drug monitoring (TDM), measuring APS plasma levels in the context of a population expected range at the point-of-care (POC) may provide valuable clinical insights for differentiating lack of efficacy from a lack of adherence to medication.

Au-free, Ti/Al/Ta ohmic contact on the AlGaN/AlN/GaN heterostructure using low annealing temperature is studied in this paper. With SiCl4 plasma treatment at the recess-etched contact region, a low contact resistance of 0.52 Ω mm and a low sheet resistance of 373 Ω/sq are achieved after annealing at 550 °C for 30 s. The low annealing temperature also leads to better surface morphology. Furthermore, AlGaN/AlN/GaN high-electron-mobility transistors (HEMTs) are fabricated with the 550 °C, 30 s annealed Ti/Al/Ta ohmic contacts, and a maximum transconductance of 123 mS/mm and a maximum drain current of 510 mA/mm are obtained for a gate length of 4 μm. Based on Silvaco's Atlas device simulation framework, a scaled-down device with a short gate length of 1 μm would produce a maximum drain current density of 815 mA/mm. It indicates that the direct current performance of the HEMTs with the ohmic metal proposed in this work is considerably better than that with Au-based ohmic contact.

Rabeprazole sodium is a proton pump inhibitor used for the treatment of gastroesophageal reflux disease (GERD). The objective of this study was to develop a population pharmacokinetic model for rabeprazole that describes concentration–time data arising from phase I and phase III studies in adult and pediatric subjects, including neonates and preterm infants, and propose dosing recommendations for pediatric subjects aged 1–11 years. A total of 4,417 pharmacokinetic observations from 597 subjects aged 6 days to 55.7 years with body weights of 1.15–100 kg were used to develop the population pharmacokinetic model using non-linear mixed-effects modeling techniques. Weight and age were included in the structural model to describe clearance (CL) and central volume of distribution (V c). Other covariates considered during model development included sex, race, creatinine clearance, hepatic function, formulation, feeding status, and route of administration. The final model was used to determine doses for pediatric subjects aged 1–11 years to achieve a steady-state area under the plasma concentration–time curve across the dose interval of 24 h (AUC24) within the target adult AUC24 range obtained following a rabeprazole 10 mg dose. The best model was a two-compartment disposition model with a sequential zero-order duration of input (Dur), first-order absorption (k a) following a lag time (T lag), with weight and age effects on CL and V c. Formulation type and feeding status described some of the variability in bioavailability and the absorption parameters T lag, Dur, and k a. A dosage regimen of 5 mg once daily for children

The aim of this study was to assess and compare fat content within the liver for normal (body mass index (BMI) < 25 kg/m2), overweight (25-30 kg/m2) and obese (≥ 30 kg/m2) subjects using a noninvasive, non-contrast computed tomography (CT) quantification method. Adult subjects aged 18-60 yrs scheduled to undergo CT examination of the abdominal region were recruited for this study, stratified across BMI categories. Liver volume, fat content, and lean liver volume were determined using CT methods. A total of 100 subjects were recruited, including 30 normal weight, 31 overweight, and 39 obese. Total liver volume increased with BMI, with mean values of 1138 ± 277, 1374 ± 331, and 1766 ± 389 cm3 for the normal, overweight, and obese, respectively (P < 0.001), which was due to an increase in both liver fat content and lean liver volume with BMI. Some obese subjects had no or minimal hepatic fat content. The prevalence of mild fatty liver in this study of 100 subjects was overestimated for all BMI categories using a range of qualitative diagnostic measures, with predicted prevalence of fatty liver in obese subjects ranging from 76.9% for liver-to-spleen ratio ≤ 1.1 to 89.7% for liver attenuation index (liver HU - spleen HU) ≤ 40, compared to 66.7% by quantification of fat content. Results show that total liver volume increases with BMI, however, not all obese subjects display fatty infiltration of the liver. CT quantification of liver fat content may be suitable for accurate diagnosis of hepatic steatosis in clinical practice and assessment of donor livers for transplantation.

Abstract 503 The optimal dosing strategy of low molecular weight heparins (LMWH) for the treatment of antenatal venous thromboembolism (VTE) is not known. The physiological changes associated with pregnancy alter the pharmacokinetic (PK) profile of LMWH, and this has led to controversy and subsequent variation in practice, when pregnant women are managed with LMWH for VTE [Voke et al., 2009]. The perceived impact of these PK changes has led to the Royal College of Obstetrics and Gynaecologists (RCOG) recommending a twice daily dose of LMWH, whilst the American College of Chest Physicians recommend that either a once or twice daily dose of LMWH can be used in this setting. We conducted a population PK modelling study of enoxaparin during pregnancy in order to address this issue. Women requiring antenatal enoxaparin, all indications and doses, referred to the specialist haematology clinic at King's College Hospital, a London teaching hospital, were eligible to enrol in the study. Recruited women were reviewed monthly in clinic during their pregnancy, and had up to three anti-Xa activities (trough, 1 hour post dose, and 3 hours post dose) drawn at each clinic attendance. This anti-Xa sampling strategy was based on d-optimal design, to ensure gestation related changes in enoxaparin clearance (CL) and volume of distribution (Vd) were captured in the PK model developed [van Hasselt et al., 2012]. Women under 18 years of age, those with impaired renal function and those non-adherent to enoxaparin were excluded. Compartmental PK modelling was conducted using non linear mixed effects modelling (NONMEM version 7.2.2). One hundred and twenty three patients contributed 795 anti-Xa activities (712 antenatal, 83 postnatal), for PK modelling purposes. A one compartment model with exponential between subject variability on CL and Vd, with a combined proportional and additive error model best fitted the data, with both enoxaparin CL and Vd found to have increased during pregnancy (table). Enoxaparin PK parameter CL (L/hr) Vd (L) Non-pregnancy (literature values) 0.5-0.7 3-7 Pregnancy (this study) 1.6 13.2 Time dependent changes during pregnancy were found to be significant covariates on both CL and Vd. A full covariate analysis identified weight to be a significant covariate for enoxaparin CL and gestation and baseline lean body weight to be significant covariates for Vd during pregnancy. The final pregnancy enoxaparin PK models for CL and Vd can be represented mathematically as: where Wt is the women's actual weight, GEST is their gestational stage, and LBW is their baseline lean body weight. Goodness of fit plots, a bootstrap analysis and a visual predictive check revealed that a robust enoxaparin model for use in pregnancy had been developed. Simulations of women injecting enoxaparin once versus twice daily demonstrate that both dosing regimens will reach RCOG target 3 hour plasma concentrations throughout the duration of the pregnancy (Figure 1). This should provide confidence to clinicians who prescribe a once daily dose of enoxaparin for the antenatal population. Perhaps the more important concentration to assess however is the trough anti-Xa activity, due to the historical thinking that during pregnancy CL increases, therefore so should the dose/dosing frequency. When the trough activity is simulated, the majority of women on a once daily dose, will have measurable anti-Xa activity; with both once and twice daily regimes demonstrating an increase in trough anti-Xa activity with the progression of pregnancy. This occurs due to the increase in Vd and demonstrates that enoxaparin never reaches a steady state during pregnancy. The measurable trough activity confirms the appropriateness of a once daily dose of enoxaparin in this setting. Our work provides compelling evidence that a once daily dose of enoxaparin for the treatment of antenatal VTE is appropriate. As a result, the current guidelines should be revised. Figure 1: Simulation of 3 hour (red) and trough (blue) anti-Xa activity of women receiving once daily and twice daily treatment doses of enoxaparin during their pregnancy. The solid line is the median concentration and the dashed lines represent the 5th and the 95th percentile concentrations. Grey horizontal lines represent RCOG 3 hour target anti-Xa concentration. Figure 1:. Simulation of 3 hour (red) and trough (blue) anti-Xa activity of women receiving once daily and twice daily treatment doses of enoxaparin during their pregnancy. The solid line is the median concentration and the dashed lines represent the 5th and the 95th percentile concentrations. Grey horizontal lines represent RCOG 3 hour target anti-Xa concentration. Disclosures: Off Label Use: Enoxaparin use during the antenatal period.

Etravirine is currently approved for HIV treatment-experienced patients at a dose of 200 mg twice daily. The long terminal elimination half-life of etravirine should support once-daily dosing.In the double-blind 48-week SENSE trial, 157 antiretroviral treatment-naïve patients were randomly assigned to receive etravirine 400 mg once daily (n = 79) or efavirenz 600 mg once daily (n = 78), plus 2 nucleoside reverse transcriptase inhibitors (NRTIs). Sparse sampling for etravirine plasma concentrations was conducted during the 48-week trial. Area under the curve over the dosing interval (AUC24h) and trough concentration (C0h) were estimated using a population pharmacokinetic model and compared with previous results using the 200-mg twice-daily dosage. The relationship between etravirine AUC24h and C0h with efficacy and safety was also assessed.By week 48, the percentage of patients in the etravirine arm with HIV RNA50 copies/ mL was 75.9% in the intent-to-treat switch equals failure analysis and 92.3% in the on-treatment analysis; no patient developed genotypic or phenotypic resistance to NRTIs or non-nucleoside reverse transcriptase inhibitors (NNRTIs) after virologic failure. Seventy-one subjects had evaluable etravirine pharmacokinetics. The median (interquartile range) of etravirine AUC24h and C0h were 12,447 (8,261-15,652) ng•h/mL and 330 (188-472) ng/mL, respectively. There was no correlation between etravirine exposure and virologic response or adverse events.In the SENSE trial, etravirine 400 mg once daily achieved similar exposures to historical reference data on etravirine when dosed at 200 mg twice daily. There was no apparent relationship between the pharmacokinetics of etravirine and virologic response or adverse events.

Summary. Background: Non-adherence to prescribed medication represents a significant factor associated with treatment failure. Pregnant women identified at risk of venous thromboembolism are increasingly being prescribed low-molecular-weight heparin (LMWH) during pregnancy and the puerperium. It is important to understand women’s views on and adherence to LMWH during pregnancy and the puerperium, so that women gain maximum benefit from the treatment. Objectives: To monitor women’s adherence to enoxaparin, when prescribed during pregnancy and the puerperium, and explore their beliefs about the enoxaparin therapy prescribed. Patients/Methods: A prospective cohort study involving 95 nullparous and multiparous women prescribed enoxaparin for recognized antenatal indications. Adherence to enoxaparin was assessed through self-completion of a diary, additionally verified through laboratory tests. An adapted beliefs about medication questionnaire was administered to women during their pregnancy. Results: Women were highly adherent to enoxaparin: antenatally, mean percentage adherence 97.92%; postnatally, mean percentage adherence 93.37% (paired t-test, P = 0.000). In the cohort of women we followed, their perceived necessity for enoxaparin therapy outweighed any concerns they had regarding enoxaparin antenatally, necessity-concerns differential 2.20. In some women, however, this perceived necessity does decrease postnatally. Conclusions: Our results suggest that most women prescribed enoxaparin are highly adherent to their therapy during the antenatal period and that women’s antenatal beliefs about enoxaparin are able to predict a decrease in postnatal adherence. Our results have important clinical implications, particularly when women are initiated on LMWH just during the postnatal period.

Model Based Personalised Dosing (MBPD) requires a population pharmacokinetic (PK) or pharmacodynamic model to determine the optimal dose of medication for an individual. Often several models are published, and the decision of which model is implemented in MBPD may have a large impact on its clinical utility. As quoted by Box, “all models are wrong, the practical question is how wrong can they be and still be useful”. Voriconzole, a triazole antifungal and the example used in this manuscript, currently has nine population PK models published. To assess the impact of model-misspecification on MBPD, five structurally mis-specified models for voriconazole were developed. Intensive plasma concentrations were simulated for 100 virtual subjects. The dose adjustments required to reach a target exposure were determined by using the empirical Bayes estimates of the PK parameters under each of the mis-specified models. The predicted plasma concentrations and the probability of clinical outcomes, upon following the dose recommendations, were determined. Models that did not contain non-linear clearance performed poorly, with a median dose recommendation 155–310 mg higher than appropriate doses, when only one plasma concentration was available. Removal of body weight and CYP2C9 genotype as covariates had no clinically significant impact on outcomes. In summary, the removal of important structural components, such as non-linear clearance in the case of voriconazole, had a large impact on the clinical utility of MBPD. The removal of patient covariates, even highly influential covariates such as CYP2C9 genotype for voriconazole, had no clinical impact.

A variety of body size covariates have been used in population pharmacokinetic analyses to describe variability in drug clearance (CL), such as total body weight (TBW), body surface area (BSA), lean body weight (LBW) and allometric TBW. There is controversy, however, as to which body size covariate is most suitable for describing CL across the whole population. Given the increasing worldwide prevalence of obesity, it is essential to identify the best size descriptor so that dosing regimens can be developed that are suitable for patients of any size.The aim of this study was to explore the use of body size covariates in population pharmacokinetic analyses for describing CL. In particular, we sought to determine if any body size covariate was preferential to describe CL and quantify its relationship with CL, and also identify study design features that result in the identification of a nonlinear relationship between TBW and CL.Population pharmacokinetic articles were identified from MEDLINE using defined keywords. A database was developed to collect information about study designs, model building and covariate analysis strategies, and final reported models for CL. The success of inclusion for a variety of covariates was determined. A meta-analysis of studies was then performed to determine the average relationship reported between CL and TBW. For each study, CL was calculated across the range of TBW for the study population and normalized to allow comparison between studies. BSA, LBW, and allometric TBW and LBW relationships with exponents of 3/4, 2/3, and estimated values were evaluated to determine the relationship that best described the data overall. Additionally, joint distributions of TBW were compared between studies reporting a 'nonlinear' relationship between CL and TBW (i.e. LBW, BSA and allometric TBW-shaped relationships) and those reporting 'other' relationships (e.g. linear increase in CL with TBW, ideal body weight or height).A total of 458 out of 2384 articles were included in the analysis, from which 484 pharmacokinetic studies were reviewed. Fifty-six percent of all models for CL included body size as a covariate, with 52% of models including a nonlinear relationship between CL and TBW. No single size descriptor was more successful than others for describing CL. LBW with a fixed exponent of 2/3, i.e. (LBW/50.45)(2/3), or estimated exponent of 0.646, i.e. ∼2/3, was found to best describe the average reported relationship between CL and TBW. The success of identifying a nonlinear increase in CL with TBW was found to be higher for those studies that included a wider range of subject TBW.To the best of our knowledge, this is the first study to have performed a meta-analysis of covariate relationships between CL and body size. Although many studies reported a linear relationship between CL and TBW, the average relationship was found to be nonlinear. LBW with an allometric exponent of ∼2/3 may be most suitable for describing an increase in CL with body size as it accounts for both body composition and allometric scaling principles concerning differences in metabolic rates across size.

Enoxaparin is an anticoagulant used in the treatment of thromboembolic diseases. It is a hydrophilic molecule that is, predominantly, eliminated renally with few data to support dosing for subjects with renal impairment and/or obesity. A recently conducted randomized controlled clinical trial compared individualized enoxaparin doses based on lean body weight and renal function to conventional dosing. During this trial, anti-Xa concentrations were collected using a sparse sampling design and a population pharmacokinetic model was developed to describe the data. The current study evaluated the ability of the individualized dose to achieve and maintain anti-Xa concentrations within the therapeutic range (0.5-1.0 IU/mL) in subjects with renal impairment and/or obesity. A matched comparison of the two dosing strategies was undertaken using individual model predicted anti-Xa concentrations generated every 30 minutes to 120 hours post initiation of therapy. Concentration-time curves were generated for each subject and the proportion of time in the therapeutic, supratherapeutic, and subtherapeutic ranges were determined. When compared with conventional dosing, individualized dosing in subjects with renal impairment resulted in a significantly greater proportion of time in the therapeutic range (median [range] = 69.9% (11.3-91.8) versus 42.6% [13.9-71.4], P = 0.02) and a significantly reduced proportion of time in the supratherapeutic range (median [range] = 9.3% (0%-67.0%) versus 37.1% (0%-85.7%), P = 0.02). Although there was a trend toward a greater proportion of time in the therapeutic range in obese subjects, this did not achieve statistical significance. Individualized dosing in subjects with renal impairment is more effective than conventional dosing at achieving and maintaining therapeutic anti-Xa concentrations, which could decrease the risk of bleeding events and mortality in these subjects.

Advances in gallium nitride (GaN) device technology over the last 25 years have enabled commercial radio frequency (RF) applications to benefit from its high-power handling capability and speed. Because of these advances, GaN has emerged as a leading technology for future 4G and 5G communications systems. This presentation will cover GaN device technology starting with the basics of GaN materials and device structures. It will show how the step-function improvement in materials and device capability with GaN translates to step-function advances in system capability. It will then give examples of GaN power amplifier applications for present day 4G wireless communications applications. Along the way, the presentation will address industry progress that has enabled GaN technology to become commercially viable. Finally, the presentation will preview opportunities for GaN technology in future 5G communications applications.

Monoclonal antibodies (mAbs) have complex pharmacology; pharmacokinetics and pharmacodynamics depend on mAb structure and target antigen. mAbs targeting soluble antigens often exhibit linear pharmacokinetic behavior, whereas mAbs targeting cell surface antigens frequently exhibit nonlinear behavior due to receptor-mediated clearance. Where nonlinear kinetics exist, clearance can change due to receptor loss following repeated dosing and/or disease severity. mAb pharmacodynamics are often indirect, with delayed clinically relevant outcomes. This behavior provides challenges during clinical development; studies must be carefully planned to account for complexities specific to each agent. Selection of a starting dose for human studies can be difficult. Species differences in pharmacology need to be considered. Various metrics are available for scaling from animals to humans. Optimal dose selection should ensure uniform mAb exposure across all individuals. Traditional approaches such as flat dosing and variable dosing based upon body surface area or weight should be supported by pharmacokinetic and pharmacodynamic behavior, including target antigen and concurrent disease states. The use of loading doses or dose adjustments to improve clinical response is also a consideration. The evaluation of drug interactions requires innovative designs. Due to the pharmacokinetic properties of mAbs, interacting drugs may need to be administered for protracted periods. Consequently, population pharmacokinetic and pharmacodynamic model-based approaches are often implemented to evaluate mAb drug interactions.

This study explored how study design influences the probability of selecting a 'true' covariate from two competing covariate models. The probability of selecting the 'True Model' (lean body weight on clearance) over the 'False Model' (total body weight (WT) on clearance) was compared for designs where WT was either lognormally distributed (i.e. non-stratified), or stratified into 3 equal strata. The probability of selecting the 'True Model' increased as the WT inclusion criterion widened, and was always greater under the stratified design. Incorporating stratification into study designs, in combination with a wide covariate range, can aid identification of true parameter-covariate relationships. This has particular importance if the model is to be extrapolated beyond the studied population (e.g. dosing in obesity).

The global epidemic of obesity has led to an increased prevalence of chronic diseases and need for pharmacological intervention. However, little is known about the influence of obesity on the drug exposure profile, resulting in few clear dosing guidelines for the obese. Here we present a semi-mechanistic model for lean body weight (LBW) that we believe is sufficiently robust to quantify the influence of body composition on drug clearance, and is therefore an ideal metric for adjusting chronic dosing in the obese.

PIANO (NCT00665847) investigated etravirine pharmacokinetics, efficacy, and safety in children and adolescents. Treatment-experienced, HIV-1-infected patients (≥6 to18 years) received etravirine 5.2 mg/kg twice daily (maximum 200 mg twice daily) plus background antiretrovirals. A population pharmacokinetic model was developed, and etravirine C

Background: AMD3100 is a small-molecule CXCR4 antagonist that has been shown to induce the mobilization of CD34+ hematopoietic progenitor cells from bone marrow to peripheral blood. AMD3100 has also been shown to augment the mobilization of CD34+ cells in cancer patients when administered in combination with granulocyte colony-stimulating factor (G-CSF) (filgrastim). The purpose of this study was to characterize the exposure-response relationship of AMD3100 in mobilizing CD34+ cells when administered as a single agent in healthy volunteers. Methods: AMD3100 concentrations and CD34+ cell counts obtained from 29 healthy subjects in a single-dose, intensively sampled pharmacokinetic/pharmacodynamic (PK-PD) study were analyzed by use of nonlinear mixed effects regression with the software NONMEM. FOCE (first order conditional estimation) with interaction was the estimation method, and simultaneous PK-PD fitting was adopted. Results: The pharmacokinetics of AMD3100 was described by a 2-compartment model with first-order absorption. The population estimates (SE) for clearance and central volume of distribution were 5.17 0.49 L/h and 16.9 3.79 L, respectively. CD34+ cell mobilization was best described by an indirect effect model that stimulates the entry process of CD34+ from bone marrow to peripheral blood in the form of a sigmoid maximum effect model. The population estimates (SE) of maximum effect, concentration causing 50% of maximum response, and equilibration time were 12.6 4.89, 53.6 11.9 g/L, and 5.37 1.31 hours, respectively. Conclusions: This study characterizes the exposure-response relationship of AMD3100 in mobilizing CD34+ cells after subcutaneous administration. This PK-PD model will be useful in assessing relevant covariates and for optimizing the use of AMD3100 in various patient populations.

Background Phase III clinical studies have confirmed that enoxaparin is superior to standard heparin in reducing the rate of recurrent ischaemic events in patients with non-ST elevation acute coronary syndromes. Patients with moderate to severe renal impairment were, however, excluded from these studies. Due to the hydrophilic disposition of enoxaparin, accumulation is likely in patients with renal dysfunction, thereby increasing the risk of haemorrhagic complications if standard weight adjusted treatment doses are used. Arbitrary dose reduction has been reported to increase the risk of ischaemic events, presumably due to inadequate enoxaparin concentrations. Aim The aims of this study were to investigate the influence of glomerular filtration rate (GFR) on the pharmacokinetics of subcutaneously administered enoxaparin, and to develop a practical dosing algorithm in renal impairment that can easily be used at the bedside. Methods Thirty-eight patients, median age 78 years (range 44–87), mean GFR 32 ml min1 (range 16–117) and mean weight 69 kg (range 32–95), presenting with acute coronary syndrome were recruited into the study. Approximately 10 anti-Xa concentrations were taken per patient over their period of therapy. A population pharmacokinetic model was developed using non linear mixed effects modelling techniques, utilizing the software NONMEM. Stochastic simulations were performed to identify the most suitable dosing regimen. Results Three hundred and thirteen anti-Xa concentrations were collected. A two compartment, first order input model was identified as the best baseline model. Covariates found to improve model fitting were GFR as a linear function on clearance (CL) and weight as a linear function on the central volume compartment (Vc). The fraction of drug excreted unchanged (Fu) was estimated at 71%. CL and Vc from the final covariate model were estimated as; CL (l h1) = 0.681 per 4.8 l hr1 (GFR) + 0.229 Vc (l) = 5.22 per 80 kg (total body weight) Conclusions Clearance of enoxaparin was predictably related to GFR estimated using the Cockroft and Gault equation, with ideal body weight used as the size descriptor. According to our model no dosage adjustment from the standard 1.0 mg kg1 12 hourly is required for the first 48 h of treatment. Maintenance doses thereafter can be calculated using standard proportional adjustments based on Fu equal to 0.71.

Background: Metformin is commonly prescribed to treat type 2 diabetes mellitus, however it is associated with the potentially lethal condition of lactic acidosis. Prescribing guidelines have been developed to minimize the risk of lactic acidosis development, although some suggest they are inappropriate and have created confusion amongst prescribers. The aim of this study was to investigate whether metformin dose was influenced by the presence of risk factors for lactic acidosis. Methods: The study was prospective, and retrieved information from patients admitted to hospital who were prescribed metformin at their time of admission. Results: Eighty-three patients were included in the study, 60 of whom had a least one risk factor for lactic acidosis. Of those 60 patients, 78.3% had a dose adjustment, with renal impairment, hepatic impairment, surgery and use of radiological contrast media - the risk factors most likely to result in a dose adjustment. When dose adjustments did occur, metformin was withheld on 88.7% of occasions. Conclusion: Metformin dose was influenced by the presence of risk factors for lactic acidosis, although it was dependent upon the number and particular risk factor/s present.

The prevalence of obesity in the western world is dramatically rising, with many of these individuals requiring therapeutic intervention for a variety of disease states. Despite the growing prevalence of obesity there is a paucity of information describing how doses should be adjusted, or indeed whether they need to be adjusted, in the clinical setting. This review is aimed at identifying which descriptors of body size provide the most information about the relationship between dose and concentration in the obese. The size descriptors, weight, lean body weight, ideal body weight, body surface area, body mass index, fat-free mass, percent ideal body weight, adjusted body weight and predicted normal body weight were considered as potential size descriptors. We conducted an extensive review of the literature to identify studies that have assessed the quantitative relationship between the parameters clearance (CL) and volume of distribution (V) and these descriptors of body size. Surprisingly few studies have addressed the relationship between obesity and CL or V in a quantitative manner. Despite the lack of studies there were consistent findings: (i) most studies found total body weight to be the best descriptor of V. A further analysis of the studies that have addressed V found that total body weight or another descriptor that incorporated fat mass was the preferred descriptor for drugs that have high lipophilicity; (ii) in contrast, CL was best described by lean body mass and no apparent relationship between lipophilicity or clearance mechanism and preference for body size descriptor was found. In conclusion, no single descriptor described the influence of body size on both CL and V equally well. For drugs that are dosed chronically, and therefore CL is of primary concern, dosing for obese patients should not be based on their total weight. If a weight-based dose individualization is required then we would suggest that chronic drug dosing in the obese subject should be based on lean body weight, at least until a more robust size descriptor becomes available.

Aims: Enoxaparin dosing is currently based on total body weight. It is not known how to dose adjust for patients who are overweight or obese. This population pharmacokinetic pharmacodynamic (PKPD) study was undertaken to determine a suitable dosing strategy for such patients. Methods: Patients admitted to the Royal Brisbane Hospital and prescribed enoxaparin as part of their normal care were eligible for inclusion into the study. Approximately three blood samples were taken per patient to determine anti-Xa concentrations. The occurrence of bruising was also recorded. A population pharmacokinetic-pharmacodynamic analysis using NONMEM was undertaken. Simulations were performed using MATLAB. Results: Ninety-six patients were recruited in a prospective study. One-third of patients had a body mass index 30 kg m. A two-compartment linear model with additive error was fitted to the data. A covariate analysis showed clearance was best described by lean body weight and the central volume compartment by total body weight. The probability of bruising using a logistic regression model was best described by C and age. Simulations suggest that patients over 50 years of age whose total body weight is >90 kg, or under 50 years of age whose total body weight is >1.20 kg are likely to have a smoother concentration-time profile and less bruising if a dose of 100 IU kg (1 mg kg) based on lean body weight is administered every 8 h. Conclusions: Dose adjustments of enoxaparin in obese patients are likely to reduce the prevalence of bruising, although prospective validation of this is required.

Resiniferatoxin (RTX) is an analogue of capsaicin with more than 1,000 times its potency in desensitizing C-fiber bladder afferent neurons. This study investigated the safety and efficacy of intravesical RTX in patients with refractory detrusor hyperreflexia (DH).Thirty-six (22 males, 14 females) neurologically impaired patients (20 spinal cord injury, 7 multiple sclerosis, 9 other neurologic diseases) with urodynamically verified DH and intractable urinary symptoms despite previous anticholinergic drug use were treated prospectively with intravesical RTX using dose escalation in a double-blind fashion at 4 centers. Patients received a single instillation of 100 mL of placebo (n = 8 patients) or 0.005, 0.025, 0.05, 0.10, 0.2, 0.5, or 1.0 microM of RTX (n = 4 each group). A visual analog pain scale (VAPS) (0-10; 10 = highest level of pain) was used to quantify discomfort of application. Treatment effect was monitored using a bladder diary and cystometric bladder capacity at weeks 1, 3, 6, and 12 posttreatment.Mean VAPS scores revealed minimal to mild discomfort with values of 2.85 and 2.28 for the 0.5-microM and 1.0-microM RTX treatment groups, respectively. Due to the small sample size, there were no statistically significant changes in mean cystometric capacity (MCC) or incontinence episodes in each treatment dose group. However, at 3 weeks, MCC increased by 53% and 48% for the 0.5-microM and 1.0-microM RTX treatment groups, respectively. Patients in the 0.5-microM and 1.0-microM groups with MCC300 mL at baseline showed greater improvements in MCC at 120.5% and 48%, respectively. In some patients, MCC increased up to 500% over baseline, despite a low RTX dose. Incontinence episodes decreased by 51.9% and 52.7% for the 0.5-microM and 1.0-microM RTX treatment groups, respectively. There were no long-term complications.Intravesical RTX administration, in general, is a well-tolerated new therapy for DH. This patient group was refractory to all previous oral pharmacologic therapy, yet some patients responded with significant improvement in bladder capacity and continence function shortly after RTX administration. Patients at risk for autonomic dysreflexia require careful monitoring during RTX therapy.

See also Liesenfled K-H, Lehr T, Dansirikul C, Reilly PA, Connolly SJ, EzekowitzMD, Yusuf S,Wallentin L, Haertter S, Staab A. Population pharmacokinetic analysis of the oral thrombin inhibitor dabigatran etexilate in patients with non-valvular atrial fibrillation from the RE-LY trial. J Thromb Haemost 2011; 9: 2168–75; and Liesenfeld K-H, Lehr T, Dansirikul C, Reilly PA, Connolly SJ, Ezekowitz MD, Yusuf S, Wallentin L, Haertter S, Staab A. Population pharmacokinetic analysis of the oral thrombin inhibitor dabigatran etexilate in patients with on-valvular atrial fibrillation from the RE-LY trial: reply to a rebuttal. This issue, pp 502–4.

Objectives: To compare variability of blood glucose concentration in patients with type II diabetes with (cases) and without (controls) myocardial infarction. A secondary objective was identification of predictive factors for higher blood glucose on discharge from hospital. Design: A retrospective matched case-control study. Participants: Medical notes of 101 type II diabetic patients admitted with a myocardial infarction (MI) and 101 type II diabetic patients (controls) matched on gender and age with no MI were reviewed. Blood glucose concentrations over two consecutive 48-h periods were collected. Demographic data and therapy on admission/discharge were also collected. Results: Patient characteristics were comparable on recruitment excluding family history of cardiovascular disease (P =0.003), dyslipidaemia (P =0.004) and previous history of MI (P =0.007). Variability of blood glucose in cases was greater over the first 48 h compared with the second 48 h (P =0.03), and greater when compared with controls over the first 48 h (P =0.01). Cases with blood glucose on discharge >8.2 mmol / L (n =45) were less likely to have a history of previous MI (P =0.04), ischaemic heart disease (P =0.03) or hypertension (P =0.02). Conclusions: Type II diabetics with an MI have higher and more variable blood glucose concentrations during the first 48 h of admission. Only cardiovascular 'high risk' patients had target blood glucose set on discharge. The desirability of all MI patients with diabetes, having standardized-glucose infusions to reduce variability of blood glucose, should be evaluated in a randomized controlled trial.

We report the synthesis of grafted polystyrene (PS) films on gold via a surface-initiated polymerization strategy. The polymerization proceeded by a “grafted-from” strategy in which the polystyrene grew by free-radical polymerization from a surface-bound photoinitiator. These experiments exploited the spontaneous formation of alkanethiolate monolayers on gold to immobilize the alkylthiol photoinitiator to the gold substrate. The polymerization was initiated by irradiation with UV light (λ = 300 nm) and resulted in the formation of a PS film. This film was found to be 25−30 nm thick by contact-mode AFM and ellipsometry. Water contact angles, X-ray photoelectron spectroscopy, and reflection−absorption infrared spectroscopy confirmed the monolayer formation and the presence of polystyrene, and all data was consistent with a grafted polymer film.

Background It is well accepted that the gravid state is hypercoagulable and a significant cause of both maternal morbidity and mortality in the Western world. Although thrombin generation is reported to be increased in pregnant women, uncertainty exists on the pattern of thrombin generation change during this time. The aim of this study is to describe thrombin generation changes and D-dimer concentrations in women injecting enoxaparin during pregnancy the postnatal period. Methods One hundred and twenty-three women injecting enoxaparin had their thrombin generation, as measured by Calibrated Automated Thombinography (CAT), repeatedly assayed during pregnancy, once in each trimester, at delivery and 8 weeks post-partum. Furthermore, to understand the impact enoxaparin has on D-dimer concentrations during pregnancy, D-dimer concentrations were measured monthly in the recruited women. Results Thrombin generation was found to increase in the first trimester (mean endogenous thrombin potential (ETP): 1391 nmol/L.min), further increasing during the second trimester (mean ETP: 1757 nmol/L.min), after which it plateaued through to delivery, where it peaked (mean ETP: 1857 nmol/L.min) and then fell back at 8 weeks post-partum (ETP: 1293 nmol/L.min). In contrast D-dimer concentrations increased exponentially during the antenatal period, despite the enoxaparin prescription. Conclusion Our results provide further evidence on alterations of thrombin generation during pregnancy and the postnatal period. Electronic supplementary material The online version of this article (doi:10.1186/s12884-014-0384-0) contains supplementary material, which is available to authorized users.

Bedaquiline is a novel agent for the treatment of pulmonary multidrug-resistant Mycobacterium tuberculosis infections, in combination with other agents. The objective of this study was to develop a population pharmacokinetic (PK) model for bedaquiline to describe the concentration-time data from phase I and II studies in healthy subjects and patients with drug-susceptible or multidrug-resistant tuberculosis (TB). A total of 5,222 PK observations from 480 subjects were used in a nonlinear mixed-effects modeling approach. The PK was described with a 4-compartment disposition model with dual zero-order input (to capture dual peaks observed during absorption) and long terminal half-life ( t 1/2 ). The model included between-subject variability on apparent clearance (CL/F), apparent central volume of distribution ( V c /F), the fraction of dose via the first input, and bioavailability (F). Bedaquiline was widely distributed, with apparent volume at steady state of >10,000 liters and low clearance. The long terminal t 1/2 was likely due to redistribution from the tissue compartments. The final covariate model adequately described the data and had good simulation characteristics. The CL/F was found to be 52.0% higher for subjects of black race than that for subjects of other races, and V c /F was 15.7% lower for females than that for males, although their effects on bedaquiline exposure were not considered to be clinically relevant. Small differences in F and CL/F were observed between the studies. The residual unexplained variability was 20.6% and was higher (27.7%) for long-term phase II studies.

The key purpose of performing pharmacometric research is to aid optimization of drug dosing strategies. The statistical techniques required for this research are advanced, which can make interpretation of results difficult to convey to the target audience if they are unfamiliar with pharmacometric concepts. This article provides a basic guide for authors who wish to publish pharmacometric analyses in peer-reviewed journals. This guide is intended to enhance the readability, reproducibility and understanding of the work for a general readership, which may include clinicians, pharmacists and pharmacometricians. Presentation techniques and examples are offered, as well as a checklist of suggested contents for the manuscript.

Aim: To evaluate the efficacy of oral menadiol compared to intravenous phytomenadione when correcting coagulopathies associated with cholestasis. Methods: A total of 26 patients with cholestasis and an international normalized ratio (prothrombin time) greater than 1.2, were randomized to receive either 20 mg o.d. for 3 days of oral menadiol (n=12), or 10 mg o.d. of intravenous phytomenadione (n=14) prior to endoscopic retrograde cholangeopancreatography. Liver function tests and international normalized ratio were measured daily for 3 days. Results: Liver function tests and international normalized ratio were comparable between groups at entry into the study (P > 0.05), but serum albumin was significantly lower in the intravenous phytomenadione group following treatment (P

Purpose: We determine the long-term efficacy and safety of the UroLume stent as minimally invasive treatment for external detrusor-sphincter dyssynergia in spinal cord injured men.Materials and Methods: A total of 160 spinal cord injured men with a mean age plus or minus standard deviation of 36.3 +/− 12.1 years (range 16 to 74) were prospectively treated with an endoprosthesis at 15 centers as part of the North American UroLume trial for external detrusor-sphincter dyssynergia. Urodynamic parameters, including voiding pressure, residual urine volume and bladder capacity, were compared before treatment and at 1, 2, 3, 4 and 5 years after treatment.Results: Mean voiding pressure was 75.1 +/− 28.2 cm. water before treatment in the 160 patients, and 37.4 +/− 23.9 at year 1 in 97, 39.5 +/− 22.2 at year 2 in 84, 42.6 +/− 27.3 at year 3 in 61, 46.3 +/− 33.2 at year 4 in 57 and 44.2 +/− 28.9 cm. at year 5 in 41 after stent insertion (p

The gallium nitride (GaN) semiconductor market continues to rapidly expand because GaN device technology offers considerable performance advantages compared to gallium arsenide (GaAs) and silicon (Si) devices. GaN has inherently higher breakdown field strength, charge density, and electron velocity at high voltage. These material properties permit GaN devices to operate at higher bias voltages and higher current densities than GaAs and Si devices. Commercial applications can utilize RF power amplifiers at higher frequencies (> 2 GHz) and higher power (> 400 W) in a single packaged GaN transistor. However, this higher power density operation requires examination of the degradation and reliability of these GaN devices at elevated temperatures. The evaporation deposited gold interconnect metallization of GaN HFET devices was stressed to evaluate its high temperature reliability. Optimized test structures were designed to assess the electromigration wear-out in evaporated deposited Au films encapsulated with SiN passivation. A current density of 1 MA/cm2 with oven stress temperatures in excess of 335 °C was applied to large quantities of Au interconnects. The selected failure criteria of 50% resistance increase yielded Au lifetime distributions that followed typical log-normal electromigration failure statistics. All log-normal sigma values were less than 0.6 which is an indication of a mono-modal failure mechanism. The activation energy value was measured from multiple stress temperatures. Physical characterization of the evaporated Au interconnect structures are discussed along with a comparison to electroplated Au interconnects.