Confidence Intervals For AUC Research Articles

Comparison of methods for calculating confidence intervals of AUC in ROC curve considering sampling error

Comparison of methods for calculating confidence intervals of AUC in ROC curve considering sampling error

Physiologically based pharmacokinetic modeling to characterize enterohepatic recirculation and predict food effect on the pharmacokinetics of hyzetimibe

Background and ObjectiveHyzetimibe is a cholesterol absorption inhibitor indicated for the treatment of hypercholesterolemia. This study aims to describe the multiple-peak pharmacokinetics (PK) of hyzetimibe and its active metabolite M1 through physiologically-based pharmacokinetic (PBPK) modeling, and to compare the model predictions of a virtual food effect study with the results of a clinical food effect study. MethodsThe plasma concentration data used for PBPK modeling were obtained from a single-dose, two-period crossover bioequivalence study in the fasted state. Advanced Compartmental Absorption and Transit model was used for absorption. Enterohepatic recirculation process was modeled by changing the gut physiological state from fasted to fed at meal time. Based on the established PBPK models, a virtual food effect study was simulated. A clinical food effect study was used for model external validation. ResultsPK profiles of hyzetimibe and M1 under fasting condition could be well described by the PBPK model, and the errors of Cmax, AUC0-∞, and AUC0-t were within the two-fold range. Simulated geometric mean ratios (GMRs, fed/fasted) showed that a high-fat breakfast slightly affected the PK of hyzetimibe, expressed as increased Cmax of hyzetimibe (130.6%). Simulated GMRs and 90% confidence intervals of AUC were within the preset bioequivalent range. The results of the simulated virtual food effect trial were consistent with those of the clinical food effect trial. ConclusionsThe established PBPK model could describe the concentration-time profiles of hyzetimibe and M1 well with good prediction performance. A fully mechanistic model of enterohepatic recirculation warrants further investigation.

Development of a UPLC-ESI-MS/MS method for the determination of triamcinolone acetonide in human plasma and evaluation of its bioequivalence after a single intramuscular injection in healthy volunteers.

Introduction: Triamcinolone acetonide (TA) is commonly used in the treatment of various inflammatory conditions. To ensure its efficacy and safety, it is important to accurately determine its concentration in human plasma and evaluate its bioequivalence. In this study, an efficient ultra-performance liquid chromatography-electrospray ionization-tandem mass spectrometry (UPLC-ESI-MS/MS) method was developed for the quantification of TA in human plasma after a single intramuscular injection. The internal standard used in this method was cortisone acetate (CA). Methods: TA and CA were extracted from plasma using ethyl acetate and N-hexane (4:1, v/v), separated on a C18 reverse-phase column with a mobile phase of acetonitrile-water containing 1% formic acid (55:45, v/v), and analyzed by UPLC-ESI-MS/MS. Multiple-reaction monitoring was performed using the transitions m/z 435.4→397.3 for TA and m/z 403.4→163.1 for CA. Results: The developed UPLC-ESI-MS/MS method demonstrated linearity over a concentration range of 0.53-21.20ng/mL, with a lower limit of quantification of 0.53ng/mL. The intra- and inter-run precision values ranged from 3.007% to 9.960% and 3.528% to 11.26%, respectively. The intra- and inter-run accuracy ranges were -1.962% to -6.577% and -3.371% to 0.348%, respectively. The matrix effect, extraction recovery, and stability of TA all met the acceptance criteria recommended by the National Medical Products Administration (NMPA) for bioassays. In healthy volunteers who received a single intramuscular injection of 80mg of either the test or reference formulation of TA, various pharmacokinetic parameters were determined. C max was found to be 8.616 ± 1.232 and 8.285 ± 1.218ng/mL for the test and reference formulations, respectively. T max was approximately 1.833 ± 0.243 and 1.861 ± 0.230h. The t 1/2 was calculated to be 181.249 ± 78.585 and 201.782 ± 83.551h. AUC 0-720 was 835.642 ± 297.209 and 830.684 ± 331.168ngh/mL, AUC 0-∞ was 991.859 ± 355.939 and 1018.665 ± 420.769ngh/mL for the test and reference formulations, respectively. The average relative bioavailability of TA, determined using AUC 0-720, was 105.4 ± 26.9%. Bioequivalence was evaluated through variance analysis and a double unilateral test, and the 90% confidence intervals of AUC 0-720, C max, and AUC 0-∞ were 92.8%-113.4%, 99.1%-109.1%, and 89.7%-110.9%, respectively (all p > 0.05). Discussion: These results met the bioequivalence criteria set by the NMPA, indicating that the developed UPLC-ESI-MS/MS method accurately determined TA concentrations in the plasma of healthy Chinese volunteers and that the test and reference formulations exhibited bioequivalence in these individuals.

Diagnostic and predictive value of resistive / pulsatility indices of ophthalmic artery and common carotid artery for the development of diabetic retinopathy.

Ophthalmic artery resistive index (OA RI) was a controversial parameter to show hemodynamic changes due to diabetic retinopathy (DRP). To investigate the diagnostic and predictive value of resistive and pulsatility index (RI and PI, respectively) of OA and common carotid artery (CCA) for the development of DRP. A total of 60 patients with diabetes mellitus (DM) type 2 (study group) and 30 healthy participants (control group) were evaluated between January and June 2021 by Doppler ultrasonography (DUS). RI and PI values were compared between groups with a Student's t-test. Cutoff value, sensitivity, and specificity were calculated for the significant variables with receiver operating characteristic (ROC) analysis. In total, there were 20 (22.2%) patients with DM without DRP (DMwoRP), 20 (22.2%) patients in the non-proliferative diabetic retinopathy group (NPDRP), and 20 (22.2%) patients in the proliferative diabetic retinopathy group (PDRP). The mean of CCA RI and OA RI in the PDRP group was significantly higher than in the other three groups (P < 0.001). The mean of CCA RI and OA RI was significantly higher in the PDRP group than in the NPDRP group, and in the NPDRP group compared to the DMwoRP group. CCA RI and OA RI showed a significantly high correlation (r = 0.849; P < 0.001). Sensitivity was 95% and specificity was 100% for the diagnosis of PDRP for the 0.82 cutoff value of OA RI (AUR = 0.999, 95% confidence interval for AUC = 0.997-0.1000; P < 0.001). The OA RI accurately reflects DRP-induced orbital blood flow changes and is a predictive index for DRP prognosis.

High dimensional Selection with Interactions for Binary Outcome (HDSI-BO) Algorithm in Classifying Height Indicators Through Social-life and Well-being Factors

Introduction: High dimensional Selection with Interactions for Binary Outcome (HDSI-BO) algorithm can incorporate interaction terms and combine with existing techniques for feature selection. Simulation studies have validated the ability of HDSI-BO to select true features and consequently, improve prediction accuracy compared to standard algorithms. Our goal is to assess the applicability of HDSI-BO in combining different techniques and measure its predictive performance in a real data study of predicting height indicators by social-life and well-being factors.&#x0D; Methods: HDSI-BO was combined with logistic regression, ridge regression, LASSO, adaptive LASSO, and elastic net. Two-way interaction terms were considered. Hyperparameters used in HDSI-BO were optimized through genetic algorithms with five-fold cross-validation. To measure the performance of feature selection, we fitted final models by logistic regression based on the sets of selected features and used the model’s AUC as a measure. 30 trials were repeated to generate a range of the number of selected features and a 95% confidence interval for AUC.&#x0D; Results: When combined with all of the above methods, HDSI-BO methods achieved higher final AUC values both in terms of mean and confidence interval. In addition, HDSI-BO methods effectively narrowed down the sets of selected features and interaction terms compared with standard methods.&#x0D; Conclusion: The HDSI-BO algorithm combines well with multiple standard methods and has comparable or better predictive performance compared with the standard methods. The computational and time complexity of HDSI-BO is higher but still acceptable. Considering AUC as the single metric cannot comprehensively measure the feature selection performance. More effective metrics of performance should be explored for future work.

Obstructive sleep apnea predicts 10-year cardiovascular disease-related mortality in the Sleep Heart Health Study: a machine learning approach.

Obstructive sleep apnea (OSA) is considered to be an important risk factor for the development of cardiovascular disease (CVD). This study aimed to develop and evaluate a machine learning approach with a set of features for assessing the 10-year CVD mortality risk of the OSA population. This study included 2,464 patients with OSA who met study inclusion criteria and were selected from the Sleep Heart Health Study. We evaluated the importance of potential features by mutual information. The top 9 features were selected to develop a random forest model. We evaluated the model performance on a test set (n = 493) using the area under the receiver operating curve with 95% confidence interval and confusion matrix. A random forest model awarded the highest area under the receiver operating curve of 0.84 (95% confidence interval: 0.78-0.89). The specificity and sensitivity were 73.94% and 81.82%, respectively. Sixty-three years old was a threshold for increased risk of 10-year CVD mortality. Persons with severe OSA had higher risk than those with mild OSA. This study demonstrated that a random forest model can provide a quick assessment of the risk of 10-year CVD mortality. Our model may be more informative for patients with OSA in determining their future CVD mortality risk. Li A, Roveda JM, Powers LS, Quan SF. Obstructive sleep apnea predicts 10-year cardiovascular disease-related mortality in the Sleep Heart Health Study: a machine learning approach. J Clin Sleep Med. 2022;18(2):497-504.

An efficient variance estimator of AUC and its applications to binary classification.

The area under the ROC (receiver operating characteristic) curve, AUC, is one of the most commonly used measures to evaluate the performance of a binary classifier. Due to sampling variation, the model with the largest observed AUC score is not necessarily optimal, so it is crucial to assess the variation of AUC estimate. We extend the proposal by Wang and Lindsay and devise an unbiased variance estimator of AUC estimate that is of a two-sample U-statistic form. The proposal can be easily generalized to estimate the variance of a K-sample U-statistic (K ≥ 2). To make our developed variance estimator more applicable, we employ a partition-resampling scheme that is computationally efficient. Simulation studies suggest that the developed AUC variance estimator yields much better or comparable performance to jackknife and bootstrap variance estimators, and computational times that are about 10 to 30 times faster than the times of its counterparts. In practice, the proposal can be used in the one-standard-error rule for model selection, or to construct an asymptotic confidence interval of AUC in binary classification. In addition to conducting simulation studies, we illustrate its practical applications using two real datasets in medical sciences.

Pharmacokinetics and Bioequivalence of Branded and Generic Formulations of Dofetilide 0.5‐mg Capsules After Single‐Dose Administration in Healthy Subjects

Class III antiarrhythmics are preferred therapy for managing atrial fibrillation/flutter. Dofetilide 0.5-mg capsules were US Food and Drug Administration (FDA) approved in 1999 to treat atrial fibrillation/flutter. Bioequivalence of generic dofetilide is important for treating arrhythmias because drug concentrations must be consistent to maintain normal sinus rhythm. Generic dofetilide 0.5-mg capsule pharmacokinetics were compared with branded product in 2 open-label, 2-way crossover, single-dose studies - 1 study each in fasted and fed healthy subjects. Blood samples were collected before and up to 48 hours after dosing. Safety was assessed by tabulating adverse events and vital signs. Seventy-three subjects were enrolled; 59 completed the studies. In fasted subjects, the 90% confidence intervals (CIs) for generic dofetilide 0.5 mg versus the reference formulation were 0.996-1.026 for the area under the plasma concentration-time curve from 0 to infinity (AUC) and 0.974-1.066 for the maximum observed concentration (Cmax ). In fed subjects, the 90%CIs for AUC and Cmax were 0.988-1.015 and 0.928-0.992, respectively. All ratios were within the FDA-established bioequivalence range. Twenty-six subjects experienced 37 adverse events (generic, 15; reference, 22); all but 1 were mild or moderate in severity. Generic dofetilide 0.5-mg capsules can be considered bioequivalent to the reference product.

Frailty Assessment in Hospitalized Older Adults Using the Electronic Health Record.

Frailty, a clinical syndrome of decreased physiologic reserve and dysregulation in multiple physiologic systems, is associated with increased risk for adverse outcomes. The aim of this retrospective, cross-sectional, correlational study was to characterize frailty in older adults admitted to a tertiary-care hospital using a biopsychosocial frailty assessment and to determine associations between frailty and time to in-hospital mortality and 30-day rehospitalization. The sample included 278 patients ≥55 years old admitted to medicine units. Frailty was determined using clinical data from the electronic health record (EHR) for symptoms, syndromes, and conditions and laboratory data for four serum biomarkers. A frailty risk score (FRS) was created from 16 risk factors, and relationships between the FRS and outcomes were examined. The mean age of the sample was 70.2 years and mean FRS was 9.4 ( SD, 2.2). Increased FRS was significantly associated with increased risk of death (hazard ratio = 1.77-2.27 for 3 days ≤ length of stay (LOS) ≤7 days), but depended upon LOS ( p < .001). Frailty was marginally associated with rehospitalization for those who did not die in hospital (adjusted odds ratio = 1.18, p = .086, area under the curve [AUC] = 0.66, 95% confidence interval for AUC = [0.57, 0.76]). Clinical data in the EHR can be used for frailty assessment. Informatics may facilitate data aggregation and decision support. Because frailty is potentially preventable and treatable, early detection is crucial to delivery of tailored interventions and optimal patient outcomes.

The Pharmacokinetic Properties and Bioequivalence of Methyldopa Formulations: Results of an Open-label, Randomized, Two-period, Crossover, Single-dose Study

Comparative assessment of the pharmacokinetic properties and bioequivalence (BE) of two methyldopa formulations (Methyldopa, 250 mg tablets, R-Pharm CJSC, Russia-investigational medicinal product, and Dopegyt®, 250 mg tablets, EGIS Pharmaceuticals PLC, Hungary-reference product) were investigated in 24 healthy volunteers (13 women and 11 men, caucasian) in an open-label, randomized, crossover, two-period, two-sequence trial with 7-day washout period. A comparative dissolution test was carried out in advance in 3 media, including quantitative determination of methyldopa by UV spectrophotometry. The release patterns of the active ingredient from the test and reference products were equivalent. Methyldopa concentrations in plasma were measured by validated method of high-performance liquid chromatography-tandem mass spectrometry, using the deuterated internal standard. The validation method yields data meeting all acceptance criteria for the plasma methyldopa concentration range of 0.020-3.000 μg/mL. Stabilization of plasma samples was developed that involved addition of ascorbic acid to the plasma during the sampling procedure at the study site. The BE assessment involved calculation of 90% confidence intervals for AUC, Cmax, and Cmax/AUC using analysis of variance (ANOVA) of log-transformed data within an range of 80.00-125.00%. No statistically significant differences were observed between the two drugs. The point estimates and 90% confidence interval limits were as follows: AUC0-t-92.93% (80.69-107.03%), Cmax-94.89% (80.88-111.34%), Cmax/AUC0-t-102.11% (93.95-110.98%), corresponding to the acceptable ranges (80.00-125.00%). The test and reference drug products are characterized by a high degree of pharmacokinetic similarity and thus are bioequivalent.

Pharmacokinetics and pharmacodynamics of an extrafine fixed pMDI combination of beclometasone dipropionate/formoterol fumarate in adolescent asthma.

The aim was to investigate the pharmacokinetics and pharmacodynamics of an extrafine pressurized metered-dose inhaler (pMDI) fixed combination of beclometasone dipropionate (BDP)/formoterol fumarate (FF) in adolescent and adult asthma. This was a three-way crossover study, on 30 asthmatic adolescents receiving BDP/FF pMDI with or without a valved holding chamber (VHC) or a free licenced combination of BDP pMDI and FF pMDI plus a parallel arm of 30 asthmatic adults receiving BDP/FF pMDI. All patients received a single dose of BDP and FF of 400 µg and 24 µg, for each treatment, respectively. Assessments were performed over 8 hours. In adolescents, the 90% confidence intervals (CIs) for the systemic exposure (AUC(0,t)) geometric mean ratio of the fixed combination with or without VHC vs. the free combination were within the bioequivalence range 0.80-1.25, both for beclometasone-17-monopropionate (B17MP, the active metabolite of BDP) and formoterol. Pharmacodynamic variables for plasma potassium and glucose, pulse rate and pulmonary function in adolescents were equivalent between treatments, 95% CI within 0.9, 1.09. The upper level of 90% CIs for AUC(0,t) geometric mean ratio adolescents : adults of B17MP and formoterol after treatment with BDP/FF pMDI was lower than 1.25, 90% CI 0.78, 1.04 and 0.86, 1.17, respectively. In adolescents the pharmacodynamics and the overall systemic exposure to the active ingredients of an extrafine fixed combination of BDP/FF pMDI with or without a VHC was equivalent to that of a free licenced combination of pMDIs of established safety and efficacy profiles. The systemic exposure in adolescents was not higher than in adults. These results support the indication for use of inhaled corticosteroid/long acting β2 -adrenoceptor agonist pMDIs in adolescents at the same dosage as in adults.

Pharmacokinetic study between a bilayer matrix fentalyl patch and a monolayer matrix fentanyl patch: single dose administration in healthy volunteers.

AimsTransdermal fentanyl is a well established treatment for cancer pain. The aim of the present study is to assess the relative bioavailability of fentanyl from two different transdermal systems by evaluating plasma drug concentrations after single administration of Fentalgon® (test), a novel bilayer matrix type patch, and Durogesic SMAT (reference), a monolayer matrix type patch. In the Fentalgon patch the upper 6% fentanyl reservoir layer maintains a stable concentration gradient between the lower 4% donor layer and the skin. The system provides a constant drug delivery over 72 h.MethodsThis was an open label, single centre, randomized, single dose, two period crossover clinical trial, that included 36 healthy male volunteers. The patches were applied to non-irritated and non-irradiated skin on the intraclavicular pectoral area. Blood samples were collected at different time points (from baseline to 120 h post-removal of the devices) and fentanyl concentrations were determined using a validated LC/MS/MS method. Bioequivalence was to be claimed if the 90% confidence interval of AUC(0,t) and Cmax ratios (test: reference) were within the acceptance range of 80–125% and 75–133%, respectively.ResultsThe 90% confidence intervals of the AUC(0,t) ratio (116.3% [109.6, 123.4%]) and Cmax ratio (114.4% [105.8, 123.8%] were well included in the acceptance range and the Cmax ratio also met the narrower bounds of 80–125%. There was no relevant difference in overall safety profiles of the two preparations investigated, which were adequately tolerated, as expected for opioid-naïve subjects.ConclusionsThe new bilayer matrix type patch, Fentalgon®, is bioequivalent to the monolayer matrix type Durogesic SMAT fentanyl patch with respect to the rate and extent of exposure of fentanyl (Eudra/CT no. 2005-000046-36).

The predictive performance and stability of six species distribution models.

BackgroundPredicting species’ potential geographical range by species distribution models (SDMs) is central to understand their ecological requirements. However, the effects of using different modeling techniques need further investigation. In order to improve the prediction effect, we need to assess the predictive performance and stability of different SDMs.MethodologyWe collected the distribution data of five common tree species (Pinus massoniana, Betula platyphylla, Quercus wutaishanica, Quercus mongolica and Quercus variabilis) and simulated their potential distribution area using 13 environmental variables and six widely used SDMs: BIOCLIM, DOMAIN, MAHAL, RF, MAXENT, and SVM. Each model run was repeated 100 times (trials). We compared the predictive performance by testing the consistency between observations and simulated distributions and assessed the stability by the standard deviation, coefficient of variation, and the 99% confidence interval of Kappa and AUC values.ResultsThe mean values of AUC and Kappa from MAHAL, RF, MAXENT, and SVM trials were similar and significantly higher than those from BIOCLIM and DOMAIN trials (p<0.05), while the associated standard deviations and coefficients of variation were larger for BIOCLIM and DOMAIN trials (p<0.05), and the 99% confidence intervals for AUC and Kappa values were narrower for MAHAL, RF, MAXENT, and SVM. Compared to BIOCLIM and DOMAIN, other SDMs (MAHAL, RF, MAXENT, and SVM) had higher prediction accuracy, smaller confidence intervals, and were more stable and less affected by the random variable (randomly selected pseudo-absence points).ConclusionsAccording to the prediction performance and stability of SDMs, we can divide these six SDMs into two categories: a high performance and stability group including MAHAL, RF, MAXENT, and SVM, and a low performance and stability group consisting of BIOCLIM, and DOMAIN. We highlight that choosing appropriate SDMs to address a specific problem is an important part of the modeling process.

Empirical likelihood ratio confidence interval estimation of best linear combinations of biomarkers

A novel smoothed empirical likelihood (EL) approach that incorporates kernel estimation of the area under the receiver operating characteristic curve (AUC) to construct nonparametric confidence intervals of AUC based on the best linear combination (BLC) of biomarkers is proposed. The method has several advantages including the feasibility to use gradient-based techniques for fast computation of BLC coefficients and to employ powerful likelihood methods without specification of underlying data distributions. Simulation results show that the new method performs well even when the distribution of biomarkers is skewed, a situation commonly met in practice. A data set from a clinical experiment related to atherosclerotic coronary heart disease is used to illustrate the efficiency of the proposed method.

Bioequivalence of oxycodone hydrochoride extended release tablets to marketed reference products OxyContin® in Canada and US

Oxycodone is a semisynthetic opioid agonist used for the relief of moderate to severe pain. A new generic oxycodone hydrochloride (HCl) extended release (ER) tablet is currently being developed by Ranbaxy Pharmaceutical Inc., New Brunswick, NJ, USA. To assess relative bioavailability of a new generic (test) formulation of oxycodone hydrochloride (HCl) extended release (ER) tablets with that of marketed reference products, OxyContin®, in Canada and USA, in healthy adult subjects under fasting and fed conditions. Five studies were conducted in all, three of which were designed to comply with the regulatory criteria for marketing a new generic formulation of OxyContin® in Canada and the remaining two to comply with regulatory criteria for marketing a new generic formulation of OxyContin® in the USA. Each study was a balanced, randomized two-period, two-treatment, two-sequence, crossover design. A single oral dose of test or reference product was given in Period 1, followed by a 7-day washout period, after which subjects received the alternative product in Period 2. In order to block the pharmacological effects of oxycodone, subjects were administered naltrexone HCl (1 × 50 mg tablet) 12 hours prior to oxycodone HCl administration, concurrent with oxycodone HCl administration, and 12 hours after oxycodone HCl administration. Throughout the confinement portion of the study, adverse events were closely monitored. Serial blood samples were collected, following which oxycodone in plasma was estimated using a validated analytical procedure. Oxycodone was well tolerated by subjects in both periods of each study under both fed and fasted conditions. No serious adverse events were observed. The ratios of geometric means for AUC0-t and Cmax and the affiliated 90% confidence intervals for AUC were within acceptance range recommended by Health Canada. These criteria were met for both the raw data as well as data corrected for measured drug content (potency). The ratios of geometric means and the 90% confidence intervals for AUC0-t, AUC0-∞ and Cmax were within acceptance range recommended by United States Food and Drug Administration (FDA). Results demonstrate that the test formulation of oxycodone HCl ER tablets is bioequivalent to marketed OxyContin® reference formulations in Canada and USA, when administered both under fasted and fed conditions. Additionally, oxycodone HCl ER tablets were well tolerated as a single oral dose when administered to healthy adult subjects under fasted and fed conditions.

Semiparametric empirical likelihood confidence intervals for AUC under a density ratio model

Inferences on the area under a receiver operating characteristic curve (AUC) are usually based on a fully parametric approach or a fully nonparametric approach. A semiparametric empirical likelihood method is proposed to construct confidence intervals for AUC by assuming a density ratio model for the diseased and non-diseased population densities. The limiting distribution of the semiparametric empirical log likelihood ratio statistic for AUC has a scaled chi-square distribution. The proposed semiparametric empirical likelihood approach is shown, via a simulation study, to be more robust than a fully parametric approach and is more accurate than a fully nonparametric approach. Some results on simulation and an analysis of two real examples are presented.

GW24-e2115 Study of urinary IL-18 on early diagnosis of contrast-induced nephropathy in patients undergoing coronary angiography and / or percutaneous coronary intervention and the intervention of Danhong Injection

ObjectivesTo investigate the level of IL-18 in patients underwent coronary angiography (CAG) and/or Percutaneous coronary intervention (PCI) before and after operation and to explore IL-18 value in predicting of contrast-induced...

The pharmacokinetics of darexaban are not affected to a clinically relevant degree by rifampicin, a strong inducer of P‐glycoprotein and CYP3A4

We investigated the effects of rifampicin on the pharmacokinetics (PK) of the direct clotting factor Xa inhibitor darexaban (YM150) and its main active metabolite, darexaban glucuronide (YM-222714), which almost entirely determines the antithrombotic effect. In this open-label, single-sequence study, 26 healthy men received one dose of darexaban 60 mg on day 1 and oral rifampicin 600 mg once daily on days 4-14. On day 11, a second dose of darexaban 60 mg was given with rifampicin. Blood and urine were collected after study drug administration on days 1-14. The maximal plasma drug concentration (C(max)) and exposure [area under the plasma concentration-time curve from time zero to time of quantifiable measurable concentration; (AUC(last)) or AUC(last) extrapolated to infinity (AUC(∞))] were assessed by analysis of variance of PK. Limits for statistical significance of 90% confidence intervals for AUC and C(max) ratios were predefined as 80-125%. Darexaban glucuronide plasma exposure was not affected by rifampicin; the geometric mean ratio (90% confidence interval) of AUC(last) with/without rifampicin was 1.08 (1.00, 1.16). The C(max) of darexaban glucuronide increased by 54% after rifampicin [ratio 1.54 (1.37, 1.73)]. The plasma concentrations of darexaban were very low (<1% of darexaban glucuronide concentrations) with and without rifampicin. Darexaban alone or in combination with rifampicin was generally safe and well tolerated. Overall, rifampicin did not affect the PK profiles of darexaban glucuronide and darexaban to a clinically relevant degree, suggesting that the potential for drug-drug interactions between darexaban and CYP3A4 or P-glycoprotein-inducing agents is low.

Effect of food on the pharmacokinetics of the hydrocodone extended-release tablet in healthy volunteers

Hydrocodone is available for the treatment of pain in the United States only as immediate-release formulations in combination with other medications. A new extended-release hydrocodone tablet has been developed that employs OraGuard technology, a novel platform that is intended to resist dose dumping when taken with alcohol or when pulverized. Two randomized, open-label, crossover studies were conducted to assess the effect of food on the pharmacokinetics of the hydrocodone bitartrate extended-release tablet (Study 1, 15 mg; Study 2, 90 mg). Each participant received hydrocodone extended-release (15 or 90 mg) in both fed and fasted states with 240 mL of water. Hydrocodone doses were separated by a minimum of 5 (Study 1) or 14 days (Study 2). Subjects had received naltrexone to block opioid receptors. Blood samples were collected pre-dose and through 72 hours post-dose. Pharmacokinetic parameters included peak plasma hydrocodone concentration (Cmax) and area under the plasma hydrocodone concentration-versus-time curve from time 0 to infinity (AUC0-∞). Safety was also assessed. Thirty-one subjects completed Study 1; 35 completed Study 2. In Study 1, geometric mean Cmax in the fed and fasted state was 18.5 and 12.5 ng/mL and geometric mean AUC0-∞ was 210.8 and 193.5 ng•hr/mL, respectively. In Study 2, the corresponding Cmax was 86.1 and 60.6 ng/mL and AUC0-∞ was 1262 and 1135 ng•hr/mL, respectively. In both studies, confidence intervals for AUC met bioequivalence criteria (0.8, 1.25) for the fed and fasted states (Study 1: AUC0-∞ 1.035, 1.111; Study 2: AUC0-∞ 1.055, 1.161), while those for Cmax did not (Study 1: 1.354, 1.548; Study 2: 1.306, 1.509). Cmax was 40-45% higher under fed conditions in both studies. Adverse events were similar in fed and fasted states in Study 1 (36% vs 34%), but higher in the fasted state in Study 2 (16% vs 8%). Sponsored by Cephalon, Inc.

In vivo Biopharmaceutical Characterisation of a New Formulation Containing the Antiepileptic Drug Lamotrigine in Comparison to Plain and Dispersible/Chewable Lamotrigine Tablets

Two studies in healthy male volunteers were carried out to evaluate the pharmacokinetic profile of a new divisible formulation of lamotrigine (CAS 84057-84-1, Plexxo, Lamotrigin Desitin) in plasma in comparison to plain or dispersible lamotrigine tablets. The plasma pharmacokinetics of lamotrigine were analysed after administration of single doses of 100 mg lamotrigine given as one tablet of the new formulation and either the plain or the dispersible reference formulation in two separate studies. In each study the data of 24 subjects were analysed according to the study protocol. Venous blood samples were taken at appropriate intervals up to 120 h after dosing. Concentrations of lamotrigine were determined in plasma by a validated HPLC method using UV detection. In both studies, mean plasma concentration-time profiles of the new lamotrigine formulation and both reference formulations ran nearly in parallel. The pharmacokinetic mean data calculated from different subject groups of the two studies were very similar. The mean ratios of the main pharmacokinetic parameters and the corresponding 90% confidence intervals of AUC(0-t), AUC(0-inf) and C(max) were 103% (99.7-105.7), 103% (99.6-107.3) and 101% (95.2-106.6) for the comparison with the plain lamotrigine tablet and 100% (98.0-102.8), 100% (96.5-102.8) and 102% (99.1-105.3) for the comparison with the dispersible/chewable tablet, respectively. The most frequently reported adverse events possibly related to the administration of lamotrigine were headache and dizziness in both studies. It is concluded that the new divisible lamotrigine formulation is bioequivalent with regard to rate and extent of absorption to both the plain reference lamotrigine product and to the dispersible/chewable reference product.