The population pharmacokinetics (PK) of rivaroxaban have been evaluated in several population‐specific models. We developed an integrated population PK model using pooled data from 4,918 patients in 7 clinical trials across all approved indications. Effects of gender, age, and weight on apparent clearance (CL/F) and apparent volume of distribution (V/F), renal function, and comedication on CL/F, and relative bioavailability as a function of dose (F) were analyzed. Virtual subpopulations for exposure simulations were defined by age, creatinine clearance (CrCL) and body mass index (BMI). Rivaroxaban PK were adequately described by a one‐compartment disposition model with a first‐order absorption rate constant. Significant effects of CrCL, use of comedications, and study population on CL/F, age, weight, and gender on V/F, and dose on F were identified. CrCL had a modest influence on exposure, whereas age and BMI had a minor influence. The model was suitable to predict rivaroxaban exposure in patient subgroups of special interest.

There are still challenges when meta-analyzing data from studies on diagnostic accuracy. This is mainly due to the bivariate nature of the response where information on sensitivity and specificity must be summarized while accounting for their correlation within a single trial. In this paper, we propose a new statistical model for the meta-analysis for diagnostic accuracy studies. This model uses beta-binomial distributions for the marginal numbers of true positives and true negatives and links these margins by a bivariate copula distribution. The new model comes with all the features of the current standard model, a bivariate logistic regression model with random effects, but has the additional advantages of a closed likelihood function and a larger flexibility for the correlation structure of sensitivity and specificity. In a simulation study, which compares three copula models and two implementations of the standard model, the Plackett and the Gauss copula do rarely perform worse but frequently better than the standard model. We use an example from a meta-analysis to judge the diagnostic accuracy of telomerase (a urinary tumor marker) for the diagnosis of primary bladder cancer for illustration.

Available evidence suggests that IABP may have a beneficial effect on the haemodynamics, however there is no convincing randomised data to support the use of IABP in infarct related cardiogenic shock.

BackgroundBAY 81-8973 is a full-length, unmodified, recombinant human factor VIII (FVIII) for the treatment of hemophilia A.ObjectiveThe aim of this study was to compare the pharmacokinetic (PK) profile of BAY 81-8973 with antihemophilic factor (recombinant) plasma/albumin-free method (rAHF-PFM)Patients/MethodsIn this phase I, open-label, crossover study, men aged 18–65 years with severe hemophilia A and ≥150 exposure days to FVIII were randomized to receive a single intravenous infusion of 50 IU/kg BAY 81-8973 or rAHF-PFM, followed by crossover to a single infusion of the other treatment. FVIII levels were measured in plasma over 48 h using one-stage and chromogenic assays. PK parameters, including area under the curve from time zero to the last data point (AUClast; primary outcome) and half-life (t ½) were calculated. A population PK model was developed to simulate various treatment scenarios.ResultsEighteen patients were randomized and analyzed. Using both assays, geometric mean (coefficient of variation [%CV]) AUClast was significantly higher, and t ½ was significantly longer, for BAY 81-8973 versus rAHF-PFM (one-stage, AUClast: 1660 IU·h/dL [29.4] vs. 1310 IU·h/dL [29.0], p < 0.0001; one-stage, t ½: 14.5 [25.7] vs. 11.7 h [27.3], p < 0.0001). Simulations showed that median time to 1 IU/dL was approximately 27% longer for BAY 81-8973 versus rAHF-PFM over doses of 25–50 IU/kg; plasma levels >1 IU/dL could be maintained with 14.4 IU/kg BAY 81-8973 or 39.1 IU/kg rAHF-PFM 3×/week.ConclusionsBAY 81-8973 showed a superior PK profile versus rAHF-PFM. The same FVIII trough threshold level could be achieved with lower doses of BAY 81-8973 versus rAHF-PFM.ClinicalTrials.gov: NCT02483208.

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P harmacokinetic-based prophylaxis of replacement factor VIII (FVIII) products has been encouraged in recent years, but the relationship between exposure (factor VIII activity) and response (bleeding frequency) remains unclear. The aim of this study was to characterize the relationship between FVIII dose, plasma FVIII activity, and bleeding patterns and individual characteristics in severe hemophilia A patients. Pooled pharmacokinetic and bleeding data during prophylactic treatment with BAY 81-8973 (octocog alfa) were obtained from the three LEOPOLD trials. The population pharmacokinetics of FVIII activity and longitudinal bleeding frequency, as well as bleeding severity, were described using non-linear mixed effects modeling in NONMEM. In total, 183 patients [median age 22 years (range, 1-61); weight 60 kg (11-124)] contributed with 1,535 plasma FVIII activity observations, 633 bleeds and 11 patient/study characteristics [median observation period 12 months (3.1-13.1)]. A parametric repeated time-tocategorical bleed model, guided by plasma FVIII activity from a 2-compartment population pharmacokinetic model, described the time to the occurrence of bleeds and their severity. Bleeding probability decreased with time of study, and a bleed was not found to affect the time of the next bleed. Several covariate effects were identified, including the bleeding history in the 12-month pre-study period increasing the bleeding hazard. However, unexplained inter-patient variability in the phenotypic bleeding pattern remained large (111%CV). Further studies to translate the model into a tool for dose individualization that considers the individual bleeding risk are required. Research was based on a post-hoc analysis of the LEOPOLD studies registered at clinicaltrials.

BAY 94-9027 is an extended-half-life, recombinant factor VIII (rFVIII) product conjugated with a 60-kDa branched polyethylene glycol (PEG) molecule indicated for use in previously treated patients (aged ≥ 12 years) with hemophilia A. This randomized, open-label, two-way crossover study compared the pharmacokinetics (PK) of BAY 94-9027 and rFVIII Fc fusion protein (rFVIIIFc) in patients with hemophilia A. Patients aged 18–65 years with FVIII < 1% and ≥ 150 exposure days to FVIII were randomized to receive intravenous single-dose BAY 94-9027 60 IU/kg followed by rFVIIIFc 60 IU/kg or vice versa, with ≥ 7-day wash-out between doses. FVIII activity was measured by one-stage assay. PK parameters, including area under the curve from time 0 to the last data point (AUC last , primary parameter), half-life, and clearance were calculated. Eighteen patients were randomized and treated. No adverse events were observed. In the analysis set excluding one outlier, geometric mean (coefficient of variation [%CV, 95% confidence interval {CI}]) AUC last was significantly higher for BAY 94-9027 versus rFVIIIFc (2940 [37.8, 2440–3550] IU h/dL versus 2360 [31.8, 2010–2770] IU h/dL, p = 0.0001). A population PK model was developed to simulate time to reach FVIII threshold levels; median time to 1 IU/dL was approximately 13 h longer for BAY 94-9027 versus rFVIIIFc after a single infusion of 60 IU/kg. In conclusion, BAY 94-9027 had a superior PK profile versus rFVIIIFc. ClinicalTrials.gov : NCT03364998. Electronic supplementary material The online version of this article (10.1007/s00277-019-03747-2) contains supplementary material, which is available to authorized users.