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Anticoagulant treatment of pediatric cancer–associated venous thromboembolism (VTE) has not been prospectively evaluated. Management of anticoagulation for cancer-associated VTE is often challenged by drug interactions and treatment interruptions. A total of 56 of the 500 children (11.2%) with VTE who participated in the recent EINSTEIN-Jr randomized study had cancer (hematologic malignancy, 64.3%, solid malignant tumor, 35.7%). Children were allocated to either therapeutic-dose bodyweight-adjusted oral rivaroxaban (n=40) or standard anticoagulation with heparins, with or without vitamin K antagonists (n=16) and received a median of 30 concomitant medications. Based on sparse blood sampling at steady-state, pharmacokinetic (PK) parameters of rivaroxaban were derived using population PK modeling. During the 3 months of treatment, no recurrent VTE or major bleeding occurred (95% confidence interval, 0.0%-6.4%), and 3-month repeat imaging showed complete or partial vein recanalization in 20 and 24 of 52 evaluable children (38.5% and 46.2%, respectively). Anticoagulant treatment was interrupted 70 times in 26 (46.4%) children because of thrombocytopenia, invasive procedures, or adverse events, for a mean individual period of 5.8 days. Anticoagulant therapy was resumed in therapeutic doses and was not associated with thrombotic or bleeding complications. Rivaroxaban exposures were within the adult exposure range and similar to those observed in children with VTE who did not have cancer-associated VTE. Rivaroxaban and standard anticoagulants appeared safe and efficacious and were associated with reduced clot burden in most children with cancer-associated VTE, including those who had anticoagulant treatment interruptions. Rivaroxaban exposures were within the adult exposure range despite significant polypharmacy use. This trial was registered at www.clinicaltrials.gov as #NCT02234843.

Rivaroxaban has been investigated in the EINSTEIN‐Jr program for the treatment of acute venous thromboembolism (VTE) in children aged 0 to 18 years and in the UNIVERSE program for thromboprophylaxis in children aged 2 to 8 years with congenital heart disease after Fontan‐procedure. Physiologically‐based pharmacokinetic (PBPK) and population pharmacokinetic (PopPK) modeling were used throughout the pediatric development of rivaroxaban according to the learn‐and‐confirm paradigm. The development strategy was to match pediatric drug exposures to adult exposure proven to be safe and efficacious. In this analysis, a refined pediatric PopPK model for rivaroxaban based on integrated EINSTEIN‐Jr data and interim PK data from part A of the UNIVERSE phase III study was developed and the influence of potential covariates and intrinsic factors on rivaroxaban exposure was assessed. The model adequately described the observed pediatric PK data. PK parameters and exposure metrics estimated by the PopPK model were compared to the predictions from a previously published pediatric PBPK model for rivaroxaban. Ninety‐one percent of the individual post hoc clearance estimates were found within the 5th to 95th percentile of the PBPK model predictions. In patients below 2 years of age, however, clearance was underpredicted by the PBPK model. The iterative and integrative use of PBPK and PopPK modeling and simulation played a major role in the establishment of the bodyweight‐adjusted rivaroxaban dosing regimen that was ultimately confirmed to be a safe and efficacious dosing regimen for children aged 0 to 18 years with acute VTE in the EINSTEIN‐Jr phase III study.

Background Coagulation factor XI (FXI) contributes to the development of thrombosis but appears to play only a minor role in hemostasis and is therefore an attractive anticoagulant drug target. Objectives To evaluate the safety, pharmacodynamic, and pharmacokinetic properties of BAY 1213790, a fully human immunoglobulin (Ig) G1 antibody targeting activated coagulation FXI (FXIa), in healthy men. Methods In this phase 1, single‐blind, parallel‐group, placebo‐controlled, dose‐escalation study, 83 healthy Caucasian men were randomized 4:1 to receive a single 60‐minute intravenous infusion of BAY 1213790 (0.015‐10 mg/kg) or placebo. Adverse events, pharmacodynamic parameters (including activated partial thromboplastin time [aPTT]) and pharmacokinetic parameters were determined. Volunteers were followed up for 150 days. Results BAY 1213790 demonstrated favorable safety and tolerability; there were no observed cases of bleeding or clinically relevant antidrug antibody formation. One volunteer (1.2%) experienced an infusion reaction. Following intravenous administration of BAY 1213790, dose‐dependent increases in aPTT (maximal mean increase relative to baseline: 1.85 [conventional method] and 2.17 [kaolin‐triggered method]) and rotational thromboelastometry whole blood clotting time were observed, as well as dose‐dependent reductions in FXI activity. Bleeding times did not increase following administration of BAY 1213790 and were similar for all dose cohorts, including placebo. Measurable and dose‐dependent increases in systemic exposure were detected for all doses of BAY 1213790 of 0.06 mg/kg or higher. Conclusions Based on these safety, pharmacodynamic, and pharmacokinetic results, further evaluation of BAY 1213790 in patients with, or at risk of, thrombosis is warranted.

Background: Recently, the randomized EINSTEIN-Jr study showed similar efficacy and safety for rivaroxaban and standard anticoagulation for treatment of pediatric venous thromboembolism (VTE). The rivaroxaban dosing strategy was established based on phase 1 and 2 data in children and through pharmacokinetic (PK) modeling. Methods: Rivaroxaban treatment with tablets or the newly developed granules-for-oral suspension formulation was bodyweight-adjusted and administered once-daily, twice-daily, or thrice-daily for children with bodyweights of ≥30, ≥12 to (0-24)ss] and trough [C trough,ss] and maximum [C max,ss] steady-state plasma concentrations were derived using population PK modeling. Exposure-response graphs were generated to evaluate the potential relationship of individual PK parameters with recurrent VTE, repeat imaging outcomes, and bleeding or adverse events. A taste-and-texture questionnaire was collected for suspension-recipients. Results: Of the 335 children (aged 0-17 years) allocated to rivaroxaban, 316 (94.3%) were evaluable for PK analyses. Rivaroxaban exposures were within the adult exposure range. No clustering was observed for any of the PK parameters with efficacy, bleeding, or adverse event outcomes. Results were similar for the tablet and suspension formulation. Acceptability and palatability of the suspension were favorable. Discussion: Based on this analysis and the recently documented similar efficacy and safety of rivaroxaban compared with standard anticoagulation, we conclude that bodyweight-adjusted pediatric rivaroxaban regimens with either tablets or suspension are validated and provide for appropriate treatment of children with VTE.

The non-vitamin K antagonist oral anticoagulant, rivaroxaban, is used in several thromboembolic disorders. Rivaroxaban is eliminated via both metabolic degradation and renal elimination as unchanged drug. Therefore, renal and hepatic impairment may reduce rivaroxaban clearance, and medications inhibiting these clearance pathways could lead to drug-drug interactions. This physiologically-based pharmacokinetic (PBPK) study investigated the pharmacokinetic behavior of rivaroxaban in clinical situations where drug clearance is impaired. A PBPK model was developed using mass balance and bioavailability data from adults and qualified using clinically observed data. Renal and hepatic impairment were simulated by adjusting disease-specific parameters and concomitant drug use was simulated by varying enzyme activity in virtual populations (n = 1000) and compared with pharmacokinetic predictions in virtual healthy populations and clinical observations. Rivaroxaban doses of 10 mg or 20 mg were used. Mild-to-moderate renal impairment had a minor effect on area under the concentration-time curve (AUC) and maximum plasma concentration (Cmax ) of rivaroxaban, whereas severe renal impairment caused a more pronounced increase in these parameters versus normal renal function. AUC and Cmax increased with severity of hepatic impairment. These effects were smaller in the simulations compared with clinical observations. AUC and Cmax increased with the strength of cytochrome P450 3A4 and P-glycoprotein inhibitors in simulations and clinical observations. This PBPK model can be useful for estimating the effects of impaired drug clearance on rivaroxaban pharmacokinetics. Identifying other factors that affect the pharmacokinetics of rivaroxaban could facilitate the development of models that approximate real-world pharmacokinetics more accurately. This article is protected by copyright. All rights reserved.

Background: Recently, the randomised EINSTEIN-Jr. study showed similar efficacy and safety for rivaroxaban and standard anticoagulation for acute and continued treatment of paediatric venous thromboembolism (VTE). The rivaroxaban dosing strategy was established based on phase 1 and 2 data in children and through pharmacokinetic (PK) modeling. Methods: Rivaroxaban treatment with tablets or the newly-developed granules-for-oral suspension formulation was bodyweight-adjusted and administered once-daily, twice-daily or thrice-daily for children with bodyweights of ≥30, ≥12

Contains fulltext : 219893.pdf (Publisher’s version ) (Closed access) BACKGROUND: Treatment of venous thromboembolism in children is based on data obtained in adults with little direct documentation of its efficacy and safety in children. The aim of our study was to compare the efficacy and safety of rivaroxaban versus standard anticoagulants in children with venous thromboembolism. METHODS: In a multicentre, parallel-group, open-label, randomised study, children (aged 0-17 years) attending 107 paediatric hospitals in 28 countries with documented acute venous thromboembolism who had started heparinisation were assigned (2:1) to bodyweight-adjusted rivaroxaban (tablets or suspension) in a 20-mg equivalent dose or standard anticoagulants (heparin or switched to vitamin K antagonist). Randomisation was stratified by age and venous thromboembolism site. The main treatment period was 3 months (1 month in children /=1 dose), were centrally assessed by investigators who were unaware of treatment assignment. Repeat imaging was obtained at the end of the main treatment period and compared with baseline imaging tests. This trial is registered with ClinicalTrials.gov, number NCT02234843 and has been completed. FINDINGS: From Nov 14, 2014, to Sept 28, 2018, 500 (96%) of the 520 children screened for eligibility were enrolled. After a median follow-up of 91 days (IQR 87-95) in children who had a study treatment period of 3 months (n=463) and 31 days (IQR 29-35) in children who had a study treatment period of 1 month (n=37), symptomatic recurrent venous thromboembolism occurred in four (1%) of 335 children receiving rivaroxaban and five (3%) of 165 receiving standard anticoagulants (hazard ratio [HR] 0.40, 95% CI 0.11-1.41). Repeat imaging showed an improved effect of rivaroxaban on thrombotic burden as compared with standard anticoagulants (p=0.012). Major or clinically relevant non-major bleeding in participants who received >/=1 dose occurred in ten (3%) of 329 children (all non-major) receiving rivaroxaban and in three (2%) of 162 children (two major and one non-major) receiving standard anticoagulants (HR 1.58, 95% CI 0.51-6.27). Absolute and relative efficacy and safety estimates of rivaroxaban versus standard anticoagulation estimates were similar to those in rivaroxaban studies in adults. There were no treatment-related deaths. INTERPRETATION: In children with acute venous thromboembolism, treatment with rivaroxaban resulted in a similarly low recurrence risk and reduced thrombotic burden without increased bleeding, as compared with standard anticoagulants. FUNDING: Bayer AG and Janssen Research & Development. 01 januari 2020

The EINSTEIN-Jr program will evaluate rivaroxaban for the treatment of venous thromboembolism (VTE) in children, targeting exposures similar to the 20 mg once-daily dose for adults. A physiologically based pharmacokinetic (PBPK) model for pediatric rivaroxaban dosing has been constructed. We quantitatively assessed the pharmacokinetics (PK) of a single rivaroxaban dose in children using population pharmacokinetic (PopPK) modelling and assessed the applicability of the PBPK model. Plasma concentration–time data from the EINSTEIN-Jr phase I study were analysed by non-compartmental and PopPK analyses and compared with the predictions of the PBPK model. Two rivaroxaban dose levels, equivalent to adult doses of rivaroxaban 10 mg and 20 mg, and two different formulations (tablet and oral suspension) were tested in children aged 0.5–18 years who had completed treatment for VTE. PK data from 59 children were obtained. The observed plasma concentration–time profiles in all subjects were mostly within the 90% prediction interval, irrespective of dose or formulation. The PopPK estimates and non-compartmental analysis-derived PK parameters (in children aged ≥6 years) were in good agreement with the PBPK model predictions. These results confirmed the applicability of the rivaroxaban pediatric PBPK model in the pediatric population aged 0.5–18 years, which in combination with the PopPK model, will be further used to guide dose selection for the treatment of VTE with rivaroxaban in EINSTEIN-Jr phase II and III studies. ClinicalTrials.gov number, NCT01145859 ; registration date: 17 June 2010.

Essentials In this crossover study the anticoagulant effects of rivaroxaban and apixaban were compared. Healthy volunteers received rivaroxaban 20 mg once daily or apixaban 5 mg twice daily. Rivaroxaban was associated with more prolonged inhibition of thrombin generation than apixaban. Rivaroxaban induced a clear prolongation of prothrombin time and activated partial thromboplastin time. SummaryBackground The anticoagulant actions of the oral direct activated factor Xa inhibitors, rivaroxaban and apixaban, have not previously been directly compared. Objectives To compare directly the steady-state pharmacokinetics and anticoagulant effects of rivaroxaban and apixaban at doses approved for stroke prevention in patients with non-valvular atrial fibrillation. Methods Twenty-four healthy Caucasian male volunteers were included in this open-label, two-period crossover, phase 1 study (EudraCT number: 2015-002612-32). Volunteers were randomized to receive rivaroxaban 20 mg once daily or apixaban 5 mg twice daily for 7 days, followed by a washout period of at least 7 days before they received the other treatment. Plasma concentrations and anticoagulant effects were measured at steady state and after drug discontinuation. Results Overall exposure was similar for both drugs: the geometric mean area under the plasma concentration–time curve for the 0–24-h interval was 1830 μg h L−1 for rivaroxaban and 1860 μg h L−1 for apixaban. Rivaroxaban was associated with greater inhibition of endogenous thrombin potential (geometric mean area under the curve relative to baseline during the 0–24-h interval: 15.5 h versus 17.5 h) and a more pronounced maximal prolongation relative to baseline of prothrombin time (PT) (1.66-fold versus 1.14-fold) and activated partial thromboplastin time (APTT) (1.43-fold versus 1.16-fold) at steady state than apixaban. Conclusions Despite similar exposure to both drugs, rivaroxaban 20 mg once daily was associated with greater and more sustained inhibition of thrombin generation than apixaban 5 mg twice daily. Sensitive PT and APTT assays can be used to estimate the anticoagulant effects of rivaroxaban.

Background Rivaroxaban has been shown to be efficacious for treatment of venous thromboembolism in adults, and has a reduced risk of bleeding compared with standard anticoagulants. We aimed to develop paediatric rivaroxaban regimens for the treatment of venous thromboembolism in children and adolescents. Methods In this phase 2 programme, we did three studies to evaluate rivaroxaban treatment in children younger than 6 months, aged 6 months to 5 years, and aged 6-17 years. Our studies used a multicentre, single-arm design at 54 sites in Australia, Europe, Israel, Japan, and north America. We included children with objectively confirmed venous thromboembolism previously treated with low-molecular weight heparin, fondaparinux, or a vitamin K antagonist for at least 2 months or, in children who had catheter-related venous thromboembolism for at least 6 weeks. We administered rivaroxaban orally in a bodyweight-adjusted 20 mg-equivalent dose, based on physiologically-based pharmacokinetic modelling predictions and EINSTEIN-Jr phase 1 data in young adults, in either a once-daily (tablets; for those aged 6-17 years), twice-daily (in suspension; for those aged 6 months to 11 years), or three times-daily (in suspension; for those younger than 6 months) dosing regimen for 30 days (or 7 days for those younger than 6 months). The primary aim was to define rivaroxaban treatment regimens that match the target adult exposure range. The principal safety outcome was major bleeding and clinically relevant non-major bleeding. Analyses were per-protocol. The predefined efficacy outcomes were symptomatic recurrent venous thromboembolism, asymptomatic deterioration on repeat imaging at the end of the study treatment period. These trials are registered at ClinicalTrials.gov, numbers NCT02564718, NCT02309411, and NCT02234843. Findings Between Feb 11, 2013, and Dec 20, 2017, we enrolled 93 children (ten children younger than 6 months; 15 children aged 6 months to 1 year; 25 children aged 2-5 years; 32 children aged 6-11 years; and 11 children aged 12-17 years) into our study. 89 (96%) children completed study treatment (30 days of treatment, or 7 days in those younger than 6 months), and 93 (100%) children received at least one dose of study treatment and were evaluable for the primary endpoints. None of the children had a major bleed, and four (4%, 95% CI 1.2-10.6) of these children had a clinically relevant non-major bleed (three children aged 12-17 years with menorrhagia and one child aged 6-11 years with gingival bleeding). We found no symptomatic recurrent venous thromboembolism in any patients (0%, 0.0-3.9). 24 (32%) of 75 patients with repeat imaging had their thrombotic burden resolved, 43 (57%) patients improved, and eight (11%) patients were unchanged. No patient deteriorated. We confirmed therapeutic rivaroxaban exposures with once-daily dosing in children with bodyweights of at least 30 kg and with twice-daily dosing in children with bodyweights of at least 20 kg and less than 30 kg. Children with low bodyweights (

Background: Treatment of venous thromboembolism (VTE) in children is based on data obtained in adults with little direct documentation of its efficacy and safety in children. Methods: In a parallel-group open-label randomised study, 500 children aged birth to 17 years with documented acute VTE who had started heparinisation were assigned, in a 2:1 ratio, to receive bodyweight-adjusted rivaroxaban (tablets or suspension) in a 20-mg equivalent dose or standard anticoagulants. The main treatment period was 3 months (1 month in children under 2 years with catheter-related VTE). Symptomatic recurrent VTE and bleeding were centrally assessed unaware of treatment assignment. Repeat imaging was obtained at the end of the treatment period. Findings: Recurrent VTE was the primary efficacy outcome and occurred in 4 of the 335 (1.2%) children allocated to rivaroxaban and in 5 of the 165 (3.0%) children allocated to standard anticoagulants (64.2% of whom received subcutaneous heparins only), for a hazard ratio of 0.40 (95% confidence interval, 0.11 to 1.41). Repeat imaging showed an improved effect of rivaroxaban on thrombotic burden as compared with standard anticoagulants (P=0.012). Major or clinically relevant non-major bleeding was the principal safety outcome and occurred in 10 children (3.0%; all non-major) with rivaroxaban and in 3 children (1.9%; two major and 1 non-major) with standard anticoagulants. Absolute and relative efficacy and safety estimates of rivaroxaban versus standard anticoagulation estimates were comparable those obtained in rivaroxaban studies in adults. Interpretation: In children with acute VTE, treatment with rivaroxaban resulted in a low recurrence risk and a reduced thrombotic burden without increased bleeding, as compared to standard anticoagulants. Trial Registration: This trial is registered with ClinicalTrials.gov, number NCT02234843. Funding Statement: Bayer AG and Janssen Research & Development, LLC. Declaration of Interests: CM reports receiving personal fees and fees, paid to his institution, from Bayer, Bristol-Myers-Squibb, Pfizer and fees, paid to his institution, from BoehringerIngelheim; AWAL being employed by Bayer; RK receiving personal fees from Bayer, CSL Behring, and Kedrion; DB receiving personal fees and grant support from Actelion Pharmaceuticals, Bayer, Eli Lilly, BMS, and Novartis and grant support from AbbVie; PC receiving personal fees from Onyx Health Limited; AKC receiving personal fees from Bayer and fees, paid to his institution, from Bayer, Pfizer, Daiichi Sankyo, and Bristol-Myers-Squibb; GK receiving personal fees from Bayer, Boehringer Ingelheim, and Daiichi-Sankyo and fees, paid to her institution from Pfizer; SH receiving personal fees from P and fees, paid to her institution, from Bayer, Pfizer, and Daiichi Sankyo; AS receiving personal fees from Bayer, Pfizer, Daiichi Sankyo and Boehringer Ingelheim; PA receiving personal fees and fees, paid to his institution, from Abbvie and Bayer, and fees paid to his institution from Actelion, Novartis, and Daiichi Sankyo; EC receiving personal fees from Boehringer Ingelheim and Bristol-Myers-Squibb, and fees, paid to her institution from Bayer, Pfizer, and Daiichi Sankyo; DLY receiving fees, paid to his institution, from Bayer, Pfizer, and Bristol-Myers Squibb; OL receiving personal fees from Bayer, Pfizer, Boehringer Ingelheim, and Novartis, and fees, paid to her institution, from Bayer; JB-W receiving personal fees and fees, paid to his institution, from Bayer, Daiichi Sankyo, DOASENSE and Portola and fees, paid to his institution, from Pfizer; TTB receiving fees from Boehringer Ingelheim and Bayer, and grant support from Leo Pharma; IM receiving fees from Sanofi and Bayer; MP receiving grant support from Pfizer and Sobi; MPM receiving personal fees from Bayer; GY receiving receiving personal fees from GlaxoSmithKline and Portola and personal fees and fees paid to his institution from Bayer and Daiichi Sankyo; AFP, MM, WTS, SDB, KT, DK being employed by Bayer; JH was employed by Bayer; MC receiving grant support from and serving on a data and safety monitoring board for Bayer, receiving advisory board fees from Shionogi, Octapharma, Bristol-Myers Squibb Canada, and Asahi Kasei, receiving educational funding from Alexion Pharmaceuticals, Pfizer, CSL Behring, and Diagnostica Stago, receiving grant support, paid to his institution, from Leo Pharma, serving on a data and safety monitoring board for Daiichi Sankyo, owning stock in Alnylam Pharmaceuticals, and receiving educational funding and advisory board fees from Servier Canada; MHP receiving personal fees from Bayer; no other potential conflict of interest relevant to this article was reported. Ethics Approval Statement: The protocol was approved by the institutional review board at each participating center. Written permission from a parent or guardian and, when appropriate, child assent, were obtained.

Background Because of the vulnerability and frailty of elderly adults, clinical drug development has traditionally been biased towards young and middle-aged adults. Recent efforts have begun to incorporate data from paediatric investigations. Nevertheless, the elderly often remain underrepresented in clinical trials, even though persons aged 65 years and older receive the majority of drug prescriptions. Consequently, a knowledge gap exists with regard to pharmacokinetic (PK) and pharmacodynamic (PD) responses in elderly subjects, leaving the safety and efficacy of medicines for this population unclear. Objectives The goal of this study was to extend a physiologically based pharmacokinetic (PBPK) model for adults to encompass the full course of healthy aging through to the age of 100 years, to support dose selection and improve pharmacotherapy for the elderly age group. Methods For parameterization of the PBPK model for healthy aging individuals, the literature was scanned for anthropometric and physiological data, which were consolidated and incorporated into the PBPK software PK-Sim®. Age-related changes that occur from 65 to 100 years of age were the main focus of this work. For a sound and continuous description of an aging human, data on anatomical and physiological changes ranging from early adulthood to old age were included. The capability of the PBPK approach to predict distribution and elimination of drugs was verified using the test compounds morphine and furosemide, administered intravenously. Both are cleared by a single elimination pathway. PK parameters for the two compounds in younger adults and elderly individuals were obtained from the literature. Matching virtual populations—with regard to age, sex, anthropometric measures and dosage—were generated. Profiles of plasma drug concentrations over time, volume of distribution at steady state (V ss) values and elimination half-life (t ½) values from the literature were compared with those predicted by PBPK simulations for both younger adults and the elderly. Results For most organs, the age-dependent information gathered in the extensive literature analysis was dense. In contrast, with respect to blood flow, the literature study produced only sparse data for several tissues, and in these cases, linear regression was required to capture the entire elderly age range. On the basis of age-informed physiology, the predicted PK profiles described age-associated trends well. The root mean squared prediction error for the prediction of plasma concentrations of furosemide and morphine in the elderly were improved by 32 and 49 %, respectively, by use of age-informed physiology. The majority of the individual V ss and t ½ values for the two model compounds, furosemide and morphine, were well predicted in the elderly population, except for long furosemide half-lifes. Conclusion The results of this study support the feasibility of using a knowledge-driven PBPK aging model that includes the elderly to predict PK alterations throughout the entire course of aging, and thus to optimize drug therapy in elderly individuals. These results indicate that pharmacotherapy and safety-related control of geriatric drug therapy regimens may be greatly facilitated by the information gained from PBPK predictions. Electronic supplementary material The online version of this article (doi:10.1007/s40262-016-0422-3) contains supplementary material, which is available to authorized users.

Background The EINSTEIN-Jr program will evaluate rivaroxaban for the treatment of venous thromboembolism (VTE) in children, targeting exposures similar to the 20 mg once-daily dose for adults. Methods This was a multinational, single-dose, open-label, phase I study to describe the pharmacodynamics (PD), pharmacokinetics (PK) and safety of a single bodyweight-adjusted rivaroxaban dose in children aged 0.5–18 years. Children who had completed treatment for a venous thromboembolic event were enrolled into four age groups (0.5–2 years, 2–6 years, 6–12 years and 12–18 years) receiving rivaroxaban doses equivalent to 10 mg or 20 mg (either as a tablet or oral suspension). Blood samples for PK and PD analyses were collected within specified time windows. Results Fifty-nine children were evaluated. In all age groups, PD parameters (prothrombin time, activated partial thromboplastin time and anti-Factor Xa activity) showed a linear relationship versus rivaroxaban plasma concentrations and were in line with previously acquired adult data, as well as in vitro spiking experiments. The rivaroxaban pediatric physiologically based pharmacokinetic model, used to predict the doses for the individual body weight groups, was confirmed. No episodes of bleeding were reported, and treatment-emergent adverse events occurred in four children and all resolved during the study. Conclusions Bodyweight-adjusted, single-dose rivaroxaban had predictable PK/PD profiles in children across all age groups from 0.5 to 18 years. The PD assessments based on prothrombin time and activated partial thromboplastin time demonstrated that the anticoagulant effect of rivaroxaban was not affected by developmental hemostasis in children. Trial registration ClinicalTrials.gov number, NCT01145859.

Background Venous thromboembolism (VTE) is a relatively rare condition in childhood with treatment mainly based on extrapolation from studies in adults. Therefore, clinical trials of anticoagulation in children require novel approaches to deal with numerous challenges. The EINSTEIN-Jr program identified pediatric rivaroxaban regimens commencing with in vitro dose finding studies followed by evaluation of children of different ages through phase I and II studies using extensive modeling to determine bodyweight-related doses. Use of this approach resulted in drug exposure similar to that observed in young adults treated with rivaroxaban 20 mg once-daily. Methods EINSTEIN-Jr phase III is a randomized, open-label, study comparing the efficacy and safety of rivaroxaban 20 mg-equivalent dose regimens with those of standard anticoagulation for the treatment of any types of acute VTE in children aged 0–18 years. A total of approximately 500 children are expected to be included during the 4-year study window. Flexibility of treatment duration is allowed with study treatment to be given for 3 months with the option to continue treatment in 3-month increments, up to a total of 12 months. However, based on most common current practice, children younger than 2 years with catheter-related thrombosis will have a main treatment period of 1 month with the option to prolong treatment in 1-month increments, up to a total of 3 months. Conclusions EINSTEIN-Jr will compare previously established 20 mg-equivalent rivaroxaban dosing regimens with standard anticoagulation for the treatment of VTE in children. Demonstration of similarity of disease, as well as equivalent rivaroxaban exposure and exposure-response will enable extrapolation of efficacy from adult trials, which is critical given the challenges of enrollment in pediatric anticoagulation trials. Trial registration Clinicaltrials.gov NCT02234843, registered on 9 September 2014.

Background: Venous thromboembolism (VTE) in young children is not well documented. Methods: Clinicians from 12 institutions retrospectively evaluated the presentation, therapeutic management, and outcome of VTE in children younger than 2 years seen in 2011-2016. Feasibility of recruiting these children in EINSTEIN-Jr. phase III, a randomized trial evaluating rivaroxaban versus standard anticoagulation for VTE, was assessed. Results: We identified 346 children with VTE, of whom 227 (65.6%) had central venous catheter-related thrombosis (CVC-VTE), 119 (34.4%) had non-CVC-VTE, and 156 (45.1%) were younger than 1 month. Of the 309 children who received anticoagulant therapy, 86 (27.8%) had a short duration of therapy (i.e. < 6 weeks for CVC-VTE and < 3 months for non-CVC-VTE) and 17 (5.5%) had recurrent VTE during anticoagulation (n = 8, 2.6%) or shortly after its discontinuation (n = 9, 2.9%). A total of 37 (10.7%) children did not receive anticoagulant therapy and 4 (10.5%) had recurrent VTE. The average number of children aged < 0.5 years and 0.5-2 years who would have been considered for enrolment in EINSTEIN-Jr is approximately 1.0 and 0.9 per year per site, respectively. Conclusions: Young children with VTE most commonly have CVC-VTE and approximately one-tenth and one-fourth received no or only short durations of anticoagulant therapy, respectively. Recurrent VTE rates without anticoagulation, during anticoagulation or shortly after its discontinuation seem comparable to those observed in adults. Short and flexible treatment durations could potentially increase recruitment in EINSTEIN-Jr. phase III.

Aims Evidence suggests that the rate of oral drug absorption changes during early childhood. Yet, respective clinical implications are currently unclear, particularly for preterm neonates. The objective of this study was to evaluate changes in oral drug absorption after birth for different Biopharmaceutics Classification System (BCS) class I and II compounds to better understand respective implications for paediatric pharmacotherapy. Methods Two paradigm compounds were selected for BCS class I (paracetamol (acetaminophen) and theophylline) and II (indomethacin and ibuprofen), respectively, based on the availability of clinical literature data following intravenous and oral dosing. A comparative population pharmacokinetic analysis was performed in a step-wise manner in nonmem® 7.2 to characterize and predict changes in oral drug absorption after birth for paracetamol, theophylline and indomethacin. Results A one compartment model with an age-dependent maturation function for oral drug absorption was found appropriate to characterize the pharmacokinetics of paracetamol. Our findings indicate that the rate at which a drug is absorbed from the GI tract reaches adult levels within about 1 week after birth. The maturation function for paracetamol was found applicable to theophylline and indomethacin once solubility limitations were overcome via drug formulation. The influence of excipients on solubility and, hence, oral bioavailability was confirmed for ibuprofen, a second BCS class II compound. Conclusions The findings of our study suggest that the processes underlying changes in oral drug absorption after birth are drug-independent and that the maturation function identified for paracetamol may be generally applicable to other BCS class I and II compounds for characterizing drug absorption in preterm as well as term neonates.

The physiological absorption model presented in part I of this work is now extended to account for dosage-form-dependent gastrointestinal (GI) transit as well as disintegration and dissolution processes of various immediate-release and modified-release dosage forms. Empirical functions of the Weibull type were fitted to experimental in vitro dissolution profiles of solid dosage forms for eight test compounds (aciclovir, caffeine, cimetidine, diclofenac, furosemide, paracetamol, phenobarbital, and theophylline). The Weibull functions were then implemented into the model to predict mean plasma concentration-time profiles of the various dosage forms. On the basis of these dissolution functions, pharmacokinetics (PK) of six model drugs was predicted well. In the case of diclofenac, deviations between predicted and observed plasma concentrations were attributable to the large variability in gastric emptying time of the enteric-coated tablets. Likewise, oral PK of furosemide was found to be predominantly governed by the gastric emptying patterns. It is concluded that the revised model for GI transit and absorption was successfully integrated with dissolution functions of the Weibull type, enabling prediction of in vivo PK profiles from in vitro dissolution data. It facilitates a comparative analysis of the parameters contributing to oral drug absorption and is thus a powerful tool for formulation design.

Within the last decades, computational models have developed rapidly and some of these models have proven useful in understanding how physiological, physicochemical and formulation factors affect oral drug absorption. Nowadays, complex computer-based absorption models are being used as standard tools in both academia and the pharmaceutical industry at several stages of the drug development process.Areas covered include the progress of computational tools for predicting drug absorption. The various qualitative and quantitative approaches that have been proposed are summarized, with special emphasis on a key tool for predicting oral drug absorption, physiologically based pharmacokinetic modeling (PBPK). The theories of the different models are described and recent applications within drug research and development are summarized and evaluated. Additionally, the current state of computational absorption models is discussed, including areas for potential improvements.The field of pharmacokinetics modeling has undergone a major transformation over the last 10 - 20 years and there will most likely be even more exciting developments ahead. With the availability of generic physiologically based absorption models, more and more case examples using PBPK models have been published that demonstrate either improved ability to predict oral drug absorption or have allowed a more mechanistic interpretation of experimentally observed data.

Delayed absorption of nifedipine when administered as a 20 mg immediate release soft gelatin capsule to fasted volunteers has been reported. Physiologically based pharmacokinetic (PBPK) modeling and in vitro dissolution data were used to explore our hypothesis that at high doses of nifedipine it precipitates in the stomach. Plasma concentration-time profiles following different doses of nifedipine were simulated using commercial PBPK software and compared to in vivo data. In vitro dissolution tests were performed with Adalat 10 mg capsules in different volumes of fasted state simulated gastric fluid (FaSSGF). The discrepancy in plasma concentration-time profiles between the different nifedipine doses could be well simulated, assuming protracted dissolution for the 20 mg dose. Nifedipine release from one Adalat 10 capsule in 250 or 500 mL FaSSGF was completed within 15 min whereas when release from two capsules, corresponding to 20 mg nifedipine, was studied in 250 mL FaSSGF, a maximum of about 75% drug dissolved was observed after 15 min followed by a decline in the % dissolved to a final value of approximately 40%. Based on the in silico and in vitro results it can be concluded that the observed prolongation in nifedipine absorption following the 20 mg dose was likely caused by nifedipine precipitation in human stomach.

Objectives Inter-individual variability of gastrointestinal physiology and transit properties can greatly influence the pharmacokinetics of an orally administered drug in vivo. To predict the expected range of pharmacokinetic plasma concentrations after oral drug administration, a physiologically based pharmacokinetic population model for gastrointestinal transit and absorption was developed and evaluated. Methods Mean values and variability measures of model parameters affecting the rate and extent of cimetidine absorption, such as gastric emptying, intestinal transit times and effective surface area of the small intestine, were obtained from the literature. Various scenarios incorporating different extents of inter-individual physiological variability were simulated and the simulation results were compared with experimental human study data obtained after oral cimetidine administration of four different tablets with varying release kinetics. Key findings The inter-individual variability in effective surface area was the largest contributor to absorption variability. Based on in-vitro dissolution profiles, the mean plasma cimetidine concentration–time profiles as well as the inter-individual variability could be well described for three cimetidine formulations. In the case of the formulation with the slowest dissolution kinetic, model predictions on the basis of the in-vitro dissolution profile underestimated the plasma exposure. Conclusions The model facilitates predictions of the inter-individual pharmacokinetic variability after oral drug administration for immediate and extended-release formulations of cimetidine, given reasonable in-vitro dissolution kinetics.

Objective Although the human small intestine serves primarily as an absorptive organ for nutrients and water, it also has the ability to metabolise drugs. Interest in the small intestine as a drug-metabolising organ has been increasing since the realisation that it is probably the most important extrahepatic site of drug biotransformation. Key findings Among the metabolising enzymes present in the small intestinal mucosa, the cytochromes P450 (CYPs) are of particular importance, being responsible for the majority of phase I drug metabolism reactions. Many drug interactions involving induction or inhibition of CYP enzymes, in particular CYP3A, have been proposed to occur substantially at the level of the intestine rather than exclusively within the liver, as originally thought. CYP3A and CYP2C represent the major intestinal CYPs, accounting for approximately 80% and 18%, respectively, of total immunoquantified CYPs. CYP2J2 is also consistently expressed in the human gut wall. In the case of CYP1A1, large interindividual variation in the expression levels has been reported. Data for the intestinal expression of the polymorphic CYP2D6 are conflicting. Several other CYPs, including the common hepatic isoform CYP2E1, are expressed in the human small intestine to only a very low extent, if at all. The distribution of most CYP enzymes is not uniform along the human gastrointestinal tract, being generally higher in the proximal regions of the small intestine. Summary This article reviews the current state of knowledge of CYP enzyme expression in human small intestine, the role of the gut wall in CYP-mediated metabolism, and how this metabolism limits the bioavailability of orally administered drugs. Possible interactions between drugs and CYP activity in the small intestine are also discussed.

Among pediatric patients, preterm neonates and newborns are the most vulnerable subpopulation. Rapid developmental changes of physiological factors affecting the pharmacokinetics of drug substances in newborns require extreme care in dose and dose regimen decisions. These decisions could be supported by in silico methods such as physiologically-based pharmacokinetic (PBPK) modeling. In a comprehensive literature search, the physiological information of preterm neonates that is required to establish a PBPK model has been summarized and implemented into the database of a generic PBPK software. Physiological parameters include the organ weights and blood flow rates, tissue composition, as well as ontogeny information about metabolic and elimination processes in the liver and kidney. The aim of this work is to evaluate the model's accuracy in predicting the pharmacokinetics following intravenous administration of two model drugs with distinct physicochemical properties and elimination pathways based on earlier reported in vivo data. To this end, PBPK models of amikacin and paracetamol have been set up to predict their plasma levels in preterm neonates. Predicted plasma concentration-time profiles were compared to experimentally obtained in vivo data. For both drugs, plasma concentration time profiles following single and multiple dosing were appropriately predicted for a large range gestational and postnatal ages. In summary, PBPK simulations in preterm neonates appear feasible and might become a useful tool in the future to support dosing decisions in this special patient population. ispartof: Current Pharmaceutical Design vol:21 issue:39 pages:5688-5698 ispartof: location:United Arab Emirates status: published

Background Venous thromboembolism has been increasingly recognised as a clinical problem in the paediatric population. Guideline recommendations for antithrombotic therapy in paediatric patients are based mainly on extrapolation from adult clinical trial data, owing to the limited number of clinical trials in paediatric populations. The oral, direct Factor Xa inhibitor rivaroxaban has been approved in adult patients for several thromboembolic disorders, and its well-defined pharmacokinetic and pharmacodynamic characteristics and efficacy and safety profiles in adults warrant further investigation of this agent in the paediatric population. Objective The objective of this study was to develop and qualify a physiologically based pharmacokinetic (PBPK) model for rivaroxaban doses of 10 and 20 mg in adults and to scale this model to the paediatric population (0–18 years) to inform the dosing regimen for a clinical study of rivaroxaban in paediatric patients. Methods Experimental data sets from phase I studies supported the development and qualification of an adult PBPK model. This adult PBPK model was then scaled to the paediatric population by including anthropometric and physiological information, age-dependent clearance and age-dependent protein binding. The pharmacokinetic properties of rivaroxaban in virtual populations of children were simulated for two body weight-related dosing regimens equivalent to 10 and 20 mg once daily in adults. The quality of the model was judged by means of a visual predictive check. Subsequently, paediatric simulations of the area under the plasma concentration–time curve (AUC), maximum (peak) plasma drug concentration (Cmax) and concentration in plasma after 24 h (C24h) were compared with the adult reference simulations. Results Simulations for AUC, Cmax and C24h throughout the investigated age range largely overlapped with values obtained for the corresponding dose in the adult reference simulation for both body weight-related dosing regimens. However, pharmacokinetic values in infants and preschool children (body weight 70 kg body weight, the simulated 90 % prediction interval values of AUC and C24h were much higher than the 90 % confidence interval of the adult reference population, owing to the weight-based simulation approach, but for these patients rivaroxaban would be administered at adult fixed doses of 10 and 20 mg. Conclusion The paediatric PBPK model developed here allowed an exploratory analysis of the pharmacokinetics of rivaroxaban in children to inform the dosing regimen for a clinical study in paediatric patients. Electronic supplementary material The online version of this article (doi:10.1007/s40262-013-0090-5) contains supplementary material, which is available to authorized users.

One of the most prominent food-drug interactions is the inhibition of intestinal cytochrome P450 (CYP) 3A enzymes by grapefruit juice ingredients, and, as many drugs are metabolized via CYP 3A, this interaction can be of clinical importance. Calcium channel-blocking agents of the dihydropyridine type, such as felodipine and nifedipine, are subject to extensive intestinal first pass metabolism via CYP 3A, thus resulting in significantly enhanced in vivo exposure of the drug when administered together with grapefruit juice. Physiologically based pharmacokinetic (PBPK) modeling was used to simulate pharmacokinetics of a nifedipine immediate release formulation following concomitant grapefruit juice ingestion, that is, after inhibition of small intestinal CYP 3A enzymes. For this purpose, detailed data about CYP 3A levels were collected from the literature and implemented into commercial PBPK software. As literature reports show that grapefruit juice (i) leads to a marked delay in gastric emptying, and (ii) rapidly lowers the levels of intestinal CYP 3A enzymes, inhibition of intestinal first pass metabolism following ingestion of grapefruit juice was simulated by altering the intestinal CYP 3A enzyme levels and simultaneously decelerating the gastric emptying rate. To estimate the in vivo dispersion and dissolution behavior of the formulation, dissolution tests in several media simulating both the fasted and fed state stomach and small intestine were conducted, and the results from the in vitro dissolution tests were used as input function to describe the in vivo dissolution of the drug. Plasma concentration-time profiles of the nifedipine immediate release formulation both with and without simultaneous CYP 3A inhibition were simulated, and the results were compared with data gathered from the literature. Using this approach, nifedipine plasma profiles could be simulated well both with and without enzyme inhibition. A reduction in small intestinal CYP 3A levels by 60% was found to yield the best results, with simulated nifedipine concentration-time profiles within 20% of the in vivo observed results. By additionally varying the dissolution input of the PBPK model, a link between the dissolution characteristics of the formulation and its in vivo performance could be established.

Objectives In-silico methods are a cost-effective possibility to support decision making at different stages of the drug development process. Among the various computational methods available, physiologically-based pharmacokinetic (PBPK) modelling represents a well-established tool for mechanistically predicting the pharmacokinetics of drugs and drug candidates. PK-Sim, a component of the Computational Systems Biology Software Suite of Bayer Technology Services GmbH (Leverkusen, Germany) is a commercial PBPK software tool. It is based on a generic model structure for typical animal species from mice to monkey and humans, and allows simultaneous simulation of drug liberation, absorption, distribution, metabolism, and excretion in one model. In this study PK-Sim has been used for the prediction of the in-vivo pharmacokinetics of drugs with a particular focus on the integration of dissolution properties and, due to its leading role in the drug development process, for the performance of different dosage forms administered via the oral route. Methods Three real life case studies have been presented to exemplify the benefits of using PBPK absorption modelling. Key findings In the first example, the in-vivo dissolution rate was directly predicted from the physical properties of different particle formulations using a mechanistic dissolution model of the Noyes–Whitney type. In the second case study, the PBPK tool was successfully used to predict the food effect in humans based on data obtained in Beagle dogs. In the third example, the utilization of the software for the support of the development of a combined immediate release–controlled release formulation has been described. Conclusions Future perspectives of the use of PBPK modelling have been discussed, with a special focus on the integration of in-vitro dissolution data into PBPK models for oral and non-oral administration of drugs.

Today, in silico studies and trial simulations already complement experimental approaches in pharmaceutical R&D and have become indispensable tools for decision making and communication with regulatory agencies. While biology is multi-scale by nature, project work and software tools usually focus on isolated aspects of drug action, such as pharmacokinetics at the organism scale or pharmacodynamic interaction on the molecular level. We present a modeling and simulation software platform consisting of PK-Sim® and MoBi® capable of building and simulating models that integrate across biological scales. A prototypical multiscale model for the progression of a pancreatic tumor and its response to pharmacotherapy is constructed and virtual patients are treated with a prodrug activated by hepatic metabolization. Tumor growth is driven by signal transduction leading to cell cycle transition and proliferation. Free tumor concentrations of the active metabolite inhibit Raf kinase in the signaling cascade and thereby cell cycle progression. In a virtual clinical study, the individual therapeutic outcome of the chemotherapeutic intervention is simulated for a large population with heterogeneous genomic background. Thereby, the platform allows efficient model building and integration of biological knowledge and prior data from all biological scales. Experimental in vitro model systems can be linked with observations in animal experiments and clinical trials. The interplay between patients, diseases, and drugs and topics with high clinical relevance such as the role of pharmacogenomics, drug-drug or drug-metabolite interactions can be addressed using this mechanistic, insight driven multiscale modeling approach.

To enable more precise prediction of oral drug absorption, an existing physiologically based absorption model was revised. The revised model reflects detailed knowledge of human gastrointestinal (GI) physiology including fluid secretion and absorption, and comprises an elaborate representation of the intestinal mucosa. The alimentary canal from the stomach to the rectum was divided into 12 compartments. A mucosal compartment was added to each luminal segment of the intestine. A training set of 111 passively absorbed drugs with reported fractions of dose absorbed was used to optimize the semiempirical equation, which calculates intestinal permeability coefficients. The model was subsequently integrated into an established physiologically based pharmacokinetic software and validated by prediction of plasma concentration-time profiles of eight test compounds with diverse physicochemical properties. A good correlation between the simulated and experimental fractions of dose absorbed was established for the 111 compounds in the training set. Subsequently, the concentration-time profiles of six out of eight test compounds were predicted with high accuracy. The detailed model for GI transit and absorption presented in this study can help to understand the complex processes of oral absorption better and will be useful during the drug development process.

A previously developed physiologically based pharmacokinetic (PBPK) model for gastro-intestinal transit and absorption was combined with a mechanistic dissolution model of the Noyes-Whitney type for spherical particles with a predefined particle size distribution. To validate the combined model, the plasma concentration-time curves for cilostazol obtained in beagle dogs using three different types of suspensions with varying particle diameters were simulated. In vitro dissolution information was also available for different formulations, but this data could only predict the in vivo outcome qualitatively. The mechanistic PBPK model, on the other hand, could predict the influence of the particle size on the rate and extent of absorption under both fasted and fed conditions accurately, and the gap between the in vitro dissolution data and the in vivo outcome could successfully be explained. We conclude that by integrating the processes of particle dissolution, gastro-intestinal transit and permeation across the intestinal epithelium into a mechanistic model, oral drug absorption from suspensions can be predicted quantitatively. The model can be applied readily to typical formulation development data packages to better understand the relative importance of dissolution and permeability and pave the way for successful formulation of solid dosage forms.

Although several routes of administration can be considered for new drug entities, the oral route remains the most popular. To predict the in vivo performance of a drug after oral administration from in vitro data, it is essential that the factors limiting absorption can be modelled. Factors limiting oral drug absorption are typically slow and/or incomplete dissolution, formation of insoluble complexes and/or decomposition in the gastrointestinal lumen, poor net permeability and first-pass metabolism. Although many attempts have been made to make global forecasts of oral bioavailability based on a single parameter (ranging from the partition coefficient [logP] to the polar surface area), it is clear from the diversity of properties that can influence delivery of drugs via the oral route that such an approach can at best lead to a qualitative estimation. To predict in vivo performance in a more quantitative way, it is instead necessary to identify the extent to which each of the aforementioned factors can limit absorption, and then combine the information into a comprehensive model of the absorptive processes. Much progress has been made in the last 10 years on developing methods to pin down the extent to which each of the factors actually limits the absorption of a given compound and, concomitantly, physiological models have been evolved, which show promise in terms of being able to integrate the information generated about each of the individual limiting factors. This article attempts to summarize recent progress on the various fronts as a kind of 'progress report' towards quantitative prediction of oral drug absorption.