Karl-Heinz Liesenfeld

Effective elimination of dabigatran by haemodialysis. A phase I single-centre study in patients with end-stage renal disease.

Dabigatran, a specific, reversible direct thrombin inhibitor, is used to prevent ischaemic and haemorrhagic strokes in patients with atrial fibrillation. As with every anticoagulant, there is a need to rapidly reverse its effects in emergency situations. In an open-label, single-centre phase I study with two fixed multiple dosing periods, we investigated the pharmacokinetics, pharmacodynamics and safety of dabigatran before, during and after 4 hour haemodialysis sessions with either 200 or 400 ml/min targeted blood flow in seven end-stage renal disease patients without atrial fibrillation. Dabigatran was administered over three days in a regimen designed to achieve peak plasma concentrations comparable to those observed in atrial fibrillation patients receiving 150 mg b.i.d. and to attain adequate distribution of dabigatran in the central and peripheral compartments. Plasma concentration-time profiles were similar in both periods on Day 3 (Cmax: 176 and 159 ng/ml). Four hours of haemodialysis removed 48.8% and 59.3% of total dabigatran from the central compartment with 200 and 400 ml/minute targeted blood flow, respectively. The anticoagulant activity of dabigatran was linearly related to its plasma levels. There was a minor redistribution of dabigatran (<16%) after the end of the haemodialysis session. In conclusion, a 4 hour haemodialysis session can rapidly eliminate a substantial amount of dabigatran from the central compartment with a concomitant marked reduction in its anticoagulant activity. There was a clinically negligible redistribution of dabigatran after haemodialysis. These results demonstrate that haemodialysis can be a suitable approach to eliminate dabigatran in emergency situations.

Population pharmacokinetic analysis of the new oral thrombin inhibitor dabigatran etexilate (BIBR 1048) in patients undergoing primary elective total hip replacement surgery.

Dabigatran etexilate (BIBR 1048) is an orally bioavailable double prodrug of the active principle dabigatran (BIBR 953 ZW), which exerts potent anticoagulant and antithrombotic activity. The objective of the analysis was to develop a population pharmacokinetic model characterizing and quantifying the relationship between covariates and model parameters. A total of 4604 BIBR 953 ZW plasma concentrations, obtained from 287 patients after once‐ or twice‐daily oral dosing for up to 10 days after surgery in the dose range 12.5, 25, 50, 100, 150, 200, and 300 mg BIBR 1048, were available for the analysis. All the analyses were performed with NONMEN V. Pharmacokinetics of dabigatran were best described by a 2‐compartment model. The data supported the estimation of different apparent first‐order absorption rate constants (ka) and apparent plasma clearances (CL/F) for days 0 and 1 and days 2 to 10 after surgery. Parameter estimates indicated a flip‐flop phenomenon. Age and serum creatinine influenced ka, whereas gastrin and creatinine clearance, only for days 2 to 10, affected CL/F (P < .001). The typical values for CL/F for a patient with gastrin of 34.58 pmol/L and creatinine clearance of 76.16 mL/min were 70.87 and 106.2 L/h on days 0 and 1 and days 2 to 10, respectively. The differences found in the pharmacokinetics of dabigatran during the first 24 hours after surgery are most likely due to alterations in gastric motility and pH following surgery. As a consequence, the rate of absorption is reduced and interindividual variability in drug exposure increased. On the following days, the disposition in plasma of BIBR 953 ZW is less variable.

Dabigatran Etexilate in Atrial Fibrillation Patients With Severe Renal Impairment: Dose Identification Using Pharmacokinetic Modeling and Simulation

Dabigatran, administered orally as the prodrug dabigatran etexilate (DE), is a direct thrombin inhibitor shown to be effective in the prevention of stroke and systemic embolism in patients with atrial fibrillation (AF). The aim of this analysis was to derive a modeling and simulation‐based dose and dosing regimen for AF patients with severe renal failure who could potentially benefit from the use of DE. The exposure was simulated for AF patients with severe renal impairment for several combinations of doses (75, 110, 150 mg) and posologies (BID, QD, Q2D). Simulations were based on a population pharmacokinetic model derived from data from 9522 patients from the pivotal phase III study (RE‐LY). Atrial fibrillation patients with a creatinine clearance (CRCL) of <30 to ≥15 mL/min treated with a dose of 75 mg DE BID have target plasma level and exposure data largely within the concentration range proven to be safe and effective in AF patients with CRCL >30 mL/min receiving 150 mg BID. This dosing algorithm was also confirmed and supported by the United States Food and Drug Administration Clinical Pharmacology Division using their model based on the data from the dedicated renal impairment study and taking into account the safety and efficacy information from RE‐LY.

A combined pharmacometric analysis of dabigatran etexilate in healthy volunteers and patients with atrial fibrillation or undergoing orthopaedic surgery

Dabigatran etexilate is the orally bioavailable pro-drug of dabigatran, a direct thrombin inhibitor. Using data from eight clinical studies in healthy volunteers and patients with non-valvular atrial fibrillation (AF) or undergoing orthopaedic surgery (OS), population pharmacokinetic (PK) and pharmacodynamic (PD) models were developed to investigate whether the PK and PD of dabigatran differ across different populations. In both healthy volunteers (n=80) and patients (n=1,965), the PK of dabigatran was best described by a two-compartment disposition model with first-order absorption and elimination. Renal function was the only covariate shown to have a clinically relevant impact on dabigatran exposure. The patient PK model was successfully applied in predicting exposure observed in the RE-LY trial evaluating dabigatran treatment in patients with non-valvular AF. The relationship between dabigatran plasma concentrations and activated partial thromboplastin time in healthy volunteers and patients (n=762) was best described with a combination of a linear model and a maximum effect (Emax) model, consistent with previous reports. PK/PD relationships were robust across the various populations tested and were not affected by any of the covariates examined. In summary, the PK of dabigatran is sufficiently consistent to allow extrapolation of data generated in healthy volunteers to patients with AF or undergoing OS.

Dabigatran treatment simulation in patients undergoing maintenance haemodialysis

Patients with atrial fibrillation requiring maintenance haemodialysis are at increased risk of ischaemic stroke and bleeds. Currently, vitamin K antagonists such as warfarin are predominantly used in these patients as limited data are available on the use of non-vitamin K oral anticoagulants, including dabigatran etexilate (dabigatran). Dabigatran is approximately 85 % renally eliminated, thus, its half-life is prolonged in renal impairment. This study simulated the doseexposure relationship of dabigatran in patients undergoing haemodialysis. Dabigatran exposure was modelled at once- and twice-daily doses of 75 mg, 110 mg and 150 mg and at variations in non-renal clearance and dialysis settings. Resultant dose exposure (area under the curve [AUC]) was compared with values simulated from typical patients in the RE-LY® trial (based on a previously characterised pharmacometric model). In this simulation, all twice-daily dosages resulted in exposures above those simulated from typical RE-LY patients (1.5- to 3.3-fold increase in AUC) and thus may not be optimal for use in haemodialysis patients. However, dabigatran doses of 75 mg or 110 mg once daily produced exposures comparable to those simulated in typical RE-LY patients (-13.3 and +4.4 %, respectively). Of patient and dialysis variables, non-renal clearance had the highest impact on exposure (≤ 30.8 % change). These data could potentially inform dose selection in patients undergoing maintenance haemodialysis and the findings warrant investigation in future clinical trials.

Population pharmacokinetic analysis of the oral thrombin inhibitor dabigatran etexilate in patients with non‐valvular atrial fibrillation from the RE‐LY trial: reply to a rebuttal

See also Liesenfled K‐H, Lehr T, Dansirikul C, Reilly PA, Connolly SJ, EzekowitzMD, Yusuf S,Wallentin L, Haertter S, Staab A. Population pharmacokinetic analysis of the oral thrombin inhibitor dabigatran etexilate in patients with non‐valvular atrial fibrillation from the RE‐LY trial. J Thromb Haemost 2011; 9: 2168–75; and Patel JP, Green B, Patel RK, Davies JG, Arya R. Population pharmacokinetic analysis of the oral thrombin inhibitor dabigatran etexilate in patients with non‐valvular atrial fibrillation from the RE‐LY trial: a rebuttal. This issue, pp 500–2.

Evaluation of Pharmacokinetics and Pharmacodynamics of BI 425809, a Novel GlyT1 Inhibitor: Translational Studies

BI 425809 is a potent and selective glycine transporter 1 (GlyT1) inhibitor being developed for the treatment of cognitive impairment in Alzheimer disease and schizophrenia. Translational studies evaluated the effects of BI 425809 on glycine levels in rat and human cerebrospinal fluid (CSF). Oral administration of BI 425809 in rats induced a dose‐dependent increase of glycine CSF levels from 30% (0.2 mg/kg, not significant) to 78% (2 mg/kg, P < 0.01), relative to vehicle. Similarly, oral administration of BI 425809 in healthy volunteers resulted in a dose‐dependent increase in glycine CSF levels at steady state, with a mean 50% increase at doses as low as 10 mg. The peak plasma concentration (Cmax) of BI 425809 was achieved earlier in plasma than in CSF (tmax 3–5 vs. 5–8 hours, respectively). Generally, BI 425809 was safe and well tolerated. These data provide evidence of functional target engagement of GlyT1 by BI 425809.

PHARMACOKINETICS OF SINGLE AND MULTIPLE RISING DOSES OF BI 425809, A NEW GLYT1 INHIBITOR, IN YOUNG AND ELDERLY HEALTHY VOLUNTEERS

Background:Omega-3 fatty acids (O-3 FAs) are highly vulnerable to oxidative damage. This study investigated whether pre-treatment oxidative stress, measured by the lipid peroxidation marker 4-hydroxynoneal (4-HNE), predicted efficacy of O-3 FA supplementation for improving immediate recall in patients with stable coronary artery disease (CAD). Methods: Immediate recall was measured by the mean of Z-scores from the immediate recall sections of the California Verbal Learning Test II and Brief Visuospatial Memory Test-Revised. Patients were then randomized (1:1) to receive 1.9 g/day O-3 FA supplements or a placebo for 12 weeks as part of the CAROTID trial (NCT00981383). Immediate recall was reassessed at week 12. Baseline serum 4-HNE concentrations were analysed from fasting blood. Repeated measures linear models were used to investigate the interaction between 4-HNE and O-3 FA efficacy. Results:86 CAD patients (age1⁄461.468.5, 77% male, n1⁄440 O-3 FA, n1⁄446 placebo) were included. Baseline immediate recall performance (F1,851⁄40.74, p1⁄4.39) and serum 4-HNE concentrations (F1,851⁄40.02, p1⁄4.90) were not different between the treatment groups. O-3 FA treatment did not increase immediate recall performance over 12 weeks compared to placebo (treatment x time interaction: F1,851⁄40.34, p1⁄4.56). Higher baseline 4-HNE concentrations predicted greater improvements in immediate recall over 12 weeks in the O-3 FA group (F1,391⁄45.34, p1⁄4.03), but not in the placebo (F1,451⁄40.21, p1⁄4.65). Conclusions: These findings suggest that greater pre-treatment oxidative stress might predict greater improvements in immediate recall with O-3 FA treatment. Future work may clarify the relationship between oxidative stress and O-3 FAmetabolism as it pertains to potential cognitive efficacy.