Oral bioavailability of dabigatran etexilate (Pradaxa(®) ) after co-medication with verapamil in healthy subjects.

AIM: To investigate the effect of the P-glycoprotein inhibitor verapamil on the pharmacokinetics and pharmacodynamics of dabigatran etexilate (DE). METHOD: In this two part multiple crossover trial in 40 healthy subjects, DE 150 mg was given alone or with verapamil at different doses, duration of treatment (single vs. multiple dosing), formulations, and timings (before, concurrently or after DE). Primary pharmacokinetic endpoints were determined from concentrations of total dabigatran (unconjugated plus conjugated). Pharmacodynamic endpoints were determined from clotting time. RESULTS: The greatest effect was observed with single dose verapamil 120 mg immediate release given 1 h before single dose DE. Geometric mean area under the plasma concentration curve [AUC(0,∞)] and maximum analyte concentration in the plasma (Cmax ) were increased by 143% [90% confidence interval (CI) 91, 208] and 179% (90% CI 115, 262), respectively. The effect was reduced to a 71% and 91% increase in AUC and Cmax , respectively, when DE was administered with verapamil 240 mg extended release. After multiple verapamil dosing, DE AUC(0,∞) and Cmax increases were 54% and 63%, respectively. However, DE given 2 h before verapamil increased DE AUC(0,∞) and Cmax by <20%. With regard to clotting prolongation, the dabigatran plasma concentration-effect relationship was generally not affected by the co-administration of verapamil. Concomitant administration of DE and verapamil did not reveal any unexpected safety findings. CONCLUSION: Verapamil increased DE bioavailability, likely due to inhibition of P-glycoprotein. Our results suggest that an interaction between verapamil and DE can be minimized if DE is administered 2 h prior to verapamil.

Pharmacokinetic and pharmacodynamic effects of comedication of clopidogrel and dabigatran etexilate in healthy male volunteers.

PURPOSE: To evaluate the pharmacokinetic and pharmacodynamic effects of concomitant administration of single loading doses of clopidogrel or multiple doses of clopidogrel with multiple doses of dabigatran etexilate. METHODS: This was an open-label trial in healthy male subjects. In part 1 (pilot, n = 8) and part 3 (n = 12), a single dose of clopidogrel (300 or 600 mg, respectively) was given concomitantly with dabigatran etexilate at steady state; part 2 was a randomized, multiple-dose, crossover study with the test treatment being clopidogrel at steady state [300 mg loading dose on day 1, then 75 mg once daily (qd)] with concomitant dabigatran. RESULTS: Bioavailability was moderately increased when a loading dose of clopidogrel (300 mg in part 1 and 600 mg in part 3) was administered concomitantly with dabigatran etexilate 150 mg twice daily (bid). Test/reference ratios for AUC(τ,ss) were 135% (90% CI 107-169%) and 132% (90% CI 112-156%), respectively. Steady-state dosing of clopidogrel 75 mg qd and dabigatran etexilate 150 mg bid (part 2) demonstrated minor effects on dabigatran pharmacokinetics (AUC(τ,ss) ratio test/reference: 91.9%, 90% CI 78.7-107%) or its pharmacokinetic/pharmacodynamic relationships (activated partial thromboplastin time, ecarin clotting time, thrombin time). Similarly, clopidogrel bioavailability remained unchanged by chronic administration of dabigatran etexilate (part 3: ratio test/reference for AUC(0-24) was 103%; 90% CI 80.3-131%), as did its pharmacodynamic effects on the inhibition of platelet aggregation. CONCLUSIONS: When given concomitantly, dabigatran etexilate and clopidogrel at clinically relevant doses did not appear to have significant effects on the pharmacokinetic and pharmacodynamic profiles of either agent.

A comparison of dabigatran etexilate with warfarin in patients with mechanical heart valves: THE Randomized, phase II study to evaluate the safety and pharmacokinetics of oral dabigatran etexilate in patients after heart valve replacement (RE-ALIGN).

BACKGROUND: Vitamin K antagonists are the only oral anticoagulants approved for long-term treatment of patients with a cardiac valve replacement. OBJECTIVE: This study aims to test a new dosing regimen for dabigatran etexilate in patients with a mechanical bileaflet valve. METHODS: Patients aged ≥ 18 years and ≤ 75 years, either undergoing implantation of a mechanical bileaflet valve (aortic or mitral or both) during the current hospital stay or having undergone implantation a mitral bileaflet valve >3 months before randomization, will be randomized between dabigatran etexilate or warfarin (in a ratio of 2:1) in an open-label design. Initial doses of dabigatran will be based on the estimated creatinine clearance, and the doses will be adjusted based on measuring trough dabigatran plasma levels to achieve levels ≥ 50 ng/mL at steady state. Doses will range between 150 mg twice a day and 300 mg twice a day. Warfarin management and target international normalized ratio will be according to current practice guidelines at the discretion of the treating physicians. The plan is to treat 270 patients with dabigatran etexilate for a total study population of approximately 405 patients. Clinical efficacy and safety outcomes will be analyzed in an exploratory manner. CONCLUSIONS: RE-ALIGN is the first study to test an alternative to warfarin in patients with mechanical heart valves. A definitive phase III study will be planned based on the results of this study.

Decrease in the oral bioavailability of dabigatran etexilate after co-medication with rifampicin.

AIMS: This study examined the effects of the CYP3A/P-glycoprotein inducer, rifampicin, on the pharmacokinetics of dabigatran following oral administration of the prodrug, dabigatran etexilate. METHODS: This was an open-label, fixed-sequence, four-period study in healthy volunteers. Subjects received a single dose of dabigatran etexilate 150 mg on day 1, rifampicin 600 mg once daily on days 2-8, and single doses of dabigatran etexilate on days 9, 16 and 23. RESULTS: Twenty-four subjects were treated, of whom 22 received all treatments. Relative to the reference (single dose of dabigatran etexilate alone; treatment A), administration of dabigatran etexilate following 7 days of rifampicin (treatment B) decreased the geometric mean (gMean) area under the concentration-time curve (AUC(0-∞)) and maximal plasma concentration (C(max)) of total dabigatran by 67 and 65.5%, respectively. The time to peak and the terminal half-life were not affected. The gMean ratio for the primary comparison (treatment B vs. treatment A) was 33.0% (90% confidence interval 26.5, 41.2%) for AUC(0-∞) and 34.5% (90% confidence interval 26.9, 44.1%) for C(max), indicating a significant effect on total dabigatran exposure (total pharmacologically active dabigatran represents the sum of nonconjugated dabigatran and dabigatran glucuronide). After a 7 day (treatment C) or 14 day washout (treatment D), the AUC(0-∞) and C(max) of dabigatran were reduced by 18 and 20%, and by 15 and 20%, respectively, compared with treatment A, which was considered not clinically relevant. The overall safety profile of all treatments was good. CONCLUSIONS: Administration of rifampicin for 7 days resulted in a significant reduction in the bioavailability of dabigatran, which returned almost to baseline after 7 days washout.

Switching from enoxaparin to dabigatran etexilate: pharmacokinetics, pharmacodynamics, and safety profile.

PURPOSE: Dabigatran etexilate is an oral, reversible, direct thrombin inhibitor licensed for the prevention of venous thromboembolism and stroke prevention in patients with atrial fibrillation. The aim of this study was to investigate whether, and to what extent, a switch from enoxparin to dabigatran etexilate affects the pharmacokinetic (PK) and pharmacodynamic (PD) parameters and safety profile of dabigatran. METHODS: Enoxaparin 40 mg was administered subcutaneously once daily for 3 days followed by a single dose of dabigatran etexilate 220 mg (test treatment) on day 4 in an open-label, two-way cross-over trial in healthy volunteers. Dabigatran plasma levels were measured using a validated high-performance liquid chromatography tandem mass spectrometry method. Anticoagulant activity was measured using a number of clotting tests, including prothrombinase-induced clotting time (PiCT), activated partial thromboplastin time (aPTT), ecarin clotting time (ECT), and diluted thrombin time (dTT). RESULTS: PK, PD, and safety data were available for 23 subjects for each treatment. The adjusted geometric mean test/reference ratio of area under the concentration-time curve for total dabigatran was 84% (90% confidence interval 67.2-105.0%) and 86% (67.0-110.0%) for maximum plasma concentration. The PiCT test/reference ratio, which represents the activity of enoxaparin and dabigatran, was elevated by approximately 15% for peak maximum effect ratio to baseline and total area under the effect curve (AUEC0₋48) activity, suggesting that some anticoagulant activity of enoxaparin was still present. Enoxaparin pre-treatment increased the AUEC0₋48 of activated partial thromboplastin time by approximately 14%. All other dabigatran-related PD markers were unaffected. Tolerability was good, with only mild and reversible adverse events during the treatment. CONCLUSION: Prior administration of enoxaparin did not meaningfully affect the PK or PD properties of dabigatran, and the switch from enoxaparin to dabigatran etexilate was well tolerated among the study subjects. These data support the safety of switching patients from enoxaparin to dabigatran etexilate.

Therapeutic drug monitoring for optimizing amisulpride therapy in patients with schizophrenia.

Amisulpride is a clinically effective antipsychotic drug in a broad dose range with low propensity for extrapyramidal symptoms (EPS). Daily doses and plasma levels of amisulpride were analyzed within a large-scale therapeutic drug monitoring (TDM) survey to find plasma level ranges for optimized treatment under naturalistic conditions. Data of 378 schizophrenic patients treated with amisulpride (100-1550 mg) were included (40% female). Amisulpride plasma levels were analyzed at steady state; assessment comprised improvement (CGI-I) and side-effects, particularly EPS. For detection of cut-off values regarding non-response or EPS, receiver operating characteristics (ROC) curves were applied and the area under the ROC curve (AUC) was calculated. Amisulpride daily doses (594+/-262 mg) and plasma levels (315+/-277 ng/ml) were significantly correlated (r=0.53; P<0.0001). Patients with non-response to amisulpride (8.9%) had significantly (P<0.05) lower plasma levels (248+/-291 ng/ml) than patients with at least moderate improvement (316+/-253 ng/ml) despite comparable amisulpride doses (628+/-253 vs. 590+/-263 mg). Patients with EPS (14.6%) had significantly (P<0.05) higher amisulpride plasma levels (377+/-290 ng/ml) than patients without EPS (305+/-274 ng/ml) despite similar doses in both groups (595+/-266 vs. 594+/-246 mg). ROC analyses revealed significant predictive properties of amisulpride plasma levels (P<0.05) for non-response (AUC=0.65+/-0.05) and EPS (AUC=0.62+/-0.05), respectively. Daily amisulpride doses did not significantly predict non-response or EPS. Optimal amisulpride plasma level values to avoid non-response and EPS were 100 or 320 ng/ml, respectively. Analysis of clinical utility revealed that blood levels must be analyzed in 7 patients until one patient benefits from the TDM procedure by avoiding non-response or EPS. Although our results were mainly explorative, TDM of amisulpride seems very useful for clinical decision making.

Placental transfer of quetiapine in relation to P-glycoprotein activity.

Atypical antipsychotic drugs are well tolerated and thus often preferred in women of fertile age; yet the information on their placental transfer and use during the prenatal period is limited. The aim of this study was to study the placental transfer of quetiapine, a widely used atypical antipsychotic, with special reference to the role of the placental transporter protein, P-glycoprotein (P-gp). This was performed in 18 dually perfused placentas, using the well established P-gp inhibitors PSC833 (valspodar) and GG918 to inhibit the function of P-gp. We also aimed to clarify the significance of two potentially functional ABCB1 single nuclear polymorphisms (SNPs), 2677G>T/A and 3435C>T, on the transplacental transfer (TPT) of quetiapine. The placental transfer of quetiapine in the control group as measured by TPT(AUC) % (absolute fraction of the dose crossing placenta) was 3.7%, which is 29% less than the transfer of the freely diffusible antipyrine, which was 5.2%. The P-gp inhibitors had no significant effect on the transfer of quetiapine as measured by TPT(AUC) % (P = 0.77). No correlation was found between the transplacental transfer of quetiapine (TPT(AUC) %) and placental P-gp expression (P = 0.61). The 3435T allele in exon 26 was associated with significantly higher placental transfer of quetiapine (P = 0.04). We conclude that quetiapine passes the human placenta but that the blood-placental barrier partially limits the transplacental transfer of quetiapine. Administration of P-gp inhibiting drugs with quetiapine is not likely to increase fetal exposure to quetiapine, although the ABCB1 C3435T polymorphism may contribute to inter-individual variation in fetal exposure to quetiapine.

The striatal and extrastriatal D2/D3 receptor-binding profile of clozapine in patients with schizophrenia.

Positron emission tomography (PET) studies reveal that clozapine at clinically used doses occupies less than 60% of D2/D3 dopamine receptors in human striatum. Here, the occupancy of D2/D3 dopamine receptors by clozapine in patients with schizophrenia was determined to test the hypothesis that clozapine binds preferentially to extrastriatal dopamine receptors. A total of 15 clozapine-treated inpatients with schizophrenia underwent a [18F]fallypride PET scan. Receptor occupancy was calculated as percent reduction in binding potential relative to unblocked values measured in seven normal volunteers. Mean D2/D3 receptor occupancy was statistically significantly higher in cortical (inferior temporal cortex 55%) than in striatal regions (putamen 36%, caudate 43%, p<0.005). While the maximum attainable receptor occupancy Emax approached 100% both in the striatum and cortex, the plasma concentration at 50% of Emax (ED50) was much higher in the putamen (950 ng/ml) than in the inferior temporal cortex (333 ng/ml). Clozapine binds preferentially to cortical D2/D3 receptors over a wide range of plasma concentrations. This selectivity is lost at extremely high plasma levels. Occupancy of cortical receptors approaches 60% with plasma clozapine in the range 350-400 ng/ml, which corresponds to the threshold for antipsychotic efficacy of clozapine. Extrastriatal binding of clozapine may be more relevant to its antipsychotic actions than striatal. However, further studies with an intraindividual comparison of untreated vs treated state are desirable to confirm this finding.

A review of the receptor-binding and pharmacokinetic properties of dopamine agonists.

BACKGROUND: Dopamine agonists (DAs), which can be categorized as ergot derived and non-ergot derived, are used in the treatment of Parkinson's disease. OBJECTIVES: This review describes the pharmacologic and pharmacokinetic properties of selected DAs and relates these characteristics to clinical outcomes, with an emphasis on adverse events. METHODS: Relevant articles were identified through a search of MEDLINE (to May 2006) using the terms dopamine agonists (or each individual drug name) and pbarmacokinetics, metabolism, drug-drug interaction, interactions, CYP450, fibrosis, valvular heart disease, tremor, clinical trials, reviews, and meta-analyses. Abstracts from recent sessions of the International Congress of Parkinson's Disease and Movement Disorders were also examined. Clinical studies with <20 patients overall or <10 patients per treatment group in the final analysis were excluded. All DAs that were graded at least possibly useful with respect to at least 3 of 4 items connected to the treatment/prevention of motor symptoms/complications in the most recent evidence-based medical review update were included. This resulted in a focus on the ergot-derived DAs bromocriptine, cabergoline, and pergolide, and the non-ergot-derived DAs pramipexole and ropinirole. RESULTS: Bromocriptine, cabergoline, pergolide, and ropinirole, but not pramipexole, have the potential for drug-drug interactions mediated by the cytochrome P450 (CYP) enzyme system. The occurrence of dyskinesia may be linked to stimulation of the dopamine D(1) receptor, for which cabergoline and pergolide have a similar and relatively high affinity; bromocriptine, pramipexole, and ropinirole have been associated with a lower risk of dyskinesias. The valvular heart disease (VHD) and pulmonary and retroperitoneal fibrosis seen with long-term use appear to represent a class effect of the ergot-derived DAs that may be related to stimulation of serotonin 5-HT(2B) (and possibly 5-HT(2A)) receptors. The incidence of valvular regurgitation was 31% to 47% with ergot-derived DAs, 10% with non-ergot-derived DAs, and 13% with controls. CONCLUSIONS: As reflected in the results of the clinical trials included in this review, dyskinesia associated with DA therapy may be linked to stimulation of the D(1) receptor. Fibrosis (including VHD) seemed to be a class effect of the ergot-derived DAs. Each of the DAs except pramipexole has the potential to interact with other drugs via the CYP enzyme system.

Automated analysis of quetiapine and other antipsychotic drugs in human blood by high performance-liquid chromatography with column-switching and spectrophotometric detection.

An automated HPLC method with column switching is described for the determination of quetiapine, clozapine, perazine, olanzapine and metabolites in blood serum. After clean-up on silica C8 material (20 microm particle size) drugs were separated on ODS Hypersil C18 material (5 microm; column size 250 mm x 4.6 mm i.d.) within 25 min and quantified by ultraviolet (UV) detection at 254 nm. The limit of quantification ranged between 10 and 50 ng/ml. At therapeutic concentrations of the drugs, the inter-assay reproducibility was below 10%. Analyses of drug concentrations in serum of 75-295 patients treated with therapeutic doses of the antipsychotic drugs revealed mean+/-S.D. steady state concentrations of 139+/-136 ng/ml for quetiapine, 328+/-195 ng/ml for clozapine, 48+/-27 ng/ml for olanzapine and 71+/-52 ng/ml for perazine. The method was thus suitable for routine therapeutic drug monitoring and may be extended to other drugs.

Effect of caffeine intake 12 or 24 hours prior to melatonin intake and CYP1A2*1F polymorphism on CYP1A2 phenotyping by melatonin.

Earlier evidence suggests that melatonin is almost exclusively metabolised by CYP1A2 and could serve as a probe drug for CYP1A2 phenotyping. However, caffeine inhibits the metabolism of melatonin by CYP1A2 and dietary caffeine could be a potential confounder for the measurement of CYP1A2 activity with melatonin. We undertook a 3-phase cross-over study in 12 healthy volunteers to examine whether caffeine (200 mg single dose), taken 12 hr or 24 hr prior to melatonin intake, would affect the results of CYP1A2 phenotyping results as assessed by a spot sample melatonin concentration 1.5 hr after intake of 6 mg of melatonin orally. In addition we examined the influence of the CYP1A2*1F polymorphism on the phenotyping results by combining the present material with another 12 persons from a previous study. Caffeine, co-administered 12 or 24 hr prior to melatonin intake, did not have any significant effect on the 1.5 hr melatonin concentration (P=0.086 for ANOVA), but in two volunteers about 4 times increase in melatonin concentration was observed after caffeine intake 12 hr (but not 24 hr) before phenotyping with melatonin. Also, individuals homozygous for the CYP1A2*1A allele had clearly higher 1.5 hr melatonin concentration compared with the *1F/*1F or the *1F/*1A genotypes. Abstinence from caffeine for 24 hr prior to melatonin intake should be enough to overcome the possible confounding effect of caffeine on the CYP1A2 phenotyping with melatonin. Also, melatonin may be a sensitive probe to detect phenotypic differences with regard to CYP1A2*1F polymorphism. Melatonin might be, thus, advantageous for CYP1A2 phenotyping compared to the standard probe caffeine.

How does the benzamide antipsychotic amisulpride get into the brain?--An in vitro approach comparing amisulpride with clozapine.

This study evaluated the disposition of the two atypical antipsychotics, amisulpride (AMS) and clozapine (CLZ), and its main metabolite N-desmethylclozapine (DCLZ), to their target structures in the central nervous system by applying an in vitro blood-brain barrier and blood-cerebrospinal fluid (CSF) barrier based on monolayers of porcine brain microvessel endothelial cells (PMEC) or porcine choroid plexus epithelial cells (PCEC). Permeation studies through PMEC- and PCEC-monolayers were conducted for 60 min at drug concentrations of 1, 5, 10, and 30 muM applied to the donor compartment. PMEC were almost impermeable for AMS (permeation coefficient, P<1 x 10(-7) cm/s) in the resorptive direction, whereas transport in the secretory direction was observed with a P (+/-SD) of 5.2+/-3.6 x 10(-6) cm/s. The resorptive P of CLZ and DCLZ were 2.3+/-1.2 x 10(-4) and 9.6+/-5.0 x 10(-5) cm/s, respectively. For the permeation across PCEC in the resorptive direction, a P of 1.7+/-2.5 x 10(-6) cm/s was found for AMS and a P of 1.6+/-0.9 x 10(-4) and 2.3+/-1.3 x 10(-5) cm/s was calculated for CLZ and DCLZ, respectively. Both, CLZ and DCLZ, could easily pass both barriers with about a five-fold higher permeation rate of CLZ at the PCEC. The permeation of AMS across the BBB was restricted partly due to an efflux transport. It is thus suggested that AMS reaches its target structures via transport across the blood-CSF barrier.

Automated determination of amisulpride by liquid chromatography with column switching and spectrophotometric detection.

A fully automated chromatographic method including on-line blood serum or plasma clean-up, isocratic high-performance liquid chromatography (HPLC) and spectrophotometric detection was developed for quantitative analysis of the new antipsychotic drug amisulpride. After injection of serum or plasma onto the HPLC system and clean-up on a pre-column (10x4.0 mm I.D.) filled with Silica CN 20 micrometer (pore size 10 nm) by an eluent consisting of 8% acetonitrile in deionized water, the chromatographic separation was performed on Lichrospher CN (5 micrometer; 250x4.6 mm I.D.) by an eluent consisting of 50% acetonitrile and 50% aqueous potassium phosphate buffer (0.008 M, pH 6.4). The UV detector was set at 254 nm. The limit of quantification was about 10 microgram/l. The method revealed linearity between 10 and 600 microgram/l (correlation coefficients R(2)>0.9996). The inter-assay reproducibility (coefficient of variation) of quality control samples was between 2.8 and 11.3%. Inaccuracy was between -0.6 and +9.1%. The performance of daily calibration standards revealed an imprecision always below 15% and maximum inaccuracy of 7.7%. The method can be applied to therapeutic drug monitoring as well as pharmacokinetic studies of amisulpride.

Identification of P-glycoprotein substrates and inhibitors among psychoactive compounds--implications for pharmacokinetics of selected substrates.

The pharmacokinetics of antipsychotic drugs has become an integral part in understanding their pharmacodynamic activity and clinical effects. In addition to metabolism aspects, carrier-mediated transport, particularly secretion by ABC transporters, has been discussed as potentially relevant for this group of therapeutics. In this study, the psychoactive compounds perphenazine, flupentixol, domperidone, desmethyl clozapine, haloperidol, fluphenazine, fluvoxamine, olanzapine, levomepromazine, perazine, desmethyl perazine, clozapine, quetiapine and amisulpride were characterized in terms of P-glycoprotein (P-gp) affinity and transport. Experimental methods involved a radioligand displacement assay with [3H]talinolol as radioligand and transport--as well as transport inhibition--studies of the P-gp substrate [3H]talinolol across Caco-2 cell monolayers. In addition, the physicochemical descriptors log P and deltalog P were determined to test potential correlations between transporter affinity and lipophilicity parameters. All of the tested antipsychotics showed affinity to P-gp albeit their IC50 values (concentration of competitor that displaced 50% of the bound radioligand) differed by a factor exceeding 1000, when compared using the transport inhibition assay. From the group of P-gp substrates, amisulpride and fluphenazine were selected for in-vivo drug-drug interaction studies in rats to demonstrate the in-vivo relevance of the in-vitro findings. Compounds were administered by intraperitoneal injection either alone or in combination with 50 mg kg(-1) ciclosporin. The concentration versus time profiles for both drugs were followed in serum as well as in brain tissues. Significant differences between the treatments with the antipsychotic alone versus the combination of antipsychotic with ciclosporin were found for amisulpride. The distribution of amisulpride to the brain was increased and systemic serum levels were likewise increased indicating decreased systemic clearance for the combination regimen. For fluphenazine, systemic levels with and without co-administration of ciclosporin were comparable while higher brain-to-serum concentration ratios were found after co-administration of ciclosporin. The findings are explained on the basis of the limited contribution of P-gp-mediated transport to the elimination of fluphenazine and to a direct effect with respect to its distribution into the brain.

Pharmacometric characterization of dabigatran hemodialysis.

BACKGROUND: Hemodialysis has been shown to be a useful method of decreasing dabigatran plasma levels in situations that require rapid elimination of this thrombin inhibitor. However, there is currently no clinical recommendation for the accelerated/optimized elimination of dabigatran via hemodialysis (e.g., flow rates, filter type, duration of dialysis). OBJECTIVES: The primary objective of the present work was to characterize, via pharmacometric methods, the effects of different blood flow rates in hemodialysis on the pharmacokinetics of dabigatran, using data from a dedicated phase I dialysis study of end-stage renal disease (ESRD) patients. In addition, the effects of various clinically relevant hemodialysis settings were evaluated by simulation to assess their potential use in non-ESRD situations. METHODS: Seven patients with ESRD were investigated in an open-label, fixed-sequence, two-period comparison trial. A population pharmacokinetic model was developed to fit the data and then used for various simulations. Data analyses were performed using NONMEM(®), Berkeley Madonna, or SAS. RESULTS: The pharmacokinetics of dabigatran were best described by a two-compartment model with first-order absorption and a lag time. In addition to total body clearance in ESRD subjects, a first-order dialysis clearance was implemented which was greater than zero during hemodialysis and zero during the interdialytic periods. The relationship between the dialysis clearance and the blood flow rate was best described by the Michaels function. Simulations showed that varying clinically relevant dialysis settings such as filter properties or flow rates had only minor effects. Dialysis duration had the strongest impact on dabigatran plasma concentration. The observed geometric mean redistribution effect after hemodialysis was low (<16 %). The final model was successfully evaluated through the prediction of plasma concentrations from a case report undergoing dialysis. CONCLUSIONS: This analysis allowed the influences of various hemodialysis parameters on the dabigatran plasma concentration to be predicted in detail for the first time. Dialysis duration was identified as having the strongest impact on the reduction in dabigatran plasma concentration. The model developed here can potentially serve as a tool to provide guidance when considering the use of hemodialysis in patients who have received dabigatran.

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.

Pharmacokinetics and pharmacodynamics in Japanese and Caucasian subjects after oral administration of dabigatran etexilate.

Ethnic differences in drug disposition may potentially influence therapeutic response to dabigatran, a reversible direct thrombin inhibitor used for the prevention and/or treatment of various thromboembolic disorders. This analysis of data from 18 clinical studies in healthy volunteers and patients with non-valvular atrial fibrillation (AF) or undergoing knee or hip arthroplasty investigated whether there were any clinically relevant differences in the pharmacokinetics and pharmacodynamics of dabigatran, the active form of dabigatran etexilate, between Japanese and Caucasian subjects. In pooled data from 14 phase I trials, total exposure (i.e. area under the plasma concentration-time curve [AUC]) after administration of dabigatran 150 mg once or twice-daily was on average 20% higher in Japanese than Caucasian subjects (median [10th to 90th percentile] 1,110 [644-1,824] vs. 924 [420-1,654] ng·h/ml) although the difference between the groups was not significant. Within-trial comparisons in subjects treated with dabigatran 150 mg twice-daily showed that AUC and maximum plasma concentration differed by less than 10% between the two groups. In patients with AF, trough concentrations after administration of 150 mg twice-daily were similar in Japanese and Caucasian subjects (80.1 [34.5-193.8] vs. 71.0 [34.0-190] ng/ml). Various factors, including body weight and renal clearance, may explain these observed pharmacokinetic differences. The relationship between plasma concentration and coagulation markers was similar and indicative of no difference in the exposure-pharmacodynamic response between these two groups. In conclusion, the results of this analysis show that the pharmacokinetics and pharmacodynamics of dabigatran are similar in Japanese and Caucasian subjects and suggest that there is no need for dose adjustment of dabigatran in Japanese subjects.

Pramipexole extended release: a novel treatment option in Parkinson's disease.

Pramipexole, the most commonly prescribed dopamine agonist worldwide, meanwhile serves as a reference substance for evaluation of new drugs. Based on numerous clinical data and vast experiences, efficacy and safety profiles of this non-ergoline dopamine agonist are well characterized. Since October 2009, an extended-release formulation of pramipexole has been available for symptomatic treatment of Parkinson's disease. Pramipexole administration can be cut down from three times to once a day due to the newly developed extended-release formulation. This is considerable progress in regard to minimizing pill burden and enhancing compliance. Moreover, the 24 h continuous drug release of the once-daily extended-release formulation results in fewer fluctuations in plasma concentrations over time compared to immediate-release pramipexole, given three times daily. The present study summarizes pharmacokinetics and all essential pharmacological and clinical characteristics of the extended-release formulation. In addition, it provides all study data, available so far, with regard to transition and de-novo administration of extended-release formulation for patients with Parkinson's disease. It further compares efficacy and safety data of immediate-release pramipexole with the extended-release formulation of pramipexole.