Susanne Johansson

Ximelagatran, an Oral Direct Thrombin Inhibitor, Has a Low Potential for Cytochrome P450-Mediated Drug-Drug Interactions

AbstractBackground: Ximelagatran is an oral direct thrombin inhibitor currently in clinical development for the prevention and treatment of thromboembolic disorders. After oral administration, ximelagatran is rapidly absorbed and extensively bioconverted, via two intermediates (ethyl-melagatran and hydroxy-melagatran), to its active form, melagatran. In vitro studies have shown no evidence for involvement of cytochrome P450 (CYP) enzymes in either the bioactivation or the elimination of melagatran. Objective: To investigate the potential of ximelagatran, the intermediates ethyl-melagatran and hydroxy-melagatran, and melagatran to inhibit the CYP system in vitro and in vivo, and the influence of three CYP substrates on the pharmacokinetics of melagatran in vivo. Methods: The CYP inhibitory properties of ximelagatran, the intermediates and melagatran were tested in vitro by two different methods, using heterologously expressed enzymes or human liver microsomes. Diclofenac (CYP2C9), diazepam (CYP2C19) and nifedipine (CYP3A4) were chosen for coadministration with ximelagatran in healthy volunteers. Subjects received oral ximelagatran 24mg and/or diclofenac 50mg, a 10-minute intravenous infusion of diazepam 0.1 mg/kg, or nifedipine 60mg. The plasma pharmacokinetics of melagatran, diclofenac, diazepam, N-desmethyl-diazepam and nifedipine were determined when administered alone and in combination with ximelagatran. Results: No inhibition, or only minor inhibition, of CYP enzymes by ximelagatran, the intermediates or melagatran was shown in the in vitro studies, suggesting that ximelagatran would not cause CYP-mediated drug-drug interactions in vivo. This result was confirmed in the clinical studies. There were no statistically significant differences in the pharmacokinetics of diclofenac, diazepam and nifedipine on coadministration with ximelagatran. Moreover, there were no statistically significant differences in the pharmacokinetics of melagatran when ximelagatran was administered alone or in combination with diclofenac, diazepam or nifedipine. Conclusion: As ximelagatran did not exert a significant effect on the hepatic CYP isoenzymes responsible for the metabolism of diclofenac, diazepam and nifedipine, it is reasonable to expect that it would have no effect on the metabolism of other drugs metabolised by these isoenzymes. Furthermore, the pharmacokinetics of melagatran after oral administration of ximelagatran are not expected to be altered by inhibition or induction of CYP2C9, CYP2C19 or CYP3A4. Together, the in vitro and in vivo studies indicate that metabolic drug-drug interactions involving the major human CYP enzymes should not be expected with ximelagatran.

Influence of severe renal impairment on the pharmacokinetics and pharmacodynamics of oral ximelagatran and subcutaneous melagatran.

AbstractBackground: Ximelagatran is an oral direct thrombin inhibitor currently in clinical development as an anticoagulant for the prevention and treatment of thromboembolic disease. After oral administration, ximelagatran is rapidly absorbed and bioconverted to its active form, melagatran. Objective: To investigate the effect of severe renal impairment on the pharmacokinetics and pharmacodynamics of melagatran following administration of subcutaneous melagatran and oral ximelagatran. Study design: This was a nonblinded randomised crossover study with 2 study days, separated by a washout period of 1–3 weeks. Twelve volunteers with severe renal impairment and 12 controls with normal renal function were included, with median (range) glomerular filtration rates (GFR) of 13 (5–24) and 86 (70–105) mL/min, respectively. All volunteers received, in a randomised sequence, a 3mg subcutaneous injection of melagatran and a 24mg immediate-release tablet of ximelagatran. Blood samples were collected up to 12 and 14 hours after administration of the subcutaneous and oral doses, respectively, for determination of melagatran plasma concentrations and the activated partial thromboplastin time (APTT), an ex vivo measurement of coagulation time. Urine was collected for 24 hours after each dose for determination of melagatran concentration. Results: For the volunteers with severe renal impairment, the area under the plasma concentration-time curve (AUC) and the half-life of melagatran were significantly higher than in the control group with normal renal function. Least-squares mean estimates of the ratios of the mean AUC for volunteers with severe renal impairment and controls (95% confidence intervals) were 4.03 (3.29–4.93) after subcutaneous melagatran and 5.33 (3.76–7.56) after oral ximelagatran. This result was related to the decreased renal clearance (CLr) of melagatran, which was linearly correlated with GFR. In the severe renal impairment and control groups, respectively, the mean CLr of melagatran was 12.5 and 81.3 mL/ min after subcutaneous administration of melagatran and 14.3 and 107 mL/min after oral administration of ximelagatran. There was a nonlinear relationship between the APTT ratio (postdose/predose APTT value) and melagatran plasma concentration. A statistically significant higher slope of the concentration-effect relationship, described by linear regression of the APTT ratio versus the square root of melagatran plasma concentrations, was estimated for the group with severe renal impairment compared to the control group; however, the increase in slope was minor and the estimated differences in APTT ratio between the groups in the studied concentration range was less than 10% and not considered clincially relevant. Ximelagatran and melagatran were well tolerated in both groups. Conclusions: After administration of subcutaneous melagatran and oral ximelagatran, subjects with severe renal impairment had significantly higher melagatran exposure and longer half-life because of lower CLr of melagatran compared with the control group with normal renal function, suggesting that a decrease in dose and/or an increase in the administration interval in patients with severe renal impairment would be appropriate.

The Pharmacokinetics and Pharmacodynamics of Ximelagatran, an Oral Direct Thrombin Inhibitor, Are Unaffected by a Single Dose of Alcohol

Ximelagatran—a direct thrombin inhibitor rapidly converted to its active form, melagatran, after oral administration—is being developed for the prevention and treatment of thromboembolic disease. The pharmacokinetics, pharmacodynamics, and tolerability/safety of ximelagatran following a single 36‐mg oral dose of ximelagatran ± a single oral dose of alcohol (0.5 and 0.6 g ethanol/kg to women and men, respectively) were assessed in a randomized, open‐label, two‐way crossover study (n = 26). The 90% confidence intervals (CIs) and least squares mean estimates for the ratio of ximelagatran plus alcohol to ximelagatran alone for melagatran AUC (1.04 [90% CI = 1.00–1.08]) and Cmax (1.08 [90% CI = 1.03–1.14]) fell within the bounds demonstrating no interaction. Alcohol did not alter the melagatran‐induced prolongation of the activated partial thromboplastin time or the good tolerability/safety profile of ximelagatran. In conclusion, the pharmacokinetics, pharmacodynamics, and tolerability/safety of oral ximelagatran were not affected by alcohol.

Effect of Tenapanor on Serum Phosphate in Patients Receiving Hemodialysis

Hyperphosphatemia is common among patients with CKD stage 5D and is associated with morbidity and mortality. Current guidelines recommend lowering serum phosphate concentrations toward normal. Tenapanor is a minimally absorbed small molecule inhibitor of the sodium/hydrogen exchanger isoform 3 that functions in the gut to reduce sodium and phosphate absorption. This randomized, double-blind, placebo-controlled trial assessed the effects of tenapanor on serum phosphate concentration in patients with hyperphosphatemia receiving hemodialysis. After a 1- to 3-week washout of phosphate binders, we randomly assigned 162 eligible patients (serum phosphate =6.0 to <10.0 mg/dl and a 1.5-mg/dl increase from before washout) to one of six tenapanor regimens (3 or 30 mg once daily or 1, 3, 10, or 30 mg twice daily) or placebo for 4 weeks. The primary efficacy end point was change in serum phosphate concentration from baseline (randomization) to end of treatment. In total, 115 patients (71%) completed the study. Mean serum phosphate concentrations at baseline (after washout) were 7.32-7.92 mg/dl for tenapanor groups and 7.87 mg/dl for the placebo group. Tenapanor provided dose-dependent reductions in serum phosphate level from baseline (least squares mean change: tenapanor =0.47-1.98 mg/dl; placebo =0.54 mg/dl; P=0.01). Diarrhea was the most common adverse event (tenapanor =18%-68%; placebo =12%) and frequent at the highest tenapanor doses. In conclusion, tenapanor treatment resulted in statistically significant, dose-dependent reductions in serum phosphate concentrations in patients with hyperphosphatemia receiving hemodialysis. Additional studies are required to clarify the optimal dosing of tenapanor in patients with CKD-related hyperphosphatemia.

Effect of Tenapanor on Interdialytic Weight Gain in Patients on Hemodialysis

BACKGROUND AND OBJECTIVES Interdialytic weight gain in patients on hemodialysis is associated with adverse cardiovascular outcomes and increased mortality. The degree of interdialytic weight gain is influenced by sodium intake. We evaluated the effects of tenapanor (AZD1722 and RDX5791), a minimally systemically available inhibitor of the sodium/hydrogen exchanger isoform 3, on interdialytic weight gain in patients with CKD stage 5D treated with hemodialysis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS This phase 2, randomized, double-blind study (NCT01764854; conducted January to September of 2013) enrolled adults on maintenance hemodialysis with interdialytic weight gain ≥3.0% of postdialysis weight and ≥2 kg. Patients were randomly assigned (1:1) to receive tenapanor or placebo. The primary end point was change in mean interdialytic weight gain (percentage of baseline postdialysis weight) from baseline (mean across a 2-week run-in period) to week 4. In a subgroup of inpatients, 24-hour stool sodium and stool weight were assessed for 1 week. RESULTS Sixteen patients received 1 week of inpatient treatment (tenapanor, eight; placebo, eight), and 72 patients received 4 weeks of treatment in an outpatient setting (tenapanor, 37; placebo, 35; completers: tenapanor, 31; placebo, 33). In the outpatient cohort, no significant effect on interdialytic weight gain was detected; least squares mean changes in relative interdialytic weight gain from baseline to week 4 were tenapanor, -0.26% (95% confidence interval, -0.57% to 0.06%) and placebo, -0.23% (95% confidence interval, -0.54% to 0.07%; P=0.46). During week 1 (inpatient cohort only), compared with placebo, tenapanor treatment resulted in higher stool sodium content (mean [±SD]: tenapanor, 36.6 [±21.8] mmol/d; placebo, 2.8 [±2.7] mmol/d; P<0.001) and higher stool weight (tenapanor, 172.5 [±68.1] g/d; placebo, 86.3 [±30.0] g/d; P<0.01). A similar safety profile was observed across treatment groups with the exception of diarrhea, which occurred more frequently with tenapanor treatment. CONCLUSIONS Tenapanor treatment increased stool sodium and weight over placebo in patients undergoing hemodialysis. However, over 4 weeks of treatment, there was no difference in interdialytic weight gain between patients treated with tenapanor and those receiving placebo.

Pharmacological cardioversion of atrial fibrillation—a double-blind, randomized, placebo-controlled, multicentre, dose-escalation study of AZD1305 given intravenously

AIM AZD1305 is a combined ion channel blocker developed for the treatment of atrial fibrillation (AF). The aim of this study was to determine whether AZD1305 was effective in converting AF to sinus rhythm (SR). METHODS AND RESULTS Patients with AF episodes of duration 3 h to 3 months were randomized in a 3:1 ratio to receive a maximum 30 min intravenous infusion of AZD1305 or matching placebo. The primary efficacy endpoint was the proportion of patients converting within 90 min of the start of infusion, after which patients who had not converted were to undergo direct current (DC) cardioversion. Four ascending AZD1305 dose groups were assigned sequentially, with dose rates of 50, 100, 130, and 180 mg/h. A total of 171 patients were randomized. Pharmacological conversion was achieved in 0 of 43 patients (0%) in the placebo group, and in 2 of 26 (8%; P= 0.14 vs. placebo), 8 of 45 (18%; P= 0.006), 17 of 45 (38%; P< 0.001), and 6 of 12 patients (50%; P< 0.001) in AZD1305 dose groups 1-4, respectively. Maximum QTcF (QT interval corrected according to Fridericias formula) generally increased dose-dependently up to a plateau, although there was wide variation between patients. Two patients experienced torsade de pointes (TdP): one patient without symptoms in dose group 3, and one patient requiring DC defibrillation in dose group 4. Both patients recovered without sequelae. CONCLUSIONS AZD1305 was effective in converting AF to SR, but was associated with QT prolongation and TdP. The benefit-risk profile was judged as unfavourable and the AZD1305 development programme was discontinued. CLINICAL TRIAL REGISTRATION http://clinicaltrials.gov identifier NCT00915356.

A Randomized Invasive Cardiac Electrophysiology Study of the Combined Ion Channel Blocker AZD1305 in Patients After Catheter Ablation of Atrial Flutter

Background: This study assessed the cardiac electrophysiological and hemodynamic effects of an intravenous infusion of the combined ion channel blocker AZD1305. Methods: After successful ablation of atrial flutter, patients were randomized to receive placebo (n = 12) or AZD1305 (n = 38) in 4 ascending dose groups. Electrophysiological and hemodynamic measurements were performed before and commencing 20 minutes after start of infusion. Results: Left atrial effective refractory period increased dose and the primary outcome measure increased dose and plasma concentration dependently, with a mean increase of 55 milliseconds in dose group 3. There was a corresponding increase in right atrial effective refractory period of 84 milliseconds. The right ventricular effective refractory period and the paced QT interval also increased dose and concentration dependently, by 59 and 70 milliseconds, respectively, in dose group 3. There were indications of moderate increases of atrial, atrioventricular nodal, and ventricular conduction times. No consistent changes in intracardiac pressures were observed, but there was a small transient decrease in systolic blood pressure. Adverse events were consistent with the study population and procedure, and there were no signs of proarrhythmia despite marked delay in ventricular repolarization in some individuals. Conclusions: AZD1305 shows electrophysiological characteristics indicative of potential antiarrhythmic efficacy in atrial fibrillation.

Pharmacokinetics and anticoagulant effect of the direct thrombin inhibitor melagatran following subcutaneous administration to healthy young men

The pharmacokinetic dose linearity and reproducibility, the effects on ex-vivo coagulation time assays and bleeding time, and tolerability of the direct thrombin inhibitor melagatran following subcutaneous (s.c.) dosing were investigated in two open-label studies in healthy males: (i) a dose-escalation study in which subjects received single s.c. doses of melagatran (0.1–5 mg); and (ii) a repeated-dosing study in which 3 mg s.c. melagatran was administered at 12-h intervals for 4 days. In both studies, melagatran was rapidly absorbed with maximum plasma concentrations (Cmax) observed about 0.5 h post dosing. The half-life of melagatran was about 2 h. The area under the melagatran plasma concentration versus time curve increased linearly with dose. No time dependency in the area under the curve or Cmax was observed over 4 days of twice-daily dosing. The variability in pharmacokinetic parameters was low and the bioavailability of melagatran appeared to be complete. There was a steep and linear prolongation of thrombin time, a non-linear prolongation of both activated partial thromboplastin time and activated coagulation time, and a decrease in prothrombin complex activity with increasing melagatran plasma concentration. Only moderate increases in capillary bleeding time were observed with s.c. doses up to 5 mg melagatran. Melagatran was well tolerated after s.c. injection, with good local tolerability at the injection site.

Combined in vitro-in vivo approach to assess the hepatobiliary disposition of a novel oral thrombin inhibitor.

Two clinical trials and a large set of in vitro transporter experiments were performed to investigate if the hepatobiliary disposition of the direct thrombin inhibitor prodrug AZD0837 is the mechanism for the drug-drug interaction with ketoconazole observed in a previous clinical study. In Study 1, [(3)H]AZD0837 was administered to healthy male volunteers (n = 8) to quantify and identify the metabolites excreted in bile. Bile was sampled directly from the jejunum by duodenal aspiration via an oro-enteric tube. In Study 2, the effect of ketoconazole on the plasma and bile pharmacokinetics of AZD0837, the intermediate metabolite (AR-H069927), and the active form (AR-H067637) was investigated (n = 17). Co-administration with ketoconazole elevated the plasma exposure to AZD0837 and the active form approximately 2-fold compared to placebo, which may be explained by inhibited CYP3A4 metabolism and reduced biliary clearance, respectively. High concentrations of the active form was measured in bile with a bile-to-plasma AUC ratio of approximately 75, indicating involvement of transporter-mediated excretion of the compound. AZD0837 and its metabolites were further investigated as substrates of hepatic uptake and efflux transporters in vitro. Studies in MDCK-MDR1 cell monolayers and P-glycoprotein (P-gp) expressing membrane vesicles identified AZD0837, the intermediate, and the active form as substrates of P-gp. The active form was also identified as a substrate of the multidrug and toxin extrusion 1 (MATE1) transporter and the organic cation transporter 1 (OCT1), in HEK cells transfected with the respective transporter. Ketoconazole was shown to inhibit all of these three transporters; in particular, inhibition of P-gp and MATE1 occurred in a clinically relevant concentration range. In conclusion, the hepatobiliary transport pathways of AZD0837 and its metabolites were identified in vitro and in vivo. Inhibition of the canalicular transporters P-gp and MATE1 may lead to enhanced plasma exposure to the active form, which could, at least in part, explain the clinical interaction with ketoconazole.

Preclinical and Healthy Volunteer Studies of Potential Drug–Drug Interactions Between Tenapanor and Phosphate Binders

Tenapanor (RDX5791, AZD1722), a first‐in‐class small molecule with minimal systemic availability, is an inhibitor of the sodium/hydrogen exchanger isoform 3. Tenapanor acts locally in the gut, where it reduces absorption of sodium and phosphate. It is being studied in patients with chronic kidney disease requiring dialysis, who are often administered phosphate binders such as sevelamer to help control hyperphosphatemia. We investigated whether coadministration of tenapanor with phosphate binders (sevelamer or calcium‐based binders) impacts the pharmacodynamic effects of tenapanor. In vitro studies suggested a binding interaction between tenapanor and sevelamer, but this did not translate into altered pharmacodynamic effects in rats. An open‐label, 2‐way crossover study was then conducted in healthy volunteers (NCT02346890). This showed that 4 days’ treatment with tenapanor hydrochloride (15 mg twice daily) with or without sevelamer carbonate (800 mg 3 times daily) resulted in comparable 24‐hour stool and urinary sodium and phosphorus levels. Stool frequency, consistency, and weight were also comparable between the treatments. These results suggest that the binding between sevelamer and tenapanor observed in vitro does not translate into altered pharmacodynamic effects in humans.