Introduction: CK-1827452 (CK-452) is a novel small molecule activator of cardiac myosin. In a dog heart failure model, it increased left ventricular (LV) systolic function and cardiac output, while filling pressures, heart rate, and total peripheral resistance decreased. Intravenous (iv) CK-452 also increased LV systolic function in healthy subjects, and is now under study in heart failure patients. An oral formulation of CK-452 could enable chronic oral inotropic therapy for heart failure. Purpose: The objective of the current study was to determine the absolute bioavailability of CK-452 in healthy volunteers. Methods: CK-452 (0.125 mg/kg) was administered in a randomized four-period crossover design to male volunteers as a 1 hr iv infusion, as an oral dose of the iv formulation in the fasted state, and as a capsule in the fasted and fed states. Results: All formulations of CK-452 were well tolerated. Three subjects were withdrawn due to adverse events unrelated to study drug as assessed by the investigator. There were no deaths or serious adverse events. There were no significant effects on vital signs, ECGs or laboratory tests. Conclusions: - Absolute bioavailability of CK-452 in liquid or capsule formulations approached 100%. - Food delayed absorption from the capsules in 4/7 subjects with no reduction in AUC. - All formulations were well tolerated. - Essentially complete oral bioavailability with no first-pass effect suggests that inhibitors of CYP450 enzymes that metabolize CK-452 will not increase the Cmax of a given dose. - An oral CK-452 formulation for the chronic treatment of heart failure is confirmed to be feasible.Tabled 1Pharmacokinetics of CK-18274521Intravenous infusionP.O. Liquid (fasted)P.O. Capsule (fasted)P.O. Capsule (fed)Number Dosed62777Cmax (ng/mL)92.7 (27.3)72.8 (27.9)56.9 (19.3)64.5 (34.8)tmax (h)1.0 (0.5-1.0)0.5 (0.5-1.0)1.0 (1.0-2.0)3.0 (0.5-4.9)AUCinf (ng•h/mL)800 (140)788 (123)936 (514)981 (547)t 1/2 (h)18.2 (2.70)20.7 (2.71)25.7 (12.2)23.8 (13.1)CL(i.v.) or CL/F (p.o.) (L/h/kg)0.160 (0.023)0.162 (0.026)0.158 (0.044)0.148 (0.044)Vz (i.v.) or Vz/F (p.o.) (L/kg)4.12 (0.40)4.79 (0.67)5.13 (0.83)4.38 (0.064)1Mean (SD) reported except for tmax where median (range) is reported 2 One subject was excluded due to an uncharacteristic plasma profile. Open table in a new tab 1Mean (SD) reported except for tmax where median (range) is reported 2 One subject was excluded due to an uncharacteristic plasma profile.

Ranolazine is a compound that is approved by the US FDA for the treatment of chronic angina pectoris in combination with amlodipine, beta-adrenoceptor antagonists or nitrates, in patients who have not achieved an adequate response with other anti-anginals. The anti-anginal effect of ranolazine does not depend on changes in heart rate or blood pressure. It acts through different pharmacological mechanisms where inhibition of the late inward sodium current (reducing calcium overload and thereby left ventricular diastolic tension) is one plausible mechanism of reduced oxygen consumption. Initial studies used an oral solution or an immediate-release (IR) capsule, but subsequently an extended-release (ER) formulation was developed to allow for twice-daily administration with maintained efficacy. Following administration of an oral solution or IR capsule, peak plasma concentrations (C(max)) are observed within 1 hour. After administration of radiolabelled ranolazine, 73% of the dose was excreted in urine, and unchanged ranolazine accounted for <5% of radioactivity in both urine and faeces. The absolute bioavailability ranges from 35% to 50%. Food has no effect on rate or extent of absorption from the ER formulation. Ranolazine protein binding is about 61-64% over the therapeutic concentration range. Volume of distribution at steady state ranges from 85 to 180 L. Ranolazine is extensively metabolised by cytochrome P450 (CYP) 3A enzymes and, to a lesser extent, by CYP2D6, with approximately 5% excreted renally unchanged. Elimination half-life of ranolazine is 1.4-1.9 hours but is apparently prolonged, on average, to 7 hours for the ER formulation as a result of extended absorption (flip-flop kinetics). Elimination occurs through parallel linear and saturable elimination pathways, where the saturable pathway is related to CYP2D6, which is partly inhibited by ranolazine. Oral plasma clearance diminishes with dose from, on average, 45 L/h at 500 mg twice daily to 33 L/h at 1000 mg twice daily. The departure from dose proportionality for this dose range is modest, with increases in steady-state C(max) and area under plasma concentration-time curve (AUC) from 0 to 12 hours of 2.5- and 2.7-fold, respectively. Ranolazine pharmacokinetics are unaffected by sex, congestive heart failure and diabetes mellitus. AUC increases up to 2-fold with advancing degree of renal impairment. Ranolazine is a weak inhibitor of CYP3A, and increases AUC and C(max) for simvastatin, its metabolites and HMG-CoA reductase inhibitor activity <2-fold. Digoxin AUC is increased 40-60% by ranolazine through P-glycoprotein inhibition. Ranolazine AUC is increased by CYP3A inhibitors ranging from 1.5-fold for diltiazem 180 mg once daily to 3.9-fold for ketoconazole 200 mg twice daily. Verapamil increases ranolazine exposure approximately 2-fold. CYP2D6 inhibition has a negligible effect on ranolazine exposure.

The interactions of ranolazine, a new antianginal compound, with inhibitors and substrates of the CYP3A isoenzyme family were studied in 1 open-label and 4 double-blind, randomized, multiple-dose studies. In healthy adult volunteers, the authors sought (1) to determine the steady-state pharmacokinetics, safety, and tolerability of immediate- and sustained-release ranolazine with and without ketoconazole, diltiazem, or simvastatin and (2) to evaluate the effect of ranolazine on the pharmacokinetics of diltiazem, simvastatin, simvastatin metabolites, and HMG-CoA reductase activity. Ketoconazole increased ranolazine plasma concentrations and reduced the CYP3A4-mediated metabolic transformation of ranolazine, confirming that CYP3A4 is the primary metabolic pathway for ranolazine. Diltiazem reduced oral clearance of ranolazine in a dose-dependent manner. Simvastatin did not affect ranolazine pharmacokinetics, although ranolazine increased the AUC and C(max) of simvastatin, simvastatin acid, 2 simvastatin metabolites, and HMG-CoA reductase activity by <2-fold. Administration of ranolazine in combination with diltiazem or simvastatin was safe and well tolerated during the interval studied.

The effect of hepatic impairment on the pharmacokinetics of a sustained‐release formulation of ranolazine and 3 major metabolites was investigated in an open‐label, parallel‐group study. Ranolazine (875‐mg loading dose followed by 500 mg every 12 hours for a total of 4 maintenance doses) was administered to subjects with mild (n = 8) or moderate (n = 8) hepatic impairment and a matched control group of healthy volunteers (n = 16). Moderate, but not mild, hepatic impairment significantly increased ranolazine steady‐state area under the concentration‐time curve (AUC 0–12 ) by 76% (P < .001) and maximum plasma concentration C max by 51% (P < .01). The AUC 0–12 ratio (metabolite/ranolazine) decreased for all metabolites in parallel with the degree of hepatic impairment. AUC 0‐∞ for the CYP3A substrate midazolam administered as a single dose was significantly correlated with ranolazine AUC 0–12 at steady state (r 2 = .33, P <.001). Over the time interval studied, ranolazine was well tolerated in healthy subjects and hepatically impaired subjects.

Background— Tecadenoson is a potent selective A 1 -adenosine receptor agonist with a dose-dependent negative dromotropic effect on the AV node. Tecadenoson terminates induced paroxysmal supraventricular tachycardia (PSVT) without the clinically significant side effects caused by stimulation of other adenosine receptors. This trial was designed to determine a safe and effective tecadenoson bolus for termination of electrophysiologically induced PSVT. Methods and Results— Patients with a history of symptomatic PSVT and inducible PSVT at the time of a clinically indicated electrophysiology study were randomized into a multicenter, double-blind, placebo-controlled trial. Five 2-dose tecadenoson bolus regimens were evaluated versus placebo (75/150, 150/300, 300/600, 450/900, 900 μg/900 μg). The second bolus was administered only if PSVT persisted for 1 minute after the first bolus. Each tecadenoson regimen resulted in a significant therapeutic conversion rate compared with placebo (range, 50.0% to 90.3%, analysis of all patients dosed; n=181; P <0.0005). Conversion by the first bolus was dose related (range: placebo, 3.3% to 86.7% for 900 μg/900 μg). Time to conversion was dose dependent, with a median time of <1 minute for the 3 highest dose regimens. Postconversion arrhythmias were transient, requiring no additional treatment in 4 regimens (including placebo). Transient second- and third-degree heart block occurred at higher doses (300/600, 450/900, 900 μg/900 μg) and was supported with backup pacing when needed. No effect on blood pressure was observed. Ten patients with a history of asthma or chronic obstructive pulmonary disease tolerated tecadenoson without bronchospasm. Conclusions— We identified an optimal tecadenoson regimen (300 μg/600 μg) that effectively and rapidly converted 90% (28 of 31) of PSVT patients to normal sinus rhythm with no significant adverse effects.

Ranolazine is a novel compound under development as an antianginal agent. The multiple-dose pharmacokinetics of extended-release ranolazine and 3 major metabolites was investigated in healthy subjects (N = 8) and subjects with mild to severe renal impairment (N = 21). The ranolazine AUC(0-12) (area under the concentration-time curve between 0 and 12 hours after dosing) geometric mean ratio versus healthy subjects at steady state was 1.72 (90% confidence interval [CI], 1.07-2.76) in subjects with mild impairment, 1.80 (90% CI, 1.13-2.89) in those with moderate impairment, and 1.97 (90% CI, 1.23-3.16) in those with severe renal impairment. Creatinine clearance was negatively correlated with AUC(0-12) and the maximum observed concentration for ranolazine and the O-dearylated metabolite (P < .05 for all variables), as well as the N-dealkylated metabolite (P < .001), but not for the O-demethylated metabolite. Less than 7% of the administered dose was excreted unchanged in all groups, indicating that factors other than reduced glomerular filtration rate contributed to the increase in ranolazine concentrations in renal impairment. No serious adverse events were observed in the study.

Clinical Pharmacology & Therapeutics (2003) 73, P31–P31; doi:

Background: CVT-510, N-(3(R)-tetrahydrofuranyl)-6-aminopurine riboside, is a selective A,-adenosine receptor agonist with potential potent antiarrhythmic effects in tachycardias involving the atrioventricular (AV) node. This study, the first in humans, was designed to determine the effects of CVT-5 10 on AV nodal conduction and hemodynamics. Methods and Results: Patients in sinus rhythm with normal AV nodal function at electrophysiologic study (n = 32) received a single intravenous bolus of CVT-5 10. AH and HV intervals were measured during sinus rhythm and during atrial pacing at 1, 5, 10, 15, 20, 30, 45, and 60 minutes after the bolus. Increasing doses of CVT-510 (0.3 to 10 pg/kg) caused a dosedependent increase in the AH interval. At 1 minute, a dose of 10,ug/kg increased the AH interval during sinus rhythm from 93 ± 23 msec to 114 ± 37 msec, p = 0.01 and from 114 ± 31 msec to 146 ± 44 msec during atrial pacing at 600 msec, p = 0.003). The AH interval returned to baseline by 20 minutes. CVT-510 at doses of 0.3 to 10,ug/kg had no effect on sinus rate, HV interval, or systemic blood pressure, and was not associated with serious adverse effects. At doses of 15 and 30 pg/kg, CVT-510 produced transient second/third degree AV heart block in all four patients treated. One of these patients also had a prolonged sedative effect that was reversed with aminophylline. Conclusions: CVT-510 promptly prolongs AV nodal conduction and does not affect sinus rate or blood pressure. Selective stimulation of the A,-adenosine receptor by CVT-510 may be useful for immediate control of heart rate in atrial fibrillation/flutter and to convert paroxysmal supraventricular tachycardia to sinus rhythm, while avoiding vasodilatation mediated by the A2-adenosine receptor, as well as the vasodepressor and negative inotropic effects associated with 3-adrenergic receptor blockade and/or calcium channel blockers.

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