Safety, local tolerability and pharmacokinetics of ceftaroline fosamil administered in a reduced infusion volume.

AIMS: The standard dose of ceftaroline fosamil for patients with normal renal function is 600 mg diluted in 250 ml by 60 min intravenous infusion every 12 h. This two part phase I trial (NCT01577589) assessed safety and local tolerability of multiple ceftaroline fosamil 50 ml and 250 ml infusions, and pharmacokinetics following single administrations of each infusion volume. METHODS: Part A was a placebo-controlled, double-blind, multiple dose crossover study. Twenty-four healthy subjects were randomized to simultaneous, bilateral ceftaroline fosamil 600 mg and placebo infusions in each arm (50 ml then 250 ml or vice versa) every 12 h for 72 h, with a ≥ 4.5 day washout. Local tolerability was evaluated by the Visual Infusion Phlebitis scale, with scores ≥2 considered infusion site reactions (ISRs). Part B was an open label crossover study. Ten subjects were randomized to single 50 ml and 250 ml ceftaroline fosamil 600 mg infusions on days 1 and 3 (washout on day 2). Blood samples for pharmacokinetic analysis were taken over 24 h. RESULTS: In part A, four subjects (16.7%) experienced ISRs, all of which were associated with placebo infusions. No ISRs were reported for either ceftaroline fosamil 50 ml or 250 ml. Plasma pharmacokinetics (ceftaroline fosamil, active ceftaroline and an inactive metabolite) were similar following single 50 ml and 250 ml infusions in part B. CONCLUSIONS: No new safety concerns were identified for ceftaroline fosamil 600 mg 50 ml compared with 250 ml. These findings suggest infusion volumes down to 50 ml may be used in patients with fluid intake restrictions.

Novel Relaxin Receptor RXFP1 Agonist AZD3427 in the Treatment of Heart Failure: A Phase 1a/b, First-in-Human, Randomized, Single-Blind, Placebo-Controlled Study.

BACKGROUND: Heart failure mortality remains high despite recent progress in pharmacological treatment. AZD3427 is a selective long-acting analog of relaxin, a vasodilatory hormone with antifibrotic effects. We assessed the safety, pharmacokinetics, and pharmacodynamics of AZD3427 in healthy volunteers and patients with heart failure on standard-of-care therapy. METHODS AND RESULTS: In this first-in-human, phase 1a/b, randomized, single-blind, placebo-controlled study, healthy volunteers were randomized 6:2 to receive a single dose of AZD3427 or placebo by subcutaneous injection in 5 mixed-ethnicity cohorts (5, 10, 30, 90, or 270 mg) and 1 Japanese-descent cohort (270 mg), or by intravenous injection in 1 cohort (15 mg). After confirming safety and tolerability in healthy volunteers, 3 cohorts of patients with heart failure and left ventricular ejection fraction ≤40% and 3 cohorts with ejection fraction ≥41% were randomized 6:2 to receive 5 weekly doses of AZD3427 (5, 15, or 45 mg) or placebo by subcutaneous injection. In total, 56 healthy volunteers and 48 patients with heart failure were randomized. AZD3427 was well tolerated at all doses. After subcutaneous administration, AZD3427 was absorbed slowly, and exposure was approximately linear across the dose range. In patients with heart failure, AZD3427 terminal half-life was 13 to 14 days and there were numerical increases in stroke volume and estimated glomerular filtration rate. No treatment-emergent antidrug antibodies were detected. CONCLUSIONS: AZD3427 had favorable safety and pharmacokinetic profiles. Hemodynamic changes in patients with heart failure were consistent with the anticipated effects of a relaxin analog. These findings support further development of AZD3427 as a novel long-term treatment for patients with heart failure. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique Identifier: NCT04630067.

Pharmacokinetic interaction study of ticagrelor and cyclosporine in healthy volunteers.

BACKGROUND AND OBJECTIVE: Patients with acute coronary syndrome and certain co-morbidities may receive ticagrelor, a reversibly binding P2Y(12) receptor antagonist, and cyclosporine, a commonly used immunosuppressant drug. This study assessed the potential pharmacokinetic drug-drug interaction between ticagrelor and cyclosporine. METHODS: In this single-centre, open-label, three-treatment, three-period crossover study (NCT01504906), healthy volunteers (n = 26) randomly received each of three treatments: cyclosporine (600 mg single oral dose) plus ticagrelor (180 mg single oral dose); cyclosporine alone; ticagrelor alone. Treatments were separated by a washout period of ≥14 days. Plasma concentrations of ticagrelor and its active metabolite (AR-C124910XX) and blood concentrations of cyclosporine were analyzed, and pharmacokinetic parameters were calculated. Safety and tolerability were assessed. RESULTS: Compared with ticagrelor alone, the geometric least squares mean (LSM) ratio (90 % confidence interval [CI]) for the ticagrelor area under the plasma concentration-time curve from time zero to infinity (AUC(∞)) was 2.83 (2.63-3.06), and the maximum plasma concentration (C(max)) was 2.30 (2.06-2.58), in the presence of cyclosporine. Co-administration of cyclosporine with ticagrelor significantly increased AR-C124910XX AUC(∞) (1.33 [1.23-1.42]) and decreased C(max) (0.85 [0.76-0.94]). Ticagrelor had no effect on cyclosporine pharmacokinetic parameters, as the 90 % CIs of the LSM ratios were all within the 0.80-1.25 no-effect range. Co-administration of ticagrelor and cyclosporine was generally well tolerated. CONCLUSION: Co-administration of cyclosporine with ticagrelor increased exposure to ticagrelor and its active metabolite and had no effect on cyclosporine pharmacokinetic parameters. The magnitude of cyclosporine's effect on ticagrelor pharmacokinetics does not warrant dose adjustment of ticagrelor.

Evaluation of the pharmacokinetic interaction between ticagrelor and venlafaxine, a cytochrome P-450 2D6 substrate, in healthy subjects.

PURPOSE: Ticagrelor is a reversibly binding P2Y12 receptor antagonist used clinically for the prevention of atherothrombotic events in patients with acute coronary syndromes (ACS). Ticagrelor has been shown in vitro to be a weak inhibitor of cytochrome P-450 (CYP) 2D6, a clinically important enzyme for the metabolism of many drugs. This study assessed the effects of coadministration of ticagrelor on the pharmacokinetics of the CYP2D6 substrate venlafaxine. The impact of venlafaxine on ticagrelor pharmacokinetic parameters was also investigated. METHODS: Healthy subjects (N = 22) received a single 180-mg oral dose of ticagrelor on days 1 and 9 and oral doses of venlafaxine on day 4 (37.5 mg BID) and days 5 through 10 (75 mg BID). Plasma concentrations of ticagrelor, venlafaxine, and their metabolites (AR-C124910XX and O-desmethylvenlafaxine [ODV], respectively) were quantified for pharmacokinetic analyses. Safety and tolerability were assessed throughout the study. FINDINGS: Overall, 19 of 25 subjects were male; 14 were white, 10 were black, and 1 was Asian. Mean (SD) age was 26 (6) years, and mean (SD) body mass index was 24.3 (2.9) kg/m(2). Ticagrelor had no effect on overall exposure to venlafaxine, as assessed by the AUC0-τ (geometric least squares mean ratio, 110.32 ng · h/mL [90% CI, 106.27-114.52]). Venlafaxine Cmax was increased by 22% in the presence of ticagrelor (121.83 ng/mL [90% CI, 111.80-132.75]). ODV AUC0-τ and Cmax were unaffected by coadministration with ticagrelor (98.71 ng · h/mL [90% CI, 96.61-100.85] and 101.44 ng/mL [90% CI, 98.34-104.65], respectively). Venlafaxine had no effect on the Cmax or AUC0-∞ of ticagrelor (96.54 ng/mL [90% CI, 85.03-109.61] and 89.67 ng · h/mL [90% CI, 82.78-97.14]) or AR-C124910XX (106.39 ng/mL [90% CI, 96.10-117.78] and 106.32 ng · h/mL [90% CI, 97.28-116.21], respectively). Ticagrelor and venlafaxine were well tolerated whether given alone or in combination. IMPLICATIONS: Ticagrelor had no clinically relevant effect on the plasma levels of venlafaxine and its CYP2D6-generated active metabolite, ODV. On the basis of these data, ticagrelor is not expected to affect CYP2D6-mediated drug metabolism to a clinically relevant extent. Venlafaxine had no effect on the pharmacokinetics of ticagrelor.