Intravenous Ganaxolone: Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability in Healthy Adults.

Ganaxolone, a neuroactive steroid anticonvulsant that modulates both synaptic and extrasynaptic γ-aminobutyric acid type A (GABAA ) receptors, is in development for treatment of status epilepticus (SE) and rare epileptic disorders, and has been approved in the United States for treatment of seizures associated with cyclin-dependent kinase-like 5 deficiency disorder in patients ≥2 years old. This phase 1 study in 36 healthy volunteers evaluated the pharmacokinetics, pharmacodynamics, and safety of intravenous ganaxolone administered as a (i) single bolus, (ii) infusion, and (iii) bolus followed by continuous infusion. After a single bolus over 2 minutes (20 mg) or 5 minutes (10 or 30 mg), ganaxolone was detected in plasma with a median Tmax of 5 minutes, whereas a 60-minute infusion (10 or 30 mg) or a bolus (6 mg over 5 minutes) followed by infusion (20 mg/h) for 4 hours achieved a median Tmax of approximately 1 and 3 hours, respectively. Cmax was dose and administration-time dependent, ranging from 73.8 ng/mL (10 mg over 5 minutes) to 1240 ng/mL (30 mg over 5 minutes). Bolus doses above 10 mg of ganaxolone markedly influenced the bispectral index score with a rapid decline; smaller changes occurred on the Modified Observer's Assessment of Alertness/Sedation scale and in quantitative electroencephalogram. Most adverse events were of mild severity, with 2 events of moderate severity; none were reported as serious. No effects on systemic hemodynamics or respiratory functions were reported. Overall, ganaxolone was generally well tolerated at the doses studied and demonstrated pharmacokinetic and pharmacodynamic properties suitable to treat SE.

Long-term treatment with ganaxolone for seizures associated with cyclin-dependent kinase-like 5 deficiency disorder: Two-year open-label extension follow-up.

OBJECTIVE: In the placebo-controlled, double-blind phase of the Marigold study (NCT03572933), ganaxolone significantly reduced major motor seizure frequency (MMSF) in patients with cyclin-dependent kinase-like 5 deficiency disorder (CDD). We report 2-year safety and clinical outcomes data from the open-label extension (OLE) phase of Marigold. METHODS: Patients with CDD who completed the double-blind phase were eligible to continue in the OLE. Efficacy assessments included MMSF reduction from prerandomization baseline, responder rates, and Clinical Global Impression-Improvement scores, including assessment of seizure intensity and duration (CGI-CSID). Safety assessments included treatment-emergent adverse events (TEAEs) and TEAEs leading to discontinuation. RESULTS: Of 101 patients who enrolled in Marigold, 88 (87.1%) entered the OLE (median age = 5 years, 79.5% female). Median 28-day MMSF at baseline was 50.6. At 2 years in the OLE (months 22-24), MMSF was reduced by a median of 48.2% (n = 50); when missing data were imputed, median reduction in MMSF was 43.8% using a mixed effects model and 27.4% using a last observation carried forward model. During months 22-24, 23 of 50 (46.0%) patients experienced reductions in MMSF of ≥50%; 12 of 50 (24.0%) patients experienced MMSF reductions of ≥75%. During months 22-24, 40 of 49 (81.6%) patients were rated by caregivers as having improvement in seizure-related outcomes based on CGI-CSID scores. Thirty-seven patients discontinued ganaxolone due to lack of efficacy (n = 13), withdrawal by caregiver (n = 12), adverse event (n = 10), physician decision (n = 1), or death (n = 1; unrelated to study drug). The most common treatment-related TEAEs were somnolence (17.0%), seizure (11.4%), and decreased appetite (5.7%). Patients reported serious TEAEs (n = 28, 31.8%); those reported in ≥3% of patients were seizure (n = 6), pneumonia (n = 5), acute respiratory failure (n = 3), aspiration pneumonia (n = 3), and dehydration (n = 3). SIGNIFICANCE: Sustained reductions in MMSF at 2 years in the OLE support the efficacy of ganaxolone in seizures associated with CDD. Safety findings in the OLE were consistent with the double-blind phase.

Fibrinogen Concentrate for the Treatment of Thrombolysis-Associated Hemorrhage in Adult Ischemic Stroke Patients.

In patients with ischemic stroke who receive systemic recombinant tissue plasminogen activator (rt-PA), the risk of secondary hemorrhage is 1-7%. Fibrinogen supplementation with cryoprecipitate is recommended in patients with rt-PA-associated symptomatic hemorrhage. We examined whether fibrinogen concentrate can be used safely in this setting. A single-center retrospective case series was performed in patients who received fibrinogen concentrate for post-rt-PA hemorrhage between January-2012 and December-2017. The primary outcome was the incidence of in-hospital thromboembolic events and infusion reactions. Secondary outcomes included incidence of clinically significant ICH expansion within 24-hours and patient serum fibrinogen response to fibrinogen concentrate therapy. Thromboembolic events occurred in 3 (12.5%) of 24 patients included in the analysis. No patients experienced infusion-related reactions. Five of 22 patients with ICH experienced clinically significant hemorrhage expansion. Hypofibrinogenemia was corrected in 87.5%(7/8) of patients with baseline hypofibrinogenemia, with a median increase in serum fibrinogen 166 mg/dL. Median fibrinogen increase in patients without baseline hypofibrinogenemia was 18 mg/dL. Fibrinogen concentrate is a safe potential therapeutic option to restore fibrinogen levels in acute ischemic stroke patients with thrombolysis-associated hemorrhage.

Direct oral anticoagulants in patients with atrial fibrillation and renal impairment, extremes in weight, or advanced age.

A growing number of patients with an indication for stroke prevention in atrial fibrillation have kidney-, age-, or weight-related alterations in pharmacokinetics that affect dosing of direct oral anticoagulants. Because these patients were excluded from or comprised a small number of patients in clinical trials, there is a lack of evidence to guide clinicians. As a consequence, many patients do not receive oral anticoagulation despite a high risk for atrial fibrillation-related stroke. Here, we present a review of direct oral anticoagulant pharmacokinetics and a review of the available clinical evidence in patients with weight-, kidney-, and age-related disease.

Evaluation of Warfarin Reversal with 4-Factor Prothrombin Complex Concentrate Compared to 3-Factor Prothrombin Complex Concentrate at a Tertiary Academic Medical Center.

BACKGROUND: The U.S. Food and Drug Administration recently approved a four-factor prothrombin complex concentrate (4-PCC) for warfarin reversal. The literature supporting its use over three-factor prothrombin complex concentrate (3-PCC) is limited. OBJECTIVE: Our objective was to retrospectively compare the efficacy of 3-PCC to 4-PCC in reversing warfarin in patients who were actively bleeding. METHODS: We conducted a single-center, retrospective cohort analysis of adult patients who received 3-PCC or 4-PCC for international normalized ratio (INR) reversal. Our study excluded patients not actively bleeding and not on warfarin. The main outcome was the percentage of patients who achieved warfarin reversal defined as INR ≤ 1.3 at first INR check post factor administration. We recorded baseline data including PCC dose, location of bleed, pre- and posttreatment INR, and time to INR reversal. RESULTS: We included a total of 53 patients. Intracranial hemorrhage was the most common site of bleeding (26 [74.3%] in 3-PCC vs. 12 [66.7%] in 4-PCC). The mean dose of 3-PCC was 25.5 units/kg, compared to 27.9 units/kg of 4-PCC. The mean baseline INR was 2.3 in the 3-PCC group and 3 in the 4-PCC group (p = 0.03), and the first posttreatment INRs were 1.4 and 1.2, respectively (p < 0.01). Warfarin reversal was achieved in 15 (42.9%) patients who received 3-PCC and 15 (83.3%) patients who received 4-PCC (p < 0.01). Faster time to INR reversal was noted in the 4-PCC group vs. the 3-PCC group (3.7 vs. 5 h, p = 0.48). CONCLUSION: A higher percentage of patients achieved warfarin reversal with 4-PCC compared to 3-PCC treatment. A prospective randomized control trial is necessary to confirm our results.