Pharmacokinetics, efficacy and safety of a novel fibrinogen concentrate in pediatric patients with congenital afibrinogenemia.

INTRODUCTION: Congenital afibrinogenemia treatment with plasma-derived fibrinogen concentrates in pediatric patients is limited. This study investigated the pharmacokinetics, surrogate efficacy, and safety of a plasma-derived fibrinogen concentrate (FIB Grifols) in pediatric patients with congenital afibrinogenemia. METHODS: Patients aged <18 years old diagnosed with congenital afibrinogenemia were included in this prospective, multinational, phase 1-2, single-arm study. After a single dose of a plasma-derived fibrinogen concentrate (70 mg/kg body weight), pharmacokinetic parameters were determined from plasma fibrinogen activity (Clauss method) and antigen method (ELISA), and calculated by noncompartmental and population pharmacokinetic (popPK) models. Patients were followed up over 14 days. Efficacy variables were the mean change on thromboelastographic variables (maximum clot firmness [MCF], alpha angle [ α ]) and coagulation tests (prothrombin time, activated partial thromboplastin time, and thrombin time) 1 h postinfusion. Safety parameters were assessed. RESULTS: Eleven patients with a median (range) age 8.80 (3.7-12.7) years were treated with the plasma-derived fibrinogen concentrate. Using the popPK modeling, fibrinogen activity reached a mean (standard deviation) Cmax of 1.3 (0.225) g/l, half-life ( t1/2 ) of 60.6 (4.48) h and incremental in vivo recovery (IVR) of 1.86 (0.322) (mg/dl)/(mg/kg). Surrogate efficacy was demonstrated by significant increase in MCF (9.23 [3.94] mm; P  < 0.001; 95% confidence interval 6.58, 11.87). All coagulation times were significantly shortened after fibrinogen concentrate infusion. Adverse events were mild or moderate in severity, and unrelated to fibrinogen concentrate. CONCLUSIONS: In pediatric patients with congenital afibrinogenemia, plasma-derived fibrinogen concentrate revealed a favorable and specific pharmacokinetic profile, demonstrated efficacy in coagulation and was safe and well tolerated.

Immunogenicity, reactogenicity and safety of an inactivated quadrivalent influenza vaccine in children and adolescents 6 months through 17 years of age in India.

Efficacy and safety data on quadrivalent influenza vaccines (QIVs) for immunization of Indian children are scarce. This phase 3, registration study evaluated the immunogenicity, safety, and tolerability of a QIV in Indian children aged 6-35 months (Group 1) and 3-17 y (Group 2). Subjects received one or two doses (0.5 mL each) of the study vaccine based on their priming status. Immunogenicity (post-vaccination geometric mean fold increase in hemagglutination inhibition [HI] titers and proportion of patients with seroprotection and seroconversion against the four influenza strains), unsolicited adverse events (AEs), and tolerability were analyzed. Among 118 subjects enrolled in each group, the geometric mean(standard deviation) fold increase in HI titers against A(H3N2), A(H1N1), B(Victoria), and B(Yamagata) strains were 31.7(5.33), 10.5(6.06), 4.1(5.70), and 8.6(5.34) in Group 1 and 14.0(4.37), 9.2(4.26), 14.3(6.73), and 14.4(5.41) in Group 2, respectively. Seroprotection was achieved by 91.2%, 83.3%, 41.2%, and 68.4% subjects in Group 1 and 100%, 95.8%, 73.7%, and 89.8% subjects in Group 2, respectively. Seroconversion was achieved by 87.7%, 66.7%, 41.2%, and 64.9% subjects in Group 1 and 89.0%, 78.8%, 69.5%, and 75.4% subjects in Group 2, respectively. Vaccination site pain and fever were the most common local and systemic reactions, respectively. Systemic reactions were more frequent in Group 1 (16.9% vs 7.6%). Most subjects (>90%) did not experience inconvenience within 7 d of vaccination; <10% in both groups reported unsolicited AEs. Thus, the QIV had a positive benefit/risk profile in Indian children/adolescents aged 6 months to 17 y.CTRI Registry No: CTRI/2018/05/014191Registry Name: Clinical Trials Registry - IndiaDate of Trial Registration: May 29, 2018Study Dates: August 03, 2018 (first subject first visit) to January 31, 2019 (last subject last visit)Drugs Controller General of India [DCGI] permission letter number: CT-03/2018.

Pharmacokinetics, surrogate efficacy and safety evaluations of a new human plasma-derived fibrinogen concentrate (FIB Grifols) in adult patients with congenital afibrinogenemia.

BACKGROUND AND AIMS: Congenital afibrinogenemia is a rare coagulation disorder resulting from a deficiency in fibrinogen. This study assessed the pharmacokinetics, surrogate efficacy and safety of FIB Grifols, a new human plasma-derived fibrinogen concentrate, to treat congenital afibrinogenemia. METHODS: Eleven adult patients from a multinational, phase 1-2, prospective, open-label, single-arm, uncontrolled clinical study received a single infusion of FIB Grifols, 70 mg/kg bw. Fibrinogen pharmacokinetics (fibrinogen activity: Clauss method; antigen plasma concentrations: ELISA) and efficacy parameters were determined over 14 days after infusion. Efficacy endpoints were the mean change on plasma maximum clot firmness (MCF) on viscoelastic testing and coagulation tests 1-hour post-infusion, and correlation with fibrinogen levels throughout. Safety parameters were also assessed. RESULTS: For the Clauss method, (mean [standard deviation]) baseline adjusted Cmax was 1.99 (0.40) g/L, reached 1.76 (1.00) h after infusion, and half-life was 76.94 (20.21) h. Using ELISA, Cmax after FIB Grifols infusion was 2.88 (0.86) mg/mL, with a tmax of 3.06 (2.24) h. Fibrinogen activity and antigen concentrations showed statistically significant correlation of 0.9120 (P < 0.001). Surrogate efficacy was demonstrated by a significant increase of 12.35 (3.85) mm in MCF. Prothrombin time, activated partial thromboplastin time and thrombin time, returned to normal ranges over time, indicating restoration of functionally active fibrinogen. There were no treatment-related adverse events, allergic reactions, serious adverse events, or discontinuations. CONCLUSIONS: The pharmacokinetic profile of functionally active FIB Grifols was established, hemostasis was restored, and FIB Grifols was safe and well tolerated in fibrinogen-deficient patients.