This study evaluated the pharmacokinetics (PK), efficacy, safety, and tolerability of bleselumab – a fully‐human anti‐CD40 monoclonal recombinant IgG4. Patients with moderate‐to‐severe psoriasis were randomized on day 1 to receive bleselumab or placebo on days 1, 15 and 29 in a dose‐escalation of bleselumab at 0.1, 0.3, 1.0 or 3.0 mg/kg. The safety‐analysis set (SAF) and full‐analysis set (FAS) included all patients who received bleselumab or placebo, and the PK‐analysis set (PKAS) included patients in the SAF with ≥1 quantifiable serum bleselumab concentration. Serial blood samples were collected after each dose, and the bleselumab serum concentration was measured. After each dose, the area‐under‐the‐concentration–time curve over 336 hours (AUC336) and the maximum serum concentration (Cmax), and dose proportionality of AUC336 and Cmax were determined. The psoriasis area and severity index (PASI) score, the physician static global assessment (PSGA) score, the percentage body surface area (%BSA) affected with psoriasis, adverse events and laboratory parameters were assessed. Sixty patients were randomized and included in the SAF/FAS (bleselumab, n = 49; placebo, n = 11); 48 formed the PKAS. Bleselumab Cmax and AUC336 were more than dose proportional in the range 0.1–3.0 mg/kg, suggesting nonlinear PK after single/multiple doses. No clinically significant infusion reactions, cytokine‐release syndrome, or thromboembolic events were reported. Bleselumab did not improve the PASI scores, PSGA scores, or %BSA versus placebo. Transient elevation of alanine aminotransferase and aspartate aminotransferase levels by >3 × upper limit of normal were observed in four (8.2%) and two (4.1%) patients, respectively, in the 1.0 or 3.0 mg/kg groups. Patients with liver function test increases had no concurrent changes in bilirubin. Bleselumab demonstrated nonlinear PK after single and multiple doses, with few adverse reactions.
Clinical Therapeutics e68 Volume 39 Number 8S Results: Clopidogrel laboratory resistance (PRU> 208) was found to be higher in the CYP2C19*2-carriers as compared to non-carriers: 53.8% vs 16.2% (OR= 1.8; 95% CI: 1.0-3.2; р= 0.0067). Higher risk of thrombosis was associated with low mean 6-beta-hydroxycortisol / cortisol ratio and, consequently, impaired CYP3A4 activity (β coef-ficient= 0.022, SE 0.009, p= 0.021 in the linear regression model). CYP2C19*17, ABCB1 C3435T and CYP3A5*3 polymorphisms did not affect platelet reactivity. The presence of the CYP2C19*2 polymorphism did not affect the incidence of stent thrombosis (β =-1.626, SE= 1.449, p= 0.262 in the logistic regression model), nor did the CYP2C19*17 (β =-0.907, SE= 1.438, p= 0.528 in the logistic regression model) and ABCB1 C3435T polymorphisms (β = 1.270, SE= 1.442, p= 0.378 in the logistic regression model). The CYP3A5*3 polymorphism did not affect the incidence of stent thrombosis as well (β =-17.633, p= 0.999 in the logistic regression model). Conclusions: CYP2C19*2-carriership in ACS patients undergoing PCI significantly increases the risk of clopidogrel laboratory resistance. However we did not find evidence that the presence of CYP2C19*2, CYP2C19*17, ABCB1 C3435T, CYP3A5*3 polymorphisms may jeopardize clinical effectiveness and safety of PCI in patients with an acute ACS. However, impaired CYP3A4 isoenzyme activity may increase the risk of stent thrombosis.
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