Impact of immunogenicity on pharmacokinetics, efficacy and safety of adalimumab in adult patients with moderate to severe chronic plaque psoriasis.

BACKGROUND: Adalimumab is a tumour necrosis factor-alpha antibody approved for treatment of moderate to severe chronic plaque psoriasis. OBJECTIVE: To characterise population pharmacokinetics of adalimumab 40 mg every other week dosing regimen and impact of immunogenicity on pharmacokinetics, efficacy and safety in psoriasis patients. METHODS: Patients were enrolled in a Phase 3 study comprising a 16-week double-blind, placebo-controlled period, a 17-week open-label period for Week 16 Psoriasis Area and Severity Index (PASI) 75 responders, and a 19-week double-blind, placebo-controlled period for Week 33 PASI 75 responders. Serum adalimumab and anti-adalimumab antibody (AAA) concentrations were measured and a population pharmacokinetic model devleoped to identify patient/disease factors affecting adalimumab pharmacokinetics. Impact of immunogenicity on treatment efficacy and safety was also assessed. RESULTS: Week 33 mean adalimumab concentration was 5.2 µg/mL. Week 16 responders had higher adalimumab concentrations than non-responders (6.3 vs. 2.2 µg/mL). Bodyweight and study were significant covariates in population pharmacokinetic model with weight accounting for 19% and 29% of variability in adalimumab clearance and volume of distribution, respectively. A total of 8.8% of adalimumab-treated patients tested AAA positive and had twofold higher adalimumab clearance. PASI 75 response rate was comparable between AAA+ and AAA- patients at Weeks 33 and 52 (Week 33: 36% vs. 22.5%, Week 52: 21.1% vs. 17.8%) and adverse events incidence was similar between the two groups. CONCLUSIONS: Patient weight and study significantly affect adalimumab clearance and volume of distribution in psoriasis patients. Development of AAAs result in lower adalimumab exposure and efficacy with no effect on adverse events incidence.

Intravascular administration of polymerized gelatin versus isotonic saline for prevention of spinal-induced hypotension.

This report tests the hypothesis that intravascular prehydration with 3% gelatin in electrolyte solution maintains arterial blood pressure after spinal anesthesia better than with an equal volume of isotonic saline solution. Thirty-four patients undergoing elective transurethral resection of the prostate were allocated randomly to receive either 7 mL/kg of isotonic saline 0.9% (17 patients) or 7 mL/kg of 3% gelatin in electrolyte solution (17 patients) before spinal anesthesia. There was a significant increase in central venous pressure in the gelatin group without any significant change in the isotonic saline group. After spinal anesthesia, the mean systolic blood pressure significantly decreased in both groups; however, the incidence of systolic blood pressure greater than 75% of control value was higher in the gelatin group (15/17) than in the normal saline group (9/17). Also, the mean dose of phenylephrine required to maintain arterial blood pressure > 75% of the baseline value was significantly larger in the normal saline group than in the gelatin group. We conclude that prophylactic administration of gelatin is more effective than saline in attenuating spinal anesthesia-induced hypotension.

Transient atrioventricular block after release of aortic cross-clamp.

To determine the incidence of atrioventricular (A-V) block, 86 patients, aged 58.9 +/- 10.4 yr, undergoing elective coronary artery bypass grafting (CABG) during aortic cross-clamping (ACC) and cold potassium cardioplegia were investigated. The incidence and duration of complete A-V block after release of the aortic cross-clamp was monitored. Twenty-four percent of the patients developed complete A-V block that required temporary pacing for a mean time of 66 +/- 39 min. The volume of cardioplegia used was not significantly different between the patients who developed A-V block and the patients who had no block. The serum potassium level at the time of release of the aortic cross-clamp was within the normal range in both groups. Six factors were correlated with the development of A-V block: old age, preparation by a combination of beta-adrenergic blockers and calcium channel blockers, preoperative bradycardia, the number of vessels grafted, as well as the duration of ACC. Also, the serum potassium level at the time of release of the aortic cross-clamp was significantly higher in the patients who developed A-V block. The high incidence of A-V block in elderly patients undergoing multiple coronary vessel grafting during a prolonged ACC time suggests that suboptimal myocardial preservation may be the main predisposing factor.