Pharmacokinetic comparability of Prolastin®-C to Prolastin® in alpha1-antitrypsin deficiency: a randomized study

Abstract

BackgroundAlpha1-antitrypsin (AAT) deficiency is characterized by low blood levels of alpha1-proteinase inhibitor (alpha1-PI) and may lead to emphysema. Alpha1-PI protects pulmonary tissue from damage caused by the action of proteolytic enzymes. Augmentation therapy with Prolastin® (Alpha1-Proteinase Inhibitor [Human]) to increase the levels of alpha1-PI has been used to treat individuals with AAT deficiency for over 20 years. Modifications to the Prolastin manufacturing process, incorporating additional purification and pathogen-reduction steps, have led to the development of an alpha1-PI product, designated Prolastin®-C (Alpha1-Proteinase inhibitor [Human]). The pharmacokinetic comparability of Prolastin-C to Prolastin was assessed in subjects with AAT deficiency.MethodsIn total, 24 subjects were randomized to receive 60 mg/kg of functionally active Prolastin-C or Prolastin by weekly intravenous infusion for 8 weeks before crossover to the alternate treatment for another 8 weeks. Pharmacokinetic plasma samples were drawn over 7 days following last dose in the first treatment period and over 10 days following the last dose in the second period. The primary end point for pharmacokinetic comparability was area under the plasma concentration versus time curve over 7 days post dose (AUC0-7 days) of alpha1-PI determined by potency (functional activity) assay. The crossover phase was followed by an 8-week open-label treatment phase with Prolastin-C only.ResultsMean AUC0-7 days was 155.9 versus 152.4 mg*h/mL for Prolastin-C and Prolastin, respectively. The geometric least squares mean ratio of AUC0-7 days for Prolastin-C versus Prolastin had a point estimate of 1.03 and a 90% confidence interval of 0.97-1.09, demonstrating pharmacokinetic equivalence between the 2 products. Adverse events were similar for both treatments and occurred at a rate of 0.117 and 0.078 per infusion for Prolastin-C (double-blind treatment phase only) and Prolastin, respectively (p = 0.744). There were no treatment-emergent viral infections in any subject for human immunodeficiency virus, hepatitis B or C, or parvovirus B19 during the course of the study.ConclusionProlastin-C demonstrated pharmacokinetic equivalence and a comparable safety profile to Prolastin.Trial RegistrationClinicalTrials.gov Identifier: NCT00295061

European Respiratory Society statement: diagnosis and treatment of pulmonary disease in α1-antitrypsin deficiency

“…In order to obtain all the evidence about augmentation and minimise bias we used standard systematic review methods as described in the online supplementary material. There have been eight RCTs of intravenous augmentation, three against placebo [51][52][53]87] and five against another active comparator [88][89][90][91][92], generally a newer brand of augmentation therapy. In addition there have been six observational studies reporting a control group [8,[93][94][95][96][97], largely assessing data from registries, and 11 uncontrolled observational studies [82,[98][99][100][101][102][103][104][105][106][107][108], focused on pharmacokinetics, safety or novel outcomes.…”

A review of augmentation therapy for alpha-1 antitrypsin deficiency

“…Finally, a comparison of the newer Prolastin-C with its predecessor, original Prolastin, showed a similar adverse effect profile in both drugs [59]. Adverse events occurred at a rate of 0.117 per infusion with Prolastin-C and 0.078 per infusion with Prolastin (p = 0.744).…”

Diagnosis and treatment of pulmonarydisease in α1-antitrypsin deficiency: a statement of European Respiratory Society

“…дополнительные онлайн-материалы). Найдено 8 РКИ внутривенной ЗТ, в 3 из которых активная терапия сравнивалась с плацебо [51][52][53]87] и в 5 -с другим активным лечением [88][89][90][91][92], в основном новыми для ЗТ препаратами. Кроме этого, найдено 6 наблюдательных исследований с включением контрольной группы [8,[93][94][95][96][97], по данным которых проанализированы преимущественно данные регистров, и 11 неконтролируемых наблюдательных исследований [82,[98][99][100][101][102][103][104][105][106][107][108], посвященных фармакокинетике, безопасности или новым исходам заболевания.…”