Alpha-1-antitrypsin deficiency: optimal therapeutic regimen based on population pharmacokinetics

Abstract

Background: Exogenous doses of 60 mg/kg a 1 -antitrypsin (AAT) every 7 days are recommended in patients with severe AAT deficiency. However, long term administration of weekly doses is not well accepted by patients. Using pharmacokinetic simulations, we evaluated whether steady state minimum concentrations of total AAT can be maintained above the threshold of 0.5 g/l with longer intervals between doses. Methods: Several sets of exogenous AAT versus time simulations were studied using a non-linear mixed effect approach with dosage regimens every 7, 14, 21, and 28 days. For each regimen the mean exogenous AAT trough concentrations and 5/95th percentiles were determined. The results obtained were applied to estimate the individual optimal dose at 7, 14, and 21 days in six patients using Bayesian analysis. Results: The simulations showed that a dose of 50 mg/kg AAT every 7 days was sufficient to obtain nadir concentrations. Doses of 120 and 100 mg/kg every 14 days were also adequate, but 180 mg/kg given every 21 days required total AAT monitoring to avoid underdosage. Longer intervals were inappropriate. Dosage individualisation confirmed that AAT infusions given every 14 days maintained the nadir level of 0.5 g/l without a significant dose increase compared with current practice. When the time span between doses was fixed at 21 days, a mean relative AAT dose enhancement of 91% and 13%, respectively, was required to achieve sustained total AAT concentrations above the target level for 100% and 85% of the interval between doses. Conclusions: It is feasible to extend the interval between doses of AAT to 14 or 21 days to achieve adequate trough total AAT concentrations. This study might be used as a starting point for clinical evaluation of the regimens described.

Reduction of severe exacerbations and hospitalization-derived costs in alpha-1-antitrypsin-deficient patients treated with alpha-1-antitrypsin augmentation therapy

“…Chronic augmentation therapy has been shown to effectively raise serum and lung levels of AAT in deficient subjects [Barker et al 1994;Gadek et al 1981;Soy et al 2006;Tirado-Conde et al 2008;Wewers et al 1987] and is well tolerated [Hubbard et al 1988;Vidal et al 2010]. Furthermore, augmentation therapy has been reported to lower the likelihood of admission to hospital due to severe exacerbations [Dirksen et al 2009].…”

Clinical utility of alpha-1 proteinase inhibitor in the management of adult patients with severe alpha-1 antitrypsin deficiency: a review of the current literature

“…This approach has been shown in pharmacokinetic studies to be valid,35 but the effect on adherence has not been published.…”

Deficiência de alfa-1 antitripsina: diagnóstico e tratamento

“…In addition to weekly regimens of 50 or 60 mg/kg, regimens of 100 or 120 mg/kg every 14 days, regimens of 150 or 180 mg/kg every 21 days, and regimens of 250 mg/kg every 28 days have been tested. (46) Infusions of 50 or 60 mg/kg every 7 days and infusions of 100 or 120 mg/kg every 14 days maintained serum levels above the "protective threshold" in more than 85% of the interval between the doses (reaching 100% in the weekly regimen), and were considered appropriate. However, in order to achieve efficient serum levels (greater than 50 mg/dL) in the regimens with intervals of 21 and 28 days, higher doses of AAT would be necessary, which, in practice, would increase treatment costs.…”