Alpha-1-Antitrypsin Deficiency: Optimal Therapeutic Regimen Based On Population Pharmacokinetics

Dolors Soy ¹, Cristian De la Roza ¹, Beatriz Lara ¹, Cristina Esquinas ¹, Antoni Torres ² and Marc Miravitlles ^1*

¹ Hospital Clinic, Spain
² Hospital Clinic i Provincial, Spain

^* To whom correspondence should be addressed. E-mail: marcm{at}clinic.ub.es.

Accepted 15 July 2006

Abstract

Background: Exogenous doses of 60 mg/kg/7days of alpha-1- antitrypsin (AAT) are recommended in patients with severe deficiency. However, long-term administration of weekly doses is not well accepted by patients. With pharmacokinetic simulations, we evaluated whether extended intervals of AAT administration can maintain steady-state minimum concentrations of total AAT above the threshold of 0.5g/L.

Method: We simulated several sets of exogenous AAT versus time, with a non-linear-mixed-effect approach, considering dosage regimens every 7, 14, 21 and 28 days. For each regimen, mean exogenous AAT trough concentrations and percentiles 5/95 were determined. The results obtained were applied to estimate the individual optimal dose at 7, 14 and 21 days in six patients using a Bayesian analysis.

Results: The simulations showed that 50 mg/kg/7days of AAT were sufficient to obtain nadir concentrations. Both, 120 and 100 mg/kg/14days were suitable but 180 mg/kg/21days required total AAT monitoring to avoid underdosage. Longer intervals were inappropriate. Dosage individualization confirmed that biweekly AAT infusions maintained the nadir level of 0.5 g/L without a remarkable dose increase compared to current practices. Fixing the time-span between doses at 21 days, a mean relative AAT dose enhancement of 91% and 13% was required to achieve sustained total AAT above the target during the entire interval or 85% of it, respectively.

Conclusions: It is feasible to expand the AAT interdose interval to 14 or 21 days with adequate trough total AAT concentrations. This study might be used as a starting point for clinical evaluation of the regimens described.

Keywords: alpha-1-antitrypsin deficiency, dosage optimisation, population pharmacokinetics, replacement therapy

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