Intravenous human plasma-derived augmentation therapy in alpha 1-antitrypsin deficiency: from pharmacokinetic analysis to individualizing therapy.

BACKGROUND: Severe forms of alpha(1)-antitrypsin (AAT) deficiency require augmentation therapy by intravenous administration of purified preparations of AAT concentrate. Although standard AAT treatment schedules are widely available, pharmacokinetic studies characterizing AAT serum decay are scarce, and data on the variability of individual patients are almost nonexistent. OBJECTIVE: To establish individual AAT pharmacokinetics and develop a predictive model based on simple pharmacokinetic characterization that can be used to optimize individual AAT dosing regimens. METHODS: Seven patients with severe hereditary AAT deficiency (PI(*)ZZ phenotype) with serum AAT levels less than 0.50 g/L initially received AAT 180 mg/kg every 3 weeks. At 7, 14, and 21 days after AAT administration, serum samples were taken for quantitative AAT analysis and further one-compartment pharmacokinetic analysis. Subsequently, patients were rescheduled (dose and dosing interval) according to their individual responses. The influence of baseline AAT level, age, sex, body weight, and commercial AAT preparation was evaluated. RESULTS: The mean +/- SD AAT pharmacokinetic profile was: volume of distribution 127.6 +/- 31.9 mL/kg, clearance 10.13 +/- 1.84 mL/kg/day, and half-life 8.7 +/- 1.0 days. Hence, the mean optimized final AAT dose was 123.1 mg/kg every 2 weeks (range 118.5-125.6). AAT concentrations differed by a mean (geometrical) value of 3.9% (range -4.2% to 6.7%) from the minimum desired AAT serum trough of 0.50 g/L. The impact of baseline AAT levels and commercial AAT preparation used was statistically significant (p = 0.033 and p = 0.035, respectively). Differences between estimated and actual values were slightly lower when baseline AAT levels were taken into consideration, with a mean value of 3.3% (range -4.2% to 6.1%). CONCLUSIONS: AAT augmentation therapy can be effectively individualized on a pharmacokinetic basis with a simple, easily executed method.

Angiotensin-converting enzyme i/d polymorphism in patients with malignant hypertension.

The angiotensin-converting enzyme (ACE) gene has been implicated in the manifestation of the phenotype of malignant hypertension (MH). In 1990 the ACE gene polymorphism characterized by the insertion or deletion of a 287-base pair fragment in the 17q23 chromosome was identified. The DD genotype is associated with increased tissue and circulating ACE levels and elevated angiotensin II. ACE polymorphism was studied in 48 patients with MH, 25 patients with non-MH, and a control group of 78 normotensive individuals by real-time polymerase chain reaction using the LightCycler system (Roche Diagnostics Corporation, Indianapolis, IN). The DD genotype was found statistically more frequently in MH patients than controls (p=0.028; odds ratio, 2.5; confidence interval, 1.1-5.5). Presence of the DD genotype of the ACE gene is more frequent in MH patients than in controls, indicating that this genotype could be a significant risk factor and a predictor for the development of MH.