Clinical Pharmacokinetics of α1-Antitrypsin in Homozygous PiZ Deficient Patients

Constans, J.; Carlès, Pierre; Boneu, A; Arnaud, Jacques; Tufenkji, A E; Pujazon, M.-C.; Tavera, Catherine

doi:10.2165/00003088-199223020-00007

Cited by 9 publications

(8 citation statements)

References 30 publications

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“…The study design originally required subjects receiving AAT augmentation therapy to discontinue that therapy 28 days before vector administration, on the basis of published data indicating that the elimination half-life of infused AAT is 2 to 3 days (20,21). Although this resulted in total AAT levels that were well within the expected range for PI*ZZ subjects at day Ϫ1, substantial residual levels of M-type AAT were detected in these subjects, and the ''washout'' period was extended to 56 days for subjects enrolled in cohorts 2 and 3.…”

Section: Discussionmentioning

confidence: 99%

“…Among the 4 subjects who had received the rAAV2 vector, all had substantial neutralizing antibody titers against AAV2 at baseline (range, 160 to 2,560) and lower baseline titers against AAV1 (range, Ͻ20 to 640). Among the 5 subjects who not had received the rAAV2 vector, only 1 (subject 302) had a baseline titer (640) against AAV2 and a low but detectable titer (20) against AAV1. After i.m.…”

Section: Time Course Of Immune Responses To Aat and Aav And Ck Levelsmentioning

confidence: 99%

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Sustained transgene expression despite T lymphocyte responses in a clinical trial of rAAV1-AAT gene therapy

Brantly

Chulay

Wang

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

288

239

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Fig. 2.Transformants releasing E␤C suffered less damage than control lines when EPNs were present. (A) Root damage measured on plants that had received neither WCR eggs nor nematodes was minimal, and there was no difference between transformed and nontransformed plants (n ϭ 5, P ϭ 0.87). (B) Root damage on plants that received only WCR eggs, but no nematodes, was substantial. Again, no significant difference was found between the transformed and nontransformed plants (n ϭ 5, P ϭ 0.18). (C) In plots that received WCR eggs and H. megidis, roots from transformed plants (pooled) had significantly less damage than roots from control lines (n ϭ 30, P ϭ 0.007). Approximately one-quarter of the transformed plants were found not to emit E␤C. Removing these plants from the statistical analysis did not significantly affect the results. The letters above the bars indicate significant differences within a graph. Error bars indicate standard errors.

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Section: Discussionmentioning

confidence: 99%

Section: Time Course Of Immune Responses To Aat and Aav And Ck Levelsmentioning

confidence: 99%

Sustained transgene expression despite T lymphocyte responses in a clinical trial of rAAV1-AAT gene therapy

Brantly

Chulay

Wang

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

288

239

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“…A tri-compartmental pharmacokinetic model seems to be the most plausible for describing exogenous AAT disposition in the body. 9 However, in most of the published exogenous AAT pharmacokinetic analyses, the lack of intensive data during the first 2 hours after exogenous AAT administration makes it difficult to characterise the first rapid phase. A simpler bicompartmental pharmacokinetic model has therefore been applied with no real loss of accuracy.…”

Section: Discussionmentioning

confidence: 99%

“…6 13 Moreover, pharmacokinetic data in healthy volunteers, untreated Pi*ZZ patients, and treated patients showed no differences in the AAT elimination half life between endogenous and manufactured AAT. 9 Thus, only exogenous AAT was considered in our simulations. Exogenous AAT (type M) is assumed to be more functional than endogenous AAT (type Z), so it seems reasonable to use exogenous AAT serum concentrations to monitor treatment.…”

Section: Discussionmentioning

confidence: 99%

“…Previously published reports showed no differences between endogenous and manufactured AAT in elimination half life. 9 We therefore decided to measure total serum AAT concentrations because the recommended target of 0.5 g/l refers to the total AAT concentrations (native plus exogenous AAT). 5 Patients were then scheduled for drug administration and at least five trough samples were obtained at steady state conditions and analysed by nephelometry.…”

Section: Study Design and Population Pharmacokinetic Modelmentioning

confidence: 99%

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

Soy

Roza

Lara

et al. 2006

Thorax

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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.

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Scintigraphic Documentation of α1-Antitrypsin in Deficient PiZZ Patients

et al. 1994

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SummaryPiZZ-deficient patients affected by a severe panlobular emphysema were treated with an infusion of industrial concentrates of purified (XI -antitrypsin (AAT) . A treatment protocol was followed and the pharmacokinetic parameters were determined. The aim of this investigation was to consider the tissue distribution of AAT injected into untreated and treated patients, as well as into controls, in order to locate the labelled protein and map the kinetics of the protein deposit.Scintigraphies carried out on PiZZ patients and on controls confirmed a 3-pool pharmacokinetic model of AAT distribution. Three organs accounted for the predominant deposition of AAT: the liver, lungs and a very limited area of the upper digestive tract. At time 0, the distribution of the protein differed between controls and untreated patients. After 6 months of replacement therapy, the tissue distribution of AAT among treated and untreated PiZZ-deficient patients was not similar.The liveris one of the essential organs affected by the infusion of AAT. This study demonstrated that the digestive tissues are also affected by this replacement therapy. These observations should be useful in predicting tissue metabolism ofthe injected preparation, particularly when alternative routes of AAT administration are now possible.

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Clinical Pharmacokinetics of α1-Antitrypsin in Homozygous PiZ Deficient Patients

Cited by 9 publications

References 30 publications

Sustained transgene expression despite T lymphocyte responses in a clinical trial of rAAV1-AAT gene therapy

Sustained transgene expression despite T lymphocyte responses in a clinical trial of rAAV1-AAT gene therapy

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

Scintigraphic Documentation of α1-Antitrypsin in Deficient PiZZ Patients

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