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document
Safety , pharmacokinetics and pharmocodynamics of recombinant human porphobilinogen deaminase in healthy subjects and asymptomatic carriers of the acute intermittent porphyria gene who have increased porphyrin precursor excretion . BACKGROUND AND OBJECTIVE Acute intermittent porphyria is an autosomal dominant disorder caused by deficient activity of the third enzyme in the haem biosynthetic pathway , porphobilinogen deaminase . It is characterised by acute , potentially life-threatening neurological attacks that are precipitated by various drugs , reproductive hormones and other factors . During acute attacks , the porphyrin precursors 5-aminolevulinic acid and porphobilinogen accumulate and are excreted at high concentrations in the urine . Current treatment is based on glucose loading and parenteral haem replenishment , which reduce the accumulation of 5-aminolevulinic acid and porphobilinogen . Recently , a new form of treatment based on porphobilinogen deaminase enzyme replacement therapy has been shown to be effective in an acute intermittent porphyria mouse model which , during phenobarbital ( phenobarbitone ) induction of haem biosynthesis , mimics the biochemical pattern of acute porphyric attacks . The objective of the present study was to investigate the safety , pharmacokinetics and pharmacodynamics of recombinant human porphobilinogen deaminase ( P 9808 ) , administered to healthy subjects and asymptomatic porphobilinogen deaminase-deficient subjects with high concentrations of porphobilinogen , the substrate of porphobilinogen deaminase . STUDY DESIGN Forty individuals participated in this two-part study : 20 asymptomatic porphobilinogen deaminase-deficient subjects ( both male and female ) with > or =4 times the upper reference urinary porphobilinogen level , and 20 healthy male subjects . Four different doses of recombinant human porphobilinogen deaminase were studied ( 0.5 , 1 , 2 and 4 mg/kg bodyweight ) . Part A included 12 asymptomatic porphobilinogen deaminase-deficient subjects , and the enzyme was administered in an open-label , single-dose design . Part B included 20 asymptomatic porphobilinogen deaminase-deficient subjects and 20 healthy subjects . The same enzyme dosages were administered as divided doses every 12 hours for 4 consecutive days in a randomised , double-blinded , placebo-controlled design . The washout period between Parts A and B was 2 weeks . METHODS The concentrations of recombinant human porphobilinogen deaminase and titres of antibodies against recombinant human porphobilinogen deaminase were analysed by ELISA . Plasma porphobilinogen and 5-aminolevulinic acid concentrations were analysed using a novel liquid chromatography-tandem mass spectrometry method . Urinary porphobilinogen , 5-aminolevulinic acid and porphyrin concentrations , as well as plasma porphyrin concentrations , were analysed using standard methods . The pharmacodynamic effect of the enzyme was studied through changes in plasma porphobilinogen concentrations . RESULTS No serious adverse events were observed . Seven subjects ( four healthy men and three asymptomatic porphobilinogen deaminase-deficient subjects ) developed antibodies against recombinant human porphobilinogen deaminase but did not experience allergic manifestations . The mean elimination half-lives of the highest doses of recombinant human porphobilinogen deaminase ranged between 1.7 and 2.5 hours for both healthy men and asymptomatic porphobilinogen deaminase-deficient subjects . The area under the plasma concentration-time curve was proportional to the respective dose . In asymptomatic porphobilinogen deaminase-deficient subjects , plasma porphobilinogen concentrations decreased below measurable levels almost instantaneously after administration of any dose of the enzyme . The effect lasted for approximately 2 hours , after which the plasma porphobilinogen concentration slowly increased , reaching about 70 % of the initial values 12 hours after administration . There was no effect on plasma 5-aminolevulinic acid concentrations , and there was a transitory increment in porphyrin concentrations . The corresponding concentrations of metabolites in the urine reflected the pattern observed in the plasma . CONCLUSIONS The recombinant human porphobilinogen deaminase enzyme preparation was found to be safe to administer and effective for removal of the accumulated metabolite porphobilinogen from plasma and urine . The pharmacokinetic profile of recombinant human porphobilinogen deaminase showed dose proportionality , and the elimination half-life was about 2.0 hours for the two highest doses . Thus , clinical grounds were established for investigation of the therapeutic efficacy of the enzyme during periods of overt disease in patients with acute intermittent porphyria .
30223
Intervention_Pharmacological
recombinant human porphobilinogen deaminase
30224
Intervention_Pharmacological
porphobilinogen deaminase enzyme replacement therapy
30225
Intervention_Pharmacological
recombinant human porphobilinogen deaminase
30226
Intervention_Pharmacological
recombinant human porphobilinogen deaminase
30227
Intervention_Pharmacological
porphobilinogen deaminase
30228
Intervention_Pharmacological
human porphobilinogen deaminase
30229
Intervention_Pharmacological
human porphobilinogen deaminase
30230
Intervention_Physical
recombinant human porphobilinogen deaminase enzyme preparation
30231
Intervention_Pharmacological
recombinant human porphobilinogen deaminase
30232
Outcome_Other
Safety , pharmacokinetics and pharmocodynamics
30233
Outcome_Physical
5-aminolevulinic acid and porphobilinogen .
30234
Outcome_Physical
concentrations of recombinant human porphobilinogen deaminase and titres of antibodies against recombinant human porphobilinogen deaminase
30235
Outcome_Physical
Plasma porphobilinogen and 5-aminolevulinic acid concentrations
30236
Outcome_Physical
Urinary porphobilinogen , 5-aminolevulinic acid and porphyrin concentrations
30237
Outcome_Physical
plasma porphyrin concentrations
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Outcome_Adverse-effects
serious adverse events
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Outcome_Adverse-effects
antibodies against recombinant human porphobilinogen deaminase
30240
Outcome_Adverse-effects
allergic manifestations .
30241
Outcome_Physical
mean elimination half-lives of the highest doses of recombinant human porphobilinogen deaminase
30242
Outcome_Physical
area under the plasma concentration-time curve
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Outcome_Physical
plasma porphobilinogen concentrations
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Outcome_Physical
plasma porphobilinogen concentration
30245
Outcome_Physical
plasma 5-aminolevulinic acid concentrations
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Outcome_Physical
porphyrin concentrations .
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Outcome_Physical
corresponding concentrations of metabolites in the urine
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Outcome_Other
therapeutic efficacy
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Participant_Condition
porphyrin
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Participant_Condition
with high concentrations of porphobilinogen
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Participant_Sex
Forty individuals participated in this two-part study : 20 asymptomatic porphobilinogen deaminase-deficient subjects ( both male and female ) with > or =4 times the upper reference urinary porphobilinogen level , and 20 healthy male subjects .
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Participant_Condition
porphobilinogen deaminase-deficient subjects