PMID- 28641995
OWN - NLM
STAT- MEDLINE
DCOM- 20171226
LR  - 20220330
IS  - 1879-114X (Electronic)
IS  - 0149-2918 (Linking)
VI  - 39
IP  - 7
DP  - 2017 Jul
TI  - Acetylator Status Impacts Amifampridine Phosphate (Firdapse) Pharmacokinetics 
      and Exposure to a Greater Extent Than Renal Function.
PG  - 1360-1370
LID - S0149-2918(17)30662-8 [pii]
LID - 10.1016/j.clinthera.2017.05.353 [doi]
AB  - PURPOSE: The purpose of this study is to evaluate safety, tolerability, and 
      pharmacokinetic (PK) properties of amifampridine phosphate (Firdapse) and its 
      major inactive 3-N-acetyl metabolite in renally impaired and healthy individuals 
      with slow acetylator (SA) and rapid acetylator (RA) phenotypes. METHODS: This was 
      a Phase I, multicenter, open-label study of the PK properties and safety profile 
      of amifampridine phosphate in individuals with normal, mild, moderate, or 
      severely impaired renal function. Amifampridine phosphate was given as a single 
      10 mg (base equivalent) dose, and the plasma and urine PK properties of 
      amifampridine and its 3-N-acetyl metabolite were determined. The safety profile 
      was evaluated by monitoring adverse events (AEs), clinical laboratory tests, and 
      physical examinations. FINDINGS: Amifampridine clearance was predominantly 
      metabolic through N-acetylation, regardless of renal function in both acetylator 
      phenotypes. In individuals with normal renal function, mean renal clearance 
      represented approximately 3% and 18% of the total clearance of amifampridine in 
      RA and SA, respectively. Large differences in amifampridine exposure were 
      observed between acetylation phenotypes across renal function levels. Mean 
      amifampridine exposure values of AUC(0-infinity) and C(max) were up to 8.8-fold higher 
      in the SA group compared with the RA group across renal function levels. By 
      comparison, mean AUC(0-infinity) was less affected by renal function within an 
      acetylator group, only 2- to 3-fold higher in individuals with severe renal 
      impairment (RI) compared with those with normal renal function. Exposure to 
      amifampridine in the SA group with normal renal function was higher (AUC(0-infinity,) 
      approximately 1.8-fold; C(max,) approximately 4.1-fold) than the RA group with 
      severe RI. Exposure to the inactive 3-N-acetyl metabolite was higher than 
      amifampridine in both acetylator groups, independent of renal function level. The 
      metabolite is cleared by renal excretion, and exposure was clearly dependent on 
      renal function with 4.0- to 6.8-fold increases in AUC(0-infinity) from normal to severe 
      RI. No new tolerability findings were observed. IMPLICATIONS: A single dose of 10 
      mg of amifampridine phosphate was well tolerated, independent of renal function 
      and acetylator status. The results indicate that the PK profile of amifampridine 
      is affected by metabolic acetylator phenotype to a greater extent than by renal 
      function level, supporting Firdapse administration in individuals with RI in 
      line with current labeling recommendations. Amifampridine should be dosed to 
      effect per the individual patient need, altering administration frequency and 
      dose in normal through severe RI. The therapeutic dose of amifampridine phosphate 
      should be tailored to the individual patient needs by gradual dose titration up 
      to the present maximum recommended dose (60-80 mg/day) or until dose-limiting AEs 
      intervene to avoid overdosing and underdosing. EudraCT identifier: 
      2013-005349-35.
CI  - Copyright (c) 2017 The Authors. Published by Elsevier Inc. All rights reserved.
FAU - Haroldsen, Peter E
AU  - Haroldsen PE
AD  - BioMarin Pharmaceutical Inc, Novato, California, USA. Electronic address: 
      pacificpete@yahoo.com.
FAU - Sisic, Zlatko
AU  - Sisic Z
AD  - BioMarin Europe Ltd, London, United Kingdom.
FAU - Datt, Joe
AU  - Datt J
AD  - BioMarin Europe Ltd, London, United Kingdom.
FAU - Musson, Donald G
AU  - Musson DG
AD  - BioMarin Pharmaceutical Inc, Novato, California, USA.
FAU - Ingenito, Gary
AU  - Ingenito G
AD  - Catalyst Pharmaceuticals Inc, Coral Gables, Florida, USA.
LA  - eng
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Multicenter Study
DEP - 20170619
PL  - United States
TA  - Clin Ther
JT  - Clinical therapeutics
JID - 7706726
RN  - 0 (Potassium Channel Blockers)
RN  - BH3B64OKL9 (4-Aminopyridine)
RN  - RU4S6E2G0J (Amifampridine)
SB  - IM
MH  - 4-Aminopyridine/adverse effects/*analogs & derivatives/pharmacokinetics
MH  - Acetylation
MH  - Adult
MH  - Aged
MH  - Amifampridine
MH  - Female
MH  - Humans
MH  - Kidney/*metabolism
MH  - Male
MH  - Middle Aged
MH  - Potassium Channel Blockers/adverse effects/*pharmacokinetics
MH  - Renal Insufficiency/*metabolism
OTO - NOTNLM
OT  - Lambert-Eaton myasthenic syndrome
OT  - amifampridine
OT  - arylamine N-acetyltransferase
OT  - pharmacokinetics
OT  - renal function
EDAT- 2017/06/24 06:00
MHDA- 2017/12/27 06:00
CRDT- 2017/06/24 06:00
PHST- 2017/02/09 00:00 [received]
PHST- 2017/05/12 00:00 [revised]
PHST- 2017/05/24 00:00 [accepted]
PHST- 2017/06/24 06:00 [pubmed]
PHST- 2017/12/27 06:00 [medline]
PHST- 2017/06/24 06:00 [entrez]
AID - S0149-2918(17)30662-8 [pii]
AID - 10.1016/j.clinthera.2017.05.353 [doi]
PST - ppublish
SO  - Clin Ther. 2017 Jul;39(7):1360-1370. doi: 10.1016/j.clinthera.2017.05.353. Epub 
      2017 Jun 19.