PMID- 20110012
OWN - NLM
STAT- MEDLINE
DCOM- 20100409
LR  - 20220331
IS  - 1879-114X (Electronic)
IS  - 0149-2918 (Linking)
VI  - 31
IP  - 11
DP  - 2009 Nov
TI  - Pharmacokinetics of a once-daily extended-release formulation of pramipexole in 
      healthy male volunteers: three studies.
PG  - 2698-711
LID - 10.1016/j.clinthera.2009.10.018 [doi]
AB  - BACKGROUND: Pramipexole is a dopamine agonist used in the treatment of 
      Parkinson's disease. The currently available immediate-release (IR) formulation 
      is taken orally 3 times daily. OBJECTIVES: These studies were conducted to 
      evaluate the pharmacokinetic properties of a variety of prototypes for a 
      once-daily extended-release (ER) formulation of pramipexole and to further 
      characterize the prototype whose pharmacokinetics best matched those of the IR 
      formulation. METHODS: Three Phase I studies were conducted, all in healthy adult 
      men aged <or=50 years with a body mass index of 18.5 to 29.9 kg/m(2). In the 
      first study, 7 prototypes of a once-daily ER formulation with various release 
      properties, including rate and pH dependence, were compared with the IR 
      formulation taken 3 times daily to identify the optimal pharmacokinetic 
      resemblance based on predefined criteria derived from plasma AUC(0-24h), C(max), 
      and C(min). In the second study, a level A in vitro/in vivo correlation (IVIVC) 
      suitable for predicting an entire in vivo bioavailability time course based on in 
      vitro dissolution was established and validated, and the single-dose 
      pharmacokinetics of the optimal ER formulation identified in the first study were 
      analyzed for food effect. In the third study, steady-state pharmacokinetics of 
      the optimal ER formulation were assessed across a range of pramipexole doses 
      (0.375-4.5 mg/d), including investigation of the food effect at steady state for 
      the highest dose. Tolerability was assessed throughout all studies based on 
      physical examinations, laboratory measurements, and adverse events (AEs). 
      RESULTS: The 3 studies included 18, 15, and 39 subjects, respectively. Among the 
      ER prototypes tested at 0.75 mg once daily in study 1, a matrix tablet had the 
      optimal pharmacokinetic resemblance to IR pramipexole 0.25 mg TID, with a 
      geometric mean AUC(0-24h,ss) of 17.4 ng.h/mL (vs 16.0 ng.h/mL for the IR 
      formulation), C(max,ss) of 0.967 ng/mL (vs 1.09 ng/mL), and C(min,ss) of 0.455 
      ng/mL (vs 0.383 ng/mL). For single-dose ER 0.375 mg administered in the fasted 
      state in study 2, in vivo bioavailability was predictable from in vitro 
      dissolution data, with internal mean absolute percent prediction errors of 3.18% 
      for AUC(0-30h) and 4.87% for C(max), and external mean absolute prediction errors 
      of 6.61% and 3.34%, respectively, satisfying current guidelines for a level A 
      IVIVC. For single-dose ER 0.375 mg administered in the fed state, the upper bound 
      of the 90% CI for fed:fasted values was 119.8 for AUC(0-30h) (within the 
      bioequivalence limits of 80%-125%) and 134.1 for C(max). At steady state in study 
      3 (subjects' 5th treatment day), dosing at 0.375 to 4.5 mg in the fasted state 
      was associated with a linear, dose-proportional increase in pharmacokinetic 
      parameters, including AUC(0-24h,ss) and C(max,ss). At the highest fasted dose 
      (4.5 mg), the geometric coefficient of variation for interindividual variability 
      at steady state was 30.1% for AUC(0-24h,ss) (vs 21.4% for IR pramipexole 1.5 mg 
      TID) and 22.3% for C(max,ss) (vs 19.0%). At steady state, the upper bounds of the 
      90% CIs for fed:fasted values with ER 4.5 mg were 122.1 for AUC(0-24h) and 126.8 
      for C(max). No serious AEs occurred, and the dropout rate was low. CONCLUSIONS: 
      In these studies in healthy male volunteers, an ER pramipexole formulation was 
      identified that resembled the IR formulation in terms of both pharmacokinetics 
      and tolerability. In patients with Parkinson's disease, once-daily use of an ER 
      formulation may improve the convenience of treatment relative to the IR 
      formulation taken 3 times daily and thus increase compliance.
CI  - Copyright 2009 Excerpta Medica Inc. All rights reserved.
FAU - Jenner, Peter
AU  - Jenner P
AD  - Neurodegenerative Disease Research Centre, School of Biomedical and Health 
      Sciences, King's College London, London, United Kingdom.
FAU - Konen-Bergmann, Michael
AU  - Konen-Bergmann M
FAU - Schepers, Cornelia
AU  - Schepers C
FAU - Haertter, Sebastian
AU  - Haertter S
LA  - eng
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Clin Ther
JT  - Clinical therapeutics
JID - 7706726
RN  - 0 (Antiparkinson Agents)
RN  - 0 (Benzothiazoles)
RN  - 0 (Delayed-Action Preparations)
RN  - 0 (Dietary Fats)
RN  - 83619PEU5T (Pramipexole)
SB  - IM
MH  - Adolescent
MH  - Adult
MH  - Antiparkinson Agents/*administration & dosage/adverse effects/*pharmacokinetics
MH  - Area Under Curve
MH  - Benzothiazoles/*administration & dosage/adverse effects/*pharmacokinetics
MH  - Biological Availability
MH  - Body Mass Index
MH  - Chemistry, Pharmaceutical
MH  - Delayed-Action Preparations
MH  - Dietary Fats
MH  - Food-Drug Interactions
MH  - Humans
MH  - Male
MH  - Pramipexole
MH  - Reproducibility of Results
MH  - Young Adult
EDAT- 2010/01/30 06:00
MHDA- 2010/04/10 06:00
CRDT- 2010/01/30 06:00
PHST- 2009/09/20 00:00 [accepted]
PHST- 2010/01/30 06:00 [entrez]
PHST- 2010/01/30 06:00 [pubmed]
PHST- 2010/04/10 06:00 [medline]
AID - S0149-2918(09)00375-0 [pii]
AID - 10.1016/j.clinthera.2009.10.018 [doi]
PST - ppublish
SO  - Clin Ther. 2009 Nov;31(11):2698-711. doi: 10.1016/j.clinthera.2009.10.018.