PMID- 23794414
OWN - NLM
STAT- MEDLINE
DCOM- 20140318
LR  - 20220408
IS  - 1099-081X (Electronic)
IS  - 0142-2782 (Linking)
VI  - 34
IP  - 6
DP  - 2013 Sep
TI  - Population pharmacokinetics of tolvaptan in healthy subjects and patients with 
      hyponatremia secondary to congestive heart failure or hepatic cirrhosis.
PG  - 336-47
LID - 10.1002/bdd.1849 [doi]
AB  - Tolvaptan is a selective V2 -receptor antagonist used to treat hypervolemic and 
      euvolemic hyponatremia. A population pharmacokinetic (PK) analysis was performed 
      for tolvaptan in NONMEM(R) based upon data obtained from three trials conducted in 
      93 healthy subjects and six trials conducted in 628 congestive heart failure 
      (CHF) patients or 24 hepatic cirrhosis patients receiving oral tolvaptan (5 to 
      240 mg). A two-compartment model with first-order absorption and elimination best 
      described tolvaptan PK. Relative oral bioavailability was modeled relative to 
      100% for a 30 mg dose and ranged from 79.4% to 122%. Body weight and the impact 
      of CHF or hepatic cirrhosis relative to healthy subjects were statistically 
      significant (p < 0.001) predictors of both the apparent oral clearance (CL/F) and 
      apparent central volume of distribution (Vc /F). The CL/F was reduced to 58.2% 
      for New York Heart Association (NYHA) Class 1 or 2 CHF, 45.5% for NYHA Class 3 or 
      4 CHF, and 58.0% for hepatic cirrhosis relative to healthy subjects. Vc /F was 
      reduced to 59.9% for NYHA Class 1 or 2 CHF and 51.3% for NYHA Class 3 or 4 CHF, 
      and was 64.8% larger for severe hepatic cirrhosis (Child-Pugh score >/= 10) 
      relative to healthy subjects. A slight additional decrease in CL/F of 18.3% was 
      also detected for patients with moderate hyponatremia (serum sodium of 115-130 
      mEq/l) after adjusting for CHF or cirrhosis (p < 0.001). This population PK model 
      enabled assessment of tolvaptan PK with varying degrees of CHF and hepatic 
      cirrhosis with fluid overload and may be used to explore PK-PD relationships with 
      respect to fluid and electrolyte balance.
CI  - Copyright (c) 2013 John Wiley & Sons, Ltd.
FAU - Van Wart, Scott A
AU  - Van Wart SA
AD  - Institute for Clinical Pharmacodynamics, Latham, NY 12110, USA. svanwart@icpd.com
FAU - Shoaf, Susan E
AU  - Shoaf SE
FAU - Mallikaarjun, Suresh
AU  - Mallikaarjun S
FAU - Mager, Donald E
AU  - Mager DE
LA  - eng
PT  - Journal Article
PT  - Multicenter Study
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
DEP - 20130806
PL  - England
TA  - Biopharm Drug Dispos
JT  - Biopharmaceutics & drug disposition
JID - 7911226
RN  - 0 (Antidiuretic Hormone Receptor Antagonists)
RN  - 0 (Benzazepines)
RN  - 21G72T1950 (Tolvaptan)
SB  - IM
MH  - Adolescent
MH  - Adult
MH  - Aged
MH  - Aged, 80 and over
MH  - Antidiuretic Hormone Receptor Antagonists
MH  - Benzazepines/blood/*pharmacokinetics
MH  - Cross-Over Studies
MH  - Double-Blind Method
MH  - Female
MH  - Heart Failure/*blood/complications
MH  - Humans
MH  - Hyponatremia/*blood/etiology
MH  - Liver Cirrhosis/*blood/complications
MH  - Male
MH  - Middle Aged
MH  - *Models, Biological
MH  - Tolvaptan
MH  - Young Adult
OTO - NOTNLM
OT  - cirrhosis
OT  - heart failure
OT  - hyponatremia
OT  - pharmacokinetics
OT  - tolvaptan
EDAT- 2013/06/25 06:00
MHDA- 2014/03/19 06:00
CRDT- 2013/06/25 06:00
PHST- 2013/04/14 00:00 [received]
PHST- 2013/06/10 00:00 [revised]
PHST- 2013/06/20 00:00 [accepted]
PHST- 2013/06/25 06:00 [entrez]
PHST- 2013/06/25 06:00 [pubmed]
PHST- 2014/03/19 06:00 [medline]
AID - 10.1002/bdd.1849 [doi]
PST - ppublish
SO  - Biopharm Drug Dispos. 2013 Sep;34(6):336-47. doi: 10.1002/bdd.1849. Epub 2013 Aug 
      6.