PMID- 22943924
OWN - NLM
STAT- MEDLINE
DCOM- 20121218
LR  - 20161125
IS  - 0946-1965 (Print)
IS  - 0946-1965 (Linking)
VI  - 50
IP  - 11
DP  - 2012 Nov
TI  - Pharmacokinetics and tolerability of anagrelide hydrochloride in young (18 - 50 
      years) and elderly (>/= 65 years) patients with essential thrombocythemia.
PG  - 787-96
LID - 10.5414/CP201711 [doi]
AB  - OBJECTIVE: To ascertain the role of patient age as an influencing factor in the 
      pharmacokinetics of anagrelide and to clarify whether different dosing is 
      required in young (18 - 50 years) vs. elderly (>/= 65 years) patients with 
      essential thrombocythemia (ET). METHOD: This Phase II, multicenter, open-label 
      study compared the pharmacokinetics, pharmacodynamics and tolerability of 
      anagrelide and its active metabolite, 3-hydroxy-anagrelide, in young and elderly 
      patients with ET. Three days prior to pharmacokinetic assessment, patients 
      divided their normal daily anagrelide into a structured twice-daily dosing (BID) 
      schedule. Serial blood samples were obtained for pharmacokinetic and 
      pharmacodynamic analysis over a 12-h dosing interval. Anagrelide and 
      3-hydroxy-anagrelide plasma concentrations were normalized to a common dose (1 mg 
      BID) to control for dosing differences between patients. Patients were monitored 
      routinely for adverse events (AEs) and vital signs. RESULTS: A total of 24 
      patients (12 young; 12 elderly) completed the study. The dose-normalized 
      anagrelide maximum observed plasma concentration (Cmax) and area under the plasma 
      concentration vs. time curve over one dosing interval (AUCtau), were higher in 
      elderly patients compared with young patients (Cmax: 3.63 vs. 2.66 ng/ml; p = 
      0.09, AUCtau: 10.3 vs. 6.4 ngxh/ml; p = 0.01). In contrast, the dose-normalized 
      3-hydroxy-anagrelide Cmax and AUCtau were lower in the elderly patients when 
      compared with young patients (Cmax: 4.19 vs. 7.26 ng/ml; p = 0.02, AUCtau: 17.4 vs. 
      27.6 ngxh/ml; p = 0.03). No significant difference was observed in the geometric 
      mean terminal half-life (t1/2) of anagrelide in elderly and young patients (1.4 
      vs. 1.3 h, respectively; p = 0.38), whereas the geometric mean t1/2 of 
      3-hydroxy-anagrelide was significantly longer in the elderly patients compared 
      with the young patients (3.5 vs. 2.7 h, respectively; p = 0.01). There were no 
      significant differences in platelet count or vital signs between the age groups. 
      Anagrelide was well tolerated; there were no serious AEs or AEs that led to 
      withdrawal from the study. CONCLUSIONS: To conclude, the differences observed in 
      anagrelide and 3-hydroxy-anagrelide pharmacokinetics do not justify using a 
      different dosing regimen in young vs. elderly patients with ET.
FAU - Besses, Carlos
AU  - Besses C
AD  - Department of Hematology, Cancer Research Programme, Hospital del Mar-IMIM, 
      Passeig Maritim 25-29, 08003 Barcelona, Spain. cbesses@parcdesalutmar.cat
FAU - Zeller, Wolfgang
AU  - Zeller W
FAU - Alvarez-Larran, Alberto
AU  - Alvarez-Larran A
FAU - Coll, Ruth
AU  - Coll R
FAU - Troy, Steven
AU  - Troy S
FAU - Purkayastha, Jaideep
AU  - Purkayastha J
FAU - Martin, Patrick
AU  - Martin P
FAU - Freitag, Christian
AU  - Freitag C
LA  - eng
SI  - ClinicalTrials.gov/NCT00413634
PT  - Clinical Trial, Phase II
PT  - Comparative Study
PT  - Journal Article
PT  - Multicenter Study
PT  - Research Support, Non-U.S. Gov't
PL  - Germany
TA  - Int J Clin Pharmacol Ther
JT  - International journal of clinical pharmacology and therapeutics
JID - 9423309
RN  - 0 (Hematologic Agents)
RN  - 0 (Quinazolines)
RN  - K9X45X0051 (anagrelide)
SB  - IM
MH  - Adolescent
MH  - Adult
MH  - Age Factors
MH  - Aged
MH  - Area Under Curve
MH  - Biotransformation
MH  - Europe
MH  - Female
MH  - Half-Life
MH  - Hematologic Agents/administration & dosage/adverse 
      effects/blood/*pharmacokinetics
MH  - Humans
MH  - Hydroxylation
MH  - Male
MH  - Metabolic Clearance Rate
MH  - Middle Aged
MH  - Models, Biological
MH  - Platelet Count
MH  - Quinazolines/administration & dosage/adverse effects/blood/*pharmacokinetics
MH  - Thrombocythemia, Essential/blood/diagnosis/*drug therapy
MH  - Thrombopoiesis/*drug effects
MH  - Treatment Outcome
MH  - Young Adult
EDAT- 2012/09/05 06:00
MHDA- 2012/12/19 06:00
CRDT- 2012/09/05 06:00
PHST- 2012/10/19 00:00 [accepted]
PHST- 2012/09/05 06:00 [entrez]
PHST- 2012/09/05 06:00 [pubmed]
PHST- 2012/12/19 06:00 [medline]
AID - 9946 [pii]
AID - 10.5414/CP201711 [doi]
PST - ppublish
SO  - Int J Clin Pharmacol Ther. 2012 Nov;50(11):787-96. doi: 10.5414/CP201711.