PF-04447943, a Phosphodiesterase 9A Inhibitor, in Stable Sickle Cell Disease Patients: A Phase Ib Randomized, Placebo-Controlled Study.
3',5'-Cyclic-AMP Phosphodiesterases
/ antagonists & inhibitors
Adolescent
Adult
Aged
Anemia, Sickle Cell
/ blood
Biomarkers
/ blood
Dose-Response Relationship, Drug
Double-Blind Method
Drug Administration Schedule
Drug Therapy, Combination
/ adverse effects
E-Selectin
/ blood
Female
Humans
Hydroxyurea
/ administration & dosage
Male
Middle Aged
Phosphodiesterase Inhibitors
/ administration & dosage
Placebos
/ administration & dosage
Platelet Aggregation
/ drug effects
Pyrazoles
/ administration & dosage
Pyrimidinones
/ administration & dosage
Treatment Outcome
Young Adult
Journal
Clinical and translational science
ISSN: 1752-8062
Titre abrégé: Clin Transl Sci
Pays: United States
ID NLM: 101474067
Informations de publication
Date de publication:
03 2019
03 2019
Historique:
received:
21
08
2018
accepted:
21
10
2018
pubmed:
1
1
2019
medline:
4
7
2020
entrez:
1
1
2019
Statut:
ppublish
Résumé
This phase Ib study randomized patients with stable sickle cell disease (SCD) aged 18-65 years to twice-daily PF-04447943 (a phosphodiesterase 9A inhibitor; 5 or 25 mg) or placebo, with/without hydroxyurea coadministration, for up to 29 days. Blood samples were collected at baseline and various posttreatment time points for assessments of PF-04447943 pharmacokinetics (PKs)/pharmacodynamics (PDs). Change from baseline in potential SCD-related biomarkers was evaluated. Of 30 patients, 15 received hydroxyurea and 28 completed the study. PF-04447943, with/without hydroxyurea, was generally well tolerated, with no treatment-related serious adverse events. Plasma PF-04447943 exposure was dose proportional. Twice-daily PF-04447943 25 mg significantly reduced the number and size of circulating monocyte-platelet and neutrophil-platelet aggregates and levels of circulating soluble E-selectin at day 29 vs. baseline (adjusted P < 0.15). PF-04447943 demonstrated PK/PD effects suggestive of inhibiting pathways that may contribute to vaso-occlusion. This study also provides guidance regarding biomarkers for future SCD studies.
Identifiants
pubmed: 30597771
doi: 10.1111/cts.12604
pmc: PMC6440678
doi:
Substances chimiques
6-(4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo(3,4-d)pyrimidin-4-one
0
Biomarkers
0
E-Selectin
0
Phosphodiesterase Inhibitors
0
Placebos
0
Pyrazoles
0
Pyrimidinones
0
SELE protein, human
0
3',5'-Cyclic-AMP Phosphodiesterases
EC 3.1.4.17
PDE9A protein, human
EC 3.1.4.17
Hydroxyurea
X6Q56QN5QC
Banques de données
ClinicalTrials.gov
['NCT02114203']
Types de publication
Clinical Trial, Phase I
Journal Article
Randomized Controlled Trial
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
180-188Informations de copyright
© 2018 Pfizer Inc. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of the American Society for Clinical Pharmacology and Therapeutics.
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