Abstract
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.
Trial registration:
ClinicalTrials.gov NCT02114203.
© 2018 Pfizer Inc. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of the American Society for Clinical Pharmacology and Therapeutics.
Publication types
-
Clinical Trial, Phase I
-
Randomized Controlled Trial
-
Research Support, Non-U.S. Gov't
MeSH terms
-
3',5'-Cyclic-AMP Phosphodiesterases / antagonists & inhibitors*
-
Adolescent
-
Adult
-
Aged
-
Anemia, Sickle Cell / blood
-
Anemia, Sickle Cell / diagnosis
-
Anemia, Sickle Cell / drug therapy*
-
Biomarkers / blood
-
Dose-Response Relationship, Drug
-
Double-Blind Method
-
Drug Administration Schedule
-
Drug Therapy, Combination / adverse effects
-
Drug Therapy, Combination / methods
-
E-Selectin / blood
-
Female
-
Humans
-
Hydroxyurea / administration & dosage
-
Hydroxyurea / adverse effects
-
Male
-
Middle Aged
-
Phosphodiesterase Inhibitors / administration & dosage*
-
Phosphodiesterase Inhibitors / adverse effects
-
Phosphodiesterase Inhibitors / pharmacokinetics
-
Placebos / administration & dosage
-
Placebos / adverse effects
-
Platelet Aggregation / drug effects
-
Pyrazoles / administration & dosage*
-
Pyrazoles / adverse effects
-
Pyrazoles / pharmacokinetics
-
Pyrimidinones / administration & dosage*
-
Pyrimidinones / adverse effects
-
Pyrimidinones / pharmacokinetics
-
Treatment Outcome
-
Young Adult
Substances
-
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
-
Biomarkers
-
E-Selectin
-
Phosphodiesterase Inhibitors
-
Placebos
-
Pyrazoles
-
Pyrimidinones
-
SELE protein, human
-
3',5'-Cyclic-AMP Phosphodiesterases
-
PDE9A protein, human
-
Hydroxyurea
Associated data
-
ClinicalTrials.gov/NCT02114203