title: Exposure vs. response of blood pressure in patients with rheumatoid arthritis following treatment with fostamatinib.
abstract: Fostamatinib is an oral spleen tyrosine kinase (SYK) inhibitor which has been evaluated as a potential treatment for rheumatoid arthritis (RA). Treatment with fostamatinib has been associated with an increase in blood pressure (BP). In this work, we present a pooled analysis of the pharmacokinetic-pharmacodynamic (PKPD) relationship for BP, based on 3 Phase III studies, aiming to increase the knowledge about fostamatinib's effect on BP in the RA population. Fostamatinib is rapidly and extensively converted to R406 after oral administration of fostamatinib, and the PK of R406 could be described by a two-compartment population PK model with first order absorption, with an estimated CL/F of 18.7 L/h. Average steady-state concentrations, predicted based on the individual CL/F estimates, were subsequently used in the PKPD analysis. The population PKPD analysis revealed a concentration dependent increase of BP with increasing R406 concentrations, where a power model and an Emax model best described the increase in SBP and DBP, respectively. The predicted increases were +5.2 mmHg for SBP and +4.2 mmHg for DBP, for a 100 mg bid dose. The impact of covariates on the PKPD relationship was investigated but covariates did only explain a minor part of the overall high variability in BP.
authors.affiliation: AstraZeneca R&D, Södertälje, Sweden.
authors.forename: Emma
authors.initials: E
authors.lastname: Boström
authors.forename: Fredrik
authors.initials: F
authors.lastname: Öhrn
authors.forename: Eva
authors.initials: E
authors.lastname: Hanze
authors.forename: Marie
authors.initials: M
authors.lastname: Sandström
authors.forename: Paul
authors.initials: P
authors.lastname: Martin
authors.forename: Ulrika
authors.initials: U
authors.lastname: Wählby-Hamrén
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000631:Aminopyridines; D018501:Antirheumatic Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D001794:Blood Pressure / Q000187:drug effects*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009025:Morpholines; D010078:Oxazines / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000627:therapeutic use; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011725:Pyridines / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000627:therapeutic use; D011743:Pyrimidines; D000072377:Syk Kinase; D055815:Young Adult
chemical_list: D000631:Aminopyridines; D018501:Antirheumatic Agents; D047908:Intracellular Signaling Peptides and Proteins; D009025:Morpholines; C510788:N4-(2,2-dimethyl-3-oxo-4H-pyrid(1,4)oxazin-6-yl)-5-fluoro-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine; D010078:Oxazines; D011725:Pyridines; D011743:Pyrimidines; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C523665:fostamatinib
keywords: NONMEM; PKPD; blood pressure; fostamatinib; population pharmacokinetics