title: A semi-mechanistic model of CP-690,550-induced reduction in neutrophil counts in patients with rheumatoid arthritis.
abstract: CP-690,550, a selective inhibitor of the Janus kinase family, is being developed as an oral disease-modifying antirheumatic drug for the treatment of rheumatoid arthritis (RA). A semi-mechanistic model was developed to characterize the time course of drug-induced absolute neutrophil count (ANC) reduction in a phase 2a study. Data from 264 RA patients receiving 6-week treatment (placebo, 5, 15, 30 mg bid) followed by a 6-week off-treatment period were analyzed. The model included a progenitor cell pool, a maturation chain comprising transit compartments, a circulation pool, and a feedback mechanism. The model was adequately described by system parameters (BASE(h), ktr(h), gamma, and k(circ)), disease effect parameters (DIS), and drug effect parameters (k(off) and k(D)). The disease manifested as an increase in baseline ANC and reduced maturation time due to increased demand from the inflammation site. The drug restored the perturbed system parameters to their normal values via an indirect mechanism. ANC reduction due to a direct myelosuppressive drug effect was not supported. The final model successfully described the dose- and time-dependent changes in ANC and predicted the incidence of neutropenia at different doses reasonably well.
authors.affiliation: Pfizer, Inc, Clinical Pharmacology Department, B3208, 50 Pequot Avenue, New London, CT 06320, USA. pankaj.gupta@pfizer.com
authors.forename: Pankaj
authors.initials: P
authors.lastname: Gupta
authors.forename: Lena E
authors.initials: LE
authors.lastname: Friberg
authors.forename: Mats O
authors.initials: MO
authors.lastname: Karlsson
authors.forename: Sriram
authors.initials: S
authors.lastname: Krishnaswami
authors.forename: Jonathan
authors.initials: J
authors.lastname: French
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D018501:Antirheumatic Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000494:pharmacology; D001172:Arthritis, Rheumatoid / Q000097:blood* / Q000188:drug therapy; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009503:Neutropenia / Q000139:chemically induced*; D010880:Piperidines; D011743:Pyrimidines / Q000008:administration & dosage / Q000009:adverse effects* / Q000494:pharmacology; D011758:Pyrroles / Q000008:administration & dosage / Q000009:adverse effects* / Q000494:pharmacology; D013997:Time Factors
chemical_list: D018501:Antirheumatic Agents; D010880:Piperidines; D011743:Pyrimidines; D011758:Pyrroles; C479163:tofacitinib