Phase 1 dose-escalation study of CP-690 550 in stable renal allograft recipients: preliminary findings of safety, tolerability, effects on lymphocyte subsets and pharmacokinetics.
CP-690 550 inhibits Janus kinase 3 with nanomolar potency. In this dose-escalation study, we assessed the safety, tolerability, effects on lymphocyte subsets, and pharmacokinetics of CP-690 550 when coadministered with mycophenolate mofetil in stable renal allograft recipients for 28 days. Twenty-eight patients were enrolled. Six patients received CP-690 550 5 mg twice daily (BID), 6 patients received 15 mg BID, 10 patients received 30 mg BID, and 6 patients received placebo. The most frequent adverse events were infections and gastrointestinal (abdominal pain, diarrhea, dyspepsia, and vomiting). CP-690 550 15 mg BID and 30 mg BID were associated with a mean decrease in hemoglobin from baseline of 11% and a mean decrease in absolute natural killer cell counts of 50%. CP-690 550 30 mg BID was also associated with a mean increase in absolute CD19(+) B-lymphocytes of 130%. There were no changes in the number of neutrophils, total lymphocytes, platelets, or CD4(+) or CD8(+) T cells; clinical chemistry; vital signs; or electrocardiograms from the pretreatment baseline. Administration of CP-690 550 without a concomitant calcineurin inhibitor resulted in CP-690 550 exposures consistent with previous studies in nontransplant subjects. Additional dose-ranging studies are warranted to evaluate the safety and efficacy of CP-690 550 in renal transplant recipients over longer treatment duration.
Department of Internal Medicine, Section of Nephrology and Transplant, Erasmus Medical Center, Rotterdam, The Netherlands.
E
E
van Gurp
W
W
Weimar
R
R
Gaston
D
D
Brennan
R
R
Mendez
J
J
Pirsch
S
S
Swan
M D
MD
Pescovitz
G
G
Ni
C
C
Wang
S
S
Krishnaswami
V
V
Chow
G
G
Chan
D000293:Adolescent; D000328:Adult; D000368:Aged; D004311:Double-Blind Method; D005260:Female; D006085:Graft Survival / Q000187:drug effects*; D006801:Humans; D053616:Janus Kinase 3 / Q000378:metabolism*; D016030:Kidney Transplantation; D008214:Lymphocytes / Q000187:drug effects*; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives; D010880:Piperidines; D011743:Pyrimidines / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D011758:Pyrroles / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D014184:Transplantation, Homologous
D010880:Piperidines; D011743:Pyrimidines; D011758:Pyrroles; C479163:tofacitinib; D053616:Janus Kinase 3; D009173:Mycophenolic Acid