No inference was made with respect to whether tofacitinib influences the clearance or production of SCr despite the functional form of the model. An early dose ranging Phase 2 study assessed SCr re versibility. patients with RA received tofacitinib 5, 15 or 30 mg BID for six weeks, followed by a six week washout period, and SCr levels were monitored. To explore a possible relationship between inflamma tion and changes in SCr, the influence of baseline CRP was estimated on four model parameters R0, Kout, Emax, and ED50. Likelihood ratio tests were applied to evaluate improvement in goodness of fit when baseline CRP was added to the model. All analyses were performed using the first order conditional estimation method as imple mented in the NONMEM software.

Data from Phase 3 studies, not used in the modeling ana lysis, were analyzed descriptively by comparing the mean changes in SCr based on quartiles of baseline CRP, as well as quartiles of change from baseline in CRP at Week 12. Small increases in CK were observed in the Phase 3 clinical program. therefore, a similar analysis was performed for changes in CK as a function of CRP and for changes in SCr as a function of changes in CK. Adverse event analysis AE data from Phase 3 and LTE studies were classified using the narrow SMQ Queries term of acute renal failure and was further narrowed to include all pa tients whose AE met one of the following criteria coded to the narrow SMQ of ARF . required permanent or temporary discontinuation of the study drug. or required a dose re duction of the study drug.

This included laboratory investi gations as well as clinical renal and urinary disorders. Patients with clinical ARF were defined by the MedDRA terms renal failure, azotemia, or renal impairment. Patient data were then reviewed in order to ascertain a potential etiology for the renal AE. Data reviewed included demographics, investigator reported term for the event, day of onset, and day of reso lution or last evaluation all relative to the start of the study drug, SCr, creatinine clearance, maximum SCr value achieved, tofacitinib dose, concomitant medications, past medical history, asso ciated or concurrent events, action taken, outcome of the event, and investigator and Pfizer case assessments.

The focus of the concomitant medication review was on those medications with known associations with changes in renal function such as angiotensin converting enzyme inhibitors or angiotensin receptor blockers, non steroidal anti Anacetrapib inflammatory drugs , diuretics, and nephrotoxic agents. Results Across Phase 3, 3,315 patients received 1 dose of study drug for durations that ranged up to 474 days. In the LTE studies, as of March 29, 2011, 3,227 patients received 1 dose of tofacitinib. of those, 2,019 received tofacitinib with background DMARDs and 1,208 received tofacitinib monotherapy.