Gary Chan

Effect of CP-690,550, an Orally Active Janus Kinase Inhibitor, on Renal Function in Healthy Adult Volunteers

CP‐690,550 is a Janus kinase inhibitor being developed to prevent allograft rejection and treat several autoimmune diseases. This study examines the effect of multiple doses of CP‐690,550 on renal function in healthy volunteers. Thirty‐four volunteers are randomized in a 2:1 ratio in a double‐blinded manner to receive CP‐690,550 15 mg twice daily or placebo twice daily for 14 days. Volunteers are confined in‐house to receive a controlled regimen of water intake and sodium intake of 4 to 5 g/d. The effect of CP‐690,550 on glomerular filtration rate (GFR) is measured by iohexol serum clearance, effective renal plasma flow (ERPF) by para‐aminohippuric acid (PAH) urinary clearance, and creatinine clearance by 24‐hour urine collection on day 1 (predose) and day 15. Steady‐state pharmacokinetics and tolerability are assessed. Comparing the day 15 and day 1 (predose) values shows that geometric mean ratios for iohexol serum clearance, PAH urinary clearance, and creatinine clearance are 0.995, 0.925, and 0.948, respectively. When adjusted for the corresponding placebo day ratios, the geometric mean ratios are 1.09, 0.978, and 1.05, respectively. CP‐690,550 is well tolerated. These findings indicate that CP‐690,550 does not affect GFR, ERPF, or creatinine clearance in healthy volunteers.

Pharmacokinetics of tofacitinib, a janus kinase inhibitor, in patients with impaired renal function and end‐stage renal disease

The pharmacokinetics (PK) of tofacitinib were assessed in patients with mild (Cockcroft–Gault creatinine clearance >50 and ≤80 mL/min), moderate (≥30 and ≤50 mL/min), and severe (<30 mL/min) renal impairment, and end‐stage renal disease (ESRD) requiring dialysis. Six patients each with normal, mild, moderate, or severely impaired renal function, and 12 patients with ESRD, received single tofacitinib doses of 10 mg. PK data were obtained from blood and dialyzate (patients with ESRD only) samples prior and subsequent to dosing and/or hemodialysis (patients with ESRD only). Relative to patients with normal renal function, mean (90% CI) AUC(0–∞) ratios were 137% (97–195), 143% (101–202), and 223% (157–316) in patients with mild, moderate, and severe renal impairment, respectively. Maximum plasma concentrations (Cmax) were similar across the four treatment groups. Terminal phase half‐life (t1/2) increased with severity of renal impairment. Mean AUC(0–∞) in patients with ESRD on a non‐dialysis day was similar to that in patients with moderate renal impairment and approximately 40% greater than healthy volunteer data. Mean (SD) dialyzer efficiency (ratio of dialyzer clearance/blood flow entering the dialyzer) was 0.73 (0.15). However, due to extensive non‐renal clearance, dialysis procedure is unlikely to result in significant elimination of tofacitinib.

A Supratherapeutic Dose of the Janus Kinase Inhibitor Tasocitinib (CP‐690,550) Does Not Prolong QTc Interval in Healthy Participants

Tasocitinib (CP‐690,550), a selective inhibitor of the Janus kinase (JAK) family, is being developed for the treatment of several autoimmune diseases and prevention of allograft rejection. The aim of this study was to characterize the effect of tasocitinib on QT interval. Sixty male and female healthy adults were enrolled in a single‐dose, randomized, 3‐period, crossover study of a supratherapeutic dose of tasocitinib (100 mg), placebo, and moxifloxacin 400 mg. Triplicate electrocardiograms were performed at predose baseline and serially over 24 hours postdose in each treatment period. The upper limits of the 2‐sided 90% confidence intervals (CIs) for the difference in QTc interval, corrected using Fridericia correction (QTcF), between tasocitinib and placebo were less than 5 ms at all time points. Concentration‐QTcF analysis showed that the predicted mean change (90% CI) in QTcF at the observed mean Cmax was −0.12 (−1.18, 0.94) ms. For moxifloxacin, mean (90% CI) estimates of the change in QTcF from placebo were 11.3 (9.4, 13.1) and 12.5 (10.7, 14.4) ms at 2 and 4 hours, respectively, thereby establishing study sensitivity. A single supratherapeutic dose of tasocitinib 100 mg was well tolerated and not associated with QTc prolongation.

Herpes Zoster Infection in Patients With Ulcerative Colitis Receiving Tofacitinib

Abstract Background Tofacitinib is an oral, small molecule Janus kinase inhibitor that is being investigated for ulcerative colitis (UC). Tofacitinib is approved for rheumatoid arthritis and psoriatic arthritis, where it has been shown to increase herpes zoster (HZ) risk. We evaluated HZ risk among UC patients using tofacitinib. Methods HZ cases were identified in tofacitinib phase II/III/ongoing, open-label, long-term extension (OLE) UC trials. We calculated HZ incidence rates (IRs) per 100 patient-years of tofacitinib exposure within phase III maintenance (Maintenance Cohort) and phase II/III/OLE (Overall Cohort) studies, stratified by baseline demographics and other factors. HZ risk factors were evaluated in the Overall Cohort using Cox proportional hazard models. Results Overall, 65 (5.6%) patients developed HZ. Eleven patients had multidermatomal involvement (2 nonadjacent or 3–6 adjacent dermatomes), and 1 developed encephalitis (resolved upon standard treatment). Five (7.7%) events led to treatment discontinuation. HZ IR (95% confidence interval [CI]) in the Overall Cohort was 4.07 (3.14–5.19) over a mean (range) of 509.1 (1–1606) days, with no increased risk observed with increasing tofacitinib exposure. IRs (95% CI) were highest in patients age ≥65 years, 9.55 (4.77–17.08); Asian patients, 6.49 (3.55–10.89); patients with prior tumor necrosis factor inhibitor (TNFi) failure, 5.38 (3.86–7.29); and patients using tofacitinib 10 mg twice daily, 4.25 (3.18–5.56). Multivariate analysis identified older age and prior TNFi failure as independent risk factors. Conclusions In tofacitinib-treated UC patients, there was an elevated risk of HZ, although complicated HZ was infrequent. Increased HZ rates occurred in patients who were older, Asian, or had prior TNFi failure (NCT00787202, NCT01465763, NCT01458951, NCT01458574, NCT01470612).

The effect of mild and moderate hepatic impairment on the pharmacokinetics of tofacitinib, an orally active Janus kinase inhibitor

Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis. We report here an evaluation of the pharmacokinetics of a single 10 mg dose of tofacitinib in healthy volunteers (n = 6) and subjects with mild (n = 6) or moderate (n = 6) hepatic impairment. Compared to healthy volunteers, tofacitinib area under the plasma concentration–time profile from time 0 to infinity (AUCinf) and maximum observed concentration (Cmax) in subjects with mild hepatic impairment were not altered. In subjects with moderate hepatic impairment, the geometric mean AUCinf and Cmax of tofacitinib were increased (90% confidence intervals of percentage increase) by approximately 65% (25%, 117%) and 49% (12%, 97%), respectively. A single dose of tofacitinib 10 mg resulted in two treatment‐emergent adverse events (AE) in the mild hepatic impairment group, and one in the moderate hepatic impairment group; they were not considered related to study treatment. There were no deaths, serious AEs, discontinuations due to AEs, or dose reductions due to AEs. Data from this study were critical to deriving dose adjustments for subjects with hepatic impairment.