Upadacitinib is a novel selective Janus kinase 1 inhibitor developed for treatment of rheumatoid arthritis and other autoimmune diseases. The objective of this study was to assess the pharmacokinetics and safety of a single upadacitinib dose in subjects with normal renal function and in subjects with renal impairment. A total of 24 subjects between the ages of 18 and 75 years were assigned to 1 of 4 renal function groups based on estimated glomerular filtration rate (normal, mild, moderate, severe; N = 6/group). A single 15‐mg dose of upadacitinib extended‐release formulation was administered under fasting conditions. Serial plasma and urine samples were assayed to evaluate the effect of renal impairment on upadacitinib exposure through regression analysis and analysis of covariance. The primary analysis was the regression analysis of upadacitinib exposures versus estimated glomerular filtration rate. The point estimates for upadacitinib plasma exposure ratios (90% confidence interval [CI]) in subjects with mild, moderate, and severe renal impairment were 1.18 (90%CI, 1.06–1.32), 1.33 (90%CI, 1.11–1.59), and 1.44 (90%CI, 1.14–1.82) for area under the plasma concentration–time curve and 1.06 (90%CI, 0.92–1.23), 1.11 (90%CI, 0.88–1.40), and 1.14 (90%CI, 0.84–1.56) for maximum observed plasma concentration, respectively, relative to subjects with normal renal function based on the regression analysis. The analysis of covariance categorical analysis provided consistent results. Upadacitinib was well tolerated by all subjects, and no safety issues were identified in subjects with renal impairment. Renal impairment has a limited effect on upadacitinib pharmacokinetics. This is in agreement with the known limited role of urinary excretion in upadacitinib elimination. Based on the limited impact on exposure, no dose adjustment is necessary for upadacitinib in subjects with impaired renal function.

Upadacitinib is a selective Janus Kinase 1 inhibitor which is being developed for the treatment of several inflammatory diseases including rheumatoid arthritis. Upadacitinib was evaluated in Phase 3 studies as an oral extended-release (ER) formulation administered once daily. The purpose of this study was to develop a level A in vitro–in vivo correlation (IVIVC) for upadacitinib ER formulation. The pharmacokinetics of four upadacitinib extended-release formulations with different in vitro release characteristics and an immediate-release capsule formulation of upadacitinib were evaluated in 20 healthy subjects in a single-dose, randomized, crossover study. In vivo pharmacokinetic data and in vitro dissolution data (USP Dissolution Apparatus 1; pH 6.8; 100 rpm) were used to establish a level A IVIVC. Three formulations were used to establish the IVIVC, and the fourth formulation was used for external validation. A non-linear IVIVC best described the relationship between upadacitinib in vitro dissolution and in vivo absorption profiles. The absolute percent prediction errors (%PE) for upadacitinib Cmax and AUC were less than 10% for all three formulations used to establish the IVIVC, as well as for the %PE for the external validation formulation and the overall mean internal validation. Model was cross-validated using the leave-one-out approach; all evaluated cross-validation runs met the regulatory acceptance criteria. A level A IVIVC was successfully developed and validated for upadacitinib ER formulation, which meets the FDA and EMA regulatory validation criteria and can be used as surrogate for in vivo bioequivalence.Electronic supplementary materialThe online version of this article (10.1208/s12248-019-0378-y) contains supplementary material, which is available to authorized users.

Upadacitinib is a novel selective oral Janus kinase 1 (JAK) inhibitor being developed for treatment of several inflammatory diseases. Oral contraceptives are anticipated to be a common concomitant medication in the target patient populations. This study was designed to evaluate the effect of multiple doses of upadacitinib on the pharmacokinetics of ethinylestradiol and levonorgestrel in healthy female subjects. This phase I, single‐center, open‐label, 2‐period crossover study evaluated the effect of multiple doses of 30 mg once daily extended‐release upadacitinib on the pharmacokinetics of a single oral dose of ethinylestradiol/levonorgestrel (0.03/0.15 mg; administered alone in period 1 and on day 12 of a 14‐day regimen of upadacitinib in period 2) in 22 healthy female subjects. The ratios (90% confidence intervals) for maximum plasma concentration and area under the plasma drug concentration–time curve from time zero to infinity following administration of ethinylestradiol/levonorgestrel with upadacitinib compared with administration of ethinylestradiol/ levonorgestrel alone were 0.96 (0.89–1.02) and 1.1 (1.04–1.19), respectively, for ethinylestradiol, and 0.96 (0.87–1.06) and 0.96 (0.85–1.07), respectively, for levonorgestrel. The harmonic mean terminal half‐life for ethinylestradiol (7.7 vs 7.0 hours) and levonorgestrel (37.1 vs 33.1 hours) was similar in the presence and absence of upadacitinib. Ethinylestradiol and levonorgestrel were bioequivalent in the presence and absence of upadacitinib. Therefore, upadacitinib can be administered concomitantly with oral contraceptives containing ethinylestradiol or levonorgestrel.

Upadacitinib is a selective Janus kinase 1 inhibitor being developed for the treatment of several inflammatory autoimmune diseases, including rheumatoid arthritis. Upadacitinib is a nonsensitive substrate for metabolism by cytochrome P450 3A enzymes. This open‐label, single‐dose, multicenter study assessed the pharmacokinetics of upadacitinib following oral administration of a single 15‐mg dose of the upadacitinib extended‐release formulation in subjects with mild (n = 6) and moderate (n = 6) hepatic impairment relative to demographically matched healthy subjects (n = 6). Subjects were assigned to 1 of the 3 groups according to the Child‐Pugh classification. Relative to subjects with normal hepatic function, the ratios (90% confidence intervals) of upadacitinib area under the plasma concentration‐versus‐time profile from time 0 to infinity (AUCinf) for subjects with mild and moderate hepatic impairment were 1.28 (0.91‐1.79) and 1.24 (0.87‐1.76), respectively. The central ratios of upadacitinib maximum observed concentration (Cmax) were 1.04 (0.77‐1.39) and 1.43 (1.05‐1.95) in subjects with mild and moderate hepatic impairment, respectively, compared with subjects with normal hepatic function. No clinically significant changes in vital signs or hematology measurements were observed, and no new safety events were identified in this study. These results indicate that mild and moderate hepatic impairment has no clinically relevant effect on upadacitinib pharmacokinetics.

Sustained intratumoral delivery of cytotoxic agents is a major challenge for effective cancer treatment, and motivated the development of MM-398, a stable nanoliposomal irinotecan (nal-IRI) with an extended plasma half-life and greater tumor deposition than free irinotecan. By using a systems pharmacology approach, we have previously shown that tumor deposition of nal-IRI and the subsequent conversion of irinotecan to the active metabolite, SN-38, by carboxylesterases are important determinants for nal-IRI activity in vivo. Ferumoxytol (FMX) is a 30nm iron-oxide, super-paramagnetic nanoparticle, known to be taken up by macrophages (as is nal-IRI), and for exhibiting magnetic resonance imaging properties. Since the size of a nanoparticle affects the rate of transcapillary transport significantly, we hypothesized that nal-IRI tumor biodistribution may be predicted by FMX-based MRI (Fe-MRI). Biodistribution and imaging studies were performed in mice bearing cell-line derived (A2780, HT29, A549) and patient-derived (pancreatic adenocarcinoma) tumor xenografts. The protocol consisted of a baseline MRI scan, i.v. injection of FMX (20mg/kg), and then i.v. injection of fluorescently labeled nal-IRI (10mg/kg) 24hr later. Mice were sacrificed 24hr and 72hr after nal-IRI injection, and irinotecan and SN-38 concentrations were determined in plasma, tumor, and tissues by HPLC analysis. The presence of FMX did not interfere with nal-IRI PK or biodistribution. Cellular distribution of liposomes within tumors was also not affected by FMX at up to 50mg/kg as measured by flow cytometry. Furthermore, immunohistochemistry showed that both liposomes and FMX were co-localized with tumor-associated macrophages. The drug metabolite measurements from tissue samples showed that the xenograft tumor models display wide ranges of nal-IRI deposition capacity (irinotecan concentrations at 24hr: ∼2,104 to 20,096ng/g). A2780 tumors displayed highest concentration of both iron (3.92 μg/ml) and irinotecan (9,466 ng/g) at 72hr after nal-IRI injection, whereas A549 tumors displayed lowest levels of both iron (0.23 μg/ml ) and irinotecan (436 ng/g). We observed a correlation between the tumor Fe-MRI signal and intratumoral levels of irinotecan 72hr after nal-IRI injection (R2=0.9, p<0.001). Furthermore, in vivo activity studies confirmed that xenograft models having higher intratumoral levels of irinotecan and SN-38 at 72hr showed greater tumor growth inhibition. In summary, preclinical studies demonstrate the potential of utilizing Fe-MRI as a potential diagnostic tool to identify patients with higher tumor permeability. Based on encouraging preclinical data, a pilot study in patients with advanced solid tumors with extensive Fe-MRI scanning and paired tumor biopsies (NCT # 01770353) is being conducted. Citation Format: Ashish V. Kalra, Joseph Spernyak, Jaeyeon Kim, Arnold Sengooba, Stephan Klinz, Nancy Paz, Jason Cain, Walid Kamoun, Ninfa Straubinger, Yang Qu, Sheryl Trueman, Eliel Bayever, Ulrik Nielsen, Daryl Drummond, Jonathan Fitzgerald, Robert Straubinger. Magnetic resonance imaging with an iron oxide nanoparticle demonstrates the preclinical feasibility of predicting intratumoral uptake and activity of MM-398, a nanoliposomal irinotecan (nal-IRI). [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2065. doi:10.1158/1538-7445.AM2014-2065