Background and Objective This study measured and compared the exposure and safety of peficitinib (ASP015K), a novel oral Janus kinase inhibitor, in subjects with normal and impaired renal function after a single oral, clinically relevant peficitinib dose. Methods This was an open-label, parallel-group study conducted at two centres in Japan. Subjects with normal and mildly, moderately, or severely impaired renal function received a single oral dose of peficitinib (one 150 mg tablet) under fasting conditions in a hospital setting. Blood samples were collected prior to administration and up to 72 h post-dose for pharmacokinetic assessment. Safety was assessed up to 7 days post-dose. Results Peficitinib plasma concentration-time profiles were similar between those with normal and impaired renal function. In subjects with impaired renal function, area under the plasma concentration-time curve and maximum concentration were 0.8-to 1.1-fold those in subjects with no impairment. Two subjects (one in the normal group and one in the mildly impaired group) each experienced a treatment-emergent adverse event (TEAE). There were no serious TEAEs, deaths or TEAEs leading to treatment withdrawal. Conclusions Peficitinib exposure and TEAEs were similar in subjects with and without renal impairment after a single oral 150 mg dose. Based on these findings, it is not expected that peficitinib dose adjustment will be required in clinical practice, according to the degree of renal impairment. ClinicalTrials.gov identifier NCT02603497.

Roxadustat is a hypoxia-inducible factor prolyl hydroxylase inhibitor in late-stage clinical development for the treatment of anemia in chronic kidney disease. Spherical carbon adsorbent (SCA) is used in patients with chronic kidney disease and has been shown to impact absorption of certain concomitant drugs. Two phase 1, open-label, randomized, crossover studies were conducted in healthy adult Japanese males to investigate the effect of food and SCA on the pharmacokinetics of a single oral dose of roxadustat. Subjects in the food effect study received a single dose of 100-mg roxadustat under fed and fasted conditions. Subjects in the SCA/roxadustat drug-drug interaction study received a single dose of 100-mg roxadustat alone, concomitantly with SCA, and 1 and 2 hours before and after SCA to consider the real-world clinical situation and assess any potential impact of a lag time on the pharmacokinetics of roxadustat. Primary outcomes for both studies were area under the concentration-time curve from the time of dosing extrapolated to infinity and maximum concentration of drug in blood plasma. In the food effect study (N = 16), the geometric mean ratio (fed/fasted) and 90% confidence interval for area under the concentration-time curve from the time of dosing extrapolated to infinity and maximum concentration of roxadustat were 94. 44 (89.93-99.18) and 79.88 (72.09-88.52), respectively. In the SCA/roxadustat drug-drug interaction study, all geometric mean ratios and 90% confidence intervals (roxadustat + SCA/roxadustat) were within the no-effect boundaries of 80% and 125%. Roxadustat was generally well tolerated. The effect of food on the pharmacokinetics of roxadustat and the drug-drug interaction between roxadustat and SCA do not appear to be clinically relevant and support the safe use of roxadustat under these conditions. Keywords drug-drug interaction, food-drug interaction, pharmacokinetics, roxadustat, spherical carbon adsorbent Chronic kidney disease (CKD) is a condition characterized by long-term decline in renal function that typically requires dialysis treatment in later stages and is often associated with other comorbidities such as hypertension, diabetes, and cardiovascular disease. 1,2Anemia is a complication that often accompanies CKD, and is characterized by reduced hemoglobin levels, resulting, in part, from the inability of the failing kidneys to produce sufficient erythropoietin. The incidence of anemia among subjects with CKD increases with the severity of disease 3 and is associated with an impaired quality of life. Roxadustat (ASP1517, FG-4592, AZD9941) is an orally active, hypoxia-inducible factor prolyl hydroxylase inhibitor 5 that promotes erythropoiesis by increasing endogenous erythropoietin. Roxadustat has demonstrated safety and efficacy in phase 2 studies by increasing hemoglobin levels in subjects with 1 Clinical Pharmacology, Development, Astellas Pharma Inc., Tokyo, Japan 2 Research Program Management, Drug Discovery Research, Astellas Pharma Inc., Tokyo, Japan 3 Clinical ...

Peficitinib (ASP015K) is a novel Janus kinase inhibitor developed for the treatment of rheumatoid arthritis (RA). The impact of hepatic impairment on the peficitinib pharmacokinetic (PK) and safety profile was investigated in non-RA subjects (n = 24) in an open-label, parallel-group, multicenter comparative study in Japan. Subjects received a single, clinically relevant, oral dose of a peficitinib 150 mg tablet under fasting conditions. Plasma PK parameters were measured for peficitinib and its metabolites H1 (sulfate and methylated metabolite), H2 (sulfate metabolite), and H4 (methylated metabolite) in subjects with normal hepatic function, mild hepatic impairment, or moderate hepatic impairment. The peficitinib area under the plasma-concentration-time curve from time 0 to infinity (AUC inf) and maximum observed concentration (C max) were not markedly different in subjects with mild hepatic impairment versus normal hepatic function. In subjects with moderate hepatic impairment versus normal hepatic function, the geometric mean ratios for peficitinib AUC inf and C max , were 1.92 (90% CI: 1.39, 2.66) and 1.82 (90% CI: 1.24, 2.69), respectively. Five treatment-emergent adverse events (TEAEs) were experienced by 3 subjects, 1 in each group. There were no deaths, no serious TEAEs, and no TEAEs leading to withdrawal. In summary, the PK profile was unaltered in subjects with mild hepatic impairment after a single clinically relevant dose of peficitinib, but exposure almost doubled in subjects with moderate hepatic impairment. Peficitinib dose reduction may be considered in RA patients with moderate hepatic impairment.

SummaryWhat is known and objective: Roxadustat is a hypoxia-inducible factor prolyl hydroxylase inhibitor currently being investigated for the treatment of anemia in chronic kidney disease. Lanthanum carbonate is a phosphate binder that is commonly used to treat hyperphosphatemia in patients with chronic kidney disease. This study investigated the effect of lanthanum carbonate on the pharmacokinetics, safety and tolerability of a single oral dose of roxadustat in healthy non-elderly adult male subjects. Methods:This was an open-label, randomized, two-period, two-sequence crossover study in non-elderly healthy adult males. Subjects randomized to Group 1 received roxadustat alone during Period 1 and roxadustat concomitantly with lanthanum carbonate during Period 2; subjects randomized to Group 2 received roxadustat concomitantly with lanthanum carbonate during Period 1 and roxadustat alone during Period 2. All subjects received a single oral dose of 100 mg roxadustat on Day 1 in both periods. Subjects receiving concomitant lanthanum carbonate received 750 mg lanthanum carbonate three times daily on Days 1 and 2. Pharmacokinetic assessments were conducted on Days 1-4 in both periods. The primary study outcomes were the area under the concentration-time curve from the time of dosing extrapolated to infinity (AUC inf ), and maximum concentration (C max ); the geometric least squares mean ratio (GMR; roxadustat + lanthanum carbonate/roxadustat alone) and corresponding 90% confidence interval (CI) was calculated for AUC inf and C max .Safety was assessed by the occurrence of treatment-emergent adverse events (TEAEs), laboratory test results, vital signs and standard 12-lead electrocardiogram.Results and discussion: A total of 18 subjects were enrolled (Group 1, n = 9; Group 2, n = 9); no subjects discontinued from the study. Roxadustat was rapidly absorbed, reaching maximum plasma concentration between 1 and 4 hours. The GMRs for AUC inf and C max were 88.00% (90% CI: 84.01, 92.17) and 98.58% (90% CI: 92.92, 104.58), respectively. The 90% CIs for both parameters were within the no-effect boundaries of 80% and 125%, indicating a lack of effect of lanthanum carbonate on roxadustat absorption. No deaths or serious TEAEs occurred.

Roxadustat inhibits breast cancer resistance protein and organic anion transporting polypeptide 1B1, which can affect coadministered statin concentrations. Three open-label, 1-sequence crossover phase 1 studies in healthy subjects were conducted to assess effects from steady-state 200-mg roxadustat on pharmacokinetics and tolerability of 40-mg simvastatin (CL-0537 and CL-0541), 40-mg atorvastatin (CL-0538), or 10-mg rosuvastatin (CL-0537). Statins were dosed concomitantly with roxadustat in 28 (CL-0537) and 24 (CL-0538) healthy subjects, resulting in increases of maximum plasma concentration (C max ) and area under the plasma concentration-time curve from the time of dosing extrapolated to infinity (AUC inf ) 1.87-and 1.75-fold for simvastatin, 2.76-and 1.85-fold for simvastatin acid, 4.47-and 2.93-fold for rosuvastatin, and 1.34-and 1.96-fold for atorvastatin, respectively. Additionally, simvastatin dosed 2 hours before, and 4 and 10 hours after roxadustat in 28 (CL-0541) healthy subjects, resulted in increases of C max and AUC inf 2.32-to 3.10-fold and 1.56-to 1.74-fold for simvastatin and 2.34-to 5.98-fold and 1.89-to 3.42-fold for simvastatin acid, respectively. These increases were not attenuated by time-separated statin dosing. No clinically relevant differences were observed for terminal elimination half-life. Concomitant 200-mg roxadustat and a statin was generally well tolerated during the study period. Roxadustat effects on statin C max and AUC inf were statin and administration time dependent. When coadministered with roxadustat, statin-associated adverse reactions and the need for statin dose reduction should be evaluated.

Aims: Our objective was to develop a population pharmacokinetic (PK) model to describe roxadustat plasma concentrations in Japanese dialysis-dependent chronic kidney disease (DD-CKD) patients with renal anaemia and to identify the covariate factors that affect exposure of roxadustat.Methods: In total, 367 patients (male, 256; female, 111) contributing 1285 concentration values from 4 clinical studies were analysed using a nonlinear mixed-effects modelling approach. Candidate covariates included clinical characteristics hypothesized to affect roxadustat clearance and bioavailability, such as demographics, hepatic parameters and concomitant drugs. Results:The roxadustat PK data in Japanese DD-CKD patients with renal anaemia were well described by a 2-compartment disposition model with first-order absorption and interindividual variability on clearance, central volume of distribution and absorption rate constant. Age was identified as a significant covariate on clearance.PK profiles of haemodialysis and peritoneal dialysis patients were comparable.Eighty-two percent of patients were administered at least 1 phosphate binder (PB).The effect of PBs on roxadustat concentration was modelled as a decrease in bioavailability. Staggered administration of PBs reduced the effect on roxadustat bioavailability. The clinical impact of all covariates on roxadustat PK was mild and manageable as the roxadustat dose was titrated based on haemoglobin level and administered starting from a low dose. Conclusion:Roxadustat PK in Japanese DD-CKD patients were successfully described by a population PK model. The identified key covariates included coadministration of PBs on the roxadustat bioavailability and age on clearance of roxadustat.

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BackgroundPeficitinib (ASP015K), a novel oral Janus kinase inhibitor, demonstrated efficacy as once-daily therapy for moderate–severe rheumatoid arthritis in a phase 2b study (NCT01649999)1 and 2 phase 3 studies (NCT023081632; NCT02305849).3 Mean urinary excretion of peficitinib accounted for 9–15% of the oral dose.4 It produces 3 conjugated metabolites (H1, H2, H4), which show very weak in-vitro pharmacological action.ObjectivesTo assess pharmacokinetics (PK) and safety of a single oral dose of peficitinib 150 mg in subjects with normal and impaired hepatic function.MethodsThis phase 1, open-label, single-dose, parallel-group study was conducted at six centres in Japan. Eligible subjects were aged 20–75 years, with body mass index ≥17.0–<30.0 kg/m2. Hepatic impairment was defined at screening using Child-Pugh classification: Class A, mild (5–6 points); Class B, moderate (7–9 points). Subjects with severe hepatic impairment (Child-Pugh classification Class C, 10–15 points) were excluded. Subjects received a single oral dose of peficitinib 150 mg under fasting conditions, based on daily dose in the 2 phase 3 studies. Blood samples for plasma PK analysis of peficitinib and its metabolites were collected before and up to 72 h post dose. Safety was assessed throughout the study.Results24 subjects were enrolled (70.8% male): 16 with impaired and 8 with normal hepatic function ( Table 1 ); all received study medication according to protocol. The peficitinib concentration-time profiles from dosing to 72 h ( Fig. 1 ), extrapolated to infinity (AUCinf), and maximum concentration (Cmax) were similar in subjects with normal and mildly impaired hepatic function; however, AUCinf and Cmax were increased in subjects with moderate hepatic impairment ( Table 2 ). There was a trend of greater exposure to H1, H2 and H4 metabolites in subjects with mild or moderate hepatic impairment, except for H2 in moderate hepatic impairment, although geometric mean ratios versus subjects with normal function were variable ( Table 2 ). One subject in each group experienced a total of 5 TEAEs ( Table 3 ), all of which were considered drug-related except back pain. No serious TEAEs, deaths or clinically significant mean changes from baseline in clinical laboratory parameters were reported during the study.ConclusionPeficitinib exposure in subjects with mild hepatic impairment was similar to that in subjects with normal hepatic function; subjects with moderate hepatic impairment had greater exposure. A single dose of peficitinib was well tolerated.References[1] Takeuchi T, et al. Ann Rheum Dis 2016; 75: 1057–64; 2. Tanaka Y, et al. ACR/ARHP Annual Meeting 2018: Abstract 887; 3. Takeuchi T, et al. ACR/ARHP Annual Meeting 2018: Abstract 888; 4. Cao YJ, et al. Clin Pharmacol Drug Dev 2016;5:435–49AcknowledgementThis study was sponsored by Astellas Pharma, Inc. Medical writing support was provided by Iona Easthope of Cello Health MedErgy and funded by Astellas Pharma, Inc.Disclosure of InterestsDaisuke Miyatake Employee of: Astellas Pharma, Inc., Tomohi...