Background and ObjectiveRoxadustat is a hypoxia-inducible factor prolyl hydroxylase inhibitor in phase III development for the treatment of anaemia associated with chronic kidney disease. This study evaluated the effects of moderate hepatic impairment on roxadustat pharmacokinetics, pharmacodynamics and tolerability.MethodsThis was an open-label study in which eight subjects with moderate hepatic impairment (liver cirrhosis Child–Pugh score 7–9) and eight subjects with normal hepatic function (matched for body mass index, age and sex) received a single oral 100 mg roxadustat dose under fasted conditions. Blood samples were collected until 144 h post-dose in subjects with moderate hepatic impairment and until 96 h post-dose in subjects with normal hepatic function.ResultsIn subjects with moderate hepatic impairment, area under the concentration–time curve (AUC) from the time of drug administration to infinity (AUC∞) and observed maximum concentration (Cmax) were 23 % higher [geometric least-squares mean ratio (GMR) 123 %; 90 % CI 86.1–175] and 16 % lower (GMR 83.6 %; 90 % CI 67.5–104), respectively, than in subjects with normal hepatic function. Mean terminal half-life (t½) appeared to be longer (17.7 vs. 12.8 h) in subjects with moderate hepatic impairment, however intersubject variability on apparent total systemic clearance after single oral dosing (CL/F), apparent volume of distribution at equilibrium after oral administration (Vz/F) and t½ was approximately twofold higher. Erythropoietin (EPO) baseline-corrected AUC from administration to the last measurable EPO concentration (AUCE,last) and maximum effect (Emax) were 31 % (GMR 68.95 %; 90 % CI 29.29–162.29) and 48 % (GMR 52.29 %; 90 % CI 28.95–94.46) lower, respectively, than in subjects with normal hepatic function. The single oral roxadustat dose was generally well tolerated.ConclusionsThis study demonstrated the effect of moderate hepatic impairment on the pharmacokinetics and pharmacodynamics of roxadustat relative to subjects with normal hepatic function. These differences are not expected to be of clinical significance.

IntroductionAmenamevir (ASP2151) is a nonnucleoside antiherpesvirus compound available for the treatment of varicella–zoster virus infections. In this article we summarize the findings of four phase 1 studies in healthy participants.MethodsFour randomized phase 1 studies investigated the safety and pharmacokinetics of single and multiple doses of amenamevir, including the assessment of age group effect (nonelderly vs elderly), food effect, and the relative bioavailability of two formulations. Amenamevir was administered orally at various doses as a single dose (5–2400 mg) or daily (300 or 600 mg/day) for 7 days.ResultsFollowing single and multiple oral doses, amenamevir demonstrated a less than dose proportional increase in the pharmacokinetic parameters area under the plasma drug concentration versus time curve from time zero to infinity (AUCinf) and C max. After single and multiple oral 300-mg doses of amenamevir, no apparent differences in pharmacokinetics were observed between nonelderly and elderly participants. In contrast, with the amenamevir 600-mg dose both the area under the plasma drug concentration versus time curve from time zero to 24 h and C max were slightly increased and renal clearance was decreased in elderly participants. The pharmacokinetics of amenamevir was affected by food, with AUCinf increased by about 90%. In the bioavailability study, AUCinf and C max were slightly lower following tablet versus capsule administration (decreased by 14 and 12%, respectively), with relative bioavailability of 86%. The different amenamevir doses and formulations were safe and well tolerated; no deaths or serious adverse events were reported.ConclusionAmenamevir had less than dose proportional pharmacokinetic characteristics. Age may have an influence on amenamevir pharmacokinetics; however, the effect was considered minimal. The pharmacokinetics of amenamevir were affected by food, with AUCinf almost doubling when amenamevir was administered with food. The concentration versus time profile of the tablet was slightly lower than that of the capsule; the relative bioavailability of the tablet versus the capsule was 86%. Amenamevir was safe and well tolerated in the dose range investigated.FundingAstellas Pharma.Trial registrationClinicalTrials.gov identifiers NCT02852876 (15L-CL-002) and NCT02796118 (15L-CL-003).Electronic supplementary materialThe online version of this article (10.1007/s12325-017-0642-4) contains supplementary material, which is available to authorized users.

Purpose: Roxadustat, a hypoxia-inducible factor prolyl hydroxylase inhibitor, treats anemia in chronic kidney disease. Hyperphosphatemia, a common complication in chronic kidney disease, is treated with phosphate binders (PBs). This study in healthy individuals investigated the effect of 2 PBs, sevelamer carbonate and calcium acetate, on the pharmacokinetic properties of a single oral dose of roxadustat administered concomitantly or with a time lag.Methods: This 2-part, Phase I study was conducted with an open-label, randomized, 3-way (part 1) or 5way (part 2) crossover design, with 5-day treatment periods. On day 1 of each period, participants received 200 mg roxadustat administered alone or (1) concomitantly with sevelamer carbonate (2400 mg) or calcium acetate (1900 mg) (part 1) or ( 2) 1 hour before or 1, 2, or 3 hours after sevelamer carbonate (part 2A) or calcium acetate (part 2B); 5 additional PB doses were administered during 2 days. In both parts, PBs were administered with meals. Primary pharmacokinetic variables were AUC 0-∞ and C max.Findings: Twenty-four individuals were randomized in part 1; 60 individuals were randomized in part 2 (part 2A, n = 30; part 2B, n = 30). All participants completed the study in part 1; 28 and 27 individuals completed the study in part 2A and part 2B, respectively. Compared with roxadustat alone, concomitant sevelamer carbonate and calcium acetate administration reduced roxadustat's AUC 0-∞ by 67% (90% CI, 63.5%-69.3%) and 46% (90% CI, 41.7%-50.9%), respectively, and reduced roxadustat's C max by 66% (90% CI, 61.6%-69.4%) and 52% (90% CI, 46.2%-57.2%), respectively. This effect was attenuated when roxadustat and PB administration occurred with a time lag. Roxadustat's AUC 0-∞ was reduced by 41% and 22% to 25%, respectively, when roxadustat was administered 1 hour before or 1 to 3 hours after sevelamer carbonate and by 31% and 14% to 18%, respectively, when administered 1 hour before or 1 to 3 hours after calcium acetate. Roxadustat's C max was reduced by 26% and 12%, respectively, when roxadustat was administered 1 hour before and 1 hour after sevelamer carbonate; it was reduced by 19% when administered 1 hour before calcium acetate and was not affected when administered 1 hour after. Roxadustat was well tolerated.Implications: Concomitant administration of roxadustat with sevelamer carbonate or calcium acetate reduced exposure to roxadustat in healthy individuals. This effect was attenuated when roxadustat was administered ≥1 hour before or after either PB. Results from this study helped inform dosing and administration guidelines aimed at reducing interactions between

Background and Objectives Roxadustat is an orally active hypoxia-inducible factor prolyl hydroxylase inhibitor for anemia in chronic kidney disease. The pharmacokinetics, metabolic profile, and pharmacodynamics of roxadustat were investigated in subjects with different degrees of kidney function. Methods This phase 1 open-label study enrolled subjects with normal and severely impaired kidney function, and end-stage renal disease (ESRD) on continuous ambulatory peritoneal dialysis (CAPD) or automated peritoneal dialysis (APD) or hemodialysis/hemodiafiltration (HD/HDF). All subjects received a single 100-mg dose of oral roxadustat. Within a single-sequence, two-treatment period design (P1/P2), subjects with ESRD on HD/HDF received roxadustat 2 h after (P1) and 2 h before (P2) a dialysis session. Area under the plasma concentration–time curve (AUC) from administration to infinity (AUC inf ), maximum concentration ( C max ), and terminal elimination half-life ( t 1/2 ) were assessed for roxadustat; AUC and C max were assessed for erythropoietin. Results Thirty-four subjects were enrolled and received roxadustat (normal kidney function, n = 12; severely impaired kidney function, n = 9; ESRD on CAPD/APD, n = 1; ESRD on HD/HDF, n = 12). The geometric least-square mean ratio of AUC inf was 223% and 195% in subjects with severely impaired kidney function and ESRD on HD/HDF, respectively, relative to subjects with normal kidney function; C max and t 1/2 were comparable. The pharmacokinetic profile of roxadustat was not affected by HD/HDF. AUC inf and t 1/2 for the metabolites of roxadustat increased in subjects with kidney impairment. The AUC and C max of erythropoietin increased in subjects with severely impaired kidney function or ESRD on HD/HDF. Roxadustat was well tolerated. Conclusions Kidney function impairment increased the AUC of roxadustat and its metabolites. The C max and t 1/2 of roxadustat were comparable among groups. Roxadustat and its metabolites were not cleared by HD/HDF. Clinical Trials Registration Number: NCT02965040. Electronic supplementary material The online version of this article (10.1007/s13318-020-00658-w) contains supplementary material, which is available to authorized users.

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.

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Background and ObjectivesRoxadustat is an orally active hypoxia-inducible factor prolyl hydroxylase inhibitor for the treatment of anemia in chronic kidney disease. This study investigated the effect of multiple daily oral doses of omeprazole on the pharmacokinetics, safety, and tolerability of a single oral dose of roxadustat.MethodsThis phase 1, open-label, two-period, one-sequence, crossover study enrolled healthy subjects. During Period 1, subjects received a single oral dose of 100 mg roxadustat. After a ≥ 7-day washout, subjects started Period 2 and received daily oral doses of 40 mg omeprazole on Days 1–9, and a single oral dose of 100 mg roxadustat on Day 7. Roxadustat pharmacokinetics were assessed on Days 1–4 in Period 1 and on Days 7–10 in Period 2. Primary endpoints were area under the concentration–time profile from the time of dosing extrapolated to infinity (AUCinf) and maximum concentration (Cmax). Safety was assessed by vital signs, laboratory tests, electrocardiograms, and nature, frequency, and severity of treatment-emergent adverse events (TEAEs).ResultsEighteen subjects were enrolled. The geometric least squares mean ratio for both AUCinf and Cmax of roxadustat (with omeprazole/alone) was 104.5%; 90% confidence intervals were within the no-effect boundaries of 80.0 and 125.0%, indicating no significant effect of omeprazole on the pharmacokinetics of roxadustat. No serious TEAEs were reported.ConclusionMultiple daily oral doses of 40 mg omeprazole had no significant effect on the pharmacokinetics of a single oral dose of 100 mg roxadustat. Roxadustat was considered safe and well tolerated when administered alone or in combination with multiple daily oral doses of 40 mg omeprazole in healthy subjects.Electronic supplementary materialThe online version of this article (10.1007/s13318-018-0480-z) contains supplementary material, which is available to authorized users.

IntroductionAmenamevir is a nonnucleoside antiherpes virus compound available for treating herpes zoster infections. Four studies aimed to determine any potential interactions between amenamevir and ketoconazole, rifampicin, midazolam, or warfarin in healthy male participants.MethodsTwo studies were open-label studies that evaluated the effects of multiple doses of ketoconazole (400 mg) and rifampicin (600 mg) on the pharmacokinetics of a single oral dose of amenamevir. The other two studies were randomized, double-blind, parallel-group studies that evaluated the effects of multiple doses of amenamevir on the pharmacokinetics of a single dose of midazolam (7.5 mg) and warfarin (25 mg). A drug interaction was considered to occur if the 90% confidence interval (CI) of the least squares geometric mean ratio (GMR) of amenamevir to the comparator was outside the prespecified interval of 0.80–1.25.ResultsInteractions were observed between amenamevir and ketoconazole, rifampicin, and midazolam, but not between amenamevir and warfarin. After a single 400-mg dose of amenamevir, the GMRs of amenamevir plus ketoconazole or rifampicin versus amenamevir alone for C max and the area under the plasma concentration–time curve from time zero to infinity (AUCinf) were 1.30 (90% CI 1.17–1.45) and 2.58 (90% CI 2.32–2.87), respectively, for ketoconazole and 0.42 (90% CI 0.37–0.49) and 0.17 (90% CI 0.15–0.19), respectively, for rifampicin. Following multiple doses of amenamevir (400 mg), the GMRs of midazolam plus amenamevir versus midazolam alone for AUCinf and C max were 0.53 (90% CI 0.47–0.61) and 0.63 (90% CI 0.50–0.80), respectively. After a single dose of warfarin, the (S)-warfarin and (R)-warfarin mean C max increased and mean AUCinf decreased in the presence of amenamevir; however, the 90% CIs of the GMRs for these parameters remained within the predefined limits.ConclusionThese findings confirm that amenamevir (as a cytochrome P450 3A4 substrate) can interact with ketoconazole or rifampicin, and (as a cytochrome P450 3A4 inducer) can interact with midazolam; however, no interaction between amenamevir and (S)-warfarin was observed, indicating that amenamevir is not an inducer of cytochrome P450 2C9.FundingAstellas Pharma.Trial registrationEudraCT2007-002227-33 (study 15L-CL-008), EudraCT2007-002228-14 (study 15L-CL-009), EudraCT2007-002761-13 (study 15L-CL-010), and EudraCT2007-002779-14 (study 15L-CL-018).