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Mirabegron pharmacokinetics were linear after i.v. dosing (7.5 - 50 mg), but increased more than proportionally after oral dosing (25 - 150 mg) as a result of increased F. Sex differences in exposure could be explained by body weight and for oral dosing, also by F. Mirabegron was in general well tolerated up to the highest doses studied, 50 mg i.v. and 150 mg oral.

To explore the role of β -adrenoceptors (ARs) in the heart rate response to the selective β -adrenoceptor agonist mirabegron, 12 young male volunteers received single oral doses of the nonselective β -AR antagonist propranolol (160 mg), the selective β -AR antagonist bisoprolol (10 mg), or placebo on days 1 and 5 of each period in a 3-period crossover study. On day 5, dosing was followed by a supratherapeutic dose of mirabegron (200 mg). Vital signs, impedance cardiography, and plasma renin activity were collected. Mirabegron increased heart rate and systolic blood pressure and reduced stroke volume, whereas cardiac output and diastolic blood pressure were unaffected. Mirabegron-induced changes were attenuated by propranolol and bisoprolol. The data indicate that mirabegron has a positive chronotropic effect at supratherapeutic concentrations, which is at least partly mediated by stimulation of β -AR.

Mirabegron AUC(∞) and C(max) increased 118 and 92 %, respectively, in subjects with severe renal impairment, and 65 and 175 %, respectively, in subjects with moderate hepatic impairment. Pharmacokinetic changes observed in subjects with mild or moderate renal impairment or mild hepatic impairment are of small magnitude and likely to be without clinical importance.

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.

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

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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