Influence of Renal Function on Pharmacokinetics, Pharmacodynamics, and Safety of a Single Dose of Romosozumab

Cheng-Pang Hsu, Judy Maddox, Geoffrey Block, Yessenia Bartley, Zhigang Yu, Cheng-Pang Hsu, Judy Maddox, Geoffrey Block, Yessenia Bartley, Zhigang Yu

Abstract

We evaluated the pharmacokinetics, pharmacodynamics, and safety of a single subcutaneous dose of romosozumab 210 mg, a monoclonal antibody against sclerostin, in an open-label, parallel-group study in participants with severe (stage 4) renal impairment (RI; n = 8) or end-stage renal disease requiring hemodialysis (ESRD-RH; n = 8), or healthy participants with normal renal function (n = 8). Compared with the group with normal renal function, the mean romosozumab exposure was 31% and 43% higher as measured by maximum observed serum concentration and area under the concentration-time curve, respectively, in the severe RI group and similar to those in the ESRD-RH group. For all 3 groups, the maximum mean percent increase in procollagen type 1 N terminal propeptide and decrease in serum C-telopeptide levels from baseline were observed on day 15. Changes in procollagen type 1 N terminal propeptide and serum C-telopeptide were of similar patterns in all 3 groups. The single dose of romosozumab 210 mg was well tolerated. Adverse events (AEs) were reported for 13 patients (7 patients with severe RI and 6 with ESRD-RH), with no deaths, AEs, or serious AEs leading to withdrawal. The incidence of subjects with postbaseline transient decreases in serum calcium (severe RI, n = 1; ESRD-RH, n = 5) and increases in intact parathyroid hormone (severe RI, n = 7; ESRD-RH, n = 7; healthy, n = 3) were greater in severe RI and ESRD-RH groups than in the healthy group. All reported events of hypocalcemia (severe RI, n = 1; ESRD-RH, n = 4) were asymptomatic. These results support the use of romosozumab without dose adjustment in patients with severe RI or ESRD-RH.

Keywords: biologics; clinical trial; pharmacodynamics; pharmacokinetics and drug metabolism; renal disease.

Conflict of interest statement

C.‐P.H., J.M., and Z.Y. are employees of and have stock/stock options in Amgen. Y.B. is a former employee of Amgen. G.B. is an employee of US Renal Care, Inc.

© 2022 The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.

Figures

Figure 1
Figure 1
Mean ± standard deviation serum concentration‐time profiles of romosozumab. Mean ± standard deviation serum concentration‐time profiles of romosozumab from participants with normal renal function, stage 4 RI, or ESRD‐RH after a single subcutaneous dose of romosozumab 210 mg, depicted as a log‐linear plot. The lower limit of quantification was 50 ng/mL. ESRD‐RH, end‐stage renal disease requiring hemodialysis; RI, renal impairment.
Figure 2
Figure 2
Scatterplots of individual values for romosozumab pharmacokinetics parameters. Scatterplots of individual values for (A) Cmax, (B) AUClast, and (C) AUCinf. AUCinf, area under the concentration‐time curve from time 0 to infinity; AUClast, area under the concentration‐time curve from time 0 to the time of the last quantifiable concentration; Cmax, maximum observed serum concentration; ESRD‐RH, end‐stage renal disease requiring hemodialysis; RI, renal impairment.
Figure 3
Figure 3
Mean (SD) percent change from baseline in bone turnover markers following a single subcutaneous dose of romosozumab 210 mg. BSAP, bone‐specific alkaline phosphatase; EOS, end of study; ESRD‐RH, end‐stage renal disease requiring hemodialysis; P1NP, procollagen type 1 N terminal propeptide; RI, renal impairment; sCTX, serum C‐telopeptide; SD, standard deviation; TRAP‐5b, tartrate‐resistant acid phosphatase‐5b.
Figure 4
Figure 4
Mean (SD) percent change from baseline in albumin‐adjusted serum calcium and iPTH following a single subcutaneous dose of romosozumab 210 mg. EOS, end of study; ESRD‐RH, end‐stage renal disease requiring hemodialysis; iPTH, intact parathyroid hormone; RI, renal impairment; SD, standard deviation.

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