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

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.

Romosozumab improves low bone mineral density in a postmenopausal woman undergoing chronic hemodialysis and treated with a calcium-sensing receptor agonist

“…In addition, the dose of alfacalcidol (0.25 μg/day) which had been orally administered may have been smaller than required, leading to the hypocalcemia in the romosozumab treatment in the present case. A recent pharmacokinetics/pharmacodynamics study by Hsu et al demonstrated that worsening hypocalcemia was found in patients on hemodialysis possibly due to the lack of compensatory increased PTH effect in the kidney, despite comparable levels of exposure to romosozumab between patients with normal renal function and those on hemodialysis ( Hsu et al, 2022 ). Notably, in the present case on chronic hemodialysis, oral CaSR agonist was simultaneously used with romosozumab.…”

Management of fracture risk in CKD—traditional and novel approaches

“…Furthermore, sclerostin may contribute to phosphate homeostasis by stimulating FGF23 expression in bone [ 171 ]. Of note, romosozumab therapy can induce profound hypocalcemia in patients with CKD stages 4–5D, which may be exaggerated by concomitant treatment with calcimimetics, necessitating close monitoring of serum calcium after initiation of romosozumab treatment in this population [ 172 ].…”

Romosozumab rescues impaired bone mass and strength in a murine model of diabetic kidney disease

“…However, although bisphosphonates are the gold standard for osteoporosis treatment, they are contraindicated in severe CKD as dosing is difficult to do safely when renal clearance is inhibited ( Miller et al, 2022 ). An alternative treatment may be Romosozumab (Romo), a sclerostin inhibitor that both increases bone formation and decreases resorption ( Hsu et al, 2022 ). Clinical trials have consistently shown that monthly doses of Romo outperform bisphosphonates in increasing BMD and decreasing fracture rates in osteoporotic patients with mild to severe CKD ( Miller et al, 2022 ; Hsu et al, 2022 ; Miyauchi et al, 2022 ; Suzuki et al, 2022 ).…”

“…An alternative treatment may be Romosozumab (Romo), a sclerostin inhibitor that both increases bone formation and decreases resorption ( Hsu et al, 2022 ). Clinical trials have consistently shown that monthly doses of Romo outperform bisphosphonates in increasing BMD and decreasing fracture rates in osteoporotic patients with mild to severe CKD ( Miller et al, 2022 ; Hsu et al, 2022 ; Miyauchi et al, 2022 ; Suzuki et al, 2022 ). While Romo is currently FDA-approved for use in high-risk postmenopausal osteoporosis ( Hsu et al, 2022 ), further investigation is needed to determine its efficacy in increasing bone mass in DKD patients.…”

“…Clinical trials have consistently shown that monthly doses of Romo outperform bisphosphonates in increasing BMD and decreasing fracture rates in osteoporotic patients with mild to severe CKD ( Miller et al, 2022 ; Hsu et al, 2022 ; Miyauchi et al, 2022 ; Suzuki et al, 2022 ). While Romo is currently FDA-approved for use in high-risk postmenopausal osteoporosis ( Hsu et al, 2022 ), further investigation is needed to determine its efficacy in increasing bone mass in DKD patients. We hypothesized that Romo would improve bone mass and strength in a murine model of DKD.…”