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Pharmacodynamics of evocalcet for secondary hyperparathyroidism in Japanese hemodialysis patients.

ABSTRACT: BACKGROUND:This study investigated the pharmacokinetics, pharmacodynamics, and safety of multiple doses of evocalcet in Japanese secondary hyperparathyroidism (SHPT) patients receiving hemodialysis. METHODS:In this multicenter, open-label study, conducted between August 2013 and March 2014, 27 patients received multiple doses of 1 and 4 mg evocalcet for 14 days, followed by an extension period of multiple doses of 8 and 12 mg evocalcet for 7 days using an intra-patient dose escalation protocol. Pharmacodynamic parameters consisted of measurement of intact parathyroid hormone (PTH), serum-corrected calcium, serum phosphorus and intact fibroblast growth factor 23 concentrations. Safety was assessed by analysis of adverse events. RESULTS:Plasma evocalcet levels reached steady state 3 days after the first day of administration. Pharmacodynamic analyses showed that evocalcet effectively reduced intact PTH and serum-corrected calcium levels. Adverse events (AEs) occurred in 29.6 and 62.5% of patients receiving multiple doses of 1 or 4 mg, respectively. The AE 'blood calcium decreased' occurred in eight patients (33.0%) after multiple doses of 4 mg. All events were mild, except for one patient with a moderate AE (abnormal liver function) and one patient with a severe adverse drug reaction (blood calcium decreased). CONCLUSION:Multiple doses of evocalcet reduced intact PTH levels with a concomitant decrease in serum calcium levels. Evocalcet was well tolerated in SHPT patients receiving hemodialysis.

SUBMITTER: Shigematsu T

PROVIDER: S-EPMC6510802 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Pharmacodynamics of evocalcet for secondary hyperparathyroidism in Japanese hemodialysis patients.

Shigematsu Takashi T Shimazaki Ryutaro R Fukagawa Masafumi M Akizawa Tadao T

Clinical and experimental nephrology 20180829 2

<h4>Background</h4>This study investigated the pharmacokinetics, pharmacodynamics, and safety of multiple doses of evocalcet in Japanese secondary hyperparathyroidism (SHPT) patients receiving hemodialysis.<h4>Methods</h4>In this multicenter, open-label study, conducted between August 2013 and March 2014, 27 patients received multiple doses of 1 and 4 mg evocalcet for 14 days, followed by an extension period of multiple doses of 8 and 12 mg evocalcet for 7 days using an intra-patient dose escala ...[more]

PMID: 30159688

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Project description:The dosage of evocalcet required to control serum parathyroid hormone (PTH) levels varies among secondary hyperparathyroidism (SHPT) patients. This post hoc analysis evaluated the dose-dependent efficacy of evocalcet on serum intact PTH (iPTH) levels, corrected calcium (Ca) and phosphate (P) levels, and safety, in an evaluation period (week 28 to week 30) by stratifying the previous phase 3 data with the final evocalcet dosages (low 1-2 mg [131 patients], medium 3-4 mg [90 patients], high 5-8 mg [92 patients]), and identified pre-treatment patient characteristics predicting the use of higher final evocalcet dosages via univariate and multivariate logistic regression models. At the end of the study at week 30, the median serum iPTH level was higher and the achievement ratio for the target range of Japanese Society for Dialysis Therapy (60-240 pg/mL) was lower in the final high-dose subgroup (216 pg/mL and 58%, respectively) than in the other subgroups (low: 149 pg/mL and 79%; medium: 149 pg/mL and 73%, respectively). Among the three subgroups, the mean serum corrected Ca and P levels demonstrated similar trends, and similar ratio of patients achieved the target range (corrected Ca, 8.4-10 mg/dL; P, 3.5-6.0 mg/dL) from week 28 to week 30. No dose-dependent safety concerns were identified. Younger age, prior cinacalcet use, higher serum levels of iPTH and corrected Ca, procollagen type 1 N-terminal propeptide, intact fibroblast growth factor-23, and larger maximum parathyroid gland volume were significantly associated with final high-dose evocalcet (p < 0.05 in all cases). Patients requiring final high-dose evocalcet had pre-treatment characteristics indicating severe SHPT, leading to a lower final achievement rate for the target PTH levels of Japanese Society for Dialysis Therapy. Therefore, the early initiation of evocalcet treatment for SHPT is critical. Trial registration: This trial was registered as follows: ClinicalTrials.gov: NCT02549391 and JAPIC: JapicCTI-153013.

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Pharmacodynamics of evocalcet for secondary hyperparathyroidism in Japanese hemodialysis patients.

Publications

Pharmacodynamics of evocalcet for secondary hyperparathyroidism in Japanese hemodialysis patients.

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