Comment on: Pharmacokinetics, Pharmacodynamics, and Safety of the Novel Calcimimetic Agent Evocalcet in Healthy Japanese Subjects: First-in-Human Phase I Study

Excerpt

Cinacalcet hydrochloride (Sensipar^®) has been approved for the treatment of secondary hyperparathyroidism (SHPT) in chronic kidney disease (CKD) patients [1, 2]. Due to the efficient targeting of calcium sensory receptors present in parathyroid glands, the pharmacodynamic activity elicited by cinacalcet directly leads to the lowering of serum parathyroid hormone (PTH) and reduced serum levels of both calcium and phosphorous [2]. Despite beneficial effects of cinacalcet therapy in CKD patients pertaining to delayed onset of cardiovascular events, gastrointestinal tolerability issues such as nausea and vomiting have been reported [1‐3]. Another drawback of cinacalcet therapy is with regards to cinacalcet being a perpetrator drug for cytochrome P450 (CYP) 2D6 and a victim drug especially for CYP3A4 [4‐6]. In other words, the CYP profile of cinacalcet suggests that it may precipitate the occurrence of potential drug–drug interactions of substrates and inhibitors of CYP2D6 (i.e. desipramine, dextromethorphan) and CYP3A4 (i.e. ketoconazole), respectively [4‐7]. Moreover, dosing instructions in the label for cinacalcet involve multiple dose titrations on the basis of intact PTH levels for the treatment of SHPT or calcium levels for the treatment of hypercalcemia in patients with primary hyperparathyroidism [1]. Therefore, alternative therapy options that address the tolerability/safety issues and the pharmacokinetic dilemma due to the drug–drug interactions of cinacalcet are both desirable and warranted. It is also desirable that any newer therapy options to replace cinacalcet simplify the dose titration paradigm and be less cumbersome for patients and caregivers. …