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A population pharmacokinetic (PK) and pharmacodynamic (PD) analysis of cinacalcet HCL in renal‐dialysis patients with secondary hyperparathyroidism (HPT)
Author(s) -
Wang B.,
Ludden T.,
Gonzalez M.,
Rein P.,
Harris R.
Publication year - 2004
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2003.11.236
Subject(s) - cinacalcet , secondary hyperparathyroidism , calcimimetic , medicine , population , urology , pharmacodynamics , parathyroid hormone , endocrinology , pharmacokinetics , hyperparathyroidism , dialysis , pharmacology , chemistry , calcium , environmental health
The objective of this investigation was to develop a PK/PD model for cinacalcet MCI in renal‐dialysis patients with secondary HPT. Parathyroid hormone (PTH) is regulated by a parathyroid cell‐surface calcium‐sensing receptor. The free base of cinacalcet HCl (cinacalcet) acts on this receptor and inhibits PTH secretion. In this analysis, PK and PTH observations from 218 patients were pooled from 6 clinical studies and analyzed using NONMEM. One study was a fixed‐dose trial with intensive PK/PD sampling. The remaining 5 studies used limited sampling, and patients were dose‐titrated from 30 mg to a possible max dose of 180 mg. The PK of cinacalcet was described by a 2‐compartment model with delayed first‐order absorption. The estimated population mean oral clearance (CL/F) was 234±19 L/h. Age, body weight, BMI did not affect the PK of cinacalcet. From a follow‐up analysis, concomitant vitamin D therapy had no apparent effect on cinacalcet PK. Sex and smoking had modest, although clinically insignificant effects on CL/F. Because cinacalcet is titrated for each patient, demographics‐based dose adjustments are unnecessary. The suppression of PTH by cinacalcet was described by an Imax PD model. The estimated maximum proportion of PTH suppression by cinacalcet (Imax) was 1.0, suggesting high concentrations of cinacalcet may completely Inhibit PTH production in these patients. The estimated cinacalcet concentration associated with 50% PTH suppression (IC50) was 10.6±1.2 ng/mL. Clinical Pharmacology & Therapeutics (2004) 75 , P62–P62; doi: 10.1016/j.clpt.2003.11.236