A Multi-Compartment Model Capturing the Pharmacokinetics of the Calcimimetic Cinacalcet.

BACKGROUND/AIMS: Chronic kidney disease-mineral bone disorder is a major complication affecting the vast majority of chronic kidney disease patients. A hallmark of the disorder is an altered parathyroid gland biology resulting in secondary hyperparathyroidism. This condition is widely treated by calcimimetics like cinacalcet which act by allosteric activation of the calcium sensing receptor. METHODS: Here, we present a linear multi-compartment model based on physiological principles such as first-pass metabolism and protein binding, which captures all relevant pharmacokinetic parameters of cinacalcet. RESULTS: Due to the linear structure of the model, simulations are numerically stable and allow fast and accurate short or long-term predictions of cinacalcet concentrations in the body. CONCLUSION: The model compartments are physiological meaningful and can be easily adjusted to various conditions like impaired hepatic clearance or different drug administration regimens. Moreover, the model can be easily adapted to specific patient groups.

An improved LC-MS/MS method for determination of cinacalcet in human plasma and its application to the evaluation of food intake effect on the pharmacokinetics of cinacalcet in healthy volunteers.

A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the determination of cinacalcet in human plasma was developed and validated. This assay was based on liquid-liquid extraction and cinacalcet-d4 was used as an internal standard (IS). Separation was achieved on a C18 column by the mobile phase A of water (containing 0.1% formic acid) and the mobile phase B of acetonitrile-water (95:5, v/v) (containing 0.2% formic acid) with gradient elution. Quantification was done using multiple reaction monitoring mode to monitor the precursor-to-product ion transitions of m/z 358.2 → m/z 155.2 for cinacalcet and m/z 362.3 → m/z 155.0 for IS at positive ionization mode. The calibration curve was established over the range 0.05-20.0 ng/mL and the correlation coefficient was >0.99. The intra- and inter-day relative standard deviations were <5.8%. Accuracy determined at four concentrations ranged between 96.0 and 106.0%. This method was successfully applied to a pharmacokinetic description of oral dose of cinacalcet and the significant effect of food intake on the pharmacokinetics of cinacalcet was first demonstrated in Chinese healthy volunteers.

Cholecalciferol Additively Reduces Serum Parathyroid Hormone Levels in Severe Secondary Hyperparathyroidism Treated with Calcitriol and Cinacalcet among Hemodialysis Patients.

We evaluated the improvement of intact parathyroid hormone (iPTH) levels and bone parameters by supplementing nutritional vitamin D (cholecalciferol) to combined calcimimetic (cinacalcet) and active vitamin D analog (calcitriol) among severe secondary hyperparathyroidism (SHPT) hemodialysis (HD) patients. A randomized, controlled open-label study was undertaken in 60 HD patients with serum iPTH > 1000 pg/mL or persistently high iPTH ≥ 600 pg/mL even after >3 months of calcitriol (3 µg/week). The study group received oral cholecalciferol (5000 IU/ day) and the control group received a placebo. All patients received fixed dose cinacalcet (30 mg/day, orally) and calcitriol. Calcitriol was reduced if iPTH ≤ 300 pg/mL and cinacalcet was withdrawn if serum iPTH was persistently low (iPTH ≤ 300 pg/mL) for 4 weeks after the reduction of calcitriol. A significantly lower iPTH level was noted from the 20th week in the study group compared to the placebo group, and the target iPTH ≤ 300 pg/mL was achieved at the 24th week in the study group. Most patients achieved serum 25-(OH)D3 ≥ 30 ng/mL in the study group. Nearly 40% of study patients gained >10% improvement in femoral neck (FN) bone mineral density (BMD). We conclude that cholecalciferol additively reduced serum iPTH levels, improved 25-(OH)D3 levels and improved FN BMD when used together with cinacalcet/calcitriol in severe SHPT HD patients.