This was a single-dose, open-label study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of cinacalcet in pediatric subjects with CKD on dialysis. The ethics committees of each study center reviewed and approved the study protocol and the consent forms prior to the investigators enrolling subjects. Twelve subjects were enrolled, and all subjects continued their regular therapy for management of sHPT (e.g., phosphate binder, vitamin D sterol). Oral or intravenous Ca therapy and alteration of the dialysate calcium concentration was allowed for serum Ca <1.87 mmol/L (7.5 mg/dL) or signs or symptoms of hypocalcemia subsequent to the study drug administration.
Seven girls and five boys aged 6–17 years on dialysis for at least 1 month at the time of screening were enrolled in the study. Written informed consent was obtained from the parent or guardian for all subjects; additionally, written assent was obtained from subjects ≥12 years of age. Subjects were eligible to participate if they had serum Ca level of ≥8.4 mg/dL at the time of the baseline visit and had not received any cinacalcet therapy for at least 2 weeks before Day 1 dosing.
To ensure subjects were enrolled across the entire age range of 6–17 years, three subjects were required to be enrolled into each of the following age-cohorts: 6–8, 9–11, 12–14, and 15–17 years. After a minimum 8-h fast, each subject received a single oral 15-mg dose of cinacalcet (½ of a 30-mg tablet, weighed with a Mettler balance) with 90 mL (3 oz) of water. Subjects continued to fast for 4 h after treatment administration, and they were followed for 72 h after dosing.
Rationale for dosage selection
In vitro and in vivo studies have demonstrated that cinacalcet is extensively metabolized by multiple cytochrome P450 (CYP) enzymes, including CYP3A4, CYP2D6, and CYP1A2 [18
]. The capacity to metabolize drugs in children varies throughout development of CYP enzymes and is completed by approximately 6 years of age. Therefore, the difference in pharmacokinetic properties of cinacalcet for adults and pediatric patients older than 6 years is likely to be due to differences in body surface area (BSA). Based on BSA, a 6-year-old child should receive approximately 50 % of an adult dose. The recommended starting dose for cinacalcet in adults is 30 mg; therefore, a dose of 15 mg was selected for this study.
Blood samples for safety assessments were collected at screening, baseline, and on study Day 4. Blood samples for pharmacokinetic analysis were collected at predose and at 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 48, and 72 h post-dose, and those for pharmacodynamic (Ca and iPTH) analysis were obtained at predose and at 2, 4, 8, 12, 24, 48, and 72 h post-dose.
Planned statistical analysis
All subjects who received cinacalcet were included in the safety, pharmacokinetics, and pharmacodynamics analyses. Since this was a descriptive study, the sample size of three subjects per age-cohort was based on practical considerations; no formal analyses for between-cohort comparisons were conducted.
The safety profile assessment was based on adverse events, vital signs, clinical laboratory measurements, electrocardiogram, and physical examinations. An adverse event was defined as an undesirable medical sign or symptom or worsening of a pre-existing medical condition present at baseline that occurred after initiation of the investigational product. A serious adverse event included any event deemed fatal or life threatening, an event that required or prolonged in-patient hospitalization, or a persistent, significant disability or incapacity, congenital anomaly, or birth defect, as well as any event that may have resulted in urgent investigation.
Plasma cinacalcet concentration–time data were analyzed by non-compartmental methods using WinNonlin Enterprise (ver. 5.1.1; Pharsight Corp, Mountain View, CA). The serum peak concentration (Cmax) after dosing was identified by inspection of the data, and the corresponding time to reach Cmax (tmax) was recorded. Plasma cinacalcet concentration versus time was plotted on a semi-log-scale, and the data points that described the terminal log-linear segment of the elimination phase were identified. Whenever possible, a linear regression of the log-transformed terminal data points versus time was used to estimate the terminal rate constant β. The terminal half-life, t1/sβ was calculated as 0.693/β. The area under the concentration–time curve from zero to the last measurable concentration (AUC0-t) was calculated by the linear trapezoidal method. The AUC from the time of the last measurable concentration to infinity (AUCt-inf) was calculated by dividing the predicted concentration at the time of the last measurable concentration by β. The AUC from time zero to infinity, AUCo-inf, was calculated by the summation of AUC0-t and AUCt-inf. AUC0-inf was not reported when AUCt-inf exceeded 20 % of the total AUC. The apparent oral clearance (CL/F) was calculated as dose/AUC0-inf.