. 2020 May 4;35(9):1679–1697. doi: 10.1007/s00467-020-04516-4

Table 2.

Non-Amgen-supported studies of cinacalcet in pediatric subjects

Reference, study type, and objectives	Dosage	Study population	Key findings
Arenas Morales et al [23] Retrospective chart review Primary objective To determine a safe and effective dosing regimen of cinacalcet in the treatment of infants and young children with sHPT that was refractory to standard care Other objectives To examine growth during cinacalcet treatment	Starting dose: 0.4 to 1.1 mg/kg/day (weight-adjusted) Titration: • Titrated on average every 30 days to achieve a decline in the PTH to a goal of 150–300 pg/mL • No set protocol for advancing the cinacalcet dose, although it was generally increased by 50% at each increment Provision: Administered once daily orally or via gastric tube Planned follow-up: 11 courses of cinacalcet treatment	N = 10 A retrospective case series of infants and young children with advanced CKD who developed refractory sHPT and were treated with cinacalcet Inclusion criteria • Age < 8 years • PTH > 500 pg/ml for ≥ 30 days • Unresponsive to conventional therapy (high doses of phosphate binders and active vitamin D, calcitriol and/or paricalcitol) Exclusion criteria • Not stated	Efficacy • At the beginning of the observation period, 5 subjects with advanced CKD stage 5 were being managed conservatively off dialysis. Of the remaining, 2 were on peritoneal dialysis and 3 were on chronic hemodialysis. • By the end of the observation period, 3 subjects had been transplanted, 3 were on peritoneal dialysis, 2 remained on hemodialysis, and 1 was with CKD stage 5 off dialysis. • All subjects achieved target goal PTH of 150–300 pg/ml by 8 months and within a median time of 112 days (IQR 56, 259). • Note “rebound” levels of PTH during treatment, especially in those with initial PTH levels > 1000 pg/ml—between 2 and 4 months • 8/10 subjects had improved linear growth during cinacalcet therapy compared to the previous 6 months. Safety • Predominant AEs during cinacalcet therapy were nausea, vomiting, and loss of appetite, especially at high doses of cinacalcet and when taken orally; contributed to poor adherence to cinacalcet in the hemodialysis subjects on their off-dialysis days. • 6/10 subjects experienced Ca < 8.5 mg/dL; none experienced any overt symptom of hypocalcemia such as tremor, paresthesia, or seizure. • Cinacalcet can be effective and safe in controlling PTH as adjuvant therapy with vitamin D sterols and phosphate binders. • One patient died from complications of peritonitis, had been off cinacalcet for over 6 months at the time of death
Alharthi et al. [24] A prospective cohort analysis Primary objective To assess the effect of cinacalcet on intact PTH secretion in children with uncontrolled hyperparathyroidism secondary to CKD CKD-4/5	Starting dose: 0.5 mg/kg/day Titration: Titrated every 2 weeks up to a maximum of 1.5 mg/kg/day Provision: Not stated Planned follow-up: Until the endpoint is achieved (range 3–24 months)	N = 28 A prospective, open-label, single-arm interventional study over a period of 24 months. Inclusion criteria • Age ≤ 18 years • Mean baseline PTH ≥ 300 pg/mL • Mean baseline cCa ≥ 8.4 mg/dL • Ca X P product ≥ 65 mg²/dL² • Receiving HD or automated peritoneal dialysis (APD) for > 6 months Exclusion criteria • Serum Ca < 8.4 mg/dL • Seizure disorder maintained on anti-convulsant treatment • Hepatic impairment • Hypersensitivity to cinacalcet	Efficacy • Significant reduction in PTH and alkaline phosphatase levels was demonstrated with cinacalcet treatment (mean PTH levels reduced from 1931.76 to 354.25 pg/mL; P < 0.001). • Subjects with lower baseline PTH attained target PTH levels quicker than those with initially higher PTH. • No effect on serum Ca, P, or Ca x P product despite an overall significant reduction in PTH levels. • Nine subjects did not achieve the K/DOQI recommended PTH levels at 24 months and are still on treatment. • 2 hemodialysis subjects died of CKD. • Authors recommend cinacalcet use on a wide scale in pediatric CKD-4/5 even at young age. Safety • No cases of symptomatic hypocalcemia or hypophosphatemia were reported.
Platt et al. [25] Retrospective case series Primary objective To assess the effect of cinacalcet on intact PTH secretion in children with uncontrolled hyperparathyroidism secondary to CKD5	Starting dose: 0.4–1.1 mg/kg/day Titration: Doses of cinacalcet were titrated according to serum PTH and AEs such as hypocalcemia. Provision: Not stated Planned follow-up: Not stated	N = 6 Case series of continuous cinacalcet use for up to 3 years in subjects with CKD 5. Inclusion criteria • Age ≤ 14 years • PTH > 500 pg/ml for ≥ 30 days • Unresponsive to conventional therapy Exclusion criteria • Not stated	Efficacy • All 6 cases saw a minimum reduction in PTH level of 86% (range 86–98%) over a period of continuous treatment that ranged between 3 months and 2 years. • There was a significant difference in mean PTH level between the 1-month pretreatment level (102.9 pmol/L), and the level during the month in which optimal control was achieved (7.9 pmol/L; P = 0.002). • Four subjects required dose increases during treatment; the doses administered ranged from 0.4 to 2.6 mg/kg/day. • One patient showed a decrease in PTH level from 1-month pretreatment to 24 months, but PTH control was lost after 24 months despite increasing doses of cinacalcet. • No significant difference in serum Ca, P, and Ca × P over the duration of treatment Safety • Asymptomatic hypocalcemia was observed in two subjects and hypophosphatemia occurred in three subjects; 1 patient was refractory to treatment, resulting in the discontinuation of cinacalcet for a 5-month period. • Nausea and vomiting not a significant issue
Muscheites et al. [26] A single-center study Primary objective To assess the efficacy and acceptability of cinacalcet for treatment of sHPT pediatric subjects suffering from ESRD presenting with inadequately controlled SHPT	Starting dose 0.25 mg/kg/day (body weight) during a 4-week period. Titration: No titration mentioned, final doses not reported Provision: 30-mg tablets re-pressed into tablets containing 2.5 mg, 5 mg, and 7.5 mg of cinacalcet Planned follow-up: 4 weeks	N = 7 A single-center study evaluating cinacalcet administration in pediatric subjects with CKD 5 and sHPT Inclusion criteria • Age ≤ 19 years • PTH > 500 pg/ml • Unresponsive after 2 months conventional therapy (calcitriol and phosphate binders) Exclusion criteria • Not stated	Efficacy • Median serum PTH values decreased rapidly after 4 h and 12 h. • Median PTH decrease amounted to 74% (932 pg/mL at baseline to 199 pg/mL; P = 0.028). • Median concentrations of serum Ca showed a significant decrease 4 h after the dose (from 2.69 mmol/L at baseline to 2.38 mmol/L; P < 0.05). • Both serum P levels and the Ca × P ion product showed a rapid and sustained decrease, which occurred within the first week of cinacalcet treatment and lasted throughout treatment. Safety • No AEs, e.g., symptomatic hypocalcemia, gastrointestinal symptoms (nausea, vomiting, and diarrhea), were noted. • Two subjects developed asymptomatic hypocalcemia, defined as serum calcium < 2.20 mmol/L, and were treated with calcium or vitamin D.
Silverstein et al. [27] A single-center study Primary objective To assess the efficacy of cinacalcet in pediatric subjects with sHPT (high-turnover bone disease) receiving dialysis	Starting dose: 30 mg/day (once each evening with food) Titration: Once every 4 weeks to a maximum of 120 mg once daily for persistent PTH > 500 pg/mL Provision: Not stated Planned follow-up: 3 months	N = 9 Retrospective analysis of subjects on chronic dialysis Inclusion criteria • Age 2–21 years • On hemodialysis or peritoneal dialysis for ≥ 6 months • PTH levels ≥ 400 pg/mL for 3 consecutive months Exclusion criteria • Not stated	Efficacy • n = 6 remained on 30 mg/day; n = 1 increased to 60 mg/day; n = 2 increased 120 mg/day. • In subjects on hemodialysis (n = 6), mean (± SD) PTH reduced by 41.7% from 845.73 ± 145.2 pg/mL at 1 month prior to cinacalcet therapy to 493 ± 133.4 pg/mL after 3 months of treatment (P = 0.03). • In subjects on peritoneal dialysis (n = 3), mean PTH (± SD) reduced by 82.4% from 1518.0 ± 309.5 pg/mL at 1 month prior to therapy to 266.7 ± 93.6 pg/mL after 3 months (P = 0.08). • Serum Ca and P levels and Ca x P product were unchanged after 3 months of cinacalcet therapy. Safety • n = 3 hemodialysis subjects reported mild nausea that did not require cinacalcet discontinuation. • Other potential adverse symptoms due to cinacalcet not reported.

Reference, study type, and objectives

Dosage

Study population

Key findings

Arenas Morales et al [23]

Retrospective chart review

Primary objective

To determine a safe and effective dosing regimen of cinacalcet in the treatment of infants and young children with sHPT that was refractory to standard care

Other objectives

To examine growth during cinacalcet treatment

Starting dose: 0.4 to 1.1 mg/kg/day (weight-adjusted)

Titration:

• Titrated on average every 30 days to achieve a decline in the PTH to a goal of 150–300 pg/mL

• No set protocol for advancing the cinacalcet dose, although it was generally increased by 50% at each increment

Provision: Administered once daily orally or via gastric tube

Planned follow-up: 11 courses of cinacalcet treatment

N = 10

A retrospective case series of infants and young children with advanced CKD who developed refractory sHPT and were treated with cinacalcet

Inclusion criteria

• Age < 8 years

• PTH > 500 pg/ml for ≥ 30 days

• Unresponsive to conventional therapy (high doses of phosphate binders and active vitamin D, calcitriol and/or paricalcitol)

Exclusion criteria

• Not stated

Efficacy

• At the beginning of the observation period, 5 subjects with advanced CKD stage 5 were being managed conservatively off dialysis. Of the remaining, 2 were on peritoneal dialysis and 3 were on chronic hemodialysis.

• By the end of the observation period, 3 subjects had been transplanted, 3 were on peritoneal dialysis, 2 remained on hemodialysis, and 1 was with CKD stage 5 off dialysis.

• All subjects achieved target goal PTH of 150–300 pg/ml by 8 months and within a median time of 112 days (IQR 56, 259).

• Note “rebound” levels of PTH during treatment, especially in those with initial PTH levels > 1000 pg/ml—between 2 and 4 months

• 8/10 subjects had improved linear growth during cinacalcet therapy compared to the previous 6 months.

Safety

• Predominant AEs during cinacalcet therapy were nausea, vomiting, and loss of appetite, especially at high doses of cinacalcet and when taken orally; contributed to poor adherence to cinacalcet in the hemodialysis subjects on their off-dialysis days.

• 6/10 subjects experienced Ca < 8.5 mg/dL; none experienced any overt symptom of hypocalcemia such as tremor, paresthesia, or seizure.

• Cinacalcet can be effective and safe in controlling PTH as adjuvant therapy with vitamin D sterols and phosphate binders.

• One patient died from complications of peritonitis, had been off cinacalcet for over 6 months at the time of death

Alharthi et al. [24]

A prospective cohort analysis

Primary objective

To assess the effect of cinacalcet on intact PTH secretion in children with uncontrolled hyperparathyroidism secondary to CKD CKD-4/5

Starting dose: 0.5 mg/kg/day

Titration: Titrated every 2 weeks up to a maximum of 1.5 mg/kg/day

Provision: Not stated

Planned follow-up:

Until the endpoint is achieved (range 3–24 months)

N = 28

A prospective, open-label, single-arm interventional study over a period of 24 months.

Inclusion criteria

• Age ≤ 18 years

• Mean baseline PTH ≥ 300 pg/mL

• Mean baseline cCa ≥ 8.4 mg/dL

• Ca X P product ≥ 65 mg²/dL²

• Receiving HD or automated peritoneal dialysis (APD) for

> 6 months

Exclusion criteria

• Serum Ca < 8.4 mg/dL

• Seizure disorder maintained on anti-convulsant treatment

• Hepatic impairment

• Hypersensitivity to cinacalcet

Efficacy

• Significant reduction in PTH and alkaline phosphatase levels was demonstrated with cinacalcet treatment (mean PTH levels reduced from 1931.76 to 354.25 pg/mL; P < 0.001).

• Subjects with lower baseline PTH attained target PTH levels quicker than those with initially higher PTH.

• No effect on serum Ca, P, or Ca x P product despite an overall significant reduction in PTH levels.

• Nine subjects did not achieve the K/DOQI recommended PTH levels at 24 months and are still on treatment.

• 2 hemodialysis subjects died of CKD.

• Authors recommend cinacalcet use on a wide scale in pediatric CKD-4/5 even at young age.

Safety

• No cases of symptomatic hypocalcemia or hypophosphatemia were reported.

Platt et al. [25]

Retrospective case series

Primary objective

To assess the effect of cinacalcet on intact PTH secretion in children with uncontrolled hyperparathyroidism secondary to CKD5

Starting dose: 0.4–1.1 mg/kg/day

Titration: Doses of cinacalcet were titrated according to serum PTH and AEs such as hypocalcemia.

Provision: Not stated

Planned follow-up: Not stated

N = 6

Case series of continuous cinacalcet use for up to 3 years in subjects with CKD 5.

Inclusion criteria

• Age ≤ 14 years

• PTH > 500 pg/ml for ≥ 30 days

• Unresponsive to conventional therapy

Exclusion criteria

• Not stated

Efficacy

• All 6 cases saw a minimum reduction in PTH level of 86% (range 86–98%) over a period of continuous treatment that ranged between 3 months and 2 years.

• There was a significant difference in mean PTH level between the 1-month pretreatment level (102.9 pmol/L), and the level during the month in which optimal control was achieved (7.9 pmol/L; P = 0.002).

• Four subjects required dose increases during treatment; the doses administered ranged from 0.4 to 2.6 mg/kg/day.

• One patient showed a decrease in PTH level from 1-month pretreatment to 24 months, but PTH control was lost after 24 months despite increasing doses of cinacalcet.

• No significant difference in serum Ca, P, and Ca × P over the duration of treatment

Safety

• Asymptomatic hypocalcemia was observed in two subjects and hypophosphatemia occurred in three subjects; 1 patient was refractory to treatment, resulting in the discontinuation of cinacalcet for a 5-month period.

• Nausea and vomiting not a significant issue

Muscheites et al. [26]

A single-center study

Primary objective

To assess the efficacy and acceptability of cinacalcet for treatment of sHPT pediatric subjects suffering from ESRD presenting with inadequately controlled SHPT

Starting dose

0.25 mg/kg/day (body weight) during a 4-week period.

Titration: No titration mentioned, final doses not reported

Provision: 30-mg tablets re-pressed into tablets containing 2.5 mg, 5 mg, and 7.5 mg of cinacalcet

Planned follow-up: 4 weeks

N = 7

A single-center study evaluating cinacalcet administration in pediatric subjects with CKD 5 and sHPT

Inclusion criteria

• Age ≤ 19 years

• PTH > 500 pg/ml

• Unresponsive after 2 months conventional therapy (calcitriol and phosphate binders)

Exclusion criteria

• Not stated

Efficacy

• Median serum PTH values decreased rapidly after 4 h and 12 h.

• Median PTH decrease amounted to 74% (932 pg/mL at baseline to 199 pg/mL; P = 0.028).

• Median concentrations of serum Ca showed a significant decrease 4 h after the dose (from 2.69 mmol/L at baseline to 2.38 mmol/L; P < 0.05).

• Both serum P levels and the Ca × P ion product showed a rapid and sustained decrease, which occurred within the first week of cinacalcet treatment and lasted throughout treatment.

Safety

• No AEs, e.g., symptomatic hypocalcemia, gastrointestinal symptoms (nausea, vomiting, and diarrhea), were noted.

• Two subjects developed asymptomatic hypocalcemia, defined as serum calcium < 2.20 mmol/L, and were treated with calcium or vitamin D.

Silverstein et al. [27]

A single-center study

Primary objective

To assess the efficacy of cinacalcet in pediatric subjects with sHPT (high-turnover bone disease) receiving dialysis

Starting dose: 30 mg/day (once each evening with food)

Titration: Once every 4 weeks to a maximum of 120 mg once daily for persistent PTH > 500 pg/mL

Provision: Not stated

Planned follow-up: 3 months

N = 9

Retrospective analysis of subjects on chronic dialysis

Inclusion criteria

• Age 2–21 years

• On hemodialysis or peritoneal dialysis for ≥ 6 months

• PTH levels ≥ 400 pg/mL for 3 consecutive months

Exclusion criteria

• Not stated

Efficacy

• n = 6 remained on 30 mg/day; n = 1 increased to 60 mg/day; n = 2 increased 120 mg/day.

• In subjects on hemodialysis (n = 6), mean (± SD) PTH reduced by 41.7% from 845.73 ± 145.2 pg/mL at 1 month prior to cinacalcet therapy to 493 ± 133.4 pg/mL after 3 months of treatment (P = 0.03).

• In subjects on peritoneal dialysis (n = 3), mean PTH (± SD) reduced by 82.4% from 1518.0 ± 309.5 pg/mL at 1 month prior to therapy to 266.7 ± 93.6 pg/mL after 3 months (P = 0.08).

• Serum Ca and P levels and Ca x P product were unchanged after 3 months of cinacalcet therapy.

Safety

• n = 3 hemodialysis subjects reported mild nausea that did not require cinacalcet discontinuation.

• Other potential adverse symptoms due to cinacalcet not reported.

AE, Adverse event; Ca, calcium; CKD, chronic kidney disease; h, hour; IQR, interquartile range; K/DOQI, National Kidney Foundation Kidney Disease Outcomes Quality Initiative; P, phosphate; PTH, parathyroid hormone; SD, standard deviation; sHPT, secondary hyperparathyroidism