ption and the renal production of 1,25 dihydroxy vitamin D. Burosumab-twza binds to and inhibits the biological activity of FGF23 restoring renal phosphate reabsorption and increasing the serum concentration of 1,25 dihydroxy vitamin D.
12.2 Pharmacodynamics
Following SC administration in XLH patients, higher burosumab-twza concentrations were associated with greater increase of serum phosphorus levels. The increase in serum phosphorus was reversible and returned to baseline with elimination of systemic burosumab-twza.
Ratio of renal tubular maximum reabsorption rate of phosphate to glomerular filtration rate (TmP/GFR) showed dose-dependent increases from baseline [see Clinical Studies (14)].
Elevation in serum total FGF23 was observed after initiation of burosumab-twza treatment, however, the clinical implication is unknown.
12.3 Pharmacokinetics
The following pharmacokinetic parameters were observed in patients with XLH administered the approved recommended starting dosage based on a 70 kg patient, unless otherwise specified.
Burosumab-twza exhibited linear pharmacokinetics following SC injections within the dose range of 0.1 to 1 mg/kg (0.08 to 0.8 times the maximum approved recommended dosage based on a 70 kg patient).
The steady-state trough mean (± SD) concentration of burosumab-twza was 5.8 (± 3.4) mcg/mL in adult patients.
Absorption
The burosumab-twza mean Tmax values ranged from 8 to 11 days.
Distribution
The apparent volume of distribution of burosumab-twza is 8 L.
Elimination
The apparent clearance is 0.290 L/day. The half-life of burosumab-twza is approximately 19 days.
Metabolism
The exact pathway for burosumab-twza metabolism has not been characterized. Burosumab-twza is expected to be degraded into small peptides and amino acids via catabolic pathways.
Specific Populations
No clinical significant difference in burosumab-twza pharmacokinetics was observed based on age.
The effect of renal or hepatic impairment on the pharmacokinetics of burosumab-twza is unknown.
Pediatric Patients
The steady-state trough concentration was 15.8 (± 9.4) mcg/mL in patients aged 5-12 years, and 11.2 (± 4.6) mcg/mL in patients aged 1-4 years.
Body Weight
Clearance and volume of distribution of burosumab-twza increases with body weight.
Drug Interaction Studies
No drug interaction studies have been conducted with CRYSVITA.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
The carcinogenic potential of burosumab-twza has not been eva luated in long term animal studies.
Studies have not been performed to eva luate the mutagenic potential of burosumab-twza.
No specific fertility studies have been performed in animals to eva luate the effects of burosumab-twza.
Toxicology studies with burosumab-twza of up to 40 weeks duration in non-XLH cynomolgus monkeys did not show significant adverse effects on female reproductive organs at doses up to 65-fold human exposure at the dose of 1 mg/kg every 4 weeks. In male monkeys, minimal mineralization of the rete testis or seminiferous tubules associated with hyperphosphatemia was observed at 11- to 37-fold human exposure, but semen analysis did not show any adverse effects.
13.2 Animal Toxicology and/or Pharmacology
In rabbits and cynomolgus monkeys, inhibition of FGF23 signaling by burosumab-twza increased serum phos |
