sábado, 21 de abril de 2018

Clinical Pharmacology Corner: FDA Approves CRYSVITA (burosumab-twza)

On April 17, 2018, the U.S. Food and Drug Administration (FDA) approved CRYSVITA (burosumab-twza), an anti-human fibroblast growth factor 23 antibody, for the treatment of X-linked hypophosphatemia (XLH) adult and pediatric patients 1 year of age and older. The approved recommended weight based dosage of CRYSVITA, a subcutaneous injection administered by a healthcare provider, varies for pediatric and adult patients as follows: 

Pediatrics (1 to less than 18 years of age)
  • The recommended starting dose regimen is 0.8 mg/kg of body weight administered every two weeks.  
  • Dose may be increased up to approximately 2 mg/kg, administered every two weeks to achieve normal serum phosphorus.  
  • Measure fasting serum phosphorus every 4 weeks for the first 3 months of treatment, and thereafter as appropriate. Decrease dose if serum phosphorous is above the normal range as described in the full prescribing information linked below. 
Adults (18 years of age and older)
  • The recommended starting dose regimen is 1 mg/kg of body weight administered every four weeks. 
  • Measure fasting serum phosphorus on a monthly basis, measured 2 weeks post-dose, for the first 3 months of treatment, and thereafter as appropriate. Decrease dose if serum phosphorous is above the normal range as described in the full prescribing information linked below.
For both pediatric and adult patients, weight based dosing should be rounded to the nearest 
10 mg, with a minimum dose of 10 mg and maximum dose of 90 mg. Discontinue oral phosphate and active vitamin D analogs 1 week prior and confirm fasting serum phosphorus concentration is below the reference range for age prior to initiation of treatment. For additional monitoring and dose adjustment recommendations, refer to the full prescribing information linked below.

Mechanism of Action (MOA), General Pharmacokinetics (PK), and Pharmacodynamics (PD) 
  • MOA: Burosumab-twza inhibits fibroblast growth factor 23.  
  • Dose Proportionality: Burosumab-twza pharmacokinetics increases proportionally from 0.1 to 1 mg/kg (0.08 to 0.8 times the maximum approved recommended dosage based on a 70 kg patient). 
  • Steady State Exposure: The steady-state trough mean (± SD) concentration of burosumab-twza was 5.8 (± 3.4) mcg/mL in adult patients, 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.
  • Absorption: Burosumab-twza mean Tmax values ranged from 8 to 11 days.
  • Distribution: Burosuma-twza apparent volume of distribution is 8 L.
  • Elimination: Burosumab-twza apparent clearance is 0.290 L/day, and half-life is approximately 19 days.
  • Metabolism: The exact metabolic pathway of burosumab-twza has not been characterized. Burosumab-twza is expected to be degraded into small peptides and amino acids via catabolic pathways.
  • Immunogenicity: Pre-existing anti-drug antibodies (ADA) have been detected in up to 10% of patients in burosumab-twza clinical studies. However, the potential clinical impact of antibodies to CRYSVITA is unknown.
Use in Specific Populations

Burosumab-twza clearance and volume of distribution increases with body weight.

No clinically significant difference in the pharmacokinetics of burosumab-twza were observed based on age. The effect of renal or hepatic impairment on burosumab-twza pharmacokinetics is unknown.

Efficacy and Safety

Efficacy of CRYSVITA was demonstrated in two randomized, open-label studies in pediatric XLH patients, an open-label, single-arm study in adult XLH patients, and a randomized, double-blind, placebo-controlled study in adult XLH patients. Additional information regarding the efficacy studies can be found in the full prescribing information linked below.

Most common adverse reactions (≥ 25%) in pediatric XLH patients are headache, injection site reaction, vomiting, pyrexia, pain in extremity, and vitamin D decreased. 

Most common adverse reactions (≥ 5% and in at least 2 patients more than placebo) in adult XLH patients are back pain, headache, tooth infection, restless leg syndrome, vitamin D decreased, dizziness, constipation, and blood phosphorus increased.

Full prescribing information is available at https://go.usa.gov/xQDww 

Visit Drugs@FDA at http://go.usa.gov/cMsjT for prescribing and patient information, approval letters, reviews and other information for FDA-approved drug products, which are often available shortly following approval. 

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online athttp://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178), or by mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).

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