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Pharmacokinetics and pharmacodynamics of alirocumab and evolocumab

Pharmacokinetics and pharmacodynamics of alirocumab and evolocumab
  Alirocumab Evolocumab
Pharmacokinetics
Absorption Median Tmax:
  • Three to seven days
Median Tmax:
  • Three to four days
Estimated absolute bioavailability:
  • 85%
Estimated absolute bioavailability:
  • 72%
Cmax:
  • 1.54 ± 1.02 ng/mL following 150 mg dose
Cmax:
  • 18.6 ± 7.3 ug/mL following 140 mg dose
  • 59.0 ± 17.2 ug/mL following 420 mg dose
AUC:
  • 129 ± 35.7 mg • day/L following 75 mg dose
AUC:
  • 188 ± 98.6 day • ug/mL following 140 mg dose
  • 924 ± 346 day • ug/mL following 420 mg dose
Distribution 0.04 to 0.05 L/kg 3.3 (0.5)* L
Metabolism and elimination Specific metabolism studies were not conducted, because the antibodies are proteins. The antibodies are expected to degrade to small peptides and individual amino acids. Specific metabolism studies were not conducted, because the antibodies are proteins. The antibodies are expected to degrade to small peptides and individual amino acids.
At low concentrations, the elimination is predominately through saturable binding to target (PCSK9), while at higher concentrations the elimination is largely through a non-saturable proteolytic pathway. At low concentrations, the elimination is predominately through saturable binding to target (PCSK9), while at higher concentrations the elimination is largely through a non-saturable proteolytic pathway.

Effective half-life of 17 to 20 days.

When co-administered with a statin, the half-life is 12 days. 		 Effective half-life of 11 to 17 days.
Pharmacodynamics
  Following a single subcutaneous administration of 75 or 150 mg, maximal suppression of free PCSK9 occurred within four to eight hours.
  • Following single subcutaneous administration of 140 mg or 420 mg, maximum suppression of circulating unbound PCSK9 occurred by four hours.
  • A mean nadir in LDL-C lowering response occurs by 14 and 21 days following 140 or 420 mg dos, respectively.
  • Subcutaneous regimens of 140 mg every two weeks and 420 mg once monthly were equivalent in average LDL-C lowering.
  • LDL-C lowering efficacy was sustained with continued use, in measurements made over 112 weeks.
Unbound PCSK9 concentrations returned toward baseline when antibody concentrations decreased below the limit of quantitation.
  • Unbound PCSK9 concentrations returned toward baseline when antibody concentrations decreased below the limit of quantitation.
  • No rebound in PCSK9 or LDL-C above baseline was observed during the washout of evolocumab.
* Standard deviation
AUC: exposure as measured by the area under the concentration x time curve; Cmax: maximum plasma concentration; PCSK9: proprotein convertase subtilisin/kexin type 9; Tmax: time to maximum plasma concentration.
References:
  1. Chung JE. Clinical pharmacology review PRALUENT (Alirocumab). U.S. Food and Drug Administration 2014.
  2. Suryanarayana Sista JE. Clinical phramacology review REPATHA (Evolocumab). U.S. Food and Drug Administration 2014.
  3. Evolocumab injection. US Food & Drug Administration (FDA) approved product information. Revised July, 2016. Available on-line at http://www.accessdata.fda.gov/scripts/cder/daf/index.cfm
  4. Alirocumab injection. US Food & Drug Administration (FDA) approved product information. Revised October, 2015. Available on-line at http://www.accessdata.fda.gov/scripts/cder/daf/index.cfm
  5. Evolocumab (Repatha) Summary of Product Characteristics; European Medicines Agency. Revised March 3, 2017. Available on-line at http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/003766/WC500191398.pdf
  6. Alirocumab (Praluent) Summary of Product Characteristics; European Medicines Agency. Revised November 18, 2016. Available on-line at http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/003882/WC500194521.pdf
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