DB06681 C 3508 H 5440 N 922 O 1096 S 32 923 kDa with glycosylation CATEGORIES Antirheumatic Agents Immunosuppressive Agents DESCRIPTION Belatacept is a soluble fusion protein which links the extracellular domain of human cytotoxic Tlymphocyteassociated a ID: 625433
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BELATACEPT
DB06681
C3508H5440N922O1096S32
92.3 kDa (with glycosylation)
CATEGORIES
Antirheumatic
Agents
Immunosuppressive AgentsSlide2
DESCRIPTION
Belatacept is a soluble fusion protein, which links the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) to the modified Fc (hinge, CH2, and CH3 domains) portion of human immunoglobulin G1 (IgG1). Structurally,
abatacept is a glycosylated fusion protein with a MALDI-MS molecular weight of 92,300 Da and it is a homodimer of two homologous polypeptide chains of 357 amino acids each. It is produced through recombinant DNA technology in mammalian CHO cells. The drug has activity as a selective co-stimulation modulator with inhibitory activity on T lymphocytes. It is approved for the treatment of rheumatoid arthritis. Belatacept selectively blocks the process of T-cell activation. It was developed by Bristol-Myers-Squibb. It differs from abatacept
(Orencia) by only 2 amino acids. FDA approved on June 15, 2011.Slide3
INDICATION For
prophylaxis of organ rejection. It is also used concomitantly with basiliximumab for induction therapy, mycophenolate
, and corticosteriods in kidney transplant recepients that are seropositive for the Epstein-Barr virusPHARMACODYNAMICS Belatacept binds to CD86 with a 4-fold higher affinity than
abatacept. It also binds to CD80 with a 2-fold higher affinity than abatacept. It was observed in non-human primates that belatacept
prolongs graft survival due to a decrease in antibody production against the donor organ. Furthermore,
belatacept
also inhibits the primary humoral immune response which is indicated by the decrease in post-transplant levels of IgG, IgM, and IgA. The magnitude of this effect is more significant in
belatacept
than it is in cyclosporine. Slide4
MECHANISM OF ACTION
Belatacept is a fusion protein in which the Fc portion of human IgG1 is attached onto the extracellular portion of human CTLA-4 (CD152). Belatacept
specifically binds to CD80 and CD86 receptors that are found on the antigen-presenting cell (B cells, macrophages, dendritic cells) to block selective T-cell lymphocyte costimulation. CD80 and CD86 would normally act as the ligands to the CD28 receptor T-cells in which this interaction triggers the activation of T lymphocytes. However in the presence of belatacept, because the extracellular CTLA-4 component binds to CD28 with higher affinity than CD80 or CD86, T lymphyocyte anergy, a state of antigen specific tolerance, occurs instead. The T cell is also no longer able to respond to their antigen.
ABSORPTION Following multiple intravenous doses of an initial 10 mg/kg dose and followed by a maintenance dose of 5 mg/kg in kidney transplant recipients, these are the following pharmacokinetic parameters:
Cmax
, 10 mg/kg = 247 µg/mL;
Cmax
, 5 mg/kg = 139 µg/mL; AUC, 10 mg/kg = 22,252 µg · h/mL; AUC, 5 mg/kg = 14,090 µg · h/mL;
Belatacept
had linear and dose-dependent pharmacokinetic profile.Slide5
VOLUME OF DISTRIBUTION Vd
, steady state, transplant patients, 10 mg/kg = 0.11 L/kg;Vd, steady state, transplant patients, 5 mg/kg = 0.12 L/kg
METABOLISM The cytochrome P450 enzyme system or uridine diphosphate-glucuronosyltransferases are not expected to be involved with the metabolism of belatacept. Because the drug is a protein, belatacept is degraded into smaller peptides and amino acids by proteolytic enzymes.
HALF LIFE
Mean
terminal elimination half-life: 10 mg/kg, kidney transplant recipients= 9.8 days; 5 mg/kg, kidney transplant recipient = 8.2 days
CLEARANCE
Increased
body weight may increase the clearance rate of
belatacept
Mean systemic clearance:
10 mg/kg, kidney transplant recipients= 0.49 mL/h/kg;
5 mg/kg, kidney transplant recipient = 0.51 mL/h/kg.Slide6
DRUG INTERACTIONS
Belimumab Belimumab increases the immunosupressive
effect. Interaction is significant so monitor closely.Denosumab Montinor therapy due to enhanced adverse effects of immunosuppressants and the risk of infections.Leflunomide Consider therapy modification due to enhanced adverse effects of leflunomide, especially hematologic toxicities.Mycophenolate mofetil
Belatacept increases the Cmax and AUC of mycophenolate mofetil
.
Natalizumab
Avoid infection due to enhanced adverse effects of
natalizumab
and the risk of infections.
Pimecrolimus
Avoid combination due to enhanced effects of
immunosuppressants
.
Pralatrexate
Increased
immunosuppresive
effects and risk of infection. Monitor for adverse effects .
Rilonacept
Belatacept
decreases immunosuppressive effects while
rilonacept
increases immunosuppressive effects. Potential risk of infection although the effect of interaction is not known; use caution and monitor closely if using both.
Rilonacept
Belatacept
decreases immunosuppressive effects while
rilonacept
increases immunosuppressive effects. Potential risk of infection although the effect of interaction is not known; use caution and monitor closely if using both.
Rilonacept
Belatacept
decreases immunosuppressive effects while
rilonacept
increases immunosuppressive effects. Potential risk of infection although the effect of interaction is not known; use caution and monitor closely if using both.
Roflumilast
Consider modifying therapy due to enhanced immunosuppressive effect.
Sipuleucel
-T Monitor therapy due to
to
potential decrease in therapeutic effect of
sipuleucel
-t.
Tacrolimus
Avoid combination due to enhanced immunosuppressive effect.
Tofacitinib
Avoid combination due to enhanced immunosuppressive effect of
tofacitinib
.
Trastuzumab
Monitor therapy due to enhanced
neutropenic
effect of
immunosuppressants
. Slide7
Nulojix
DESCRIPTION
NULOJIX® (belatacept), a selective T-cell costimulation
blocker, is a soluble fusion protein consisting of the modified extracellular domain of CTLA-4 fused to a portion (hinge-CH2-CH3 domains) of the Fc domain of a human immunoglobulin G1 antibody. Belatacept
is produced by recombinant DNA technology in a mammalian cell expression system. Two amino acid substitutions (L104 to E; A29 to Y) were made in the
ligand
binding region of CTLA-4. As a result of these modifications,
belatacept
binds CD80 and CD86 more avidly than
abatacept
, the parent CTLA4-Immunoglobulin (CTLA4-Ig) molecule from which it is derived. The molecular weight of
belatacept
is approximately 90
kilodaltons.
Lyophilized powder for injection: 250 mg per vialSlide8
DOSAGE:
Initial dose: 10 mg/kg, intravenously, once daily, on day 1 (day of transplant, prior to implantation) and day 5, and at the end of weeks 2, 4, 8, and 12.
Maintenance dose: 5 mg/kg, intravenously, at the end of week 16 and every 4 weeks (plus or minus 3 days) thereafter.VIAL Description:NULOJIX is supplied as a sterile, white or off-white lyophilized powder for intravenous administration. Prior to use, the
lyophile is reconstituted with a suitable fluid to obtain a clear to slightly opalescent, colorless to pale yellow solution, with a pH in the range of 7.2 to 7.8. Suitable fluids for constitution of the
lyophile
include SWFI, 0.9% NS, or D5W [see DOSAGE AND ADMINISTRATION]. Each 250 mg single-use vial of NULOJIX also contains: monobasic sodium phosphate (34.5 mg), sodium chloride (5.8 mg), and sucrose (500 mg).Slide9
CLEARANCE:
0.5 mL/h/kg
HALF LIFE: 8 to 10 daysADVERSE REACTION:Hives; difficult breathing; swelling of your face, lips, tongue, or throat.
DRUG INTERACTIONMycophenolate
Mofetil
(MMF)Slide10
PROTEIN SEQUENCE FOR BELATACEPT
MHVAQPAVVLASSRGIASFVCEYASPGKYTEVRVTVLRQADSQVTEVCAATYMMGNELTFLDDSICTGTSSGNQVNLTIQGLRAMDTGLYICKVELMYPPPYYEGIGNGTQIYVIDPEPC
PDSDQEPKSSDKTHTSPPSPAPELLGGSSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKSlide11
REFERENCES
Yabu
JM, Vincenti F: Novel immunosuppression: small molecules and biologics. Semin Nephrol. 2007 Jul;27(4):479-86Tedesco Silva H Jr, Pinheiro
Machado P, Rosso Felipe C, Medina Pestana JO: Immunotherapy for De Novo renal transplantation: what’s in the pipeline? Drugs. 2006;66(13):1665-84
Wekerle
T,
Grinyo
JM:
Belatacept
: from rational design to clinical application.
Transpl
Int. 2012 Feb;25(2):139-50.
doi
: 10.1111/j.1432-2277.2011.01386.×. Epub 2011 Dec 7 Garnock-Jones KP: Belatacept: in adult kidney transplant recipients. BioDrugs
. 2012 Dec 1;26(6):
413-24
Garnock
-Jones KP:
Belatacept
: in adult kidney transplant recipients.
BioDrugs
. 2012 Dec 1;26(6):
413-24
http
://www.ncbi.nlm.nih.gov/pubmed/22651565
http://www.ncbi.nlm.nih.gov/pubmed/22173428