Dose - response relationship of bevacizumab in hereditary hemorrhagic telangiectasia.
Hereditary hemorrhagic telangiectasia (HHT), a genetic vascular disorder associated with epistaxis and hepatic shunts, is responsible for high-output cardiac failure in rare cases. Bevacizumab, which targets vascular endothelial growth factor, was shown to decrease both cardiac index (CI) and epistaxis duration in HHT patients with severe liver involvement. The relationship between its serum concentration and change in both CI and epistaxis duration was investigated to design the bevacizumab maintenance dosing regimen of future therapeutic studies. Twenty-five HHT patients with dyspnea and high CI were included in a prospective non-comparative study. They received bevacizumab at a dose of 5 mg/kg per infusion every 14 days for a total of 6 injections. The relationships between bevacizumab serum concentration and both CI and epistaxis duration were described using transit compartments and direct inhibition pharmacokinetic-pharmacodynamic models. The performances of different maintenance regimens were evaluated using simulation. Infusions every 3, 2 and one months were predicted to maintain 41%, 45% and 50% of patients with CI <4 L/min/m(2) at 24 months, respectively. The fraction of patients with <20 min epistaxis per month was predicted to be 34%, 43% and 60%, with infusion every 3, 2 or one months, respectively. Simulations of the effects of different maintenance dosing regimens predict that monthly 5 mg/kg infusions of bevacizumab should allow sustained control of both cardiac index and epistaxis.
a Université François-Rabelais de Tours ; CNRS, GICC UMR 7292; Tours , France.
Nicolas
N
Azzopardi
Sophie
S
Dupuis-Girod
David
D
Ternant
Anne-Emmanuelle
AE
Fargeton
Isabelle
I
Ginon
Frédéric
F
Faure
Evelyne
E
Decullier
Adeline
A
Roux
Marie-France
MF
Carette
Brigitte
B
Gilbert-Dussardier
Pierre-Yves
PY
Hatron
Pascal
P
Lacombe
Vanessa
V
Leguy-Seguin
Sophie
S
Rivière
Romain
R
Corre
Sabine
S
Bailly
Gilles
G
Paintaud
D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics; D000068258:Bevacizumab / Q000008:administration & dosage / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D011446:Prospective Studies; D013683:Telangiectasia, Hereditary Hemorrhagic / Q000097:blood* / Q000188:drug therapy*
D020533:Angiogenesis Inhibitors; D000068258:Bevacizumab
AUC, area under the concentration vs time curve; AVM, arterovenous malformations; CI, cardiac index; ELISA, enzyme-linked immunosorbent assay; HHT, hereditary hemorrhagic telangectasia; IIV, interindividual variability; IgG, immunoglobulin G; PK-PD, pharmacokinetic-pharmacodynamic; TGF-β, transforming growth factor β; TMDD, target-mediated drug disposition; VEGF, vascular endothelial growth factor; angiogenesis factors; angiogenic; antiangiogenesis agents; bevacizumab; dose-response relationship; hereditary hemorrhagic telangiectasia; pharmacokinetics