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.