Animal pharmacokinetics of the tumor necrosis factor receptor-immunoglobulin fusion protein lenercept and their extrapolation to humans

The pharmacokinetics of the tumor necrosis factor receptor-immunoglobulin f usion protein, lenercept, were assessed in rats, rabbits, dogs and cynomolg us monkeys. Pharmacokinetic parameters were extrapolated to humans by allom etric scaling. Lenercept was dosed i,v. at doses ranging from 0.1 to 5 mg/k g, Consistent with its all-human sequence, lenercept elicits an immune resp onse in laboratory animals usually 6 to 10 days after dosing. The resulting period of more rapid clearance caused by the immune response was excluded from the pharmacokinetic evaluation. Lenercept showed a very low and simila r clearance in all species tested (0.0071-0.0097 ml . min/kg). The volume o f distribution was estimated at values between 61 and 90 ml/kg, whereas the terminal half-life ranged from 3.4 days in rabbits to 6.5 days in rats. Th us, lenercept was characterized by similar pharmacokinetic properties acros s species, irrespective of their particular body weight. Accordingly, both clearance (ml/min) and volume of distribution (ml) seated with an allometri c exponent close to 1, whereas half-lives (including literature data in mic e) yielded an allometric exponent close to 0. The predicted parameters in h umans agree well with the observed values. Overall, the results demonstrate an allometric scaling for lenercept different from that for other therapeu tic proteins, in that lenercept displays a similar pharmacokinetic behavior across species. Despite an early and pronounced immune response against th is ail-human protein in laboratory animals, the pharmacokinetic data were f ound to be predictive for humans, given that the more rapid immune-modulate d clearance component in animals could be identified and excluded from the pharmacokinetic evaluation.