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

The pharmacokinetics of the tumor necrosis factor receptorimmunoglobulin fusion protein, lenercept, were assessed in rats, rabbits, dogs and cynomolgus monkeys. Pharmacokinetic parameters were extrapolated to humans by allometric scaling. Lenercept was dosed i.v. at doses ranging from 0.1 to 5 mg/kg. Consistent with its all-human sequence, lenercept elicits an immune response 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 similar clearance in all species tested (0. 0071-0.0097 ml.min/kg). The volume of 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. Thus, lenercept was characterized by similar pharmacokinetic properties across species, irrespective of their particular body weight. Accordingly, both clearance (ml/min) and volume of distribution (ml) scaled with an allometric exponent close to 1, whereas half-lives (including literature data in mice) yielded an allometric exponent close to 0. The predicted parameters in humans agree well with the observed values. Overall, the results demonstrate an allometric scaling for lenercept different from that for other therapeutic proteins, in that lenercept displays a similar pharmacokinetic behavior across species. Despite an early and pronounced immune response against this all-human protein in laboratory animals, the pharmacokinetic data were found to be predictive for humans, given that the more rapid immune-modulated clearance component in animals could be identified and excluded from the pharmacokinetic evaluation.