Pharmacokinetic/pharmacodynamic modeling of antipyretic and anti-inflammatory effects of naproxen in the rat.

Pharmacokinetic/pharmacodynamic modeling was used to characterize the antipyretic and anti-inflammatory effects of naproxen in rats. An indirect response model was used to describe the antipyretic effects of naproxen after short intravenous infusions. The model assumes that basal temperature (T(a)) is maintained by the balance of fever mediators given by a constant (zero order) rate of synthesis (K(syn)), and a first order rate of degradation (K(out)). After an intraperitoneal injection of lipopolysaccharide, the change in T(a) was modeled assuming an increase in fever mediators described as an input rate function [IR(t)] estimated nonparametrically. An inhibitory E(max) model adequately described the inhibition of IR(t) by naproxen. A more complex model was used to describe the anti-inflammatory response of oral naproxen in the carrageenin-induced edema model. Before carrageenin injection, physiological conditions are maintained by a balance of inflammation mediators given by K(syn) and K(out) (see above). After carrageenin injection, the additional synthesis of mediators is described by IR(t) (see above). Such mediators induced an inflammatory process, which is governed by a first order rate constant (K(IN)) that can be inhibited by the presence of naproxen in plasma. The sigmoidal E(max) model also well described the inhibition of K(IN) by naproxen. Estimates for IC(50) [concentration of naproxen in plasma eliciting half of maximum inhibition of IR(t) or K(IN)] were 4.24 and 4.13 microg/ml, for the antipyretic and anti-inflammatory effects, respectively.

Bioavailability of two oral formulations of cyclosporin A in uremic children before renal transplantation.

The bioavailability of two oral formulations of cyclosporin A (Sandimmun and Neoral) was assessed in 10 children with end-stage renal disease (ESRD), while at a steady state on a dialytic procedure. The study was performed according to a randomized, double blind, cross-over design, allowing a 1-month washout period between studies. Each patient received 2.5 mg/microg of oral cyclosporin A every 12 h, either Sandimmun (SAN) or Neoral (NEO). Serum concentrations of cyclosporin A were determined serially during a 24 h period, after the 5th dose of cylosporin. Serum concentrations against time curves were constructed and bioavailability of both medications, expressed as AUC and Cmax, were compared. A statistically significant increase was observed in the AUC and Cmax of NEO, which were 90% and 130% higher, respectively, than those of SAN. Considering that the internationally accepted criteria for bioequivalence allows a 20% variation in AUC and Cmax, it appears that Neoral and Sandimmun do not bear bioequivalence in children with ESRD. Notwithstanding, there were no significant differences in trough levels between both formulations. We conclude that, if trough levels are the only source of information for dosing design, Neoral could be substituted for Sandimmun on a 1:1 basis. However, a 1:1 drug substitution is not suitable when AUC is used in children with ESRD.