Prediction of clinical pharmacokinetic parameters of linezolid using animal data by allometric scaling: applicability for the development of novel oxazolidinones

Abstract

1. Allometric scaling has previously been used as an effective tool for the prediction of human pharmacokinetic data. The pharmacokinetic data for linezolid, a novel oxazolidinone to treat Gram-positive pathogens, in mice, rats and dogs were subjected to simple allometric scaling. Generated allometric equations for parameters such as clearance (CL), volume of distribution (V_ss) and elimination rate constant (K₁₀) were used to predict human pharmacokinetic parameters including elimination half-lives. In addition, the human plasma concentration–time curve was simulated using a one-compartmental model.

2. Application of simple allometry (Y = aW^b) for animal parameters such as CL, V_ss, and K₁₀ showed excellent allometric fit (r ≥ 0.98). The allometric equations for CL, V_ss, and K₁₀ were −0.5465W^0.6595, −0.1369W^0.9246, and −0.4117W^–0.3139, respectively. The confidence in predictability of CL and V_ss parameters was particularly high since the allometric exponents of CL and V_ss almost approached the suggested values of 0.75 and 1.00, respectively.

3. Animal pharmacokinetic parameters generated in the present authors’ laboratories for linezolid were in close agreement with reported literature values. The predicted human values for CL (4.68 l h⁻¹), V_ss (37.07 litres), and K₁₀ (0.10 h⁻¹) were within the range observed for linezolid in the literature (CL = 4−10.5 l h⁻¹; V_ss = 21 − 53 litres; K₁₀ = 0.09 − 0.3 h⁻¹). The human half-life (t_1/2) predicted using allometry (6.9 h) was similar to reported values in humans of 5 h. In summary, the retrospective analysis for linezolid suggests that allometric scaling can be used as a prospective tool for predicting human pharmacokinetic parameters of novel oxazolidinones.