Pharmacokinetic/pharmacodynamic model for prednisolone inhibition of whole blood lymphocyte proliferation

Abstract

Aims Mitogen-induced ex vivo whole blood lymphocyte proliferation (WBLP) is a widely used method to assess lymphocyte responsiveness to immunosuppressive therapy. A three-component complex model was developed to characterize effects of prednisolone on cell trafficking, transduction, and lymphocyte suppression. Methods An oral dose (0.27 mg kg⁻¹) of prednisone was given to 32 subjects. The study consisted of baseline and prednisone phases each with 32 h of sampling. Measurements included plasma prednisolone concentrations, in vitro and ex vivo WBLP, and lymphocyte cell counts during baseline and prednisone phases. Results The final model consists of a precursor-dependent indirect response model with a first-order periodic influx rate for lymphocyte trafficking. This accounts for the rebound phenomenon and the circadian rhythm seen in all individual ex vivo WBLP effect-time profiles. Prednisolone was modelled as inhibiting lymphocyte influx from the precursor to the blood pools. The direct suppressive effect of prednisolone on WBLP was modelled with the simple Imax model. A transduction step with rate constant k_t was introduced to the simple Imax model to account for the delay (∼4 h) in reaching the maximum inhibition. The IC₅₀ values obtained ex vivo were circa 10 times lower than in vitro values (3.76 vs 38.8 ng ml⁻¹), suggesting additional in vivo factors may have enhanced lymphocyte response to the inhibitory effect of prednisolone. Conclusions This integrated PK/PD model enables evaluation of multicomponent direct and indirect inhibition of ex vivo WBLP by steroids and other immunosuppressants in relation to sex and race.