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

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Abstract
Aims Mitogen‐inducedex vivowhole 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 vitroandex vivoWBLP, 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 individualex vivoWBLP 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 constantktwas introduced to the simple Imax model to account for the delay (∼4 h) in reaching the maximum inhibition. The IC50values obtainedex vivowerecirca10 times lower thanin vitrovalues (3.76vs38.8 ng ml−1), suggesting additionalin vivofactors 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 ofex vivoWBLP by steroids and other immunosuppressants in relation to sex and race.

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