An integrated pharmacokinetic/pharmacodynamic (PK/PD) model for prednisolone inhibition of ex vivo whole blood lymphocyte proliferation

Purpose: 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) of prednisone was given to 32 subjects. The study consisted of baseline and prednisone phases with 32 hours sampling in each phase. Data analyzed included plasma prednisolone concentrations, in vitro and ex vivo WBLP, and lymphocyte cell counts during baseline and prednisone phases. Model discrimination was by Akaike's Information Criterion. Results: The final model consists of a precursor-dependent indirect response model with a first-order periodic influx rate for lymphocyte trafficking. This is to account for the rebound phenomenon and the circadian rhythm seen in all individual ex vivo WBLP effect-time profiles. Prednisolone was modeled as inhibiting lymphocyte influx from the precursor compartment to the blood compartment. The direct suppressive effect of prednisolone on WBLP was modeled with the sigmoid Imax model. A transduction step with rate constant kt was introduced to the sigmoid Imax model to account for the delay (∼4h) in reaching the maximum inhibition. The PK/PD modeling was performed piecewise using an iterative two-stage analysis. The IC₅₀ values obtained ex vivo were ∼six times lower than in vitro values (6.7 versus 38.8 ng/ml), suggesting an additional in vivo phenomenon may have enhanced lymphocyte response to the inhibitory effect of prednisolone. The transit time for transduction was estimated at about 2.3 hours. Conclusion: This integrated PK/PD model should enable evaluation of multi-component direct and indirect inhibition of ex vivo WBLP by steroids and other immunosuppressants.