Effects of diltiazem on the pharmacokinetics and pharmacodynamics of methylprednisolone in healthy volunteers

The effect of diltiazem (Dilt) on the pharmacokinetics (PK) and pharmacodynamics (PD) of methylprednisolone (MP) was studied in five healthy men. Subjects received a single IV dose of MP (0.3 mg/kg) on day 1; 180 mg oral dose of SR Dilt daily on days 3-7; and both drugs concomitantly on day 8. Plasma MP concentrations were assayed by HPLC and assessed by compartmental fitting using WinNonlin. PD response-time profiles for plasma cortisol concentrations (by HPLC) and CD4, CD8 lymphocyte cell counts (by FACS and hemocytometry) were evaluated by basic and extended indirect response models using ADAPT II. The mean (±SD) parameter estimates are presented in the following table (*p<0.05): T_1/2 CL Cortisol IC₅₀ CD4 IC₅₀ CD8 IC₅₀ (hr)*(L/hr)*(ng/mL) (ng/mL) (ng/mL) MP 2.28±0.37 25.2±4.84 0.45±0.44 9.2±3.4 18.5±11.8 MP+Dilt 3.12±0.40 16.8±2.14 0.78±0.77 10.7±2.9 20.9±14.9 Dilt decreased MP CL by -33%, resulting in a longer T_1/2 and greater exposure of MP shown by a higher AUC in all five men. However no adrenal suppression or lymphocyte trafficking pharmacodynamic interaction seems to occur between the two com-pounds in healthy male subjects.