Pharmacokinetic and pharmacodynamic interactions between diltiazem and methylprednisolone in healthy volunteers

The pharmacokinetics and pharmacodynamics after administration of methylprednisolone alone, diltiazem alone, and both drugs jointly were assessed in healthy volunteers.An unblinded, controlled, fixed-sequence, 2-period study was carried out in 5 healthy white men who received a single dose of intravenous methylprednisolone, 0.3 mg/kg, on day 2, followed by diltiazem alone, 180 mg, on days 5, 6, and 7, with joint dosing of both drugs on day 8. Methylprednisolone and diltiazem disposition was assessed from plasma concentrations. Pharmacodynamic factors were assessed by plasma cortisol and T-helper and T-suppressor lymphocytes by means of extended indirect response models.The clearance of methylprednisolone was significantly reduced in the presence of diltiazem (25.2 L/h versus 16.8 L/h), resulting in a longer half-life (2.28 hours versus 3.12 hours) and increased area under the plasma concentration-time curve (AUC) (871 ng x h/mL versus 1299 ng x h/mL). The AUC of diltiazem was unchanged in the presence of methylprednisolone. No significant intrinsic pharmacodynamic differences were observed for methylprednisolone versus methylprednisolone-diltiazem. The 50% inhibitory concentration values were 0.446 ng/mL versus 0.780 ng/mL for cortisol, 9.20 ng/mL versus 10.7 ng/mL for T-helper cells, and 18.5 ng/mL versus 20.9 ng/mL for T-suppressor cells (P >.05). Greater net suppression, as indicated by the area between the effect curve and suppression ratios, was observed for the methylprednisolone-diltiazem combination versus methylprednisolone alone, which was attributed to reduced elimination of methylprednisolone.Controlled-delivery diltiazem, 180 mg, significantly increased methylprednisolone AUC and half-life and reduced clearance, lending to greater systemic exposure to the steroid. However, significant differences between 50% inhibitory concentration values for methylprednisolone when given alone and for methylprednisolone in combination with diltiazem were not seen, which implies no change in cortisol or cell-trafficking sensitivity in the presence of diltiazem.