Pharmacokinetics and pharmacodynamics of methylprednisolone after one bolus dose compared with two dose fractions

Summary Objective:  Although the elimination half‐life of most glucocorticoids is short, they are usually administered once daily, or even on alternate days. Our hypothesis was that this practice might compromise the immunosuppressive effect of those drugs during the second part of the administration interval. Methods:  Eight healthy male volunteers were randomly assigned to receive intravenous methylprednisolone either 32 mg in the morning, or 16 mg in the morning and 16 mg in the evening in a cross‐over design. Methylprednisolone concentrations were determined in plasma by high‐pressure liquid chromatography. The total number of CD3+ lymphocytes, and CD4+ and CD8+ T‐cell subpopulations was measured in blood. The suppression of these cells was used as a surrogate parameter for the immunosuppressive response, and expressed as reduction of the area under the effect time curve (AUETC). Possible adverse effects on blood pressure, glucose, insulin, and endogenous cortisol levels were monitored. Results:  There were no significant differences in methylprednisolone half‐life (2ḃ2 ± 0ḃ4 h), clearance (575 ± 113 mL/min), volume of distribution (106 ± 22 l), concentration producing the half‐maximum effect on CD4+ T‐cells (1ḃ5 ± 0ḃ7 ng/mL), and Hill‐coefficient (1ḃ2 ± 0ḃ1), after single or divided dose. However, the total 24 h effect area (AUETC) of lymphocytes, and mainly CD4+ T‐cells was significantly more suppressed ( P  = 0ḃ008) with the divided dosage regimen than after the single dose (8422 ± 2163 vs. 11 545 ± 3020 h cells/ μ L). The surrogate markers for adverse events were not different, except for cortisol. Conclusion:  Within a 24‐h interval, two dose fractions of methylprednisolone produce a stronger and more sustained immunosuppressive response than one single bolus dose.