Titre du document / Document title

Pharmacoimmunodynamic interactions of interleukin-10 and prednisone in healthy volunteers

Auteur(s) / Author(s)

CHAKRABORTY A. ; BLUM R. A. ; CUTLER D. L. ; JUSKO W. J. ;

Affiliation(s) du ou des auteurs / Author(s) Affiliation(s)

Department of Pharmaceutics, School of Pharmacy, State University of New York at Buffalo, and the Clinical Pharmacokinetics Laboratory, Millard Fillmore Hospital, Buffalo, ETATS-UNIS
Schering-Plough Research Institute, Kenilworth, ETATS-UNIS

Résumé / Abstract

Objective: The pharmacoimmunodynamic interactions of recombinant human interleukin-10 and prednisolone were examined in 12 normal male volunteers. Methods: Single doses of interleukin-10 (8 μg/kg subcutaneous injection), interleukin-10 with prednisone (15 mg by mouth), placebo with prednisone, or placebo were administered. Drug concentrations yielded pharmacokinetic parameters. Response measurements included whole blood lipopolysaccharide-stimulated cytokine (tumor necrosis factor-α, interleukin-1β) production, phytohemagglutinin-stimulated whole blood lymphocyte proliferation, and differential white blood cell counts (including monocytes, lymphocytes, and neutrophils). Extended indirect-response models were used to deal with diverse drug interactions in assessing single and joint effects of interleukin-10 and prednisolone. Results: No pharmacokinetic alterations in interleukin- 10 or prednisolone were found. Dosing with interleukin-10 produced strong inhibition of ex vivo cytokine production for the 24-hour postdosing period, whereas prednisolone, the active form of prednisone, was partly inhibitory for only 3 hours. Prednisolone significantly inhibited (P <.05) ex vivo lymphocyte proliferation for 6 hours, whereas interleukin-10 failed to alter this measure. Their joint effects on these responses were inhibitory consonant with the stronger agent. Marked changes in various leukocyte kinetics occurred. The steroid caused monocytopenia, lymphocytopenia, and neutrophilia, with IC₅₀ or SC₅₀ values of 10 to 20 ng/mL. Interleukin-10 elevated monocytes and neutrophils and lowered lymphocyte counts, with IC₅₀ or SC₅₀ values of 0.7 to 1.3 ng/mL. Dynamic modeling showed loss of prednisolone effects on monocytes and additive steroid/interleukin- 10 effects on lymphocytes and neutrophils, with neutrophils exhibiting greater changes in net response. Conclusion: Interleukin-10 and prednisolone interacted favorably for the measured pharmacoimmunodynamic indices with no kinetic alterations but net responses that were similar to or greater than effects produced by the more strongly acting agent.

Revue / Journal Title

Clinical pharmacology and therapeutics   ISSN 0009-9236   CODEN CLPTAT 

Source / Source

1999, vol. 65, n^o3, pp. 304-318 (40 ref.)

Langue / Language

Anglais

Editeur / Publisher

Nature Publishing, New York, NY, ETATS-UNIS  (1960) (Revue)

Mots-clés anglais / English Keywords

Prednisone ; Interleukin 10 ; Adrenal hormone ; Antiinflammatory agent ; Immunosuppressive agent ; Recombinant protein ; Drug combination ; Drug interaction ; Biological effect ; Human ; Healthy subject ; Modeling ; Mathematical model ; Pharmacokinetics ; Corticosteroid ;

Mots-clés français / French Keywords

Prednisone ; Interleukine 10 ; Hormone surrénalienne ; Antiinflammatoire ; Immunodépresseur ; Protéine recombinante ; Association médicamenteuse ; Interaction médicamenteuse ; Effet biologique ; Homme ; Individu sain ; Modélisation ; Modèle mathématique ; Pharmacocinétique ; Corticostéroïde ;

Mots-clés espagnols / Spanish Keywords

Prednisona ; Interleuquina 10 ; Hormona suprarrenal ; Antiinflamatorio ; Inmunodepresor ; Proteína recombinante ; Asociación medicamentosa ; Interacción medicamentosa ; Efecto biológico ; Hombre ; Individuo sano ; Modelización ; Modelo matemático ; Farmacocinética ; Corticoesteroide ;

Localisation / Location

INIST-CNRS, Cote INIST : 1144, 35400007485122.0090