| Corticosteroids have been the mainstay for treatment of various immune-related disorders. However, the prolonged use of corticosteroids or other immunosuppressants causes severe side-effects. Hence, current strategy for immunosuppressive therapy involves use of combination regimens which has non-overlapping side-effects, whose dual effects are synergistic or at least additive, enabling reduced individual doses in the joint regimen. Interleukin-10 (IL-10) is a cytokine possessing strong anti-inflammatory properties which holds promise for future use in the clinic. With its discovery, there was a need for examining its joint efficacy with another immunosuppressant. Prednisolone, a commonly used systemic corticosteroid was the choice in the joint regimen. We have addressed this important therapeutic area with the aid of various approaches that include use of cell cultures, whole animals, and in vivo human systems.;A wide range of pharmacodynamic endpoints were selected that correlate to actual therapeutic outcomes. These include ex vivo and in vitro lymphocyte proliferation, ex vivo and in vivo proinflammatory cytokine (such as TNF-alpha, IL-1beta and IFN-gamma) and nitric oxide (NO) production, cell trafficking, and endogenous cortisol concentrations. As part of the interaction study, we have also examined the possibility of pharmacokinetic interactions between IL-10 and prednisolone. Data analysis was performed with the use of extensive PD modeling and statistical tools. Innovative pharmacodynamic models based on indirect response models were developed to describe in vivo PD interactions.;There were no pharmacokinetic interactions between IL-10 and prednisolone in humans. Both IL-10 and prednisolone showed appreciable anti-inflammatory effects, causing significant degrees of suppression of lymphocyte proliferation, and downregulation of proinflammatory cytokines and NO production. Prednisolone suppresses adrenal function, while IL-10 elevates endogenous cortisol concentration significantly. This may be an added benefit to long-term immunosuppressive therapy for IL-10. Both agents cause significant changes in the trafficking of various leukocyte subsets. Based on pharmacodynamic interaction models, they usually act additively during joint administration with net responses that were similar to or greater than effects produced by the more strongly acting agent. Thus IL-10 and prednisolone can offer potentially favorable joint immunosuppression.;A unique PK model for subcutaneously administered macromolecules was developed that takes into account the physiological basis for absorption-rate limited disposition for macromolecules. Based on our model, we have proposed that upon SC dosing, macromolecules owing to their molecular size are taken up from the injection site into the lymphatic compartment and then transported into the systemic circulation by the slowly flowing lymphatic fluid resulting extended profiles of serum drug concentrations. We have concluded that when extended concentrations are desired, the preferred dosing route may be SC for therapeutic proteins.;Two new approaches were introduced for characterizing biorhythmic baselines in reference to endogenous cortisol concentrations: (i) A dual cosine function which describes the circadian cortisol secretion rate, (ii) A Fourier method that describes the baseline cortisol concentration by the Fourier series and develops the equations for endogenous cortisol secretion rate from predicted baseline cortisol concentration data. The circadian model based on Fourier method was found to be most accurate and provide unbiased estimate for baseline patterns. The Fourier method can be extended to other drug-induced changes in normal periodic rhythms.;These studies have thus characterized the interactions between two important immunosuppressive and antinflammatory agents and provided improved methods of modeling pharmacokinetic and pharmacodynamic properties and interactions of these drugs. |
