Based upon these considerations, it has been suggested that varying the timing of glucocorticoid administration to coincide better with circadian rhythms could help improve therapy for RA.20 The scientific basis for this hypothesis is provided by the following three key points:
- Pain, fatigue, morning stiffness, and immobility are common symptoms affecting patient quality of life and the ability to stay gainfully employed.21
- The overnight rise in IL-6 and other proinflammatory cytokines is thought to initiate a cascade of events resulting in these symptoms.
- Preventing the nocturnal rise of IL-6 and other proinflammatory cytokines should be more effective than treating established symptoms. From this point of view, the conventional administration of glucocorticoids between 6 a.m. and 8 a.m. may not be optimal, because it is too late to target the effects of nocturnal proinflammatory stimuli (see Figure 1A).
Although administering a standard glucocorticoid drug prior to the rise of cytokine synthesis and inflammatory activity could theoretically enhance efficacy, in practical terms, this approach would necessitate having the patient wake up during the night to take the drug, because conventional glucocorticoids have only a short half-life. Evidence that timing of exogenous glucocorticoid administration can improve treatment benefits was provided by Arvidson and co-workers in a study in the late 1990s. This study showed that low doses of prednisolone taken at 2 a.m. had more effect on morning symptoms of RA than achieved by the equivalent dose taken at 7:30 a.m. (see Figure 1B).17 However, having patients awake each night at about 2 a.m. is clearly not a feasible long-term treatment option. Therefore, a MR prednisone tablet was developed to enable prednisone chronotherapy for RA, in which the delivery of treatment is coordinated with biological rhythms (see Figure 1B). This new tablet releases prednisone approximately four hours after ingestion, (i.e., at approximately 2 a.m. if taken at bedtime) as indicated in Table 1. The MR prednisone is in a tablet-in-tablet dosage form, consisting of an immediate-release prednisone core tablet surrounded by an inactive outer tablet shell (see Figure 2). Prednisone release is triggered by penetration of gastrointestinal fluid into the tablet shell and is independent of the gastrointestinal milieu (like pH). The tablet strengths of 1, 2, and 5 mg are distinguished from one another by both color and debossing.
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FIGURE 2: Cross-sectional diagram of the MR prednisone tablet-in-tablet.
The efficacy and safety of this novel medication was investigated in a three-month, double-blind, double-dummy, randomized controlled clinical study (Circadian Administration of Prednisone in Rheumatoid Arthritis, also known as the CAPRA-1 study). In total, 288 patients who had active RA and were already receiving chronic prednisone therapy were randomized to receive their current dose (2.5–10 mg prednisone per day) either as MR prednisone administered at approximately 10 p.m. or as conventional immediate-release (IR) prednisone administered in the morning. All patients continued on their background therapy with disease-modifying antirheumatic drugs (DMARDs) and nonsteroidal antiinflammatory drugs (NSAIDs).13 In this study, the new formulation was shown to be clinically superior to the conventional IR preparation with respect to reducing morning joint stiffness, which was the primary endpoint of this study (see Figure 1B). IL-6 serum concentrations also were significantly decreased by MR prednisone after three months of treatment but remained unchanged by IR prednisone. The safety profile did not show differences between the two preparations.13
