Lessons from prednisolone day curves in adrenal insufficiency: Can we tailor anti-inflammatory steroid treatment based on serum prednisolone levels?
Y Tsitsiou1, S Choudhury1,2, K Meeran1,2, R Gore3, 1Department of Endocrinology, Charing Cross Hospital, Imperial College Healthcare NHS Trust, 2Endocrinology and Investigative Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London, 3Respiratory Medicine, Addenbrooke’s Hospital, Cambridge University Hospitals NHS Foundation Trust
Background: The recent BTS/SIGN 2019 guidelines for the diagnosis and management of asthma continue to advocate a step-wise approach to treatment. In patients with difficult asthma, that cannot be managed by maximal inhaler therapy and leukotriene receptor antagonists, oral glucocorticoid therapy with prednisolone may be necessary.
With greater past-year and lifetime cumulative exposure to glucocorticoids, individuals face an increasing risk of mortality and risk of developing iatrogenic adrenal insufficiency or Cushing’s syndrome. As such, respiratory physicians managing difficult asthma will use the lowest possible dose of oral prednisolone to manage the condition and will consider biologics (anti-IgE antibody or anti-IL5 antibody treatment), if prolonged or frequent courses are required.
Case history: Patient (A), a 49-year-old female patient with difficult asthma is under the care of the respiratory physicians. Despite maximal treatment, her asthma remains poorly controlled... A dose of prednisolone of 20mg was insufficient to suppress markers of type-2 inflammation or control symptoms. Currently, she is only responding to 40mg Depo-Medrone (methyl-prednisolone), administered IM fortnightly.
In order to investigate why 20mg of prednisolone is insufficient, but 40mg of Depo-Medrone is effective, a prednisolone day curve was undertaken.
Results: Patient (A)’s prednisolone day curve data is available below. The maximum concentration (Cmax) achieved on 20mg prednisolone was 222 μg/L and the area-under-the-curve (AUC) was 1152 μg.h/L. The terminal half-life was 3.85h.
This was compared to data held on Patient (B), who had a historic day curve on 15mg prednisolone (day curve profile below). The Cmax for this patient was: 344 μg/L, with an AUC of 1969 μg.h/L. The terminal half-life was 3.38h.
Further historic data from 6 patients (with a total of 10 prednisolone day curves) receiving a mean prednisolone dose of 7.9mg (SD-4.4mg), showed a statistically significant positive correlation between dose and maximum serum concentration with coefficient r=0.788 (p=0.007) and also between dose and AUC with r=0.918 (p<0.001). Thus, both Cmax and AUC increased in a dose-dependent pattern. Mean terminal half-life of prednisolone was 3.73h (SD=0.64). Mean Cmax and AUC was 279.8 μg/L (SD- 98.7 μg/L) and 1430.1 μg.h/L (SD-542.7 μg.h/L) respectively. We now use 8-hour levels to guide glucocorticoid replacement therapy, and the target 8-hour level for those on 2mg to 5mg is 15 μg/L-25 μg/L. In the historic patients, the mean 8-hour level was 82.5 μg/L (SD- 35.3 μg/L), and the 8-hour level for Patient B was 109.2 μg/L while the 8-hour level for Patient A on 20mg was only 66.0 μg/L.
Conclusions: The terminal prednisolone half-life in Patient (A) is comparable to Patient (B) and the pooled patient data. This indicates normal prednisolone elimination in Patient (A). There is however, a lower Cmax and AUC when compared to patients taking lower doses of prednisolone, suggesting increased first pass metabolism of the tablets. Given that the patient responded to IM glucocorticoids, it is likely that the patient has an altered first pass metabolism, and that there is increased liver cytochrome activity which is bypassed by parenteral steroid administration. The respiratory team were advised to review the patient’s other medication, with a view to rationalising any liver enzyme inducers.
This case demonstrates the utility of prednisolone day curves in patients using anti-inflammatory doses of prednisolone. In this case, there was scope to escalate the patient’s prednisolone dose without concern of unnecessarily increasing steroid exposure. A better profile of the patient could have been generated with quantification of cortisol binding globulin, and urinary steroids. In type-2-high asthma, steroid doses should be titrated to anti-inflammatory markers and biologic therapies used for patients on ≥ 5mg prednisolone / day. This work shows that, with more data, greater confidence about prednisolone dosing can be obtained by investigating absorption, in those patients where there is disparity between the clinical effects of oral and injectable steroids.