Baseline is rhythmic and it moves. Cortisol has a pronounced diurnal pattern, so a constant baseline cannot describe a 24-hour profile [1]; a time-varying production rate is the usual remedy [2]. Baseline also falls during treatment and recovers slowly after withdrawal [3,4], which is one reason long courses are tapered [5].
Duration matters separately from intensity. Fracture risk tracks current daily dose, and adrenal suppression rises with dose and treatment duration [6,7]. An analysis carrying only average concentration misses the duration-dependent toxicities.
Cumulative exposure is a poor fix. A single cumulative-exposure term is a poor fix: it forces duration and intensity to be interchangeable, and can manufacture an apparent exposure-response even when intensity carries no signal at all.
References
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Chakraborty A, Krzyzanski W, Jusko WJ. Mathematical modeling of circadian cortisol concentrations using indirect response models: Comparison of several methods. Journal of Pharmacokinetics and Biopharmaceutics 1999;27:23–43.
https://doi.org/10.1023/A:1020678628317.
[2]
Ayyar VS, Krzyzanski W, Jusko WJ. Indirect pharmacodynamic models for responses with circadian removal. Journal of Pharmacokinetics and Pharmacodynamics 2019;46:89–101.
https://doi.org/10.1007/s10928-019-09620-z.
[3]
Baker EH. Is there a safe and effective way to wean patients off long-term glucocorticoids? British Journal of Clinical Pharmacology 2021;87:12–22.
https://doi.org/10.1111/bcp.14679.
[4]
Krzyzanski W, Milad MA, Jobe AH, Peppard T, Bies RR, Jusko WJ. Population pharmacodynamic modeling of intramuscular and oral dexamethasone and betamethasone effects on six biomarkers with circadian complexities in indian women. Journal of Pharmacokinetics and Pharmacodynamics 2021.
https://doi.org/10.1007/s10928-021-09755-y.
[5]
Burmester GR, Buttgereit F, Bernasconi C, Alvaro-Gracia JM, Castro N, Dougados M, et al. Continuing versus tapering glucocorticoids after achievement of low disease activity or remission in rheumatoid arthritis (SEMIRA): A double-blind, multicentre, randomised controlled trial. The Lancet 2020;396:267–76.
https://doi.org/10.1016/s0140-6736(20)30636-x.
[6]
Broersen LHA, Pereira AM, Jørgensen JOL, Dekkers OM. Adrenal insufficiency in corticosteroids use: Systematic review and meta-analysis. The Journal of Clinical Endocrinology & Metabolism 2015;100:2171–80.
https://doi.org/10.1210/jc.2015-1218.
[7]
Magee MH, Blum RA, Lates CD, Jusko WJ. Pharmacokinetic/pharmacodynamic model for prednisolone inhibition of whole blood lymphocyte proliferation. British Journal of Clinical Pharmacology 2002;53:474–84.
https://doi.org/10.1046/j.1365-2125.2002.01567.x.