{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T04:40:06Z","timestamp":1779165606639,"version":"3.51.4"},"reference-count":54,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2020,7,26]],"date-time":"2020-07-26T00:00:00Z","timestamp":1595721600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009210","name":"Food and Drug Administration","doi-asserted-by":"publisher","award":["R01FDR0006100"],"award-info":[{"award-number":["R01FDR0006100"]}],"id":[{"id":"10.13039\/100009210","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brit J Clinical Pharma"],"published-print":{"date-parts":[[2021,3]]},"abstract":"<jats:sec><jats:title>Aims<\/jats:title><jats:p>The aim of this study was to characterize the pharmacokinetic\/pharmacodynamic relationships of cortisol and the adrenal biomarkers 17\u2010hydroxyprogesterone and androstenedione in children with congenital adrenal hyperplasia (CAH).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>A nonlinear mixed\u2010effect modelling approach was used to analyse cortisol, 17\u2010hydroxyprogesterone and androstenedione concentrations obtained over 6 hours from children with CAH (<jats:italic>n<\/jats:italic> = 50). A circadian rhythm was evident and the model leveraged literature information on circadian rhythm in untreated children with CAH. Indirect response models were applied in which cortisol inhibited the production rate of all three compounds using an <jats:italic>I<\/jats:italic><jats:sub>max<\/jats:sub> model.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Cortisol was characterized by a one\u2010compartment model with apparent clearance and volume of distribution estimated at 22.9 L\/h\/70 kg and 41.1 L\/70 kg, respectively. The IC<jats:sub>50<\/jats:sub> values of cortisol concentrations for cortisol, 17\u2010hydroxyprogesterone and androstenedione were estimated to be 1.36, 0.45 and 0.75 \u03bcg\/dL, respectively. The inhibitory effect was found to be more potent on 17OHP than D4A, and the IC<jats:sub>50<\/jats:sub> values were higher in salt\u2010wasting subjects than simple virilizers. Production rates of cortisol, 17\u2010hydroxyprogesterone and androstenedione were higher in simple\u2010virilizer subjects. Half\u2010lives of cortisol, 17\u2010hydroxyprogesterone and androstenedione were 60, 47 and 77 minutes, respectively.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Rapidly changing biomarker responses to cortisol concentrations highlight that single measurements provide volatile information about a child's disease control. Our model closely captured observed cortisol, 17\u2010hydroxyprogesterone and androstenedione concentrations. It can be used to predict concentrations over 24 hours and allows many novel exposure metrics to be calculated, e.g., AUC, AUC\u2010above\u2010threshold, time\u2010within\u2010range, etc. Our long\u2010range goal is to uncover dose\u2013exposure\u2013outcome relationships that clinicians can use in adjusting hydrocortisone dose and timing.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bcp.14470","type":"journal-article","created":{"date-parts":[[2020,7,11]],"date-time":"2020-07-11T21:38:09Z","timestamp":1594503489000},"page":"1098-1110","source":"Crossref","is-referenced-by-count":25,"title":["An integrated PK\u2010PD model for cortisol and the 17\u2010hydroxyprogesterone and androstenedione biomarkers in children with congenital adrenal hyperplasia"],"prefix":"10.1111","volume":"87","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5458-0712","authenticated-orcid":false,"given":"Mahmoud","family":"Al\u2010Kofahi","sequence":"first","affiliation":[{"name":"Department of Experimental and 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