{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,23]],"date-time":"2026-01-23T08:49:30Z","timestamp":1769158170853,"version":"3.49.0"},"reference-count":40,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2004,10,27]],"date-time":"2004-10-27T00:00:00Z","timestamp":1098835200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brit J Clinical Pharma"],"published-print":{"date-parts":[[2004,12]]},"abstract":"<jats:sec><jats:title>Aims<\/jats:title><jats:p>Ibandronate, a highly potent nitrogen\u2010containing bisphosphonate, is the subject of an ongoing clinical development programme that aims to maximize the potential of simplified, less frequent oral and intravenous (i.v.) administration in osteoporosis. A modelling and simulation project was undertaken to characterize further the clinical pharmacology of ibandronate and identify convenient intermittent oral and i.v. regimens for clinical evaluation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods and results<\/jats:title><jats:p>Using selected data from clinical studies involving 174 women with postmenopausal osteoporosis (PMO), a classical multicompartmental pharmacokinetic\u2010pharmacodynamic (PK\u2010PD) model was developed that accurately described the PK of i.v. ibandronate in plasma and urine and urinary excretion of the C\u2010telopeptide of the \u03b1 chain of type I collagen (uCTX), a sensitive biomarker of PD response to ibandronate. To reduce processing times, the classical PK\u2010PD model was simplified using a \u2019kinetics of drug action\u2019 or kinetic (K)\u2010PD model (i.e. a dose\u2010response model as opposed to a dose\u2010concentration\u2010response model). The performance of the K\u2010PD model was evaluated by fitting data simulated with the PK\u2010PD model under various dosing regimens. The simplified model produced a virtually indistinguishable fit of the data from that of the PK\u2010PD model. The K\u2010PD model was extended to consider the influence of supplemental therapy (calcium with or without vitamin D) on the PD response and validated by retrospectively simulating the uCTX response in a prior Phase III and Phase II\/III study of i.v. ibandronate, given once every 3\u2003months, in 3380 women with PMO. The observed median uCTX responses at the scheduled assessment points in the completed studies were within the distribution of the simulated responses. The K\u2010PD model for i.v. ibandronate was extended further to allow simultaneous fitting of uCTX responses after i.v. and oral administration in 676 postmenopausal women with osteoporosis, and validated by retrospectively simulating the data observed in a Phase I study of oral daily ibandronate in 180 women with PMO. The K\u2010PD model adequately described the uCTX response after oral dosing.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>This validated K\u2010PD model is currently being used to evaluate a range of novel intermittent oral and i.v. ibandronate regimens in an ongoing clinical development programme.<\/jats:p><\/jats:sec>","DOI":"10.1111\/j.1365-2125.2004.02224.x","type":"journal-article","created":{"date-parts":[[2004,11,24]],"date-time":"2004-11-24T14:05:03Z","timestamp":1101305103000},"page":"618-631","source":"Crossref","is-referenced-by-count":69,"title":["A semimechanistic and mechanistic population PK\u2013PD model for biomarker response to ibandronate, a new bisphosphonate for the treatment of 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