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Erschienen in: Clinical Pharmacokinetics 3/2015

01.03.2015 | Original Research Article

Application of Modeling and Simulation to a Long-Term Clinical Trial: A Direct Comparison of Simulated Data and Data Actually Observed in Japanese Osteoporosis Patients Following 3-Year Ibandronate Treatment

verfasst von: Kiyohiko Nakai, Satofumi Iida, Masato Tobinai, Junko Hashimoto, Takehiko Kawanishi

Erschienen in: Clinical Pharmacokinetics | Ausgabe 3/2015

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Abstract

Ibandronate, a nitrogen-containing bisphosphonate, is a bone resorption inhibitor widely used to prevent and treat osteoporosis. To optimize the design for a long-term clinical study of ibandronate, modeling and simulation (M&S) was performed based on the result of population pharmacodynamic analysis using the data of a short-term clinical study. A population pharmacodynamic model was constructed by the urinary C-terminal telopeptide of type I collagen (uCTx) and the lumbar spine bone mineral density (BMD) data obtained in clinical studies, including a phase II study of Japanese osteoporosis patients treated with ibandronate for 6 months. Changes in BMD over a period of 3 years were simulated from the population pharmacodynamic parameters of the patients in this phase II study. The relationship between uCTx and BMD was well described by this modeling. The functions of disease progression and supplemental treatment were incorporated into the model to simulate a long-term clinical study with high accuracy. A long-term clinical study with a 3-year treatment was conducted after this M&S. The percentage change from baseline in observed BMD values were found to be similar to the prospectively simulated values. This study showed that M&S could be a useful and powerful tool for designing and conducting long-term clinical studies when carried out in the following sequence: (1) conduct a short-term clinical study; (2) perform M&S; and (3) conduct the long-term clinical study. Application of this procedure to various other treatment agents will establish the usefulness of M&S for long-term clinical studies and bring further efficiencies to drug development.
Literatur
1.
Zurück zum Zitat Dunford JE, Thompson K, Coxon FP, Luckman SP, Hahn FM, Poulter CD, Ebetino FH, Rogers MJ. Structure-activity relationships for inhibition of farnesyl diphosphate synthase in vitro and inhibition of bone resorption in vivo by nitrogen-containing bisphosphonates. J Pharmacol Exp Ther. 2001;296:235–42.PubMed Dunford JE, Thompson K, Coxon FP, Luckman SP, Hahn FM, Poulter CD, Ebetino FH, Rogers MJ. Structure-activity relationships for inhibition of farnesyl diphosphate synthase in vitro and inhibition of bone resorption in vivo by nitrogen-containing bisphosphonates. J Pharmacol Exp Ther. 2001;296:235–42.PubMed
2.
Zurück zum Zitat Eisman JA, Civitelli R, Adami S, Czerwinski E, Recknor C, Prince R, Reginster JY, Zaidi M, Felsenberg D, Hughes C, Mairon N, Masanauskaite D, Reid DM, Delmas PD, Recker RR. Efficacy and tolerability of intravenous ibandronate injections in postmenopausal osteoporosis: 2-year results from the DIVA study. J Rheumatol. 2008;35:488–97.PubMed Eisman JA, Civitelli R, Adami S, Czerwinski E, Recknor C, Prince R, Reginster JY, Zaidi M, Felsenberg D, Hughes C, Mairon N, Masanauskaite D, Reid DM, Delmas PD, Recker RR. Efficacy and tolerability of intravenous ibandronate injections in postmenopausal osteoporosis: 2-year results from the DIVA study. J Rheumatol. 2008;35:488–97.PubMed
3.
Zurück zum Zitat Recker RR, Ste-Marie LG, Langdahl B, Czerwinski E, Bonvoisin B, Masanauskaite D, Rowell L, Felsenberg D. Effects of intermittent intravenous ibandronate injections on bone quality and micro-architecture in women with postmenopausal osteoporosis: the DIVA study. Bone. 2010;46:660–5.CrossRefPubMed Recker RR, Ste-Marie LG, Langdahl B, Czerwinski E, Bonvoisin B, Masanauskaite D, Rowell L, Felsenberg D. Effects of intermittent intravenous ibandronate injections on bone quality and micro-architecture in women with postmenopausal osteoporosis: the DIVA study. Bone. 2010;46:660–5.CrossRefPubMed
4.
Zurück zum Zitat Sambrook P, Cranney A, Adachi JD. Risk reduction of non-vertebral fractures with intravenous ibandronate: post-hoc analysis from DIVA. Curr Med Res Opin. 2010;26:599–604.CrossRefPubMed Sambrook P, Cranney A, Adachi JD. Risk reduction of non-vertebral fractures with intravenous ibandronate: post-hoc analysis from DIVA. Curr Med Res Opin. 2010;26:599–604.CrossRefPubMed
5.
Zurück zum Zitat Bianchi G, Czerwinski E, Kenwright A, Burdeska A, Recker RR, Felsenberg D. Long-term administration of quarterly IV ibandronate is effective and well tolerated in postmenopausal osteoporosis: 5-year data from the DIVA study long-term extension. Osteoporos Int. 2012;23:1769–78.CrossRefPubMed Bianchi G, Czerwinski E, Kenwright A, Burdeska A, Recker RR, Felsenberg D. Long-term administration of quarterly IV ibandronate is effective and well tolerated in postmenopausal osteoporosis: 5-year data from the DIVA study long-term extension. Osteoporos Int. 2012;23:1769–78.CrossRefPubMed
6.
Zurück zum Zitat Nakamura T, Nakano T, Ito M, Hagino H, Hashimoto J, Tobinai M, Mizunuma H. MOVER Study Group. Clinical efficacy on fracture risk and safety of 0.5 mg or 1 mg/month intravenous ibandronate versus 2.5 mg/day oral risedronate in patients with primary osteoporosis. Calcif Tissue Int. 2013;93:137–46.CrossRefPubMedCentralPubMed Nakamura T, Nakano T, Ito M, Hagino H, Hashimoto J, Tobinai M, Mizunuma H. MOVER Study Group. Clinical efficacy on fracture risk and safety of 0.5 mg or 1 mg/month intravenous ibandronate versus 2.5 mg/day oral risedronate in patients with primary osteoporosis. Calcif Tissue Int. 2013;93:137–46.CrossRefPubMedCentralPubMed
7.
Zurück zum Zitat Nakamura T, Mizunuma H, Itabashi A, Wada H, Ishibe M, Tajima N, Yamane H, Fukuda K, Karube M, Hasunuma T, Miyazaki T, Okamoto S, Okamoto S, Koyanagi S, Fujita N, Yamamoto M, Nakatsuka K. Intravenous injections of ibandronate for six months increase bone mass in Japanese osteoporotic subjects. J Bone Miner Res. 2006;21(Suppl 1):S182. Nakamura T, Mizunuma H, Itabashi A, Wada H, Ishibe M, Tajima N, Yamane H, Fukuda K, Karube M, Hasunuma T, Miyazaki T, Okamoto S, Okamoto S, Koyanagi S, Fujita N, Yamamoto M, Nakatsuka K. Intravenous injections of ibandronate for six months increase bone mass in Japanese osteoporotic subjects. J Bone Miner Res. 2006;21(Suppl 1):S182.
8.
Zurück zum Zitat Pillai G, Gieschke R, Goggin T, Jacqmin P, Schimmer RC, Steimer JL. A semimechanistic and mechanistic population PK-PD model for biomarker response to ibandronate, a new bisphosphonate for the treatment of osteoporosis. Br J Clin Pharmacol. 2004;58:618–31.CrossRefPubMedCentralPubMed Pillai G, Gieschke R, Goggin T, Jacqmin P, Schimmer RC, Steimer JL. A semimechanistic and mechanistic population PK-PD model for biomarker response to ibandronate, a new bisphosphonate for the treatment of osteoporosis. Br J Clin Pharmacol. 2004;58:618–31.CrossRefPubMedCentralPubMed
9.
Zurück zum Zitat Reginster JY, Gieschke R. Clinical utility of a pharmacostatistical model for ibandronate in postmenopausal osteoporosis. Curr Drug Metab. 2006;7:827–36.CrossRefPubMed Reginster JY, Gieschke R. Clinical utility of a pharmacostatistical model for ibandronate in postmenopausal osteoporosis. Curr Drug Metab. 2006;7:827–36.CrossRefPubMed
10.
Zurück zum Zitat Gieschke R, Hayashi N, Vis P, Jacqmin P. Modelling the effects of ibandronate treatment on the time course of bone mineral density in osteoporotic postmenopausal women. In: 30th European Symposium on Calcified Tissues (ECTS), P-284, 8–12 May 2003; Rome. Gieschke R, Hayashi N, Vis P, Jacqmin P. Modelling the effects of ibandronate treatment on the time course of bone mineral density in osteoporotic postmenopausal women. In: 30th European Symposium on Calcified Tissues (ECTS), P-284, 8–12 May 2003; Rome.
11.
Zurück zum Zitat Kimko HC, Duffull SB. Simulation for designing clinical trials a pharmacokinetic-pharmacodynamic modeling perspective. New York: Marcel Dekker; 2003. Kimko HC, Duffull SB. Simulation for designing clinical trials a pharmacokinetic-pharmacodynamic modeling perspective. New York: Marcel Dekker; 2003.
12.
Zurück zum Zitat Ette EI, Williams PJ. Pharmacometrics: the science of quantitative pharmacology. New Jersey: Wiley; 2007.CrossRef Ette EI, Williams PJ. Pharmacometrics: the science of quantitative pharmacology. New Jersey: Wiley; 2007.CrossRef
13.
Zurück zum Zitat Pillai G, Gieschke R, Goggin T, Barrett J, Worth E, Steimer JL. Population pharmacokinetics of ibandronate in Caucasian and Japanese healthy males and postmenopausal females. Int J Clin Pharmacol Ther. 2006;44:655–67.CrossRefPubMed Pillai G, Gieschke R, Goggin T, Barrett J, Worth E, Steimer JL. Population pharmacokinetics of ibandronate in Caucasian and Japanese healthy males and postmenopausal females. Int J Clin Pharmacol Ther. 2006;44:655–67.CrossRefPubMed
14.
Zurück zum Zitat Bauss F, Wagner M, Hothorn LH. Total administered dose of ibandronate determines its effects on bone mass and architecture in ovariectomized aged rats. J Rheumatol. 2002;29:990–8.PubMed Bauss F, Wagner M, Hothorn LH. Total administered dose of ibandronate determines its effects on bone mass and architecture in ovariectomized aged rats. J Rheumatol. 2002;29:990–8.PubMed
15.
Zurück zum Zitat Bauss F, Lalla S, Endele R, Hothorn LA. Effects of treatment with ibandronate on bone mass, architecture, biomechanical properties, and bone concentration of ibandronate in ovariectomized aged rats. J Rheumatol. 2002;29:2200–8.PubMed Bauss F, Lalla S, Endele R, Hothorn LA. Effects of treatment with ibandronate on bone mass, architecture, biomechanical properties, and bone concentration of ibandronate in ovariectomized aged rats. J Rheumatol. 2002;29:2200–8.PubMed
16.
Zurück zum Zitat Reginster JY. Oral and intravenous ibandronate in the management of postmenopausal osteoporosis: a comprehensive review. Curr Pharm Des. 2005;11:3711–28.CrossRefPubMed Reginster JY. Oral and intravenous ibandronate in the management of postmenopausal osteoporosis: a comprehensive review. Curr Pharm Des. 2005;11:3711–28.CrossRefPubMed
17.
Zurück zum Zitat Thiébaud D, Burckhardt P, Kriegbaum H, Huss H, Mulder H, Juttmann JR, Schöter KH. Three monthly intravenous injections of ibandronate in the treatment of postmenopausal osteoporosis. Am J Med. 1997;103:298–307.CrossRefPubMed Thiébaud D, Burckhardt P, Kriegbaum H, Huss H, Mulder H, Juttmann JR, Schöter KH. Three monthly intravenous injections of ibandronate in the treatment of postmenopausal osteoporosis. Am J Med. 1997;103:298–307.CrossRefPubMed
18.
Zurück zum Zitat Chesnut CH III, Skag A, Christiansen C, Recker R, Stakkestad JA, Hoiseth A, Felsenberg D, Huss H, Gilbride J, Schimmer RC, Delmas PD. Effects of oral ibandronate administered daily or intermittently on fracture risk in postmenopausal osteoporosis. J Bone Miner Res. 2004;19:1241–9.CrossRef Chesnut CH III, Skag A, Christiansen C, Recker R, Stakkestad JA, Hoiseth A, Felsenberg D, Huss H, Gilbride J, Schimmer RC, Delmas PD. Effects of oral ibandronate administered daily or intermittently on fracture risk in postmenopausal osteoporosis. J Bone Miner Res. 2004;19:1241–9.CrossRef
19.
Zurück zum Zitat Black DM, Kelly MP, Genant HK, Palermo L, Eastell R, Bucci-Rechtweg C, et al.; Fracture Intervention Trial Steering Committee; HORIZON Pivotal Fracture Trial Steering Committee. Bisphosphonates and fractures of the subtrochanteric or diaphyseal femur. Engl J Med. 2010;362:1761–71. Black DM, Kelly MP, Genant HK, Palermo L, Eastell R, Bucci-Rechtweg C, et al.; Fracture Intervention Trial Steering Committee; HORIZON Pivotal Fracture Trial Steering Committee. Bisphosphonates and fractures of the subtrochanteric or diaphyseal femur. Engl J Med. 2010;362:1761–71.
20.
Zurück zum Zitat Schilcher J1, Michaëlsson K, Aspenberg P. Bisphosphonate use and atypical fractures of the femoral shaft. N Engl J Med. 2011; 364:1728–37. Schilcher J1, Michaëlsson K, Aspenberg P. Bisphosphonate use and atypical fractures of the femoral shaft. N Engl J Med. 2011; 364:1728–37.
21.
Zurück zum Zitat Lemaire V1, Tobin FL, Greller LD, Cho CR, Suva LJ. Modeling the interactions between osteoblast and osteoclast activities in bone remodeling. J Theor Biol. 2004; 229(3):293–309. Lemaire V1, Tobin FL, Greller LD, Cho CR, Suva LJ. Modeling the interactions between osteoblast and osteoclast activities in bone remodeling. J Theor Biol. 2004; 229(3):293–309.
22.
Zurück zum Zitat Post TM, Schmidt S, Peletier LA, de Greef R, Kerbusch T, Danhof M. Application of a mechanism-based disease systems model for osteoporosis to clinical data. J Pharmacokinet Pharmacodyn. 2013;40:143–56.CrossRefPubMed Post TM, Schmidt S, Peletier LA, de Greef R, Kerbusch T, Danhof M. Application of a mechanism-based disease systems model for osteoporosis to clinical data. J Pharmacokinet Pharmacodyn. 2013;40:143–56.CrossRefPubMed
23.
Zurück zum Zitat Pérez Ruixo JJ. Zheng J, Mandema JW. Similar relationship between the time course of bone mineral density improvement and vertebral fracture risk reduction with denosumab treatment in postmenopausal osteoporosis and prostate cancer patients on androgen deprivation therapy. J Clin Pharmacol. 2013. doi:10.1002/jcph.228.PubMed Pérez Ruixo JJ. Zheng J, Mandema JW. Similar relationship between the time course of bone mineral density improvement and vertebral fracture risk reduction with denosumab treatment in postmenopausal osteoporosis and prostate cancer patients on androgen deprivation therapy. J Clin Pharmacol. 2013. doi:10.​1002/​jcph.​228.PubMed
Metadaten
Titel
Application of Modeling and Simulation to a Long-Term Clinical Trial: A Direct Comparison of Simulated Data and Data Actually Observed in Japanese Osteoporosis Patients Following 3-Year Ibandronate Treatment
verfasst von
Kiyohiko Nakai
Satofumi Iida
Masato Tobinai
Junko Hashimoto
Takehiko Kawanishi
Publikationsdatum
01.03.2015
Verlag
Springer International Publishing
Erschienen in
Clinical Pharmacokinetics / Ausgabe 3/2015
Print ISSN: 0312-5963
Elektronische ISSN: 1179-1926
DOI
https://doi.org/10.1007/s40262-014-0206-6

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