Study design, dosing duration, dosage strength, regimen and formulation of OCEAN, PKPD and PK studies. (DOCX 71Â kb

B Bruguerolle

B Langdahl

BD Gelb

C Jerome

CD Conference

Chihiro Hasegawa

DS Yamashita

GA Rodan

H Yamada

HG Bone

J Wijkmans

JW Mandema

JY Gauthier

K Garber

K Tezuka

LM Atley

M Baraldo

M Gowen

M Tanaka

Makoto Tanaka

P Garnero

P Qvist

P Saftig

R Eastell

RA Adler

RA Blum

Richard Eastell

S Nagase

SA Stoch

SL Teitelbaum

Steve Deacon

T Cusick

Y Nishi

Y Ochi

Y Yasuda

Yoshitaka Hashimoto

Background: ONO-5334 is a cathepsin K inhibitor that induced bone mineral density (BMD) gain in a phase II study

in postmenopausal osteoporosis patients. Even though the antiresorptive effect could only be monitored in the

morning during the study, simulation can allow the antiresorptive effect to be assessed over 24 h, with assessment

of the relationship to BMD gain.



Methods: Inhibition of the serum C-telopeptide of type I collagen (sCTX) level at doses of ONO-5334 of 100 mg

once daily (QD), 300 mg QD, and 50 mg twice daily (BID) was simulated using plasma ONO-5334 pharmacokinetic

(PK) data for repeated dose administration in a phase I study and corresponding sCTX inhibition from the PKpharmacodynamic

(PK/PD) relationship. sCTX was selected because it has a high signal-to-noise ratio compared to

other telopeptides. A negative sigmoidal shape for the PK/PD relationship between plasma ONO-5334 and sCTX

levels was obtained in our previous study.



Results: The simulated sCTX inhibition reached >99% of the maximal inhibitory effect (Emax) at 0.5 h in all treatment

groups, and decreased to <80% Emax at 8 and 12 h at 50 mg BID and 100 mg QD, respectively. However, sCTX

inhibition at 300 mg QD was maintained at ≥82% Emax over 24 h. The mean sCTX inhibition rates for 24 h at 100 mg

QD, 300 mg QD and 50 mg BID were 63, 95 and 80% Emax, respectively. There was a positive linear relationship by

treatment group between mean sCTX inhibition over 24 h and observed BMD gain in the phase II study.



Conclusion: The dose response for BMD with ONO-5334 at 100 and 300 mg QD and higher BMD gain at 50 mg BID

vs. 100 mg QD can be explained by sCTX inhibition over 24 h. The simulation gave the antiresorptive effect of ONO5334

over 24 h and allowed prediction of BMD gain due to ONO-5334.



Trial registration: The registration number in The European Union Clinical Trials Register is 2007–002417-39. The date

of registration was August 31, 2007

Tanaka, M.

Hashimoto, Y.

Hasegawa, C.

Deacon, S.

Eastell, R.

White Rose Research Online

Antiresorptive effect of a cathepsin K

inhibitor ONO-5334 and its relationship to

BMD increase in a phase II trial for

postmenopausal osteoporosis

Matsumoto, Kohji

Kyoto University Research Information Repository

TitleASYMPTOTIC SERIES FOR DOUBLE ZETA ANDDOUBLE GAMMA FUNCTIONS OF BARNES(AnalyticNumber Theory)Author(s)Matsumoto, KohjiCitation数理解析研究所講究録 (1996), 958: 162-165Issue Date1996-08URL http://hdl.handle.net/2433/60452RightType Departmental Bulletin PaperTextversionpublisherKyoto University958 1996 162-165 162163164165

ASYMPTOTIC SERIES FOR DOUBLE ZETA AND DOUBLE GAMMA FUNCTIONS OF BARNES(Analytic Number Theory)

Crossref

BMC Musculoskeletal Disorders

Antiresorptive effect of a cathepsin K inhibitor ONO-5334 and its relationship to BMD increase in a phase II trial for postmenopausal osteoporosis

Abstract Background ONO-5334 is a cathepsin K inhibitor that induced bone mineral density (BMD) gain in a phase II study in postmenopausal osteoporosis patients. Even though the antiresorptive effect could only be monitored in the morning during the study, simulation can allow the antiresorptive effect to be assessed over 24 h, with assessment of the relationship to BMD gain. Methods Inhibition of the serum C-telopeptide of type I collagen (sCTX) level at doses of ONO-5334 of 100 mg once daily (QD), 300 mg QD, and 50 mg twice daily (BID) was simulated using plasma ONO-5334 pharmacokinetic (PK) data for repeated dose administration in a phase I study and corresponding sCTX inhibition from the PK-pharmacodynamic (PK/PD) relationship. sCTX was selected because it has a high signal-to-noise ratio compared to other telopeptides. A negative sigmoidal shape for the PK/PD relationship between plasma ONO-5334 and sCTX levels was obtained in our previous study. Results The simulated sCTX inhibition reached >99% of the maximal inhibitory effect (Emax) at 0.5 h in all treatment groups, and decreased to <80% Emax at 8 and 12 h at 50 mg BID and 100 mg QD, respectively. However, sCTX inhibition at 300 mg QD was maintained at ≥82% Emax over 24 h. The mean sCTX inhibition rates for 24 h at 100 mg QD, 300 mg QD and 50 mg BID were 63, 95 and 80% Emax, respectively. There was a positive linear relationship by treatment group between mean sCTX inhibition over 24 h and observed BMD gain in the phase II study. Conclusion The dose response for BMD with ONO-5334 at 100 and 300 mg QD and higher BMD gain at 50 mg BID vs. 100 mg QD can be explained by sCTX inhibition over 24 h. The simulation gave the antiresorptive effect of ONO-5334 over 24 h and allowed prediction of BMD gain due to ONO-5334. Trial registration The registration number in The European Union Clinical Trials Register is 2007–002417-39 . The date of registration was August 31, 2007

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Makoto Tanaka (278772)

Yoshitaka Hashimoto (4126720)

Chihiro Hasegawa (4126723)

Steve Deacon (4126717)

Richard Eastell (153287)

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Additional file 1: Table S1. of Antiresorptive effect of a cathepsin K inhibitor ONO-5334 and its relationship to BMD increase in a phase II trial for postmenopausal osteoporosis

http://repository.kulib.kyoto-u.ac.jp/dspace/bitstream/2433/60452/1/0958-23.pdf

ASYMPTOTIC SERIES FOR DOUBLE ZETA AND DOUBLE GAMMA FUNCTIONS OF BARNES(Analytic Number Theory)

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