Abstract
ONO-5334, a selective inhibitor of cathepsin K, is a potential new treatment for osteoporosis. The objectives of this study were to (1) develop population pharmacokinetic-pharmacodynamic (PK-PD) models for ONO-5334 using dose-ascending data from healthy postmenopausal females, (2) examine comparability of PK and/or PD profile between Caucasian and Japanese, and (3) compare PK-PD profile between immediate release tablet (IRT) and sustained release tablet (SRT). The population PK-PD models were developed for each formulation for post-dose levels of bone resorption markers (serum CTX and NTX). The data were provided from 4 phase 1 studies with total of 201 Caucasian and 94 Japanese subjects. Plasma concentrations of ONO-5334 and bone resorption markers were thoroughly evaluated in those studies. An indirect response model described relationships between bone resorption markers and plasma concentrations of ONO-5334. There was no significant difference in PK and pharmacodynamic potency (IC50) between Caucasian and Japanese. Based on the developed model, serum CTX and NTX after administration of ONO-5334 IRT or SRT were simulated, and the results showed that ONO-5334 SRT would provide comparable PD effect on bone resorption markers with lower dose relative to IRT.
| Original language | English |
|---|---|
| Pages (from-to) | 23-34 |
| Number of pages | 12 |
| Journal | Journal of Clinical Pharmacology |
| Volume | 54 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - Jan 1 2014 |
| Externally published | Yes |
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All Science Journal Classification (ASJC) codes
- Pharmacology
- Pharmacology (medical)
Cite this
Population pharmacokinetic and pharmacodynamic modeling of different formulations of ono-5334, cathepsin k inhibitor, in caucasian and japanese postmenopausal females. / Hasegawa, Chihiro; Ohno, Tomoya; Umemura, Takeo; Honda, Naoki; Ohyama, Michiyo; Nagase, Shinichi; Small, Maria; Deacon, Steve; Ogawa, Mikio; Ieiri, Ichiro.
In: Journal of Clinical Pharmacology, Vol. 54, No. 1, 01.01.2014, p. 23-34.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Population pharmacokinetic and pharmacodynamic modeling of different formulations of ono-5334, cathepsin k inhibitor, in caucasian and japanese postmenopausal females
AU - Hasegawa, Chihiro
AU - Ohno, Tomoya
AU - Umemura, Takeo
AU - Honda, Naoki
AU - Ohyama, Michiyo
AU - Nagase, Shinichi
AU - Small, Maria
AU - Deacon, Steve
AU - Ogawa, Mikio
AU - Ieiri, Ichiro
PY - 2014/1/1
Y1 - 2014/1/1
N2 - ONO-5334, a selective inhibitor of cathepsin K, is a potential new treatment for osteoporosis. The objectives of this study were to (1) develop population pharmacokinetic-pharmacodynamic (PK-PD) models for ONO-5334 using dose-ascending data from healthy postmenopausal females, (2) examine comparability of PK and/or PD profile between Caucasian and Japanese, and (3) compare PK-PD profile between immediate release tablet (IRT) and sustained release tablet (SRT). The population PK-PD models were developed for each formulation for post-dose levels of bone resorption markers (serum CTX and NTX). The data were provided from 4 phase 1 studies with total of 201 Caucasian and 94 Japanese subjects. Plasma concentrations of ONO-5334 and bone resorption markers were thoroughly evaluated in those studies. An indirect response model described relationships between bone resorption markers and plasma concentrations of ONO-5334. There was no significant difference in PK and pharmacodynamic potency (IC50) between Caucasian and Japanese. Based on the developed model, serum CTX and NTX after administration of ONO-5334 IRT or SRT were simulated, and the results showed that ONO-5334 SRT would provide comparable PD effect on bone resorption markers with lower dose relative to IRT.
AB - ONO-5334, a selective inhibitor of cathepsin K, is a potential new treatment for osteoporosis. The objectives of this study were to (1) develop population pharmacokinetic-pharmacodynamic (PK-PD) models for ONO-5334 using dose-ascending data from healthy postmenopausal females, (2) examine comparability of PK and/or PD profile between Caucasian and Japanese, and (3) compare PK-PD profile between immediate release tablet (IRT) and sustained release tablet (SRT). The population PK-PD models were developed for each formulation for post-dose levels of bone resorption markers (serum CTX and NTX). The data were provided from 4 phase 1 studies with total of 201 Caucasian and 94 Japanese subjects. Plasma concentrations of ONO-5334 and bone resorption markers were thoroughly evaluated in those studies. An indirect response model described relationships between bone resorption markers and plasma concentrations of ONO-5334. There was no significant difference in PK and pharmacodynamic potency (IC50) between Caucasian and Japanese. Based on the developed model, serum CTX and NTX after administration of ONO-5334 IRT or SRT were simulated, and the results showed that ONO-5334 SRT would provide comparable PD effect on bone resorption markers with lower dose relative to IRT.
UR - http://www.scopus.com/inward/record.url?scp=84893336794&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84893336794&partnerID=8YFLogxK
U2 - 10.1002/jcph.186
DO - 10.1002/jcph.186
M3 - Article
C2 - 24115072
AN - SCOPUS:84893336794
VL - 54
SP - 23
EP - 34
JO - Journal of Clinical Pharmacology
JF - Journal of Clinical Pharmacology
SN - 0091-2700
IS - 1
ER -