Morning vs evening dosing of the cathepsin K inhibitor ONO-5334: effects on bone resorption in postmenopausal women in a randomized, phase 1 trial

Abstract

The cathepsin K inhibitor, ONO-5334, improves bone mineral density in postmenopausal women with osteoporosis. The effects of morning versus evening administration of ONO-5334 were investigated by measuring bone turnover marker levels in healthy postmenopausal women. Morning administration of ONO-5334 showed a more consistent suppressive effect on bone resorption than evening administration.

Introduction: Bone turnover is thought to be subject to circadian variation, and the efficacy of osteoporosis treatments may be optimized by regulating the time of dosing. This study assessed whether evening administration of the cathepsin K inhibitor, ONO-5334, had a differential effect on the bone turnover marker, C-terminal telopeptide of type I collagen (CTX-I), compared with morning administration.

Methods: This was a single-center, single blind crossover study. Fourteen healthy postmenopausal women were assigned to receive ONO-5334 150 mg once daily for 5 days in each period; they were randomized to receive either evening doses in the first period and morning doses in the second or vice versa. Serum and urinary levels of CTX-I were measured throughout the study.

Results: Both regimens showed similar patterns of reduction in serum and urinary CTX-I; however, CTX-I suppression was more consistently >60% over 24 h following morning administration. Morning administration led to 6% greater suppression of 24-h serum CTX-I area under the effect curve (AUE; 69 vs 63%; P < .05) and 7% greater suppression of urinary CTX-I/creatinine AUE (93 vs 86%; P < .01) than evening administration. Higher plasma ONO-5334 concentrations were observed between 12 and 24 h postdose following morning administration, with mean trough concentrations for the morning and evening regimens at 9.4 and 4.0 ng/mL, respectively. There were no safety findings of concern.

Conclusion: Morning dosing of ONO-5334 is more efficacious at reducing markers of bone turnover in healthy postmenopausal women than evening dosing.

Trial registration: ClinicalTrials.gov: NCT01384188 , registered on June 27, 2011 EudraCT: 2008-006284-37.

Keywords: Anti-resorptive; Bone resorption; Menopause; Osteoporosis.

Figures

Fig. 1

Mean plasma concentration of ONO-5334 on day 5 (per protocol set). Values are expressed as mean (SD). Mealtimes are indicated with solid and dashed arrows for the morning and evening dosing groups, respectively. PK pharmacokinetics, B breakfast, L lunch, D dinner

Fig. 2

a Serum CTX-I (time-matched % change from baseline) after 5 days of ONO-5334 administration. Values are expressed as mean (SD). Mealtimes are indicated with solid and dashed arrows for the morning and evening dosing groups, respectively. CTX-I C-terminal telopeptide of type I collagen, CFB change from baseline, B breakfast, L lunch, D dinner. N=11. b Urinary CTX-I/creatinine (time-matched %CFB) after 5 days of ONO-5334 administration. Values are expressed as mean (SD). Mealtimes are indicated with solid and dashed arrows for the morning and evening dosing groups, respectively. CTX-I C-terminal telopeptide of type I collagen, CFB change from baseline, B breakfast, L lunch, D dinner. N=11

Fig. 3

a Time course of serum CTX-I levels after morning administration of ONO-5334 at 8:00 hours, N=12. b Time course of serum CTX-I levels after evening administration of ONO-5334 at 20:00 hours, N=13. Filled triangle indicates predose CTX-I levels (day 1), filled diamond indicates CTX-I levels on the day of first dosing (day 1), and open square indicates CTX-I levels on day 5. Mealtimes are indicated with arrows. CTX-I C-terminal telopeptide of type I collagen, B breakfast, L lunch, D dinner

Fig. 4

Scatter plot of plasma ONO-5334 concentration versus serum CTX-I (%CFB) on day 5. Open triangle morning dosing, filled square evening dosing. CTX-I C-terminal telopeptide of type I collagen, CFB change from baseline