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

SummaryThe 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.IntroductionBone 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.MethodsThis 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.ResultsBoth 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.ConclusionMorning dosing of ONO-5334 is more efficacious at reducing markers of bone turnover in healthy postmenopausal women than evening dosing.Trial registrationClinicalTrials.gov: NCT01384188, registered on June 27, 2011EudraCT: 2008-006284-37Electronic supplementary materialThe online version of this article (doi:10.1007/s00198-015-3342-4) contains supplementary material, which is available to authorized users.

Clinical and translational pharmacology of the cathepsin K inhibitor odanacatib studied for osteoporosis

“…Two other CatK inhibitors progressed to date to clinical studies: balicatib (Phase 1 and 2 studies) and ONO‐5334 (Phase 1 and 2 studies). PD results from these programmes are generally consistent with the key findings from odanacatib, including: robust reversible inhibition of bone resorption demonstrated by biomarkers and associated with BMD increases; modest reductions of formation biomarkers (small relative to other osteoporosis therapies) at doses with near maximal resorption inhibition, and increased formation biomarkers over baseline at subtherapeutic (very low) dose; transient acceleration of bone resorption on discontinuation of treatment of ≥3 months duration, and osteoclast effects enhancing size, number and/or CatK enzyme levels . Of note, both balicatib and ONO‐5334 were dosed daily in Phase 2, which contrasts with the weekly dosing regimens studied in Phase 2 and 3 for odanacatib.…”

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

“…However, the timing of administration may influence antiresorptive effects due to circadian rhythms in bone turnover, which reach a peak during the night/early morning and a nadir in the late afternoon [ 26 , 27 ]. Eastell et al showed that changes in sCTX inhibition with ONO-5334 SR in morning vs. evening dosing parallel changes in PK [ 30 ]. In addition, the sigmoidal Emax model of sCTX with ONO-5334 SR was similar under fed and fasted conditions [ 29 ].…”

“…Therefore, ONO-5334 SR provided a better evaluation of the PK/PD relationship in our previous study [ 29 ]. In an analysis excluding circadian variation of bone resorption markers, the plasma levels of bone resorption markers and ONO-5334 were fitted with sigmoidal maximal inhibitory effect ( Emax ) models, simply reflecting inhibition of cathepsin K. Furthermore, Eastell et al clearly showed that changes in sCTX inhibition with ONO-5334 SR morning vs. evening dosing parallel changes in the PK profile, highlighting a clear link between PK levels and antiresorptive effects [ 30 ].…”

Circadian Variation in Efficacy of Medications

“…130 Finally, in a single-blind crossover study examining bone resorption, morning administration of ONO-5334 (a cathepsin K inhibitor) was more effective than evening administration at suppressing C-terminal telopeptide of type I collagen (a marker of bone turnover) across the day. 131 Optimal timing for administration of calcitonin, an antiresorptive hormonal treatment for osteoporosis and Paget's disease, depends on route of administration. For example, 0800 hours or 2100 hours nasal salmon calcitonin treatment transiently reduced bone resorption but did not effectively alter the circadian pattern of bone resorption.…”

“…A retrospective longitudinal study examining the timing of etidronate administration determined that dosing was similarly effective when taken as single doses across the day if the patient adhered to a 2‐hour fast before and after dosing 130 . Finally, in a single‐blind crossover study examining bone resorption, morning administration of ONO‐5334 (a cathepsin K inhibitor) was more effective than evening administration at suppressing C‐terminal telopeptide of type I collagen (a marker of bone turnover) across the day 131 …”