Bone Abstracts

Aim: To determine the safety, tolerability, pharmacokinetics and pharmacodynamics of the cathepsin K inhibitor MIV-711.

Methods: A double-blind, placebo-controlled, randomized study in 27 healthy subjects of both genders. Single ascending doses 20–600 mg were investigated for adverse events, clinical chemistry, vital signs, ECG parameters, pharmacokinetics, and serum levels of CTX-I.

Results: MIV-711 was well tolerated with no apparent effect on clinical chemistry, vital signs, or ECG parameters. Adverse events included skin reactions at ECG electrode sites which appeared both after active drug and placebo, headache and muscle pain. Drug exposure increased linearly with dose. MIV-711 reduced serum CTX-I levels in a dose-dependent manner compared to placebo. At 24 h after single dose, plasma CTX-I levels were similar in placebo-treated subjects compared to baseline levels before dose (pre-dose baseline: 0.59±0.16 ng/ml vs 24 h post-dose: 0.61±0.19 ng/ml, 1±4% increase, n=10). In subjects receiving 20 mg of MIV-711, serum CTX-I levels 24 h after dose were 20±2% lower than baseline (n=7). Subsequent doses of 100 mg, 200 mg, 400 mg and 600 mg of MIV-711 reduced serum CTX-I levels by 51±4%, 61±4%, 75±3% and 79±4% respectively (n=7 in each group). Efficacy was sustained for 24 h despite a short elimination half-life of MIV-711. 48 h After dose, serum CTX-I levels were back to initial baseline levels in most groups indicating reversible efficacy.

Conclusions: Single doses of MIV-711 up to 600 mg were safe and well tolerated and displayed linear pharmacokinetics over the investigated dose range. Serum CTX-I levels were suppressed by up to 79% at 24 h after dose. A single 100 mg dose of MIV-711 reduced serum levels of CTX-I by more than 50% at 24 h post dose.