PKPD model for cathepsin K inhibition with balicatib and changes in bone turnover biomarkers, in particular NTx
Holford, Nick, Goonaseelan (Colin) Pillai, Nitin Kaila, William Collins, Sandip Roy, Serge Cremers, Ulrich Trechsel, Florilene Bouisset, Jean-Louis Steimer
Dept of Pharmacology & Clinical Pharmacology, University of Auckland, Private Bag 92019, Auckland, New Zealand
Background: Cathepsin K is a key enzyme for the breakdown of collagen during bone resorption. Balicatib inhibits cathepsin K. The drug may be active for treatment of osteoporosis.
Methods: Serum and urinary telopeptide data after oral dosing of healthy subjects and patients with post-menopausal osteoporosis were obtained during Phase 1 and Phase 2 of the clinical development of balicatib. Single doses of 5 to 400 mg and multiple daily doses of 5 to 50 mg were administered with intensive sampling on day 1 and at steady state, over up to 3 months in 140 patients and 12 months in 675 patients. A mixed effects pharmacokinetic-pharmacodynamic model for balicatib effects on telopeptide formation was developed using NONMEM Version V 1.1.
Results: Serum C-terminal (CTx) and N-terminal (NTx) collagen telopeptide (TLP) concentration fell rapidly following the first dose of balicatib, as a %change vs baseline of 70-80 at the 50mg dose. They gradually increased over subsequent weeks with a rebound above baseline after stopping the treatment at 12 weeks. The initial attenuation of effect was describable with an empirical feedback model of decreasing serum TLP leading to increased TLP formation. Subsequent longer term changes were not well described by the empirical feedback model but could be described adequately by proposing accelerated turnover of bone formed during cathepsin K inhibition. The superiority of the accelerated turnover model was confirmed in studies of serum CTx and urinary NTx excretion over a 12 month treatment period but needs to be further investigated.
|
Description |
Units |
12 week estimate |
12 month estimate |
12 week PPV |
12 month PPV |
|
Rate of cortical bone turnover |
nmol/h |
43.5 FIX |
43.5 FIX |
. |
0.232++ |
|
Rate of trabecular bone turnover |
nmol/h |
109 FIX |
109 FIX |
. |
. |
|
Half-life of cortical bone |
y |
23.1 FIX |
23.1 FIX |
. |
. |
|
Half-life of trabecular bone |
y |
2.31 FIX |
2.31 FIX |
. |
. |
|
Half-life of CKI bone |
y |
1.4 |
2.15 |
0.926 |
1.10 |
|
Balicatib EC50 |
mcg/L |
40.6 |
19.1 |
0.493 |
0.407 |
|
NTx non-renal clearance |
L/h/70kg |
6.89 |
6.89 FIX |
0.266 |
0.266 FIX |
|
NTx renal clearance |
L/h/70kg per 6 L/h CLcr |
2.1 |
1.34 |
0.215 |
0.225 |
|
NTx half-life |
h |
10.8 |
11.8 |
||
|
NTx Additive residual error |
nmol/L |
5.2 |
- |
0.187 |
- |
|
uNTx/Cr Additive residual error |
(nmol/L)/(mmol/L) |
52.2 |
16.7 |
. |
. |
PPV=Population Parameter Variability (SQRT(OMEGA)
++=PPV for combined cortical and trabecular bone turnover.
