2006 - Brugge/Bruges - Belgium

PAGE 2006: Applications- Endocrine
Jean-Louis Steimer

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.




Reference: PAGE 15 (2006) Abstr 1015 [www.page-meeting.org/?abstract=1015]
Poster: Applications- Endocrine
Click to open PDF poster/presentation (click to open)
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