Population pharmacokinetics of balicatib, a cathepsin K inhibitor
Holford, Nick, Goonaseelan (Colin) Pillai, Sandip Roy, Andrej Skerjanec, Serge Cremers, William Collins, 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 and has been shown to reduce bone turnover. .
Methods: Pharmacokinetic data after oral dosing of healthy subjects and patients with post-menopausal osteoporosis were obtained in Caucasians and Orientals during Phase 1 and Phase 2A of the clinical development of balicatib. Single doses of 5 to 400 mg and multiple daily doses of 5 to 50 mg up to 12 weeks were administered with intensive sampling on day 1 and at steady state. A mixed effects pharmacokinetic model for balicatib and a metabolite AEE325 was developed using NONMEM Version V 1.1.
Results: A two compartment disposition model with zero-order input and first-order elimination described plasma balicatib concentrations. Lag time with between occasion variability and between subject variability in extent improved the fit. An unexpected finding was a dose dependent decrease in the apparent volume of distribution of the peripheral compartment. Metabolite formation was very rapid and was well defined by assuming instantaneous conversion in a fixed ratio (population median 0.11; apparent CV 46%) to the predicted parent concentration. Parameters were scaled allometrically using body weight. Renal clearance was predicted by assuming a linear relationship to predicted creatinine clearance (CLcr) and accounted for 13% of total clearance. The variability in balicatib total clearance was unexpectedly small for a CYP3A substrate (apparent CV 12.2%).
|
Description |
Units |
Estimate |
PPV |
BOV |
|
Renal clearance (CLcr=6L/h/70kg) |
L/h/70kg |
4.19 |
||
|
Non-renal clearance |
L/h/70kg |
27.6 |
0.122* |
|
|
Central volume |
L/70kg |
304 |
0.215 |
|
|
Inter-compartmental clearance |
L/h/70kg |
5.56 |
0.531 |
|
|
Peripheral volume |
L/70kg |
390 |
0.113 |
|
|
Duration of zero-order input |
h |
0.55 |
||
|
Absorption lag-time |
h |
0.224 |
0.499 | |
|
Nominal bioavailability |
- |
1 FIXED |
0.214 |
|
|
Fractional max decrease in Vp |
- |
0.9 |
||
|
Balicatib dose at 50% of VPMIN |
mg |
17.3 |
||
|
Fractional clearance change in Orientals |
- |
1.14 |
||
|
Fractional bioavailability change with ketoconazole |
- |
2.97 |
||
|
Fractional clearance change per year of age |
y-1 |
-0.002 |
||
|
Proportional residual error |
- |
0.188 |
||
|
Additive residual error |
ug/L |
0.00805 |
||
|
Between subject variability in residual error |
- |
0.349 |
*=PPV for both renal (CLR) and non-renal (CLNR) clearance
PPV=population parameter variability (SQRT(OMEGA))
BOV=between occasion variability (SQRT(OMEGA))
