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))
Reference: PAGE 15 () Abstr 1014 [www.page-meeting.org/?abstract=1014]
Poster: Applications- Endocrine