Coadministration of Rifampin Significantly Reduces Odanacatib Concentrations in Healthy Subjects.
This open-label 2-period study assessed the effect of multiple-dose administration of rifampin, a strong cytochrome P450 3A (CYP3A) and P-glycoprotein inducer, on the pharmacokinetics of odanacatib, a cathepsin K inhibitor. In period 1, 12 healthy male subjects (mean age, 30 years) received a single dose of odanacatib 50 mg on day 1, followed by a 28-day washout. In period 2, subjects received rifampin 600 mg/day for 28 days; odanacatib 50 mg was coadministered on day 14. Blood samples for odanacatib pharmacokinetics were collected at predose and on day 1 of period 1 and day 14 of period 2. Coadministration of odanacatib and rifampin significantly reduced odanacatib exposure. The odanacatib AUC0-∞geometric mean ratio (90% confidence interval) of odanacatib + rifampin/odanacatib alone was 0.13 (0.11-0.16). The harmonic mean ± jackknife standard deviation apparent terminal half-life (t½) was 71.6 ± 10.2 hours for odanacatib alone and 16.0 ± 3.4 hours for odanacatib + rifampin, indicating greater odanacatib clearance following coadministration with rifampin. Samples were collected in period 2 during rifampin dosing (days 1, 14, and 28) and after rifampin discontinuation (days 35, 42, and 56) to evaluate the ratio of plasma 4β-hydroxycholesterol to total serum cholesterol as a CYP3A4 induction biomarker; the ratio increased ∼5-fold over 28 days of daily dosing with 600 mg rifampin, demonstrating sensitivity to CYP3A4 induction.
Merck & Co., Inc, Kenilworth, NJ, USA.
S Aubrey
SA
Stoch
Merck & Co., Inc, Kenilworth, NJ, USA.
Jeanine
J
Ballard
Merck & Co., Inc, Kenilworth, NJ, USA.
Christopher
C
Gibson
Merck & Co., Inc, Kenilworth, NJ, USA.
Filippos
F
Kesisoglou
Merck & Co., Inc, Kenilworth, NJ, USA.
Rose
R
Witter
Merck & Co., Inc, Kenilworth, NJ, USA.
Kelem
K
Kassahun
Merck & Co., Inc, Kenilworth, NJ, USA.
Stefan
S
Zajic
Merck & Co., Inc, Kenilworth, NJ, USA.
Anish
A
Mehta
Celerion, Lincoln, NE, USA.
Christine
C
Brandquist
Celerion, Lincoln, NE, USA.
Cynthia
C
Dempsey
Celerion, Lincoln, NE, USA.
Daria
D
Stypinski
Merck & Co., Inc, Kenilworth, NJ, USA.
Marc L
ML
Reitman
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000097:blood; D000328:Adult; D001713:Biphenyl Compounds / Q000008:administration & dosage* / Q000097:blood*; D065701:Cytochrome P-450 CYP3A Inducers / Q000008:administration & dosage; D004334:Drug Administration Schedule; D004347:Drug Interactions / Q000502:physiology; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D008875:Middle Aged; D012293:Rifampin / Q000008:administration & dosage*; D055815:Young Adult
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001713:Biphenyl Compounds; D065701:Cytochrome P-450 CYP3A Inducers; C527128:odanacatib; D012293:Rifampin
4β-hydroxycholesterol; ADME; CYP3A4; P-glycoprotein; odanacatib; rifampin