single doses of placebo, subcutaneous doses of abaloparatide at 80 mcg and 240 mcg (three times the recommended dose), and moxifloxacin 400 mg orally. Abaloparatide increased heart rate, with a mean peak increase of 15 beats per minute (bpm) and 20 bpm at the first time point (15 minutes) after dosing with 80 mcg and 240 mcg, respectively. There were no clinically meaningful effects of abaloparatide on QTcI (individually corrected QT intervals) or cardiac electrophysiology.
12.3 Pharmacokinetics
Following seven days of subcutaneous administration of abaloparatide 80 mcg, the mean (SD) abaloparatide exposure was 812 (118) pg/mL for Cmax and 1622 (641) pg·hr/mL for AUC0-24.
FIGURE 1 below shows the mean (SD) abaloparatide pharmacokinetic profile in postmenopausal women (N = 8) on Day 7.
Figure 1. Mean Abaloparatide Pharmacokinetic Profile in Postmenopausal Women on Day 7
Figure 1
Absorption
The median (range) time to peak concentration of abaloparatide 80 mcg was 0.51 hr (0.25 to 0.52 hr) following subcutaneous administration. The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%.
Distribution
The in vitro plasma protein binding of abaloparatide was approximately 70%. The volume of distribution was approximately 50 L.
Elimination
The mean (SD) half-life of abaloparatide is 1.7 (0.7) hrs. The peptide fragments are primarily eliminated through renal excretion.
Metabolism
No specific metabolism or excretion studies have been performed with TYMLOS. The metabolism of abaloparatide is consistent with non-specific proteolytic degradation into smaller peptide fragments, followed by elimination by renal clearance.
Specific Populations
Geriatric Patients
No age-related differences in abaloparatide pharmacokinetics were observed in postmenopausal women ranging from 49 to 86 years of age.
Race
No differences in abaloparatide pharmacokinetics based on race were observed in clinical trials.
Patients with Renal Impairment
A single 80 mcg subcutaneous dose of abaloparatide was administered to male and female patients with renal impairment: 8 patients with mild renal impairment (CLCr 60 to 89 mL/min), 7 patients with moderate renal impairment (CLCr 30 to 59 mL/min), 8 patients with severe renal impairment (CLCr 15 to 29 mL/min), and 8 healthy subjects with normal renal function (CLCr 90 or greater mL/min) matched by sex, age, and body mass index (BMI). Abaloparatide Cmax increased 1.0-, 1.3-, and 1.4-fold in patients with mild, moderate, and severe renal impairment, compared to the healthy subjects with normal renal function. Abaloparatide AUC increased 1.2-, 1.7-, and 2.1-fold in patients with mild, moderate, and severe renal impairment, compared to the healthy subjects with normal renal function. Patients undergoing dialysis were not included in the study.
Drug Interactions
In vitro studies showed that abaloparatide, at therapeutic concentrations, does not inhibit or induce Cytochrome P450 enzymes.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
In a 2-year carcinogenicity study, abaloparatide was administered once daily to male and female Fischer rats by subcutaneous injection at doses of 10, 25, and 50 mcg/kg. These doses resulted in systemic exposures to abaloparatide that were 4, 16, and 28 times, respectively, the systemic exposure observed in humans following the recommended subcutaneous dos |
