(T1130-11-65) Pharmacokinetics of LLP2A-Alendronate following Ascending Intravenous Dosing to Patients with Osteopenia Secondary to Glucocorticoids

Purpose: To assess the plasma pharmacokinetics (PK) of LLP2A-Ale in adult men and women with osteopenia secondary to glucocorticoids (patients at risk for non-traumatic osteonecrosis). LLP2A-Ale is a novel anabolic agent with two ligands covalently joined by a linker, LLP2A, and alendronate.

Methods: The study is a phase 1, randomized, double-blind, placebo-controlled single and multiple ascending dose study of the safety and tolerability of intravenous LLP2A-Alendronate in adult men and women with osteopenia secondary to glucocorticoids. LLP2A-Alendronate was administered by intravenous infusion over 120 minutes in single ascending dose cohorts (SAD) at 50, 150, 400, 750 µg/kg on Day 1 followed by multiple ascending dose cohorts (MAD) at 400, 750 and 1200 µg/kg on Days 1, 15, 29 and 43. For PK analysis, blood samples were collected at predetermined times and the plasma were analyzed for LLP2A-Alendronate concentrations by validated method (calibration range 2.00 to 1,000 ng/mL). The PK parameters were determined by noncompartmental analysis. Dose proportionality was assessed using a power-law model where the ln C_max and ln AUC were modeled as a function of ln dose, with subject being considered as a random factor (Klamerus, et al. 1992; Gough, et al., 1995). The slopes of the ln C_max and ln AUC versus ln dose and its 90% CI were used to conclude dose proportionality. For perfect dose proportionality, the 90% CI for the slope should include 1.00. A slope less than 1.00 or greater than 1.00 indicates less than or greater than dose proportionality, respectively.

Results: The highest LLP2A-Alendronate concentrations were achieved at the end of infusion (~2h). For SAD, LLP2A-Alendronate C_max were 270 ± 57.2, 864 ± 159, 2,750 ± 434 and 4,680 ± 1,260 ng/mL and AUC_0-T were 875 ± 191, 2,810 ± 712, 8,820 ± 1,270 and 16,300 ± 5,570 ng·h/mL at LLP2A‑Alendronate doses of 50, 150, 400 and 750 µg/kg, respectively (Table 1). The corresponding T_1/2 were 2.33 ± 0.279, 4.66 ± 0.277, 4.31 ± 0.319 and 4.48 ± 0.986 h, CL were 0.0585 ± 0.0142, 0.0558 ± 0.0139, 0.0458 ± 7.18E-03 and 0.0505 ± 0.0209 L/h/kg, and V_ss were 0.132 ± 0.0254, 0.165 ± 0.0295, 0.136 ± 0.0197 and 0.154 ± 0.0520 L/kg. For MAD Day 1, C_max were 2,660 ± 576, 3,890 ± 1,670 and 7,260 ± 1,950 ng/mL, AUC_0-T were 8,580 ± 1,800, 14,600 ± 4,990 and 27,800 ± 4,760 ng·h/mL, T_1/2 were 4.00 ± 0.476, 4.50 ± 1.21 and 4.28 ± 0.360 h, CL were 0.0478 ± 9.80E-03, 0.0567 ± 0.0239 and 0.0444 ± 0.0101 L/h/kg, and V_ss were 0.139 ± 0.0268, 0.273 ± 0.335 and 0.143 ± 0.0291 L/kg at LLP2A-Alendronate doses of 400, 750 and 1200 µg/kg, respectively. MAD Day 1 PK parameters are consistent with those of SAD. Day 43 C_max were 2,580 ± 315, 4,020 ± 1,650 and 6,370 ± 1,600 ng/mL, AUC_0-T were 8,860 ± 1,670, 14,400 ± 4,860 and 21,500 ± 4,550 ng·h/mL, and T_1/2 were 4.02 ± 0.272, 4.50 ± 1.44 and 4.07 ± 0.165 h at LLP2A-Alendronate doses of 400, 750 and 1200 µg/kg/dose, respectively. For both SAD and MAD, the PK exposure (C_max and AUC) increased as a function of LLP2A‑Alendronate dose in a dose‑proportional manner where the values for the slopes for ln C_max and ln AUC_0-T versus ln dose were not significantly different from 1.00 (p > 0.05) and the 90% CI of the slopes included 1.00 (Figure 1 to 3).

Conclusion: LLP2A-Alendronate PK exposure appeared to increase in a dose‑proportional manner and did not exhibit accumulation. The T_max, T_1/2, CL and V_ss were dose-independent.

References: Gough, K., Hutchison, M., Keene, O., Byrom, B., Ellis, S., Lacey, L. and McKellar. J. (1995)
Assessment of dose proportionality: Report from the statisticians in the pharmaceutical industry/pharmacokinetics UK joint working party. Drug Info. J. 29:1039 1048.

Klamerus, K. J., Maloney, K., Rudolph, R. L., Sisenwine, S. F., Jusko, W. J. and Chiang. S. T. (1992)
Introduction of a composite parameter to the pharmacokinetics of Venlafaxine and its active O-desmethyl metabolite. J. Clin. Pharmacol. 32:716-724.