Population Pharmacokinetic and Pharmacodynamic Modeling of LY2510924 in Patients With Advanced Cancer

Abstract

The objectives of this study were to characterize the pharmacokinetics (PK) of LY2510924, a potent peptide antagonist of the CXCR4 receptor, after subcutaneous administration in patients with advanced cancer forms and quantify LY2510924 stimulatory effects on the mobilization of cells bearing the cluster of differentiation 34 (CD34) as an indirect reflection of the chemokine C‐X‐C motif ligand 12/CXCR4 axis inhibition. LY2510924 PK were best characterized by a two‐compartment model with first‐order absorption and dose‐dependent clearance predicting steady state after three daily doses and little accumulation (accumulation ratio <1.17). The dynamics of CD34+ cell counts were best characterized with a precursor model with reversible transfer from the precursor to the central compartment and LY2510924‐driven stimulation of cell mobilization. Model‐based simulations show that once‐daily doses of 20 mg LY2510924 produce maximum CD34+ cell response and that peak effect typically occurs after three daily doses and slowly wanes over time.

Safety and Pharmacokinetics of CXCR4 Peptide Antagonist, LY2510924, in Combination with Durvalumab in Advanced Refractory Solid Tumors

“…In a monotherapy study of LY2510924, there was a dose relationship between CD34+ counts in peripheral blood at 24 h as the doses increased from 1.0 to 10 mg/day. 6 However, this response seemed to diminish at doses >10 mg/day, including at the 30 mg/day dose explored in this study. This study did not reveal a clear dose-response for the CD34+ levels at the three doses tested when LY2510924 was given in combination with durvalumab.…”

“…The PD parameters for LY2510924 given in combination with durvalumab were similar to those in monotherapy as reported previously. 6 Elevations of similar magnitude and temporal pattern were seen across all leukocyte subsets tested-neutrophils, lymphocytes, monocytes, T, B, NK cells, and CD34+ HSCs. In both the previously reported monotherapy study and this study, a rapid and sustained PD response was observed with treatment as demonstrated by mobilization of leukocytes and stem cells, a clear indication of target modu-lation.…”

“…The dose range of LY2510924 was selected based on the overall clinical information from three prior completed studies CXAA, CXAB (RCC), and CXAC (small-cell lung cancer). 6 Lilly proposed to increase the predefined ANC threshold criteria to 75,000 cells/mL which was a limiting factor in the first-in-human CXAA study.…”

“…The existing preclinical and emerging clinical data indicate CXCR4 to be an attractive target for antitumor drug development. 5,6 LY2510924 is a potent, selective peptide antagonist of CXCR4 both in vitro and in vivo. In several cancer xenograft models utilizing cell lines that express high levels of CXCR4, LY2510924 has demonstrated dosedependent inhibition of tumor growth and metastasis.…”

Molnupiravir: Mechanism of action, clinical, and translational science

“…Population pharmacokinetics (PK) analysis of NHC concentration has been conducted using data from early-and late-stage studies, including data from the phase III MOVe-OUT study in nonhospitalized adults with COVID-19. 16 The PK NHC was found to be similar between healthy participants and participants with COVID-19. Population PK analysis showed that intrinsic and extrinsic factors do not impact the exposures of NHC to a meaningful extent, as the geometric mean ratio of NHC exposures fell within the clinical bounds (0.7-to 2.0fold the exposure of the overall population) determined by exposure-response modeling for all populations.…”