Poster Board II-646
Siplizumab, a humanized IgG1k class monoclonal antibody that targets CD2 expressing T-and NK-cells, was evaluated in phase I dose-escalation trials in patients with CD2-positive lymphoproliferative disorder. The objective of this study was to develop a population pharmacokinetic (PK) model for siplizumab and identify covariates that could explain the variability in siplizumab pharmacokinetic parameters.
A Phase 1, open label, dose-escalation study was conducted in 29 patients (14 males/15 females, age range 34–79 years) who received 0.2–4.8 mg/kg of siplizumab as 1-3 consecutive daily doses every 14 days for a total of 1-8 cycles. Siplizumab serum concentration data was analyzed using a nonlinear mixed effects modeling approach with software (NONMEM). Based on exploratory analysis, 1-and 2-compartment non-linear models were evaluated. Demographic covariates including body weight, age, sex and race (Caucasian/Black/Asian) were screened using Generalized Additive Model (GAM) analysis. Covariates selected during the GAM analysis were further tested for significance in NONMEM using the forward inclusion and backward elimination approach.
Siplizumab concentrations were obtained from all 29 patients in the study yielding a total of 619 serum concentration observations. Pronounced non-linearity in siplizumab serum concentrations was observed after the initial and later dosing cycles, with serum concentrations declining faster at lower dose levels. The data was best described by a two-compartment pharmacokinetic model with zero-order input with parallel linear and non-linear elimination pathways. Goodness of fit plots and model diagnostics indicated good agreement between observed and model predicted serum concentration values. The population estimates for linear clearance was 0.168 L/day with inter-subject variability (ISV) of 50%, and inter-compartmental clearance was 2.83 L/day. Nonlinear elimination parameters, Vmax and Km were 10.32 mcg/day (56% ISV) and 51.8 mcg/L, respectively. Sex of the patients was identified as a significant covariate impacting volumes of distribution. Male patients had higher central and peripheral volumes of distribution of 2.8 L and 3.0 L, respectively, compared to1.38 L and 2.4 L in females [32% vs 50% ISV].
The serum concentration-time profile of siplizumab was adequately described by a two-compartment non-linear PK model. Population parameters were precisely estimated and correspond well to reported PK behaviour of monocolonal antibodies with significant target mediated elimination. The lower volume distribution in females is most likely due to lower body weight compared to males in this study. The population PK model combined with pharmacodynamic data could serve as a tool to guide selection of optimal dose regimens for siplizumab.
No relevant conflicts of interest to declare.
Asterisk with author names denotes non-ASH members.