Population Pharmacokinetics of Siplizumab (MEDI-507) Implications for Dosing E
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Population Pharmacokinetics of Siplizumab (MEDI-507) Implications for Dosing E. Gibiansky, PhD1; J. Janik, MD2; D. Mahony, MD2; K. Kaucic, MD1; L. Hammershaimb, MD1; G. Robbie, PhD1 1 MedImmune, Inc., Gaithersburg, MD, USA; 2 Metabolism Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA Abstract T-Cell Depletion Data IMPLICATIONS FOR DOSING ◗ Data too sparse for pharmacokinetic/pharmacokinetic (PK/PD) ◗ “Target-mediated” elimination is governed by Objectives: Siplizumab (MEDI-507), a humanized IgG1k class modeling. monoclonal antibody, which targets CD2 expressing T- and • Availability and affinity to target NK-cells, is being evaluated in an ongoing open-label • Efficient depetion of CD4+ and CD8+ T cells in peripheral • Distribution of drug to target outside blood phase I dose-escalation trial in patients with CD2-positive blood at all doses ◗ According to T-cell depletion data drug rapidly kills cells lymphoproliferative diseases. The aim of this report is to • All PD measurements collected at peak effect in blood. describe a population pharmacokinetic model of siplizumab • No PD measurements at trough or between doses ◗ Continued rapid elimination in the absence of target cells and simulations of alternative doses/regimens performed for in blood suggests optimization of dosing. Scaled observed T-cell counts. • presence of target cells in tissues Methods: 490 serum siplizumab samples were collected Predicted serum concentration. • distribution/elimination of drug outside of blood from 25 patients who received 0.4–4.8 mg/kg of siplizumab as ID=6 Cohort=2 1–3 consecutive daily doses every 14 days for 1–8 cycles. 8 g IMPLICATION To maximize drug effect, maintain serum concentrations The population pharmacokinetic analysis was performed using 6 NONMEM. Linear and nonlinear 1- and 2-compartment models ALWAYS above saturation, ie, several times above 15 μg/mL. 4 were evaluated. Simulations were performed to identify doses and Simulated Concentrations for Different Dosing dosing regimens that would maintain drug concentrations above 2 target levels necessary for saturation of CD2 receptors. Regimens 0 Concentration (µg/mL) Q14D AND WEEKLY DOSING Results: Siplizumab pharmacokinetics was described by a 0 20 40 60 80 1-compartment model with 2 parallel mechanisms of clearance, Time (d) linear and Michaelis-Menton (MM) elimination. The half-life of Q14D ID=10 Cohort=4 Cycle 4 the linear portion of elimination (presumably, FcRn mediated) 14 9.6 mg/kg Lower 90% CI 4.8 mg/kg 9.6 mg/kg was 31 days, consistent with expectations, while MM elimination 12 250 2.4 mg/kg 4.8 mg/kg 10 1.2 mg/kg 200 (target-mediated clearance) had a short half-life (38 hours at 8 concentrations below Km of 15 μg/mL) suggesting suboptimal 6 150 target saturation. Pharmacokinetics did not change over time, 4 100 which was expected, since no immunogenicity was observed. 2 0 50 Simulations of various dosing regimens suggested that doses Concentration (µg/mL) 0 100 200 300 400 0 >4.8 mg/kg weekly are necessary to maintain drug concentrations Time (d) Concentration (µg/mL) 42 44 46 48 50 52 54 56 Time (d) above target level (22Km, 30 μg/mL, the level at which half-life of target-mediated clearance increases 3 times) for 90% of patients. ID=12 Cohort=4 14 Weekly Cycles 7 & 8 Lower 90% CI Conclusions: Siplizumab concentrations follow 1-compartment 12 4.8 mg/kg 3.4 mg/kg 4.8 mg/kg 10 kinetics with linear FcRn-mediated and nonlinear target- 250 2.4 mg/kg 3.4 mg/kg 1.2 mg/kg mediated clearance. The short half-life of target-mediated 8 6 200 clearance suggests that tissue target saturation is suboptimal at 4 150 doses/regimens studied thus far. Dose escalation was accelerated 2 100 based on simulations, with weekly doses ≥4.8 mg/kg, to maintain 0 Concentration (µg/mL) concentrations above the target level and to possibly increase 0 20 40 60 80 100 120 50 Time (d) 0 target saturation in the tissues. Concentration (µg/mL) 42 44 46 48 50 52 54 56 Time (d) Background CI=condence intervals. ◗ Siplizumab is a humanized IgG1k class anti-CD2 monoclonal Results antibody. WEEKLY DOSING ◗ Binds to CD2 on human T-lymphocytes (T-cells), natural killer Pharmacokinetics (NK) cells, and thymocytes. ◗ One-compartment population PK model. % of time spent at concentration 200 Weekly dose ≥30 or 75 µg/mL ◗ 1 ◗ 9.6 mg/kg Mechanism of action via targeted T-cell toxicity. Two mechanisms of elimination 150 4.8 mg/kg Level (µg/mL) 30 75 3.4 mg/kg ◗ CD2 binding region derived from rat monoclonal antibody.2 • Linear (presumably FcRn) 100 Dose (mg/kg) 3.4 4.8 9.6 3.4 4.8 9.6 Cycle 1 31 77 100 0 1 89 (µg/mL) 50 ◗ • Fc region is entirely of human origin (FcRn). Nonlinear (CD2-mediated) 0 Cycle 7 46 100 100 0 73 100 2 4 6 8 At levels of 30 and 75 µg/mL, target-mediated ◗ Linear and nonlinear elimination expected for siplizumab. Concentration Trough Cycle t1/2 of siplizumab (38 h) increases 3- and 6-fold, Drug respectively. • FcRn mechanism (half-life [t ] ~26 days) ½ Parameter Est Value 90% CI Variability % CV Predicted trough levels at lower • Target-mediated elimination Vd (L/77 kg) 4.7 4.2–5.3 25 band of 90% confidence intervals. Vd • Linear at low drug concentrations K (L/d) 0.022 0.006–0.07 Km (µg/mL) 15 10–37 84 Vm/Km • Saturable at high drug concentrations K Vm (µg/mL/d) 6.6 4.7–10 Dosing Recommendation 1+Conc/K ◗ Ongoing (as of December 2006) phase 1 trial demonstrated m ◗ At least 4.8–9.0 mg/kg dose once a week to assure that most activity (27% RR) and safety (no maximum tolerated dose patients maintain high concentration levels (above 30 or reached). 75 μg/ mL) • No dose response ◗ FcRn elimination • t½ 31 days Methods ◗ “Target-mediated” elimination • t 38 hours (very short!!) at concentrations below K Study ½ m (<15 μg/mL) Conclusions ◗ Phase 1, open-label, dose-escalation study in patients with ◗ Saturation of elimination at concentrations above K . CD2-positive relapsed/refractory T-cell NHL (ATL, LGL, m ◗ Siplizumab follows a 1-compartment model with parallel linear and saturable elimination. PTCL, CTCL). Observed serum concentration. Dosing Predicted serum concentration. ◗ Half-life of the saturable pathway is 38 hours at low 0.6 mg/kg ID=5 Cohort=2 concentrations. ◗ Cohorts 1–7: 0.4, 0.6, 0.8, 1.2, 2.4, 3.4, and 4.8 mg/kg Q14Days, 8 ◗ total dose administered over 2–3 days (~2-h infusions). Rapid elimination in the absence of target cells in peripheral 6 blood suggests the presence of target cells in tissues and ◗ Cohorts 8–9: 0.8 or 3.4 mg/kg once weekly, dose over single day distribution of drug to these tissues. (no pharmacokinetic (PK) data for 3.4 mg/kg dose). 4 ◗ Weekly dosing achieves desired concentrations at lower doses (µg/mL) Treatment 2 than Q14D dosing. ◗ Until progression, but no more than 16 weeks in cohorts 1–5. 0 ◗ Dosing recommendation Siplizumab ConcentrationSiplizumab 0 10 20 30 Pharmacokinetic Data Time (d) • At least 4.8 mg/kg weekly (and preferably higher), if safety ◗ 490 serum samples from 25 patients in cohorts 1–8. 1.2 mg/kg ID=12 Cohort=4 allows ◗ Most patients’ trough values below limit of quantitation and no 15 Later Developments accumulation. 10 ◗ During trial continuation with intensified dosing, several cases ◗ Only trough and peak samples for treatment cycles >1. of Epstein-Barr Virus lymphoproliferative disease occurred Pharmacokinetic Analysis (µg/mL) 5 leading to suspension of enrollment for safety evaluation. ◗ Population PK using NONMEM V. 0 Siplizumab ConcentrationSiplizumab 0 20 40 60 80 Time (d) References 3.4 mg/kg ID=20 Cohort=7 1. Xu Y, et al. Clin Exp Immunol. 2004;138:476-483. 120 2. de la Parra B, et al. Belg J Zool. 1991;121(suppl 1):13 80 40 (µg/mL) 0 0 10 20 30 40 Siplizumab ConcentrationSiplizumab Time (d) Population Approach Group in Europe Sixteenth Annual Meeting June 13–15, 2007 Copenhagen, Denmark Research supported by MedImmune, Inc..