Semi-physiologic Population PKPD Model Characterizing the Effect of Bitopertin (RG1678) Glycine Reuptake Inhibitor on Hemoglobin Turnover in Humans Franziska Schaedeli Stark, Meret Martin-Facklam, Carsten Hofmann, Bruno Boutouyrie, Valérie Cosson F. Hoffmann-La Roche, Ltd., Basel, Switzerland PAGE 2012, abstract #2553, Venice, 06 June 2012
Background Bitopertin is a selective glycine reuptake inhibitor targeting the glycine type 1 transporter (GlyT1) Currently in late stage development as a potential novel therapeutic approach in schizophrenia In the brain, inhibition of GlyT1 results in increased synaptic glycine levels leading to improved NMDA* receptor function Outside the brain, GlyT1 is also localized on erythrocyte precursors in the bone marrow and on circulating reticulocytes Glycine is required for hemoglobin (Hb) synthesis Complete ablation of GlyT1 in knock-out mice results in a 26 % Hb decrease 1 The hematological effect of bitopertin was studied in a 4 month phase 1 study in healthy subjects 1 Schranzhofer et al., ASH meeting 2011, abstract #345 *NMDA = N-methyl-D-aspartate 2
Bitopertin Effect on Hemoglobin Synthesis Proposed mechanism: reduced Hb synthesis is due to reduced glycine uptake in erythrocyte precursors Bone Marrow Erythrocyte precursors Hemoglobin Synthesis Peripheral Blood Red blood cells (RBC) Reticulocytes + Erythrocytes Hemoglobin (Hb) RBC Other transporters Low affinity Glycine Glycine GlyT1 High affinity Bitopertin 3
Objectives A semi-mechanistic PKPD model for bitopertin was developed in order to Characterize the proposed effect of GlyT1 inhibition on the hematological system, taking into account hemoglobin synthesis and red blood cell turnover Support drug development with respect to the effect of bitopertin on hemoglobin concentrations as an important clinical parameter 4
Phase 1 Study in Healthy Subjects To assess the hematological effects of 4 month treatment Day 1 Day 120 Day 240 Placebo Screening 10 mg Bitopertin qd 30 mg Bitopertin qd Hematological follow-up 60 mg Bitopertin qd Day -1, 7, 14 2-weekly 119, 126 2-weekly Hematological sampling and trough PK Population: 67 healthy male and female subjects enrolled Aged 18 to 45 years; baseline Hb within normal lab range PK profile 5
Hematological Data Observed in Healthy Subjects Hemoglobin blood concentration Hb (g/l) Dose dependent decrease of Hb Reversible effect Plateau of effect delayed due to RBC lifespan No subject reached Hb discontinuation threshold (100 g/l in females, 110 g/l in males) About one week to PK steadystate 6
Hematological Data Observed in Healthy Subjects Abs. change from baseline Hb (g/l) RBC (10 12 /L) Hb RBC Abs. change from baseline Mean Corpuscular Hemoglobin MCH = Hb/RBC (pg/rbc) 0 mg 10 mg 30 mg 60 mg Decreased amount of Hb per red blood cell due to decreased Hb synthesis Plateau of effect delayed due to RBC lifespan MCH best reflects drug effect on Hb synthesis 7
Semi-physiologic PKPD Model for GlyT1 Inhibitory Effect on Hemoglobin + KinRBC KinHb Inhibitory drug effect on KinHb SexEff Hemoglobin = LS = Lifespan of RBC RBC1 RBC2 RBC3 RBC4 MCH1 MCH2 MCH3 MCH4 Feedback: Hb decrease stimulates RBC production 4 RRR i MMM i i=1 Two parallel chains of transit compartments 1 represent the production, senescence and elimination of RBC, with their respective MCH AUCss is driving the inhibitory drug effect Model fit to MCH and RBC data simultaneously in NONMEM 7 Estimated Parameters: KinRBC, KinHb, LS, Emax, AUC50, Feedback, SexEff 1 Hamrén et al., Clin Pharm Ther 84:228-35, 2008 8
Model Diagnostics: GoF Plots RBC MCH Individual Fits: MCH and RBC vs. TIME RBC (10 12 /L) MCH (pg/cell) TIME (days) o DV IPRED PRED 9
Model Predictive Performance for Hemoglobin VPC for hemoglobin, predicted as cumulative RBC x MCH Hemoglobin (g/l) 80 100 120 140 160 180 Placebo VPC for HGB (RBC*MCH) at GlyT1 P (N=15) 90percent PI for model glyhb350h_vpc; 15 Pat 0 50 100 150 200 Hemoglobin (g/l) 80 100 120 140 160 180 10 mg (N=17) VPC for HGB (RBC*MCH) at 10 mg G 90percent PI for model glyhb350h_vpc; 17 Pat 0 50 100 150 200 4 HH = RRR i MMM i i=1 Simulated Hb Median, 5 th, 95 th Hemoglobin (g/l) 80 100 120 140 160 180 Time (day) 30 mg (N=16) VPC for HGB (RBC*MCH) at 30 mg G 90percent PI for model glyhb350h_vpc; 16 Pat Hemoglobin (g/l) 80 100 120 140 160 180 Time (day) 60 mg (N=14) VPC for HGB (RBC*MCH) at 60 mg G 90percent PI for model glyhb350h_vpc; 14 Pat Observed Hb Median 5 th, 95 th 0 50 100 150 200 0 50 100 150 200 Time (day) Time (day) 10
Results PKPD parameter estimates Unit Estimate % RSE IIV (% CV) LS days 126 4.5 24.9 KinHB pg/cell/day 0.949 4.8 28.0 KinRBC 10^12/L/day 0.039 4.3 24.3 Feedback 1.38 12.4 Emax fraction * 13.2 AUC50 mg/l*h * 23.2 49.2 SexEff -0.119 8.0 ERR_RBC 10^12/L 0.183 3.0 ERR_MCH pg/cell 0.346 2.7 Physiological parameters estimates generally in line with values in the literature Baseline values (derived) Unit males females MCH 0 pg/cell 29.8 29.8 RBC 0 10^12/L 4.9 4.3 HB 0 g/l 147 129 % RSE: Relative Standard Error Feedback mechanism (FDB): Scaling parameter to describe the stimulation on RBC production rate as a feedback to Hb reduction KinRBC = KinRBC 0 *[1+(HB 0 -HB)/HB 0 *FDB] SexEff: Female patients have 11.9 percent lower KinRBC 11
What is the predicted long term effect on Hb? Doses up to 20 mg tested in phase 3 Predicted Hb change from baseline (%) for 360 days of treatment RBC life span - 4 % - 7 % 0 mg 10 mg 20 mg Maximum Hb change from baseline (nadir) expected shortly after one RBC life span Less than 10 % Hb drop expected at projected therapeutic doses 12
Conclusions The physiology of the hematopoietic system together with the inhibitory effect of bitopertin on Hb synthesis were integrated in the semi-physiologic PKPD model to successfully fit the data from healthy subjects The effect on hemoglobin, as the key clinical parameter, is best predicted by fitting MCH and RBC data simultaneously The model is a useful tool to support bitopertin drug development, and phase 3 trials will provide further information 13