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, Valerie Cosson
F. Hoffmann-La Roche, Ltd., Basel, Switzerland
Objectives: Bitopertin, a glycine reuptake inhibitor in development for the treatment of schizophrenia, selectively inhibits the glycine transporter type 1 (GlyT1), which is localized on pre-erythrocytes in addition to being expressed in the CNS. A reduced glycine uptake leads to a dose dependent decrease of hemoglobin (Hb) synthesis in animals and humans. A semi-physiologic PKPD model of bitopertin hematological effect in red blood cells (RBC) has been developed as a tool to estimate the long term risk of anemia due to GlyT1 inhibition.
Methods: The hematological effect of GlyT1 inhibition was studied in 62 healthy subjects treated with placebo, 10, 30, or 60 mg bitopertin daily for 120 days. Hb, RBC, and mean corpuscular Hb (MCH) data were collected during treatment and 120 days follow-up. A semi-physiologic population PKPD model taking into account the Hb and RBC turnover has been developed in NONMEM 7. Two parallel chains of four transit compartments sharing the same transit rate constant but with their own production rates represent RBC and MCH turnover. Since blood Hb is the cumulative product of RBC*MCH in all compartments, the model was fit simultaneously to the MCH and RBC data. The drug acts as an inhibitory Emax model on MCH production rate (i.e. Hb synthesis), with individual AUCss estimates driving the effect. Hb decrease triggers a feedback to increase the RBC production rate.
Results: A dose-related decrease of MCH in RBC over time was observed, which was reversible after treatment discontinuation. The RBC start to increase due to feedback after about 4 weeks at 30 and 60 mg. All observed data were well predicted. Estimates of Hb synthesis rate (0.96 pg/cell/day), RBC production rate (0.04 * 1012 /L/day) and RBC life span (124 days) are in line with expected physiological values. A 12 % lower RBC production rate was estimated for females, resulting in lower baseline RBC and Hb values. The model predicts that a nadir of Hb decrease is reached after about one RBC life span, followed by a plateau of effect at slightly higher levels when the steady-state of the hematological system, including feedback reaction, is reached. The model predicts a typical Hb decrease of 14 % at nadir for the 60 mg dose, and less than 10 % for 20 mg.
Conclusions: The semi-mechanistic PKPD model will be a useful tool to characterize the hematological effect of bitopertin in the target population, to predict the risk of anemia and to support Hb monitoring guidelines for patients treated with bitopertin.