Bitopertin, a selective oral GLYT1 inhibitor, improves anemia in a mouse model of ß-thalassemia.

Anemia of ß-thalassemia is caused by ineffective erythropoiesis and reduced red cell survival. Several lines of evidence indicate that iron/heme restriction is a potential therapeutic strategy for the disease. Glycine is a key initial substrate for heme and globin synthesis. We provide evidence that bitopertin, a glycine transport inhibitor administered orally, improves anemia, reduces hemolysis, diminishes ineffective erythropoiesis, and increases red cell survival in a mouse model of ß-thalassemia (Hbbth3/+ mice). Bitopertin ameliorates erythroid oxidant damage, as indicated by a reduction in membrane-associated free α-globin chain aggregates, in reactive oxygen species cellular content, in membrane-bound hemichromes, and in heme-regulated inhibitor activation and eIF2α phosphorylation. The improvement of ß-thalassemic ineffective erythropoiesis is associated with diminished mTOR activation and Rab5, Lamp1, and p62 accumulation, indicating an improved autophagy. Bitopertin also upregulates liver hepcidin and diminishes liver iron overload. The hematologic improvements achieved by bitopertin are blunted by the concomitant administration of the iron chelator deferiprone, suggesting that an excessive restriction of iron availability might negate the beneficial effects of bitopertin. These data provide important and clinically relevant insights into glycine restriction and reduced heme synthesis strategies for the treatment of ß-thalassemia.

Glycine Transporter Type I (GlyT1) Inhibitor, Bitopertin: A Journey from Lab to Patient.

Glycine transporter-1 (GlyT1) inhibition has been extensively studied both in pharmaceutical companies and academic institutions primarily as a potential new approach to treat schizophrenia, a severe and chronic mental illness. More recently, preclinical results have suggested that this approach could also have therapeutic potential for CNS disorders beyond schizophrenia as well as for non-CNS indications. Over the past 17 years, Roche has been a key player in the GlyT1 field with the discovery and development of bitopertin, the most advanced GlyT1 inhibitor to date and the only one which completed Phase III clinical studies for schizophrenia. In this article, we relate the eventful journey of the discovery and development of bitopertin, from project initiation in 2001 to its evaluation today in patients suffering from beta-thalassemia, a monogenic hereditary haematological disorder.

Preclinical Reproductive and Developmental Toxicity Profile of a Glycine Transporter Type 1 (Glyt1) Inhibitor.

Bitopertin is a glycine type 1 (GlyT1) inhibitor intended for the treatment of psychiatric disorders. The principle adverse effect in the regulatory reproductive toxicity studies was peri-natal pup death when rat dams were treated during parturition at a dose resulting in five-times the human therapeutic exposure (AUC). Cessation of dosing two days before parturition prevented the pup deaths. Investigatory experiments and pharmacokinetic modelling suggested that the neonatal mortality was related to transplacental passage of bitopertin leading to high systemic levels in the newborn pups. Brain levels of bitopertin in the rat fetus and neonate were two-fold higher than in the mother. As illustrated by knock-out mice models, GlyT1 function is essential for neonatal pup survival in rodents, but is not necessary for normal prenatal morphological development. The glycine transport systems are immature at birth in the rat, but are functionally well-developed in the human newborn. While the relevance to humans of the neonatal mortality seen in rats following late gestational exposure is unknown, bitopertin would not be recommended for use during late pregnancy unless the anticipated benefit for the mother outweighs the potential risk to the newborn.

Cardiovascular safety assessments in the cynomolgus monkey: Unmasking potential background arrhythmias in general toxicity studies.

INTRODUCTION: We describe experience with an unexpectedly high background incidence of atrioventricular block (AVB) observed in Mauritian cynomolgus monkeys (MCM) during preclinical safety assessment for bitopertin, a glycine-transporter-1 inhibitor. METHODS: Preclinical ECGs were reviewed to assess potential effects on cardiac conductivity, specifically AVB. RESULTS: Bitopertin administration in Chinese/Vietnamese monkeys (CVM; n=46) or MCM (n=64, from all relevant studies) revealed dose-dependent hypoactivity with a lack of expected increases in heart rate in response to chair-restraint during ECG recordings. Instances of 2° AVB were detected post-dose in two repeat-dose studies in MCM. AVB was generally restricted to animals showing a lower than expected increase in heart rate during restraint compared to placebo conditions (111-161 to 220-250bpm). A subsequent study in MCM prescreened for AVB found pre-existing 2° AVB in 15.4% of animals. After exclusion of these animals, no incidences of AVB were identified over 36weeks of bitopertin treatment. No evidence of AVB was observed in CVM in a 14-day study with continuous ECG recordings or in any clinical studies to date. DISCUSSION: Bitopertin-treatment was not associated with a direct effect on AV conduction in AVB naive MCM. Pre-test detection of AVB in MCM was likely due to the unmasking of pre-existing AVB through a slowed heart rate. The background incidence of AVB in the current MCM cohort was much higher than has been previously reported. These data suggest that ECG prescreening of unrestrained, nonstressed animals is recommended for the accurate assessment of possible treatment-related increases in AVB, especially in MCM.

Post-marketing assessment of neuropsychiatric adverse events in influenza patients treated with oseltamivir: an updated review.

A 2008 review by our group concluded that the risk of neuropsychiatric adverse events (NPAEs) in influenza patients was not increased by oseltamivir exposure, and did not identify any mechanism by which oseltamivir or its metabolites could cause or worsen such events. The current article reviews new information on this topic. Between September 16, 2007 and May 15, 2010, 1,805 spontaneously-reported NPAEs were identified in 1,330 patients receiving oseltamivir: 767 (42.5%) from Japan, 296 (16.4%) from the USA, and 742 (41.1%) from other countries. NPAEs were more common in children: 1,072 (59.4%) events were in those aged ≤16 years. NPAEs often occurred within 48 h of treatment initiation (953 events; 52.8%). Nearly half of the events were serious in nature (838; 46.4%). The three largest categories of events were abnormal behavior (457 events, 25.3%), miscellaneous psychiatric events (370; 20.5%), and delusions/perceptual disturbances (316 events, 17.5%). A total of 1,545 events (85.6%) in eight different categories were considered to be delirium or delirium-like. Twenty-eight suicide-related events were reported. A US healthcare claims database analysis showed that the risk of NPAEs in 7,798 oseltamivir-treated patients was no higher than that in 10,411 patients not on antivirals, but a study on oseltamivir and abnormal behavior in Japan was less conclusive. NPAE frequency in oseltamivir-exposed Japanese and Taiwanese children with influenza was the same as in unexposed children. New analysis of the UK General Practice Research Database showed that the relative adjusted risk of NPAEs in influenza patients was 2.18-times higher than in the general population. Other epidemiology studies report frequent occurrence of encephalitis and similar disorders in influenza patients independently of oseltamivir exposure. The new data support the findings of the original assessment. Evidence suggests that influenza-related encephalopathies are caused by influenza-induced inflammatory responses, but more work is needed to confirm the underlying mechanisms.

Development of a physiologically based model for oseltamivir and simulation of pharmacokinetics in neonates and infants.

BACKGROUND: Physiologically based pharmacokinetic (PBPK) modelling can assist in the development of drug therapies and regimens suitable for challenging patient populations such as very young children. This study describes a strategy employing PBPK models to investigate the intravenous use of the neuraminidase inhibitor oseltamivir in infants and neonates with influenza. METHODS: Models of marmoset monkeys and humans were constructed for oseltamivir and its active metabolite oseltamivir carboxylate (OC). These models incorporated physicochemical properties and in vitro metabolism data into mechanistic representations of pharmacokinetic processes. Modelled processes included absorption, whole-body distribution, renal clearance, metabolic conversion of the pro-drug, permeability-limited hepatic disposition of OC and age dependencies for all of these processes. Models were refined after comparison of simulations in monkeys with plasma and liver concentrations measured in adult and newborn marmosets after intravenous and oral dosing. Then simulations with a human model were compared with clinical data taken from intravenous and oral studies in healthy adults and oral studies in infants and neonates. Finally, exposures after intravenous dosing in neonates were predicted. RESULTS: Good simulations in adult marmosets could be obtained after model optimizations for pro-drug conversion, hepatic disposition of OC and renal clearance. After adjustment for age dependencies, including reductions in liver enzyme expression and renal function, the model simulations matched the trend for increased exposures in newborn marmosets compared with those in adults. For adult humans, simulated and observed data after both intravenous and oral dosing showed good agreement and although the data are currently limited, simulations in 1-year-olds and neonates are in reasonable agreement with published results for oral doses. Simulated intravenous infusion plasma profiles in neonates deliver therapeutic concentrations of OC that closely mimic the oral profiles, with 3-fold higher exposures of oseltamivir than those observed with the same oral dose. CONCLUSIONS: This work exemplifies the utility of PBPK models in predicting pharmacokinetics in the very young. Simulations showed agreement with a wide range of observational data, indicating that the processes determining the age-dependent pharmacokinetics of oseltamivir are well described.