Carsten Hofmann

Characterization of [11C]RO5013853, a novel PET tracer for the glycine transporter type 1 (GlyT1) in humans.

We characterize a novel radioligand for the glycine transporter type 1 (GlyT1), [(11)C]RO5013853, in humans. Ten healthy male volunteers, 23-60 years of age, were enrolled in this PET study; seven subjects participated in the evaluation of test-retest reliability and three subjects in whole body dosimetry. Subjects were administered intravenous bolus injections of approximately 1100 MBq (30 mCi) [(11)C]RO5013853 with a high specific activity of about 481 GBq (13 Ci)/μmol. Standard compartmental model analysis with arterial plasma input function, and an alternative noninvasive analysis method which was evaluated and validated by occupancy studies in both baboons and humans, were performed. Mean parameter estimates of the volumes of distribution (VT) obtained by a 2-tissue 5-parameter model were higher in the cerebellum, pons, and thalamus (1.99 to 2.59 mL/mL), and lower in the putamen, caudate, and cortical areas (0.86 to 1.13 mL/mL), with estimates showing less than 10% difference between test and retest scans. Tracer retention was effectively blocked by the specific glycine reuptake inhibitor (GRI), bitopertin (RG1678). [(11)C]RO5013853 was safe and well tolerated. Human dosimetry studies showed that the effective dose was approximately 0.0033 mSv/MBq, with the liver receiving the highest absorbed dose. In conclusion, quantitative dynamic PET of the human brain after intravenous injection of [(11)C]RO5013853 attains reliable measurements of GlyT1 binding in accordance with the expected transporter distribution in the human brain. [(11)C]RO5013853 is a radioligand suitable for further clinical PET studies. Full characterization of a novel radiotracer for GlyT1 in humans is provided. The tracer has subsequently been used to assess receptor occupancy in healthy volunteers and to estimate occupancy at doses associated with best efficacy in a clinical trial with schizophrenic patients with predominantly negative symptoms.

Effect of Saquinavir‐Ritonavir on Cytochrome P450 3A4 Activity in Healthy Volunteers Using Midazolam as a Probe

Study Objective. To investigate the inhibitory potential of multiple doses of ritonavir‐boosted saquinavir on the pharmacokinetics of oral midazolam, a cytochrome P450 (CYP) 3A4 model substrate.

Evaluation of the effects of bitopertin (RG1678) on cardiac repolarization: a thorough corrected QT study in healthy male volunteers.

BACKGROUND Bitopertin (RG1678) is a selective glycine reuptake inhibitor currently in Phase III development for the treatment of schizophrenia. Thorough QT studies to assess the effects of candidate drugs on cardiac repolarization and proarrhythmic potential are required by regulatory authorities and are a common part of the drug development process. A clinically relevant effect on QT interval is suspected if prolongation of the corrected QT interval (QTc) is ∼5 milliseconds or more, evidenced by an upper 1-sided 95% CI for the mean effect on the QTc of at least 10 milliseconds. OBJECTIVE The goal of this study was to investigate the effect of bitopertin on the QTc interval in healthy male volunteers. METHODS This was a multiple-dose, randomized, double-blind, double-dummy, placebo-controlled, parallel-group study using bitopertin 30 mg (n = 56) or bitopertin 175 mg (n = 56) once daily for 10 days plus placebo on day 11, moxifloxacin 400 mg on day 1 plus placebo once daily for 10 days (n = 29), or placebo once daily for 10 days plus moxifloxacin 400 mg on day 11 (n = 28). Continuous Holter ECGs were obtained on days -1, 1, 10, and 11, and the placebo-corrected mean change from time-matched baseline in the QT interval calculated by using Fridericias formula (QTcF) on day 10 was the primary end point. Pharmacokinetic parameters of bitopertin were determined on day 10 by using HPLC-MS/MS methods to obtain bitopertin plasma drug concentrations. Adverse events were recorded throughout the study. RESULTS A total of 169 predominantly white, healthy male volunteers (mean age, 31.8 years; range, 19-59 years) were randomized to treatment; 162 completed the study. The mean change in placebo-corrected QTcF from baseline to day 10 of bitopertin ranged from -2.8 to 3.9 milliseconds. The upper bound of the 1-sided 95% CI was <10 milliseconds at all time points with both doses. There was no relation between bitopertin concentrations and changes in QTcF or other ECG variables. Assay sensitivity was confirmed by a placebo-corrected mean change from time-matched baseline in QTcF of 10.6 milliseconds (lower bound of the 1-sided 98.3% CI, 6.9 milliseconds) 4 hours after moxifloxacin administration. Peak bitopertin plasma concentrations were achieved ∼4 hours after dosing. The terminal elimination t(½) was ∼53 hours. No safety or tolerability concerns were noted with bitopertin at either dose. Dizziness, nausea, and blurred vision were more common in the bitopertin 175-mg group compared with the bitopertin 30-mg or placebo groups. CONCLUSION Multiple dosing with bitopertin 30 mg or 175 mg did not affect QTcF in these healthy male volunteers. ClinicalTrials.gov identifier: NCT01613040.

24-MONTH AMYLOID PET RESULTS OF THE GANTENERUMAB HIGH-DOSE OPEN LABEL EXTENSION STUDIES

doses of LY3002813 resulted in significant reductions in florbetapir F18 tracer uptake on PET by 3 months, with further reduction with repeat dosing over time. For the initial dosing cohorts, reductions in florbetapir F18 at 3 months were -11.8 (SD 21.1) centiloids after a single dose of 10 mg/kg IV (n1⁄47); -39.0 (SD 18.1) centiloids after a single dose of 20mg/kg IV (n1⁄47); and -44.5 (SD 24.3) centiloids for 10mg/kg IVadministered every two weeks (n1⁄410). In patients with up to 72 weeks of follow-up after completion of treatment, the reduced post-treatment florbetapir F18 PET SUVr levels were maintained, without returning to pre-dose baseline levels. Conclusions: LY3002813 demonstrates significant, rapid and sustained reduction in cortical amyloid plaque in Alzheimer’s patients.

THE EFFECT OF LOW DOSES OF GANTENERUMAB ON AMYLOID AND TAU BIOMARKERS IN CEREBROSPINAL FLUID (CSF) IN THE MARGUERITE ROAD STUDY

doses of LY3002813 resulted in significant reductions in florbetapir F18 tracer uptake on PET by 3 months, with further reduction with repeat dosing over time. For the initial dosing cohorts, reductions in florbetapir F18 at 3 months were -11.8 (SD 21.1) centiloids after a single dose of 10 mg/kg IV (n1⁄47); -39.0 (SD 18.1) centiloids after a single dose of 20mg/kg IV (n1⁄47); and -44.5 (SD 24.3) centiloids for 10mg/kg IVadministered every two weeks (n1⁄410). In patients with up to 72 weeks of follow-up after completion of treatment, the reduced post-treatment florbetapir F18 PET SUVr levels were maintained, without returning to pre-dose baseline levels. Conclusions: LY3002813 demonstrates significant, rapid and sustained reduction in cortical amyloid plaque in Alzheimer’s patients.

Correction to: A phase III randomized trial of gantenerumab in prodromal Alzheimer’s disease

Following publication of the original article [1], the author reported errors in the formatting of the table. The details of the errors are as follows: