Characterization of anti-drug antibody responses to the T-cell engaging bispecific antibody cibisatamab to understand the impact on exposure.

An appropriately designed pharmacokinetic (PK) assay that is sensitive for anti-drug antibody (ADA) impact on relevant exposure is an alternative strategy to understand the neutralizing potential of ADAs. However, guidance on how to develop such PK assays and how to confirm the functional ADA impact on exposure is missing. Here, the PK assay of a T-cell-engaging bispecific antibody, cibisatamab, was developed based on its mechanism of action (MoA).

CEA-CD3 bispecific antibody cibisatamab with or without atezolizumab in patients with CEA-positive solid tumours: results of two multi-institutional Phase 1 trials.

Cibisatamab is a bispecific antibody-based construct targeting carcinoembryonic antigen (CEA) on tumour cells and CD3 epsilon chain as a T-cell engager. Here we evaluated cibisatamab for advanced CEA-positive solid tumours in two open-label Phase 1 dose-escalation and -expansion studies: as a single agent with or without obinutuzumab in S1 (NCT02324257) and with atezolizumab in S2 (NCT02650713). Primary endpoints were safety, dose finding, and pharmacokinetics in S1; safety and dose finding in S2.

Managing the Impact of Immunogenicity in an Era of Immunotherapy: From Bench to Bedside.

Biotherapeutics have revolutionized our ability to treat life-threatening diseases. Despite clinical success, the use of biotherapeutics has sometimes been limited by the immune response mounted against them in the form of anti-drug antibodies (ADAs). The multifactorial nature of immunogenicity has prevented a standardized approach for assessing this and each of the assessment methods developed so far does not exhibit high enough reliability to be used alone, due to limited predictiveness.

A Method for the Validation of Simulated Mixing Characteristics of Two Dynamic Mixers in Single-Screw Extrusion.

The field of simulation and optimisation of dynamic mixing elements ('mixers') is lacking good methods for spatially resolved validation and flow visualisation. For this reason, the authors present an experimental setup that gives better insight into the thermal, distributive and dispersive mixing process by measuring melt temperatures upstream of the mixer and injecting a secondary, visually distinguishable stream of melt upstream. Running extrusion trials for a polyethylene on both a rhomboidal and a Maddock mixer, temperatures, gray scale distribution of images of extrudates and size of dispersed domains in incompatible polystyrene were measured.

Safety and Tolerability of Multiple Ascending Doses of PRX002/RG7935, an Anti-α-Synuclein Monoclonal Antibody, in Patients With Parkinson Disease: A Randomized Clinical Trial.

Importance: Aggregated α-synuclein is believed to be central to the pathogenesis of Parkinson disease (PD). PRX002/RG7935 (PRX002) is a humanized monoclonal antibody designed to target aggregated forms of α-synuclein, thereby inhibiting neuron-to-neuron transfer of presumed pathogenic forms of α-synuclein, potentially resulting in neuronal protection and slowing disease progression.

Objective: To evaluate the safety and tolerability of multiple intravenous infusions of PRX002 in patients with idiopathic PD.

Progress in Prediction and Interpretation of Clinically Relevant Metabolic Drug-Drug Interactions: a Minireview Illustrating Recent Developments and Current Opportunities.

Purpose Of Review: This review gives a perspective on the current "state of the art" in metabolic drug-drug interaction (DDI) prediction. We highlight areas of successful prediction and illustrate progress in areas where limits in scientific knowledge or technologies prevent us from having full confidence.

Recent Findings: Several examples of success are highlighted.

Effect of the Wetting Agent Sodium Lauryl Sulfate on the Pharmacokinetics of Alectinib: Results From a Bioequivalence Study in Healthy Subjects.

The anaplastic lymphoma kinase (ALK) inhibitor alectinib is an effective treatment for ALK-positive non-small-cell lung cancer. This bioequivalence study evaluated the in vivo performance of test 3 formulations with the reduced wetting agent sodium lauryl sulfate (SLS) content. This randomized, 4-period, 4-sequence, crossover study compared alectinib (600 mg) as 25%, 12.

Clinical Drug-Drug Interactions Through Cytochrome P450 3A (CYP3A) for the Selective ALK Inhibitor Alectinib.

The efficacy and safety of alectinib, a central nervous system-active and selective anaplastic lymphoma kinase (ALK) inhibitor, has been demonstrated in patients with ALK-positive (ALK+) non-small cell lung cancer (NSCLC) progressing on crizotinib. Alectinib is mainly metabolized by cytochrome P450 3A (CYP3A) to a major similarly active metabolite, M4. Alectinib and M4 show evidence of weak time-dependent inhibition and small induction of CYP3A in vitro.

Effect of Food and Esomeprazole on the Pharmacokinetics of Alectinib, a Highly Selective ALK Inhibitor, in Healthy Subjects.

Alectinib, an anaplastic lymphoma kinase (ALK) inhibitor, is approved for treatment of patients with ALK+ non-small cell lung cancer who have progressed, on or are intolerant to, crizotinib. This study assessed the effect of a high-fat meal and the proton pump inhibitor, esomeprazole, on the pharmacokinetics (PK) of alectinib. This was an open-label, 2-group study in healthy subjects.

Absorption, distribution, metabolism and excretion (ADME) of the ALK inhibitor alectinib: results from an absolute bioavailability and mass balance study in healthy subjects.

1. Alectinib is a highly selective, central nervous system-active small molecule anaplastic lymphoma kinase inhibitor. 2.

Effects of the glycine reuptake inhibitors bitopertin and RG7118 on glycine in cerebrospinal fluid: results of two proofs of mechanism studies in healthy volunteers.

Rationale: Hypofunction of NMDA receptors has been implicated in neuropsychiatric disorders including schizophrenia. NMDA receptor neurotransmission can be enhanced through inhibition of glycine reuptake by the glycine transporter type 1 (GlyT1).

Objectives: The primary objective of these studies was to explore the relationship between plasma exposure and glycine cerebrospinal fluid (CSF) concentrations following administration of bitopertin and RG7118 in healthy volunteers.

Combining 'Bottom-Up' and 'Top-Down' Methods to Assess Ethnic Difference in Clearance: Bitopertin as an Example.

Background And Objectives: We propose a strategy for studying ethnopharmacology by conducting sequential physiologically based pharmacokinetic (PBPK) prediction (a 'bottom-up' approach) and population pharmacokinetic (popPK) confirmation (a 'top-down' approach), or in reverse order, depending on whether the purpose is ethnic effect assessment for a new molecular entity under development or a tool for ethnic sensitivity prediction for a given pathway. The strategy is exemplified with bitopertin.

Methods: A PBPK model was built using Simcyp(®) to simulate the pharmacokinetics of bitopertin and to predict the ethnic sensitivity in clearance, given pharmacokinetic data in just one ethnicity.

Effects of Cytochrome P450 3A4 Inhibitors-Ketoconazole and Erythromycin-on Bitopertin Pharmacokinetics and Comparison with Physiologically Based Modelling Predictions.

Objective: To assess the effect of strong and moderate cytochrome P450 (CYP) 3A4 inhibition on exposure of bitopertin, a glycine reuptake inhibitor primarily metabolized by CYP3A4, and to compare the results with predictions based on physiologically based pharmacokinetic (PBPK) modelling.

Methods: The effects of ketoconazole and erythromycin were assessed in two male volunteer studies with open-label, two-period, fixed-sequence designs. Twelve subjects were enrolled in each of the studies.

Physiologically based absorption modelling to predict the impact of drug properties on pharmacokinetics of bitopertin.

Bitopertin (RG1678) is a glycine reuptake inhibitor in phase 3 trials for treatment of schizophrenia. Its clinical oral pharmacokinetics is sensitive to changes in drug substance particle size and dosage form. Physiologically based pharmacokinetic (PBPK) absorption model simulations of the impact of changes in particle size and dosage form (either capsules, tablets, or an aqueous suspension) on oral pharmacokinetics was verified by comparison to measured plasma concentrations.

Effect of bitopertin, a glycine reuptake inhibitor, on negative symptoms of schizophrenia: a randomized, double-blind, proof-of-concept study.

Importance: In schizophrenia, the severity of negative symptoms is a key predictor of long-term disability. Deficient signaling through the N-methyl-D-aspartate receptor is hypothesized to underlie many signs and symptoms associated with schizophrenia in particular negative symptoms. Glycine acts as an N-methyl-D-aspartate receptor coagonist.

Physiologically based pharmacokinetic modelling to predict single- and multiple-dose human pharmacokinetics of bitopertin.

Background: Bitopertin (RG1678) is a glycine reuptake inhibitor currently in phase 3 trials for treatment of schizophrenia. This paper describes the use of physiologically based pharmacokinetic (PBPK) modelling and preclinical data to gain insights into and predict bitopertin clinical pharmacokinetics.

Methods: Simulations of pharmacokinetics were initiated early in the drug discovery stage by integrating physicochemical properties and in vitro measurements into a PBPK rat model.

Glycine transporter type 1 occupancy by bitopertin: a positron emission tomography study in healthy volunteers.

Deficient N-methyl-D-aspartate (NMDA) receptor transmission is thought to underlie schizophrenia. An approach for normalizing glutamate neurotransmission by enhancing NMDA receptor transmission is to increase glycine availability by inhibiting the glycine transporter type 1 (GlyT1). This study investigated the relationship between the plasma concentration of the glycine reuptake inhibitor bitopertin (RG1678) and brain GlyT1 occupancy.

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.

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.

Information deficits in the summary of product characteristics preclude an optimal management of drug interactions: a comparison with evidence from the literature.

Objective: To compare comprehensiveness and accuracy of drug interaction information in the German summary of product characteristics (SPC) with current evidence from the literature and to evaluate the SPC's usefulness with respect to management of drug interactions.

Methods: Information on clinically relevant drug interactions was compared between the SPC and three standard information sources on drug interactions (DRUGDEX, Hansten/Horn's Drug Interactions Analysis and Management, Stockley's Drug Interactions) according to five consecutive criteria (inclusion, appropriateness of class labelling, effect description, management recommendation, explicit dose adjustment). Using medication data of an outpatient population (n=4,949), we determined what percentage of insufficiently characterized combinations indeed occurred in outpatients treated with combination drug therapy.

Dose individualisation in patients with renal insufficiency: does drug labelling support optimal management?

Objective: An important information source for pharmacotherapy in populations at risk is drug labelling. We compared the recommendations for patients with renal insufficiency included in German drug labellings with evidence from the literature.

Methods: From the 120 drugs with the highest turnover in a large university hospital, all drugs with pharmacokinetics independent of renal function (n=48) and those with substantial accumulation in renal failure (n=28) were identified.

Simultaneous determination of hypericin and hyperforin in human plasma with liquid chromatography-tandem mass spectrometry.

A selective and sensitive method for the simultaneous determination of hypericin and hyperforin--the two main active ingredients of St. John's Wort (SJW) extract--in human plasma depending on liquid/liquid-extraction and LC/MS/MS detection has been developed, validated after specifying the stability of the photosensitive hypericin in plasma samples during light exposure and applied to samples of a patient. After extraction with ethyl acetate/n-hexane in the darkness, sample extracts were chromatographed isocratically within 6 min on a Kromasil RP-18 column.

Undeclared exposure to St. John's Wort in hospitalized patients.

Aim: The herbal medicine St. John's Wort (SJW) causes substantial decreases in the plasma concentrations of a range of co-administered drugs. Therefore, we evaluated the extent of systemic exposure to hyperforin and hypericin, two of the main constituents of SJW, in patients on admission and during hospital stay, and compared the results with known use of SJW as documented in the drug chart and detected in additional interviews.

High prevalence of unknown co-medication in hospitalised patients.

Objective: Co-medication unknown to the treating physician, including self-medication, may compromise drug safety by increasing the risk of duplicate therapy, drug interactions and adverse drug reactions that are not recognised as such. The aim of the current study was to estimate exposure to unknown co-medication during hospitalisation by performing an analytical screening for a broad range of drugs and drug classes in urine of patients admitted to a general internal medicine ward.

Methods: Urine samples of 44 patients were analysed with REMEDiHS (high-performance liquid chromatography) and six different immunoassays.

A drug database model as a central element for computer-supported dose adjustment within a CPOE system.

The incidence of adverse drug reactions may be decreased by computerized physician order entry (CPOE) with decision support. The authors describe the development of a drug database model for computer-supported dose adjustment within a CPOE system. The following two core elements were included: (1) To allow electronic dose and volume calculation, the relation between strength (e.