ABSTRACT
BACKGROUND: BAL101553 (lisavanbulin), the lysine prodrug of BAL27862 (avanbulin), exhibits broad anti-proliferative activity in human cancer models refractory to clinically relevant microtubule-targeting agents. METHODS: This two-part, open-label, phase 1/2a study aimed to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of 2-h infusion of BAL101553 in adults with advanced or recurrent solid tumours. The MTD was determined using a modified accelerated titration design in phase I. Patients received BAL101553 at the MTD and at lower doses in the phase 2a expansion to characterise safety and efficacy and to determine the recommended phase 2 dose (RP2D). RESULTS: Seventy-three patients received BAL101553 at doses of 15-80 mg/m2 (phase 1, n = 24; phase 2a, n = 49). The MTD was 60 mg/m2; DLTs observed at doses ≥60 mg/m2 were reversible Grade 2-3 gait disturbance with Grade 2 peripheral sensory neuropathy. In phase 2a, asymptomatic myocardial injury was observed at doses ≥45 mg/m2. The RP2D for 2-h intravenous infusion was 30 mg/m2. The overall disease control rate was 26.3% in the efficacy population. CONCLUSIONS: The RP2D for 2-h infusion of BAL101553 was well tolerated. Dose-limiting neurological and myocardial side effects were consistent with the agent's vascular-disrupting properties. CLINICAL TRIAL REGISTRATION: EudraCT: 2010-024237-23.
Subject(s)
Benzimidazoles/administration & dosage , Neoplasms/drug therapy , Oxadiazoles/administration & dosage , Adult , Aged , Aged, 80 and over , Benzimidazoles/adverse effects , Benzimidazoles/pharmacokinetics , Disease Progression , Female , Humans , Infusions, Intravenous , M Phase Cell Cycle Checkpoints/drug effects , Male , Maximum Tolerated Dose , Middle Aged , Neoplasms/pathology , Oxadiazoles/adverse effects , Oxadiazoles/pharmacokinetics , Prodrugs/administration & dosage , Prodrugs/adverse effects , Prodrugs/pharmacokinetics , Spindle Apparatus/drug effects , United KingdomABSTRACT
Purpose BAL101553, the prodrug of the microtubule-destabilizer BAL27862, previously showed signs of antitumor activity when administered as a 2-h infusion, but its use was limited by vascular toxicity. We investigated an alternative dosing strategy aimed at improving the safety profile of BAL101553. Methods This multicenter, open-label, Phase 1 dose-escalation study used a 3 + 3 design to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), pharmacokinetics, and antitumor activity of BAL101553 administered as a 48-h IV infusion on Days 1, 8, and 15 of a 28-dayĀ cycle. Patients received oral BAL101553 on Days 15-21 of cycle 2 to assess oral bioavailability. Results BAL101553 was well tolerated at doses up to ≤70Ā mg/m2. Three grade 3 DLTs occurred: hypotension (70Ā mg/m2), hyponatremia and neutropenia (both 90Ā mg/m2). The MTD for 48-h IV BAL101553 was 70Ā mg/m2. At this dose level, the AUC for BAL27862 was 8580Ā ng.h/mL and the Cmax was 144Ā ng/mL. No apparent dose-related effects on blood pressure were observed with 48-h BAL101553 IV infusion. BAL27862 oral bioavailability was >80%. Conclusions Continuous 48-h IV BAL101553 infusion achieved higher exposure of the BAL27862 active metabolite than a 2-h infusion at the RP2D and did not cause vascular toxicity. Clinicaltrials.gov registration: NCT02895360.
Subject(s)
Antineoplastic Agents/therapeutic use , Benzimidazoles/therapeutic use , Neoplasms/drug therapy , Oxadiazoles/therapeutic use , Prodrugs/therapeutic use , Administration, Oral , Adult , Aged , Antineoplastic Agents/adverse effects , Antineoplastic Agents/blood , Antineoplastic Agents/pharmacokinetics , Benzimidazoles/adverse effects , Benzimidazoles/blood , Benzimidazoles/pharmacokinetics , Female , Humans , Infusions, Intravenous , Male , Maximum Tolerated Dose , Microtubules , Middle Aged , Neoplasms/blood , Neoplasms/metabolism , Oxadiazoles/adverse effects , Oxadiazoles/blood , Oxadiazoles/pharmacokinetics , Prodrugs/adverse effects , Prodrugs/pharmacokinetics , Treatment OutcomeABSTRACT
OBJECTIVES: This analysis evaluated the variability of isavuconazole plasma concentrations between subjects and between sampling times, and assessed their relationship to outcomes for subjects with invasive fungal disease (IFD) in the SECURE trial. METHODS: Isavuconazole-treated subjects received 372 mg of isavuconazonium sulphate (corresponding to 200 mg of isavuconazole) three times daily for 2 days, then once daily. Plasma samples were collected after day 4 and analysis sets were constructed as follows: analysis set 1 included all samples from subjects with proven/probable/possible IFD who received ≥1 dose of isavuconazole; analysis set 2 included samples from subjects in analysis set 1 who had provided >1 sample; and analysis set 3 included samples from subjects in analysis set 1 with proven/probable invasive aspergillosis. Assessments included overall distributions of plasma concentrations and variability between samples (analysis sets 1 and 2) as well as relationships to outcomes [all-cause mortality (day 42), overall response (end of treatment) and treatment-emergent adverse events; analysis sets 1 and 3]. RESULTS: Analysis sets 1, 2 and 3 included samples from 160, 97 and 98 subjects, respectively. Trough concentrations for each were distributed similarly [mean (SD): 3406.6 (1511.5), 3495.6 (1503.3) and 3368.1 (1523.2) ng/mL, respectively]. The mean coefficient of variation between samples in analysis set 2 was 23.2%; differences between concentrations in first samples and subsequent samples were <2-fold for 85/97 subjects. In quartiles of subject data, no concentration-dependent relationships were observed for efficacy or safety. CONCLUSIONS: Plasma concentrations of isavuconazole were reasonably consistent between subjects and sampling times, and were not associated with differences in outcomes.
Subject(s)
Antifungal Agents/pharmacokinetics , Antifungal Agents/therapeutic use , Invasive Fungal Infections/drug therapy , Invasive Fungal Infections/microbiology , Nitriles/pharmacokinetics , Nitriles/therapeutic use , Pyridines/pharmacokinetics , Pyridines/therapeutic use , Triazoles/pharmacokinetics , Triazoles/therapeutic use , Aspergillosis/drug therapy , Aspergillosis/microbiology , Aspergillus/drug effects , Drug Monitoring , Female , Humans , Male , Treatment OutcomeABSTRACT
IL-17, a pro-inflammatory cytokine produced mainly by Th17 cells, is involved in the immune response to fungal and bacterial infections, whereas its aberrant production is associated with autoimmune and inflammatory diseases. IL-17 blocking antibodies like secukinumab (Cosentyx) have been developed and are used to treat conditions like psoriasis, psoriatic arthritis, and ankylosing spondylitis. Recently, the low molecular weight IL-17 inhibitor LY3509754 entered the clinic but was discontinued in Phase 1 due to adverse effects. In this study, we explored the replacements of furazan moiety posing a potential toxicology risk in LY3509754. By exploring replacements such as heterocycles as amide-isosteres as well as α-F-acrylamides, two compounds (18 and 26) were identified. Both compounds effectively reduced knee swelling in a rat arthritis model. However, early rat and dog toxicity studies revealed adverse findings, preventing their further development and indicating that furazan might not be responsible for the adverse effects of LY3509754.
Subject(s)
Arthritis, Experimental , Interleukin-17 , Oxadiazoles , Animals , Interleukin-17/antagonists & inhibitors , Interleukin-17/metabolism , Oxadiazoles/chemistry , Oxadiazoles/pharmacology , Oxadiazoles/therapeutic use , Rats , Arthritis, Experimental/drug therapy , Dogs , Drug Discovery , Male , Structure-Activity Relationship , Acrylates/chemistry , Acrylates/pharmacology , Acrylates/therapeutic use , Female , HumansABSTRACT
Starting from a orexin 1 receptor selective antagonist 4,4-disubstituted piperidine series a novel potent 5-azaspiro[2.4]heptane dual orexin 1 and orexin 2 receptor antagonist class has been discovered. SAR and Pharmacokinetic optimization of this series is herein disclosed. Lead compound 15 exhibits potent activity against orexin 1 and orexin 2 receptors along with low cytochrome P450 inhibition potential, good brain penetration and oral bioavailability in rats.
Subject(s)
Aza Compounds/chemistry , Heptanes/chemistry , Receptors, G-Protein-Coupled/antagonists & inhibitors , Receptors, Neuropeptide/antagonists & inhibitors , Spiro Compounds/chemistry , Animals , Biological Availability , Brain/drug effects , Brain/metabolism , Cytochrome P-450 Enzyme Inhibitors , Cytochrome P-450 Enzyme System/metabolism , Drug Evaluation, Preclinical , Half-Life , Heptanes/chemical synthesis , Heptanes/pharmacokinetics , Orexin Receptors , Rats , Receptors, G-Protein-Coupled/metabolism , Receptors, Neuropeptide/metabolism , Structure-Activity RelationshipABSTRACT
The induction and inhibition of human hepatic cytochrome P450 (CYP) isoforms by crystalline glucosamine sulfate (CGS) was investigated in vitro. Inhibition of CYP1A2, CYP2E1, CYP2C19, CYP2C9, CYP2D6, and CYP3A4 by CGS was assessed using recombinant human enzymes incubated with CGS (up to 3 mM expressed as free base). Induction of CYP1A2, CYP2B6, CYP2C9, CYP2C19 and CYP3A4 by CGS (0.01, 0.3 and 3 mM) was evaluated in cryopreserved human hepatocytes, by determining CYP mRNA expression using quantitative RT-PCR. CGS produced no inhibition or induction of any the CYP enzymes tested at concentrations hundred folds higher than the steady state peak plasma concentrations (approximately 10 microM) observed in man after therapeutic doses of CGS of 1500 mg once a day. Therefore, no clinically relevant metabolic interactions are expected between CGS and co-administered drugs that are substrates of the CYP enzymes investigated.
Subject(s)
Cytochrome P-450 Enzyme System/drug effects , Enzyme Inhibitors/pharmacology , Glucosamine/pharmacology , Cells, Cultured , Crystallization , Cytochrome P-450 Enzyme Inhibitors , Cytochrome P-450 Enzyme System/genetics , Cytochrome P-450 Enzyme System/metabolism , Dose-Response Relationship, Drug , Enzyme Induction/drug effects , Female , Gene Expression Regulation, Enzymologic/drug effects , Hepatocytes/drug effects , Hepatocytes/enzymology , Humans , Male , RNA, Messenger/genetics , Reverse Transcriptase Polymerase Chain Reaction/methodsABSTRACT
Protein binding of [14C]glucosamine (400, 1000 and 4000 ng/ml) was evaluated in human and mouse plasma and in human synovial fluid. Blood cell/plasma partitioning in human and mouse was also determined. There was no measurable protein binding of [14C]glucosamine. Its association with human and mouse blood cells ranged from 43-47% and from 27-29%, respectively. Therefore, the unbound (pharmacologically active) fraction of glucosamine in plasma and at the site of action (the joint) is the same. Protein binding displacement drug-drug interactions are unlikely during the clinical use of crystalline glucosamine sulfate. No corrections are needed, either for unbound fraction when comparing human and mouse pharmacokinetic data or for blood cell/plasma partitioning to assess glucosamine total blood clearance from plasma data in these two species.
Subject(s)
Blood Proteins/metabolism , Glucosamine/metabolism , Synovial Fluid/metabolism , Animals , Blood Cells/metabolism , Blood Specimen Collection/methods , Drug Interactions , Drug Stability , Glucosamine/blood , Humans , Male , Mice , Plasma/metabolism , Protein BindingABSTRACT
Translational medicine is the drug development phase in which preclinical and clinical applied research is conducted to aid dose and disease selection with great financial impact. Thus, during this phase, early discontinuation of a drug that will later fail due to drug interactions is a must for a proper resource allocation. It is not only important to identify a potential interaction, but also to be able to differentiate between detectable interactions and clinically relevant interactions. Due to the scientific advancement, the prediction of drug interactions during translational medicine has shifted from empirical/observational to rational based. These investigations are thus in line with the FDA's Critical Path Initiative and are facilitated by the availability of mature technologies and by current European and US guidelines for both in vitro and in vivo studies. Because drug interactions must be evaluated in a multidisciplinary fashion, even if these studies are contracted externally, pharmaceutical companies should be directly involved in the conduction of such studies to fully exploit their potential and to allow a better and faster interpretation of the results.
Subject(s)
Drug Interactions , Animals , Clinical Trials as Topic , Cytochrome P-450 Enzyme System/metabolism , Drug Evaluation, Preclinical , Drug-Related Side Effects and Adverse Reactions , Humans , Membrane Transport Proteins/metabolism , PharmacokineticsABSTRACT
Liquid chromatography-tandem mass spectrometry (LC/MS/MS) has become the technology of choice for bioanalysis, due to its high selectivity and high sample throughput. However, concerns have grown that this technique may be subject to errors due to "invisible" interferences, in particular ion-suppression. Investigations on ion-suppression from formulation agents have only been published to a limited extent. Such effects can be of particular importance in pre-clinical discovery studies where drugs may be formulated with large amount of solubilisers and bioanalysis may use fast generic methods. In a preliminary pharmacokinetic study we observed strong ion-suppression from a polysorbate co-solvent, which, if undetected, would have given highly erroneous pharmacokinetic results and possibly could have led to the inappropriate elimination of a promising drug candidate. Different chromatographic methods were tested indicating that the separation step was essential in controlling these effects. A method based on matrix dilution is proposed to check for these effects during the use of discovery support methods, where full validation is not practical. Some excipients commonly used in formulations are polydispersed polymers, for which very limited pharmacokinetic information is available. Further investigation is needed to better understand the mechanisms of ion-suppression and the kinetics of the suppressing species to allow the development of new LC/MS/MS based analytical strategies, which will not be subject to such ionisation interferences.
Subject(s)
Chromatography, High Pressure Liquid/methods , Pharmaceutical Preparations/analysis , Animals , Chemistry, Pharmaceutical , Rats , Rats, Sprague-Dawley , Reference Standards , Sensitivity and SpecificityABSTRACT
Since its introduction a decade ago, the Caco-2 in vitro model for testing intestinal permeability has found wide application, in particular for screening new molecules in the pharmaceutical industry. An important issue for the validation of the model is to verify integrity and proper functionality of the Caco-2 cells monolayer, to ensure reproducibility and consistency of results. Several of these methods are based on measuring the apparent permeability coefficients (Papp) of well-characterized reference compounds, having known absorption characteristics, and comparing the observed values to those expected. Most of them use fluorescent or radioactive chemicals to test different parameters. The main limitation of such approaches is that each parameter to be tested is associated with a single specific method, so that multiple procedures are needed to adequately characterize the cell monolayer. This work describes the use of a unique LC-MS/MS method to simultaneously determine the Papp of a set of reference substances having well-characterized absorption behavior, i.e., phenylalanine, atenolol, and propranolol. The method is routinely used in our laboratory to check on model reproducibility and proved useful in verifying the consistency of the results derived from the experiments.