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Pharmacokinetics and Pharmacodynamics of Elobixibat, A Novel Ileal Bile Acid Transporter Inhibitor
Clinical Therapeutics Pharmacokinetics and Pharmacodynamics of Elobixibat, A Novel Ileal Bile Acid Transporter Inhibitor Y. Kumagai1; H. Amano1; Y. Sasaki1; C. Nakagawa1; M. Maeda1; I. Oikawa2; and H. Furuie3 1 Kitasato University Hospital, Kanagawa, Japan; 2EA Pharma Co, Ltd, Tokyo, Japan; and 3Osaka Pharmacology Clinical Research Hospital, Osaka, Japan Background: Elobixibat is a novel oral inhibitor of the ileal bile acid transporter and is currently under development for the treatment of chronic constipation. We performed a Phase I study to evaluate the safety, pharmacokinetics, and pharmacodynamics of elobixibat in Japanese patients with chronic constipation. Methods: The study consisted of 2 parts. In part 1, a single dose of elobixibat (2.5, 5, 10, 15 or 20 mg) or placebo was administered to 60 patients (10 received placebo) in a randomized double blind design. In part 2, elobixibat was administered to 60 patients for 2 weeks in the same manner as in part 1. The main purpose of part 1 was safety and pharmacokinetics, while the main objective of part 2 was the pharmacodynamic effect of elobixibat. Plasma cholest-4en-7α -ol-3-one (C4), a biomarker reflecting bile acid synthesis, and the number of stool passages were measured as pharmacodynamic parameters. Results: Elobixibat displayed linear pharmacokinetics with very low systemic exposure. When compared to fasting conditions, the plasma exposure of elobixibat decreased to 20-30% with breakfast. After repeated administration, plasma concentrations reached steady state after 7 days and no accumulation was found up to the dose of 15 mg. Plasma levels of C4 increased in response to each dose level, however the increase was blunted at 20 mg. LDL cholesterol levels were decreased from the dose of 5 mg onwards. Constipation was improved in a dose dependent manner. The change in the number of spontaneous bowel movements and C4 levels correlated well when the data were pooled from all dose groups. Elobixibat was welltolerated except for mild gastrointestinal symptoms. Conclusions: Elobixibat showed a dose dependent effect in patients with chronic constipation and was well-tolerated. The effect on bowel movements correlated well with increased plasma C4 levels, a marker of its pharmacological action.
Population Pharmacodynamic Analysis of Effect of Three Increasing Doses of Fludrocortisone on PhenylephrineMean Arterial Pressure Dose-Response Relationship in Healthy Volunteers K. Hammas1,2; N. Hamitouche1; C. Palpacuer1,2; F. Lainé1; E. Bellissant1,2; and B. Laviolle1,2⁎ 1 Inserm, CIC 1414 Clinical Investigation Centre, Rennes, France; and 2Rennes University Hospital, Clinical Pharmacology, Rennes, France Background: A single administration of hydrocortisone has been shown to enhance the pressor response to phenylephrine in healthy volunteers and to norepinephrine in septic shock patients. Similar data does not exist for fludrocortisone, and its utility in septic shock remains under debate. We assessed the effects of 3 increasing doses of fludrocortisone on phenylephrine-mean arterial pressure (MAP) dose-response relationship in healthy volunteers. Methods: Twelve healthy male volunteers were included in this placebo-controlled, randomized, double blind, crossover study (local ethics committee approval, all subjects signed an informed consent). Subjects received fludrocortisone (100, 200, 400μ g per day or placebo, administered orally in a 4-time per day regimen) during 5 days. On day 6, 1.5h after treatment administration,
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incremental doses of phenylephrine were infused (from 0.1 to 4μ g/kg/min), each dose being infused during 5 minutes before MAP measurement. A non-linear mixed-effects model was used. A sigmoid model was chosen to describe the phenylephrine-MAP dose-response relationship: E= E0+[EmaxxDγ /(ED50γ +Dγ )], where E represents the effect on MAP, D the dose of phenylephrine, E0 the basal value of MAP, Emax the maximum theoretical effect, ED50 the dose of phenylephrine which induces an effect of 50% of Emax, and γ the Hill coefficient. The parameters of the model were estimated by the SAEM algorithm in Monolix. Results: On day 6, the dose of 400μ g per day of fludrocortisone significantly increased MAP (+10% as compared with placebo, p= 0.003) whereas the two other doses did not affect blood pressure. Only the dose of 400μ g per day significantly increased the pressor response to phenylephrine, compared with placebo (p< 0.05). At this dose ED50 was decreased (-29%, p< 0.05), E0 was increased (+10%, p< 0.05), and no significant effect was observed on Emax. Conclusions: In healthy volunteers, administration of 400μ g per day of fludrocortisone improves the pressor response to phenylephrine and increases its potency.
Safety and Efficacy of the C1S Complement Inhibitor TNT009 in a FIRST-InHuman Trial J. Bartko1; U. Derhaschnig1; J. Gilbert2; S. Panicker2; S. D’Sa3; U. Jäger1; and B. Jilma1 1 Medical University of Vienna, Vienna, Austria; 2True North Therapeutics Inc, South San Francisco, California; and 3University London College Hospitals, London, United Kingdom Background: We have taken the concept of a basket- and integrated protocol design outside the realm of oncology, which has facilitated the transition from Phase Ia in healthy volunteers to Phase Ib in patients with rare complement-mediated disorders driven by the classical pathway. Methods: We have been conducting a double-blind, randomized, placebo-controlled first-in-human study with TNT009, which is a humanized monoclonal antibody directed against the C1s subunit of human complement component C1. TNT009 was administered to 48 normal healthy volunteers and 34 patients, who suffered from various complement-mediated orphan diseases sharing the same pathophysiological mechanism, i.e. bullous pemphigoid, antibody-mediated rejection of organ transplants, cold agglutinin disease (CAD) and warm autoimmune haemolytic anaemia. Volunteers received ascending single (up to 100 mg/kg) or 4 weekly doses (up to 60 mg/kg) of TNT009, and patients received 4 weekly infusions of 60mg/kg after a test dose. After wash-out and in case of relapse, CAD patients could receive TNT009 in a named patient program. Results: All infusions were well tolerated without premedication and without relevant adverse effects. Safety and tolerability was excellent both in volunteers and patients. Proof of concept was established in patients. In particular, TNT009 rapidly stopped hemolysis and corrected anemia (~40 g/L haemoglobin increase) in patients with severe, often transfusion-dependent CAD, even in those patients who had been refractory to off-label treatments including chemotherapy, rituximab or eculizumab. TNT009 immediately decreased bilirubin and CH50 activity and increased complement C4 levels, showing the rapid onset of pharmacodynamic effect. TNT009 re-exposure unequivocally proved efficacy in CAD. Conclusions: Our trial design demonstrates that pathway specificity is a viable paradigm for defining “baskets”, and that these need not be restricted to single genetic aberrations. TNT009 proved welltolerated and highly efficacious in CAD patients.
Volume 39 Number 8S
Population Pharmacodynamic Analysis of Effect of Three Increasing Doses of Fludrocortisone on PhenylephrineMean Arterial Pressure Dose-Response Relationship in Healthy Volunteers K. Hammas1,2; N. Hamitouche1; C. Palpacuer1,2; F. Lainé1; E. Bellissant1,2; and B. Laviolle1,2⁎ 1 Inserm, CIC 1414 Clinical Investigation Centre, Rennes, France; and 2Rennes University Hospital, Clinical Pharmacology, Rennes, France Background: A single administration of hydrocortisone has been shown to enhance the pressor response to phenylephrine in healthy volunteers and to norepinephrine in septic shock patients. Similar data does not exist for fludrocortisone, and its utility in septic shock remains under debate. We assessed the effects of 3 increasing doses of fludrocortisone on phenylephrine-mean arterial pressure (MAP) dose-response relationship in healthy volunteers. Methods: Twelve healthy male volunteers were included in this placebo-controlled, randomized, double blind, crossover study (local ethics committee approval, all subjects signed an informed consent). Subjects received fludrocortisone (100, 200, 400μ g per day or placebo, administered orally in a 4-time per day regimen) during 5 days. On day 6, 1.5h after treatment administration,
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incremental doses of phenylephrine were infused (from 0.1 to 4μ g/kg/min), each dose being infused during 5 minutes before MAP measurement. A non-linear mixed-effects model was used. A sigmoid model was chosen to describe the phenylephrine-MAP dose-response relationship: E= E0+[EmaxxDγ /(ED50γ +Dγ )], where E represents the effect on MAP, D the dose of phenylephrine, E0 the basal value of MAP, Emax the maximum theoretical effect, ED50 the dose of phenylephrine which induces an effect of 50% of Emax, and γ the Hill coefficient. The parameters of the model were estimated by the SAEM algorithm in Monolix. Results: On day 6, the dose of 400μ g per day of fludrocortisone significantly increased MAP (+10% as compared with placebo, p= 0.003) whereas the two other doses did not affect blood pressure. Only the dose of 400μ g per day significantly increased the pressor response to phenylephrine, compared with placebo (p< 0.05). At this dose ED50 was decreased (-29%, p< 0.05), E0 was increased (+10%, p< 0.05), and no significant effect was observed on Emax. Conclusions: In healthy volunteers, administration of 400μ g per day of fludrocortisone improves the pressor response to phenylephrine and increases its potency.
Safety and Efficacy of the C1S Complement Inhibitor TNT009 in a FIRST-InHuman Trial J. Bartko1; U. Derhaschnig1; J. Gilbert2; S. Panicker2; S. D’Sa3; U. Jäger1; and B. Jilma1 1 Medical University of Vienna, Vienna, Austria; 2True North Therapeutics Inc, South San Francisco, California; and 3University London College Hospitals, London, United Kingdom Background: We have taken the concept of a basket- and integrated protocol design outside the realm of oncology, which has facilitated the transition from Phase Ia in healthy volunteers to Phase Ib in patients with rare complement-mediated disorders driven by the classical pathway. Methods: We have been conducting a double-blind, randomized, placebo-controlled first-in-human study with TNT009, which is a humanized monoclonal antibody directed against the C1s subunit of human complement component C1. TNT009 was administered to 48 normal healthy volunteers and 34 patients, who suffered from various complement-mediated orphan diseases sharing the same pathophysiological mechanism, i.e. bullous pemphigoid, antibody-mediated rejection of organ transplants, cold agglutinin disease (CAD) and warm autoimmune haemolytic anaemia. Volunteers received ascending single (up to 100 mg/kg) or 4 weekly doses (up to 60 mg/kg) of TNT009, and patients received 4 weekly infusions of 60mg/kg after a test dose. After wash-out and in case of relapse, CAD patients could receive TNT009 in a named patient program. Results: All infusions were well tolerated without premedication and without relevant adverse effects. Safety and tolerability was excellent both in volunteers and patients. Proof of concept was established in patients. In particular, TNT009 rapidly stopped hemolysis and corrected anemia (~40 g/L haemoglobin increase) in patients with severe, often transfusion-dependent CAD, even in those patients who had been refractory to off-label treatments including chemotherapy, rituximab or eculizumab. TNT009 immediately decreased bilirubin and CH50 activity and increased complement C4 levels, showing the rapid onset of pharmacodynamic effect. TNT009 re-exposure unequivocally proved efficacy in CAD. Conclusions: Our trial design demonstrates that pathway specificity is a viable paradigm for defining “baskets”, and that these need not be restricted to single genetic aberrations. TNT009 proved welltolerated and highly efficacious in CAD patients.
Volume 39 Number 8S