An Innovative Approach to Characterize Clinical ADME and Pharmacokinetics of the Inhaled Drug Nemiralisib Using an Intravenous Microtracer Combined with an Inhaled Dose and an Oral Radiolabel Dose in Healthy Male Subjects
An innovative open-label, crossover clinical study was used to investigate the excretion balance, pharmacokinetics, and metabolism of nemiralisib-an inhaled phosphoinositide 3-kinase delta inhibitor being developed for respiratory diseases. Six healthy men received a single intravenous microtracer o...
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| Published in: | Drug metabolism and disposition Vol. 47; no. 12; p. 1457 |
|---|---|
| Main Authors: | , , , , , , , , , , , , , , , |
| Format: | Journal Article |
| Language: | English |
| Published: |
United States
01.12.2019
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| Subjects: | |
| ISSN: | 1521-009X, 1521-009X |
| Online Access: | Get more information |
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| Abstract | An innovative open-label, crossover clinical study was used to investigate the excretion balance, pharmacokinetics, and metabolism of nemiralisib-an inhaled phosphoinositide 3-kinase delta inhibitor being developed for respiratory diseases. Six healthy men received a single intravenous microtracer of 10
g [
C]nemiralisib with a concomitant inhaled nonradiolabeled 1000
g dose followed by an oral 800
g dose of [
C]nemiralisib 14 days later. Complementary methods including accelerator mass spectrometry allowed characterization of a range of parameters including oral absorption (F
), proportion of nemiralisib escaping gut wall metabolism (F
), hepatic extraction (E
), fraction of dose absorbed from inhaled dose (F
), and renal clearance. Intravenous pharmacokinetics of nemiralisib were characterized by low blood clearance (10.0 l/h), long terminal half-life (55 hours), and high volume of distribution at steady state (728 l). Nemiralisib exhibited moderate inhaled and oral bioavailability (38% and 35%) while F
was 29%. Absorption and first-pass parameters were corrected for blood renal clearance and compared with values without correction. Any swallowed nemiralisib was relatively well absorbed (F
, 0.48) with a high fraction escaping gut wall metabolism and low extraction by the liver (F
and E
being 0.83 and 0.10, respectively). There were no major human plasma metabolites requiring further qualification in animal studies. Both unchanged nemiralisib and its oxidative/conjugative metabolites were secreted in bile, with nemiralisib likely subject to further metabolism through enterohepatic recirculation. Direct renal clearance and metabolism followed by renal clearance were lesser routes of elimination. SIGNIFICANCE STATEMENT: A number of innovative features have been combined into one small clinical study enabling a comprehensive description of the human pharmacokinetics and metabolism of an inhaled molecule. Design elements included an intravenous
C tracer administration concomitant with an inhalation dose that enabled derivation of parameters such as fraction absorbed (F
), the proportion of drug escaping first-pass extraction through the gut wall and liver (F
and F
) and hepatic extraction (E
). Entero-test bile sampling enabled characterization of biliary elimination pathways. |
|---|---|
| AbstractList | An innovative open-label, crossover clinical study was used to investigate the excretion balance, pharmacokinetics, and metabolism of nemiralisib-an inhaled phosphoinositide 3-kinase delta inhibitor being developed for respiratory diseases. Six healthy men received a single intravenous microtracer of 10
g [
C]nemiralisib with a concomitant inhaled nonradiolabeled 1000
g dose followed by an oral 800
g dose of [
C]nemiralisib 14 days later. Complementary methods including accelerator mass spectrometry allowed characterization of a range of parameters including oral absorption (F
), proportion of nemiralisib escaping gut wall metabolism (F
), hepatic extraction (E
), fraction of dose absorbed from inhaled dose (F
), and renal clearance. Intravenous pharmacokinetics of nemiralisib were characterized by low blood clearance (10.0 l/h), long terminal half-life (55 hours), and high volume of distribution at steady state (728 l). Nemiralisib exhibited moderate inhaled and oral bioavailability (38% and 35%) while F
was 29%. Absorption and first-pass parameters were corrected for blood renal clearance and compared with values without correction. Any swallowed nemiralisib was relatively well absorbed (F
, 0.48) with a high fraction escaping gut wall metabolism and low extraction by the liver (F
and E
being 0.83 and 0.10, respectively). There were no major human plasma metabolites requiring further qualification in animal studies. Both unchanged nemiralisib and its oxidative/conjugative metabolites were secreted in bile, with nemiralisib likely subject to further metabolism through enterohepatic recirculation. Direct renal clearance and metabolism followed by renal clearance were lesser routes of elimination. SIGNIFICANCE STATEMENT: A number of innovative features have been combined into one small clinical study enabling a comprehensive description of the human pharmacokinetics and metabolism of an inhaled molecule. Design elements included an intravenous
C tracer administration concomitant with an inhalation dose that enabled derivation of parameters such as fraction absorbed (F
), the proportion of drug escaping first-pass extraction through the gut wall and liver (F
and F
) and hepatic extraction (E
). Entero-test bile sampling enabled characterization of biliary elimination pathways. An innovative open-label, crossover clinical study was used to investigate the excretion balance, pharmacokinetics, and metabolism of nemiralisib-an inhaled phosphoinositide 3-kinase delta inhibitor being developed for respiratory diseases. Six healthy men received a single intravenous microtracer of 10 µg [14C]nemiralisib with a concomitant inhaled nonradiolabeled 1000 µg dose followed by an oral 800 µg dose of [14C]nemiralisib 14 days later. Complementary methods including accelerator mass spectrometry allowed characterization of a range of parameters including oral absorption (Fabs), proportion of nemiralisib escaping gut wall metabolism (Fg), hepatic extraction (Eh), fraction of dose absorbed from inhaled dose (Flung), and renal clearance. Intravenous pharmacokinetics of nemiralisib were characterized by low blood clearance (10.0 l/h), long terminal half-life (55 hours), and high volume of distribution at steady state (728 l). Nemiralisib exhibited moderate inhaled and oral bioavailability (38% and 35%) while Flung was 29%. Absorption and first-pass parameters were corrected for blood renal clearance and compared with values without correction. Any swallowed nemiralisib was relatively well absorbed (Fabs, 0.48) with a high fraction escaping gut wall metabolism and low extraction by the liver (Fg and Eh being 0.83 and 0.10, respectively). There were no major human plasma metabolites requiring further qualification in animal studies. Both unchanged nemiralisib and its oxidative/conjugative metabolites were secreted in bile, with nemiralisib likely subject to further metabolism through enterohepatic recirculation. Direct renal clearance and metabolism followed by renal clearance were lesser routes of elimination. SIGNIFICANCE STATEMENT: A number of innovative features have been combined into one small clinical study enabling a comprehensive description of the human pharmacokinetics and metabolism of an inhaled molecule. Design elements included an intravenous 14C tracer administration concomitant with an inhalation dose that enabled derivation of parameters such as fraction absorbed (Fabs), the proportion of drug escaping first-pass extraction through the gut wall and liver (Fg and Fh) and hepatic extraction (Eh). Entero-test bile sampling enabled characterization of biliary elimination pathways.An innovative open-label, crossover clinical study was used to investigate the excretion balance, pharmacokinetics, and metabolism of nemiralisib-an inhaled phosphoinositide 3-kinase delta inhibitor being developed for respiratory diseases. Six healthy men received a single intravenous microtracer of 10 µg [14C]nemiralisib with a concomitant inhaled nonradiolabeled 1000 µg dose followed by an oral 800 µg dose of [14C]nemiralisib 14 days later. Complementary methods including accelerator mass spectrometry allowed characterization of a range of parameters including oral absorption (Fabs), proportion of nemiralisib escaping gut wall metabolism (Fg), hepatic extraction (Eh), fraction of dose absorbed from inhaled dose (Flung), and renal clearance. Intravenous pharmacokinetics of nemiralisib were characterized by low blood clearance (10.0 l/h), long terminal half-life (55 hours), and high volume of distribution at steady state (728 l). Nemiralisib exhibited moderate inhaled and oral bioavailability (38% and 35%) while Flung was 29%. Absorption and first-pass parameters were corrected for blood renal clearance and compared with values without correction. Any swallowed nemiralisib was relatively well absorbed (Fabs, 0.48) with a high fraction escaping gut wall metabolism and low extraction by the liver (Fg and Eh being 0.83 and 0.10, respectively). There were no major human plasma metabolites requiring further qualification in animal studies. Both unchanged nemiralisib and its oxidative/conjugative metabolites were secreted in bile, with nemiralisib likely subject to further metabolism through enterohepatic recirculation. Direct renal clearance and metabolism followed by renal clearance were lesser routes of elimination. SIGNIFICANCE STATEMENT: A number of innovative features have been combined into one small clinical study enabling a comprehensive description of the human pharmacokinetics and metabolism of an inhaled molecule. Design elements included an intravenous 14C tracer administration concomitant with an inhalation dose that enabled derivation of parameters such as fraction absorbed (Fabs), the proportion of drug escaping first-pass extraction through the gut wall and liver (Fg and Fh) and hepatic extraction (Eh). Entero-test bile sampling enabled characterization of biliary elimination pathways. |
| Author | Harrell, Andrew W Crossman, Lee Pereira, Adrian Chambers, Robert Fahy, William A Wilson, Robert Jarvis, Emily Beaumont, Claire Marotti, Miriam Riddell, Kylie Georgiou, Alex Wilkes, Denisa Man, Yau Lun Kenworthy, David Young, Graeme Hessel, Edith M |
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RD Projects Clinical Platforms & Sciences (R.W.), Drug Metabolism and Pharmacokinetics (C.B.), Discovery Medicine (Y.L.M.), Biostatistics (E.J.), GlaxoSmithKline R&D and Refractory Respiratory Inflammation Discovery Performance Unit, GlaxoSmithKline, Stevenage, United Kingdom (E.M.H.); Safety and Medical Governance (M.M.) and Discovery Medicine (W.A.F.), GlaxoSmithKline R&D, Stockley Park, Uxbridge, United Kingdom; Global Clinical and Data Operations, GlaxoSmithKline R&D, Ermington, Australia (K.R.); Covance Laboratories, Harrogate, United Kingdom (L.C.); and Hammersmith Medicines Research, London, United Kingdom (D.W.) – sequence: 3 givenname: Yau Lun surname: Man fullname: Man, Yau Lun organization: Drug Metabolism and Pharmacokinetics (A.W.H., G.Y., R.C., D.K.) and Bioanalysis, Immunogenicity and Biomarkers (A.G., A.P.), GlaxoSmithKline R&D, Ware, United Kingdom; RD Projects Clinical Platforms & Sciences (R.W.), Drug Metabolism and Pharmacokinetics (C.B.), Discovery Medicine (Y.L.M.), Biostatistics (E.J.), GlaxoSmithKline R&D and Refractory Respiratory Inflammation Discovery Performance Unit, GlaxoSmithKline, Stevenage, United Kingdom (E.M.H.); Safety and Medical Governance (M.M.) and Discovery Medicine (W.A.F.), GlaxoSmithKline R&D, Stockley Park, Uxbridge, United Kingdom; Global Clinical and Data Operations, GlaxoSmithKline R&D, Ermington, Australia (K.R.); Covance Laboratories, Harrogate, United Kingdom (L.C.); and Hammersmith Medicines Research, London, United Kingdom (D.W.) – sequence: 4 givenname: Kylie surname: Riddell fullname: Riddell, Kylie organization: Drug Metabolism and Pharmacokinetics (A.W.H., G.Y., R.C., D.K.) and Bioanalysis, Immunogenicity and Biomarkers (A.G., A.P.), GlaxoSmithKline R&D, Ware, United Kingdom; RD Projects Clinical Platforms & Sciences (R.W.), Drug Metabolism and Pharmacokinetics (C.B.), Discovery Medicine (Y.L.M.), Biostatistics (E.J.), GlaxoSmithKline R&D and Refractory Respiratory Inflammation Discovery Performance Unit, GlaxoSmithKline, Stevenage, United Kingdom (E.M.H.); Safety and Medical Governance (M.M.) and Discovery Medicine (W.A.F.), GlaxoSmithKline R&D, Stockley Park, Uxbridge, United Kingdom; Global Clinical and Data Operations, GlaxoSmithKline R&D, Ermington, Australia (K.R.); Covance Laboratories, Harrogate, United Kingdom (L.C.); and Hammersmith Medicines Research, London, United Kingdom (D.W.) – sequence: 5 givenname: Emily surname: Jarvis fullname: Jarvis, Emily organization: Drug Metabolism and Pharmacokinetics (A.W.H., G.Y., R.C., D.K.) and Bioanalysis, Immunogenicity and Biomarkers (A.G., A.P.), GlaxoSmithKline R&D, Ware, United Kingdom; RD Projects Clinical Platforms & Sciences (R.W.), Drug Metabolism and Pharmacokinetics (C.B.), Discovery Medicine (Y.L.M.), Biostatistics (E.J.), GlaxoSmithKline R&D and Refractory Respiratory Inflammation Discovery Performance Unit, GlaxoSmithKline, Stevenage, United Kingdom (E.M.H.); Safety and Medical Governance (M.M.) and Discovery Medicine (W.A.F.), GlaxoSmithKline R&D, Stockley Park, Uxbridge, United Kingdom; Global Clinical and Data Operations, GlaxoSmithKline R&D, Ermington, Australia (K.R.); Covance Laboratories, Harrogate, United Kingdom (L.C.); and Hammersmith Medicines Research, London, United Kingdom (D.W.) – sequence: 6 givenname: Graeme surname: Young fullname: Young, Graeme organization: Drug Metabolism and Pharmacokinetics (A.W.H., G.Y., R.C., D.K.) and Bioanalysis, Immunogenicity and Biomarkers (A.G., A.P.), GlaxoSmithKline R&D, Ware, United Kingdom; RD Projects Clinical Platforms & Sciences (R.W.), Drug Metabolism and Pharmacokinetics (C.B.), Discovery Medicine (Y.L.M.), Biostatistics (E.J.), GlaxoSmithKline R&D and Refractory Respiratory Inflammation Discovery Performance Unit, GlaxoSmithKline, Stevenage, United Kingdom (E.M.H.); Safety and Medical Governance (M.M.) and Discovery Medicine (W.A.F.), GlaxoSmithKline R&D, Stockley Park, Uxbridge, United Kingdom; Global Clinical and Data Operations, GlaxoSmithKline R&D, Ermington, Australia (K.R.); Covance Laboratories, Harrogate, United Kingdom (L.C.); and Hammersmith Medicines Research, London, United Kingdom (D.W.) – sequence: 7 givenname: Robert surname: Chambers fullname: Chambers, Robert organization: Drug Metabolism and Pharmacokinetics (A.W.H., G.Y., R.C., D.K.) and Bioanalysis, Immunogenicity and Biomarkers (A.G., A.P.), GlaxoSmithKline R&D, Ware, United Kingdom; 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Global Clinical and Data Operations, GlaxoSmithKline R&D, Ermington, Australia (K.R.); Covance Laboratories, Harrogate, United Kingdom (L.C.); and Hammersmith Medicines Research, London, United Kingdom (D.W.) – sequence: 10 givenname: Adrian surname: Pereira fullname: Pereira, Adrian organization: Drug Metabolism and Pharmacokinetics (A.W.H., G.Y., R.C., D.K.) and Bioanalysis, Immunogenicity and Biomarkers (A.G., A.P.), GlaxoSmithKline R&D, Ware, United Kingdom; RD Projects Clinical Platforms & Sciences (R.W.), Drug Metabolism and Pharmacokinetics (C.B.), Discovery Medicine (Y.L.M.), Biostatistics (E.J.), GlaxoSmithKline R&D and Refractory Respiratory Inflammation Discovery Performance Unit, GlaxoSmithKline, Stevenage, United Kingdom (E.M.H.); Safety and Medical Governance (M.M.) and Discovery Medicine (W.A.F.), GlaxoSmithKline R&D, Stockley Park, Uxbridge, United Kingdom; Global Clinical and Data Operations, GlaxoSmithKline R&D, Ermington, Australia (K.R.); Covance Laboratories, Harrogate, United Kingdom (L.C.); 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Safety and Medical Governance (M.M.) and Discovery Medicine (W.A.F.), GlaxoSmithKline R&D, Stockley Park, Uxbridge, United Kingdom; Global Clinical and Data Operations, GlaxoSmithKline R&D, Ermington, Australia (K.R.); Covance Laboratories, Harrogate, United Kingdom (L.C.); and Hammersmith Medicines Research, London, United Kingdom (D.W.) – sequence: 14 givenname: Denisa surname: Wilkes fullname: Wilkes, Denisa organization: Drug Metabolism and Pharmacokinetics (A.W.H., G.Y., R.C., D.K.) and Bioanalysis, Immunogenicity and Biomarkers (A.G., A.P.), GlaxoSmithKline R&D, Ware, United Kingdom; RD Projects Clinical Platforms & Sciences (R.W.), Drug Metabolism and Pharmacokinetics (C.B.), Discovery Medicine (Y.L.M.), Biostatistics (E.J.), GlaxoSmithKline R&D and Refractory Respiratory Inflammation Discovery Performance Unit, GlaxoSmithKline, Stevenage, United Kingdom (E.M.H.); Safety and Medical Governance (M.M.) and Discovery Medicine (W.A.F.), GlaxoSmithKline R&D, Stockley Park, Uxbridge, United Kingdom; 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and Hammersmith Medicines Research, London, United Kingdom (D.W.) – sequence: 16 givenname: William A surname: Fahy fullname: Fahy, William A organization: Drug Metabolism and Pharmacokinetics (A.W.H., G.Y., R.C., D.K.) and Bioanalysis, Immunogenicity and Biomarkers (A.G., A.P.), GlaxoSmithKline R&D, Ware, United Kingdom; RD Projects Clinical Platforms & Sciences (R.W.), Drug Metabolism and Pharmacokinetics (C.B.), Discovery Medicine (Y.L.M.), Biostatistics (E.J.), GlaxoSmithKline R&D and Refractory Respiratory Inflammation Discovery Performance Unit, GlaxoSmithKline, Stevenage, United Kingdom (E.M.H.); Safety and Medical Governance (M.M.) and Discovery Medicine (W.A.F.), GlaxoSmithKline R&D, Stockley Park, Uxbridge, United Kingdom; Global Clinical and Data Operations, GlaxoSmithKline R&D, Ermington, Australia (K.R.); Covance Laboratories, Harrogate, United Kingdom (L.C.); and Hammersmith Medicines Research, London, United Kingdom (D.W.) |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/31649125$$D View this record in MEDLINE/PubMed |
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| ContentType | Journal Article |
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| PublicationDecade | 2010 |
| PublicationPlace | United States |
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| PublicationTitle | Drug metabolism and disposition |
| PublicationTitleAlternate | Drug Metab Dispos |
| PublicationYear | 2019 |
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| Snippet | An innovative open-label, crossover clinical study was used to investigate the excretion balance, pharmacokinetics, and metabolism of nemiralisib-an inhaled... |
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| SubjectTerms | Administration, Inhalation Administration, Intravenous Administration, Oral Adult Biological Availability Carbon Radioisotopes Cross-Over Studies Drug Monitoring - methods Feces - chemistry Healthy Volunteers Humans Indazoles - administration & dosage Indazoles - blood Indazoles - pharmacokinetics Indazoles - urine Indoles - administration & dosage Indoles - blood Indoles - pharmacokinetics Indoles - urine Injections, Intravenous Male Metabolic Clearance Rate Middle Aged Oxazoles - administration & dosage Oxazoles - blood Oxazoles - pharmacokinetics Oxazoles - urine Piperazines - administration & dosage Piperazines - blood Piperazines - pharmacokinetics Piperazines - urine Protein Kinase Inhibitors - administration & dosage Protein Kinase Inhibitors - blood Protein Kinase Inhibitors - pharmacokinetics Protein Kinase Inhibitors - urine Tissue Distribution |
| Title | An Innovative Approach to Characterize Clinical ADME and Pharmacokinetics of the Inhaled Drug Nemiralisib Using an Intravenous Microtracer Combined with an Inhaled Dose and an Oral Radiolabel Dose in Healthy Male Subjects |
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