Phase I and scintigraphy studies to evaluate safety, tolerability, pharmacokinetics, and lung deposition of inhaled GDC‐0214 in healthy volunteers
Abstract Several inflammatory cytokines that promote inflammation and pathogenesis in asthma signal through the Janus kinase 1 (JAK1) pathway. This phase I, randomized, placebo‐controlled trial assessed the pharmacokinetics and safety of single and multiple ascending doses up to 15 mg twice daily fo...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2022-05-01
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| Series: | Clinical and Translational Science |
| Online Access: | https://doi.org/10.1111/cts.13240 |
| _version_ | 1818210199692902400 |
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| author | Rui Zhu Hubert Chen Joshua Galanter Gaohong She Fang Cai Matthew R. Durk Yixuan Zou Liuxi Chen Jane R. Kenny Shweta Vadhavkar Simon Warren Glyn Taylor Olivia Hwang Avi Eliahu Chris Wynne Ryan Owen |
| author_facet | Rui Zhu Hubert Chen Joshua Galanter Gaohong She Fang Cai Matthew R. Durk Yixuan Zou Liuxi Chen Jane R. Kenny Shweta Vadhavkar Simon Warren Glyn Taylor Olivia Hwang Avi Eliahu Chris Wynne Ryan Owen |
| author_sort | Rui Zhu |
| collection | DOAJ |
| description | Abstract Several inflammatory cytokines that promote inflammation and pathogenesis in asthma signal through the Janus kinase 1 (JAK1) pathway. This phase I, randomized, placebo‐controlled trial assessed the pharmacokinetics and safety of single and multiple ascending doses up to 15 mg twice daily for 14 days of a JAK1 inhibitor, GDC‐0214, in healthy volunteers (HVs; n = 66). Doses were administered with a dry powder, capsule‐based inhaler. An accompanying open‐label gamma scintigraphy study in HVs examined the lung deposition of a single dose of inhaled Technetium‐99m (99mTc)‐radiolabeled GDC‐0214. GDC‐0214 plasma concentrations were linear and approximately dose‐proportional after both single and multiple doses. Peak plasma concentrations occurred at 15–30 min after dosing. The mean apparent elimination half‐life ranged from 32 to 56 h across all single and multiple dose cohorts. After single and multiple doses, all adverse events were mild or moderate, and none led to treatment withdrawal. There was no clear evidence of systemic toxicity due to JAK1 inhibition, and systemic exposure was low, with plasma concentrations at least 15‐fold less than the plasma protein binding‐corrected IC50 of JAK1 at the highest dose. Scintigraphy showed that approximately 50% of the emitted dose of radiolabeled GDC‐0214 was deposited in the lungs and was distributed well to the peripheral airways. 99mTc‐radiolabeled GDC‐0214 (1 mg) exhibited a mean plasma Cmax similar to that observed in phase I at the same dose level. Overall, inhaled GDC‐0214 exhibited pharmacokinetic properties favorable for inhaled administration. |
| first_indexed | 2024-12-12T05:12:49Z |
| format | Article |
| id | doaj.art-86f1d4d5c4f542fca1040d064b72434f |
| institution | Directory Open Access Journal |
| issn | 1752-8054 1752-8062 |
| language | English |
| last_indexed | 2024-12-12T05:12:49Z |
| publishDate | 2022-05-01 |
| publisher | Wiley |
| record_format | Article |
| series | Clinical and Translational Science |
| spelling | doaj.art-86f1d4d5c4f542fca1040d064b72434f2022-12-22T00:36:50ZengWileyClinical and Translational Science1752-80541752-80622022-05-011551225123710.1111/cts.13240Phase I and scintigraphy studies to evaluate safety, tolerability, pharmacokinetics, and lung deposition of inhaled GDC‐0214 in healthy volunteersRui Zhu0Hubert Chen1Joshua Galanter2Gaohong She3Fang Cai4Matthew R. Durk5Yixuan Zou6Liuxi Chen7Jane R. Kenny8Shweta Vadhavkar9Simon Warren10Glyn Taylor11Olivia Hwang12Avi Eliahu13Chris Wynne14Ryan Owen15Genentech, Inc. South San Francisco California USAGenentech, Inc. South San Francisco California USAGenentech, Inc. South San Francisco California USAGenentech, Inc. South San Francisco California USAGenentech, Inc. South San Francisco California USAGenentech, Inc. South San Francisco California USAGenentech, Inc. South San Francisco California USAGenentech, Inc. South San Francisco California USAGenentech, Inc. South San Francisco California USAGenentech, Inc. South San Francisco California USACardiff Scintigraphics Cardiff UKCardiff Scintigraphics Cardiff UKGenentech, Inc. South San Francisco California USAGenentech, Inc. South San Francisco California USAChristchurch Clinical Studies Trust (CCST; now New Zealand Clinical Research) Christchurch New ZealandGenentech, Inc. South San Francisco California USAAbstract Several inflammatory cytokines that promote inflammation and pathogenesis in asthma signal through the Janus kinase 1 (JAK1) pathway. This phase I, randomized, placebo‐controlled trial assessed the pharmacokinetics and safety of single and multiple ascending doses up to 15 mg twice daily for 14 days of a JAK1 inhibitor, GDC‐0214, in healthy volunteers (HVs; n = 66). Doses were administered with a dry powder, capsule‐based inhaler. An accompanying open‐label gamma scintigraphy study in HVs examined the lung deposition of a single dose of inhaled Technetium‐99m (99mTc)‐radiolabeled GDC‐0214. GDC‐0214 plasma concentrations were linear and approximately dose‐proportional after both single and multiple doses. Peak plasma concentrations occurred at 15–30 min after dosing. The mean apparent elimination half‐life ranged from 32 to 56 h across all single and multiple dose cohorts. After single and multiple doses, all adverse events were mild or moderate, and none led to treatment withdrawal. There was no clear evidence of systemic toxicity due to JAK1 inhibition, and systemic exposure was low, with plasma concentrations at least 15‐fold less than the plasma protein binding‐corrected IC50 of JAK1 at the highest dose. Scintigraphy showed that approximately 50% of the emitted dose of radiolabeled GDC‐0214 was deposited in the lungs and was distributed well to the peripheral airways. 99mTc‐radiolabeled GDC‐0214 (1 mg) exhibited a mean plasma Cmax similar to that observed in phase I at the same dose level. Overall, inhaled GDC‐0214 exhibited pharmacokinetic properties favorable for inhaled administration.https://doi.org/10.1111/cts.13240 |
| spellingShingle | Rui Zhu Hubert Chen Joshua Galanter Gaohong She Fang Cai Matthew R. Durk Yixuan Zou Liuxi Chen Jane R. Kenny Shweta Vadhavkar Simon Warren Glyn Taylor Olivia Hwang Avi Eliahu Chris Wynne Ryan Owen Phase I and scintigraphy studies to evaluate safety, tolerability, pharmacokinetics, and lung deposition of inhaled GDC‐0214 in healthy volunteers Clinical and Translational Science |
| title | Phase I and scintigraphy studies to evaluate safety, tolerability, pharmacokinetics, and lung deposition of inhaled GDC‐0214 in healthy volunteers |
| title_full | Phase I and scintigraphy studies to evaluate safety, tolerability, pharmacokinetics, and lung deposition of inhaled GDC‐0214 in healthy volunteers |
| title_fullStr | Phase I and scintigraphy studies to evaluate safety, tolerability, pharmacokinetics, and lung deposition of inhaled GDC‐0214 in healthy volunteers |
| title_full_unstemmed | Phase I and scintigraphy studies to evaluate safety, tolerability, pharmacokinetics, and lung deposition of inhaled GDC‐0214 in healthy volunteers |
| title_short | Phase I and scintigraphy studies to evaluate safety, tolerability, pharmacokinetics, and lung deposition of inhaled GDC‐0214 in healthy volunteers |
| title_sort | phase i and scintigraphy studies to evaluate safety tolerability pharmacokinetics and lung deposition of inhaled gdc 0214 in healthy volunteers |
| url | https://doi.org/10.1111/cts.13240 |
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