Population pharmacokinetics and exposure–clinical outcome relationship of remdesivir major metabolite GS‐441524 in patients with moderate and severe COVID‐19
Abstract Although remdesivir, a prodrug of nucleoside analog (GS‐441524), has demonstrated clinical benefits in coronavirus disease 2019 (COVID‐19) treatment, its pharmacokinetics (PKs) in patients with COVID‐19 remain poorly understood. Therefore, in this study, the PKs of remdesivir and its major...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2023-04-01
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| Series: | CPT: Pharmacometrics & Systems Pharmacology |
| Online Access: | https://doi.org/10.1002/psp4.12936 |
| _version_ | 1797848855157407744 |
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| author | Ryo Tamura Kei Irie Atsushi Nakagawa Hirohito Muroi Masaaki Eto Hiroaki Ikesue Nobuyuki Muroi Shoji Fukushima Keisuke Tomii Tohru Hashida |
| author_facet | Ryo Tamura Kei Irie Atsushi Nakagawa Hirohito Muroi Masaaki Eto Hiroaki Ikesue Nobuyuki Muroi Shoji Fukushima Keisuke Tomii Tohru Hashida |
| author_sort | Ryo Tamura |
| collection | DOAJ |
| description | Abstract Although remdesivir, a prodrug of nucleoside analog (GS‐441524), has demonstrated clinical benefits in coronavirus disease 2019 (COVID‐19) treatment, its pharmacokinetics (PKs) in patients with COVID‐19 remain poorly understood. Therefore, in this study, the PKs of remdesivir and its major metabolite, GS‐441524, were evaluated using a population PK (PopPK) approach to understand the PK aspect and exposure–clinical outcome relationship. The serum concentrations of remdesivir and GS‐441524 (102 points in 39 patients) were measured using liquid chromatography–tandem mass spectrometry. All patients received 200 mg remdesivir on the first day, followed by 100 mg on 2–5 days, except for one patient who discontinued remdesivir on day 4. The median (range) age, body surface area, and estimated glomerular filtration rate (eGFR) were 70 (42–85), 1.74 m2 (1.36–2.03), and 68 mL/min/1.73 m2 (33–113), respectively. A compartment model with first‐order elimination combined with remdesivir and GS‐441524 was used for nonlinear mixed‐effects model analysis. Remdesivir was rapidly eliminated after infusion, whereas GS‐441524 was eliminated relatively slowly (half‐time = 17.1 h). The estimated apparent clearance (CL) and distribution volume of GS‐441524 were 11.0 L/h (intersubject variability [ISV]% = 43.0%) and 271 L (ISV% = 58.1%), respectively. The CL of GS‐441524 was significantly related to the eGFR (CL × [eGFR/68]0.745). The post hoc area under the curve of GS‐441524 was unrelated to the recovery rate or aspartate aminotransferase/alanine aminotransferase elevation. Overall, PopPK analysis showed the rapid elimination of remdesivir in the blood, and GS‐441524 accumulation depended on eGFR in patients with COVID‐19. However, no relevance of exposure–clinical outcome was not suggestive of the dose adjustment of remdesivir. |
| first_indexed | 2024-04-09T18:35:27Z |
| format | Article |
| id | doaj.art-81089085c39e4fd985767e9beedfdef0 |
| institution | Directory Open Access Journal |
| issn | 2163-8306 |
| language | English |
| last_indexed | 2024-04-09T18:35:27Z |
| publishDate | 2023-04-01 |
| publisher | Wiley |
| record_format | Article |
| series | CPT: Pharmacometrics & Systems Pharmacology |
| spelling | doaj.art-81089085c39e4fd985767e9beedfdef02023-04-11T11:09:19ZengWileyCPT: Pharmacometrics & Systems Pharmacology2163-83062023-04-0112451352110.1002/psp4.12936Population pharmacokinetics and exposure–clinical outcome relationship of remdesivir major metabolite GS‐441524 in patients with moderate and severe COVID‐19Ryo Tamura0Kei Irie1Atsushi Nakagawa2Hirohito Muroi3Masaaki Eto4Hiroaki Ikesue5Nobuyuki Muroi6Shoji Fukushima7Keisuke Tomii8Tohru Hashida9Department of Pharmacy, Kobe City Hospital Organization Kobe City Medical Center General Hospital Kobe JapanDepartment of Pharmacy, Kobe City Hospital Organization Kobe City Medical Center General Hospital Kobe JapanDepartment of Respiratory Medicine, Kobe City Hospital Organization Kobe City Medical Center General Hospital Kobe JapanDepartment of Pharmacy, Kobe City Hospital Organization Kobe City Medical Center General Hospital Kobe JapanDepartment of Clinical Laboratory, Kobe City Hospital Organization Kobe City Medical Center General Hospital Kobe JapanDepartment of Pharmacy, Kobe City Hospital Organization Kobe City Medical Center General Hospital Kobe JapanDepartment of Pharmacy, Kobe City Hospital Organization Kobe City Medical Center General Hospital Kobe JapanDepartment of Pharmacy, Kobe City Hospital Organization Kobe City Medical Center General Hospital Kobe JapanDepartment of Respiratory Medicine, Kobe City Hospital Organization Kobe City Medical Center General Hospital Kobe JapanDepartment of Pharmacy, Kobe City Hospital Organization Kobe City Medical Center General Hospital Kobe JapanAbstract Although remdesivir, a prodrug of nucleoside analog (GS‐441524), has demonstrated clinical benefits in coronavirus disease 2019 (COVID‐19) treatment, its pharmacokinetics (PKs) in patients with COVID‐19 remain poorly understood. Therefore, in this study, the PKs of remdesivir and its major metabolite, GS‐441524, were evaluated using a population PK (PopPK) approach to understand the PK aspect and exposure–clinical outcome relationship. The serum concentrations of remdesivir and GS‐441524 (102 points in 39 patients) were measured using liquid chromatography–tandem mass spectrometry. All patients received 200 mg remdesivir on the first day, followed by 100 mg on 2–5 days, except for one patient who discontinued remdesivir on day 4. The median (range) age, body surface area, and estimated glomerular filtration rate (eGFR) were 70 (42–85), 1.74 m2 (1.36–2.03), and 68 mL/min/1.73 m2 (33–113), respectively. A compartment model with first‐order elimination combined with remdesivir and GS‐441524 was used for nonlinear mixed‐effects model analysis. Remdesivir was rapidly eliminated after infusion, whereas GS‐441524 was eliminated relatively slowly (half‐time = 17.1 h). The estimated apparent clearance (CL) and distribution volume of GS‐441524 were 11.0 L/h (intersubject variability [ISV]% = 43.0%) and 271 L (ISV% = 58.1%), respectively. The CL of GS‐441524 was significantly related to the eGFR (CL × [eGFR/68]0.745). The post hoc area under the curve of GS‐441524 was unrelated to the recovery rate or aspartate aminotransferase/alanine aminotransferase elevation. Overall, PopPK analysis showed the rapid elimination of remdesivir in the blood, and GS‐441524 accumulation depended on eGFR in patients with COVID‐19. However, no relevance of exposure–clinical outcome was not suggestive of the dose adjustment of remdesivir.https://doi.org/10.1002/psp4.12936 |
| spellingShingle | Ryo Tamura Kei Irie Atsushi Nakagawa Hirohito Muroi Masaaki Eto Hiroaki Ikesue Nobuyuki Muroi Shoji Fukushima Keisuke Tomii Tohru Hashida Population pharmacokinetics and exposure–clinical outcome relationship of remdesivir major metabolite GS‐441524 in patients with moderate and severe COVID‐19 CPT: Pharmacometrics & Systems Pharmacology |
| title | Population pharmacokinetics and exposure–clinical outcome relationship of remdesivir major metabolite GS‐441524 in patients with moderate and severe COVID‐19 |
| title_full | Population pharmacokinetics and exposure–clinical outcome relationship of remdesivir major metabolite GS‐441524 in patients with moderate and severe COVID‐19 |
| title_fullStr | Population pharmacokinetics and exposure–clinical outcome relationship of remdesivir major metabolite GS‐441524 in patients with moderate and severe COVID‐19 |
| title_full_unstemmed | Population pharmacokinetics and exposure–clinical outcome relationship of remdesivir major metabolite GS‐441524 in patients with moderate and severe COVID‐19 |
| title_short | Population pharmacokinetics and exposure–clinical outcome relationship of remdesivir major metabolite GS‐441524 in patients with moderate and severe COVID‐19 |
| title_sort | population pharmacokinetics and exposure clinical outcome relationship of remdesivir major metabolite gs 441524 in patients with moderate and severe covid 19 |
| url | https://doi.org/10.1002/psp4.12936 |
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