Pharmacokinetics and tolerability of the maturation inhibitor GSK3640254 coadministered with darunavir/ritonavir and/or etravirine in healthy adults
© 2023 ViiV Healthcare. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society..
AIMS: This phase I study investigated potential drug-drug interactions of the maturation inhibitor GSK3640254 (GSK'254) with darunavir/ritonavir (DRV/RTV) and/or etravirine (ETR).
METHODS: In this randomized, open-label, single-sequence, multiple-dose study, healthy participants received GSK'254 200 mg once daily alone or coadministered with DRV/RTV 600/100 mg twice daily (BID; n = 19), ETR 200 mg BID (n = 19) or DRV/RTV 600/100 mg + ETR 200 mg BID (n = 16) under fed conditions. Primary endpoints were steady-state area under the plasma concentration-time curve from time 0 to the end of the dosing interval (AUC0-τ ) and maximum observed concentration (Cmax ). Secondary endpoints included trough concentration (Cτ ), safety and tolerability. Pharmacokinetic parameters were calculated using standard noncompartmental analysis, and geometric least-squares mean ratios were derived from linear mixed-effects models.
RESULTS: GSK'254 AUC0-τ (geometric least-squares mean ratio [90% confidence interval], 1.14 [1.00-1.29]), Cmax (1.07 [0.92-1.24]) and Cτ (1.17 [1.01-1.35]) were similar when administered alone and with DRV/RTV. Etravirine coadministration decreased GSK'254 AUC0-τ (0.53 [0.48-0.59]), Cmax (0.60 [0.53-0.68]) and Cτ (0.51 [0.39-0.66]). Similar reductions were not observed with GSK'254 + DRV/RTV + ETR (AUC0-τ , 0.94 [0.82-1.09]; Cmax , 0.89 [0.75-1.07]; Cτ , 1.02 [0.89-1.18]). GSK'254 had no meaningful effect on DRV/RTV or ETR concentrations. All reported adverse events (AEs) were grade 1; 3 led to withdrawal and resolved (rash, asymptomatic electrocardiogram T-wave inversion, periorbital oedema). Most common AEs were diarrhoea (n = 9) and headache (n = 7). No deaths or serious AEs occurred.
CONCLUSION: GSK'254 pharmacokinetics was not meaningfully affected by DRV/RTV or DRV/RTV + ETR, but were reduced with only ETR; no new tolerability concerns were observed.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:90 |
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| Enthalten in: |
British journal of clinical pharmacology - 90(2024), 1 vom: 05. Jan., Seite 274-285 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Zhang, Ying [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 29.12.2023 Date Revised 05.03.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1111/bcp.15893 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM361193068 |
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| 100 | 1 | |a Zhang, Ying |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Pharmacokinetics and tolerability of the maturation inhibitor GSK3640254 coadministered with darunavir/ritonavir and/or etravirine in healthy adults |
| 264 | 1 | |c 2024 | |
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| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 29.12.2023 | ||
| 500 | |a Date Revised 05.03.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2023 ViiV Healthcare. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society. | ||
| 520 | |a AIMS: This phase I study investigated potential drug-drug interactions of the maturation inhibitor GSK3640254 (GSK'254) with darunavir/ritonavir (DRV/RTV) and/or etravirine (ETR) | ||
| 520 | |a METHODS: In this randomized, open-label, single-sequence, multiple-dose study, healthy participants received GSK'254 200 mg once daily alone or coadministered with DRV/RTV 600/100 mg twice daily (BID; n = 19), ETR 200 mg BID (n = 19) or DRV/RTV 600/100 mg + ETR 200 mg BID (n = 16) under fed conditions. Primary endpoints were steady-state area under the plasma concentration-time curve from time 0 to the end of the dosing interval (AUC0-τ ) and maximum observed concentration (Cmax ). Secondary endpoints included trough concentration (Cτ ), safety and tolerability. Pharmacokinetic parameters were calculated using standard noncompartmental analysis, and geometric least-squares mean ratios were derived from linear mixed-effects models | ||
| 520 | |a RESULTS: GSK'254 AUC0-τ (geometric least-squares mean ratio [90% confidence interval], 1.14 [1.00-1.29]), Cmax (1.07 [0.92-1.24]) and Cτ (1.17 [1.01-1.35]) were similar when administered alone and with DRV/RTV. Etravirine coadministration decreased GSK'254 AUC0-τ (0.53 [0.48-0.59]), Cmax (0.60 [0.53-0.68]) and Cτ (0.51 [0.39-0.66]). Similar reductions were not observed with GSK'254 + DRV/RTV + ETR (AUC0-τ , 0.94 [0.82-1.09]; Cmax , 0.89 [0.75-1.07]; Cτ , 1.02 [0.89-1.18]). GSK'254 had no meaningful effect on DRV/RTV or ETR concentrations. All reported adverse events (AEs) were grade 1; 3 led to withdrawal and resolved (rash, asymptomatic electrocardiogram T-wave inversion, periorbital oedema). Most common AEs were diarrhoea (n = 9) and headache (n = 7). No deaths or serious AEs occurred | ||
| 520 | |a CONCLUSION: GSK'254 pharmacokinetics was not meaningfully affected by DRV/RTV or DRV/RTV + ETR, but were reduced with only ETR; no new tolerability concerns were observed | ||
| 650 | 4 | |a Clinical Trial, Phase I | |
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a HIV/AIDS | |
| 650 | 4 | |a antiretrovirals | |
| 650 | 4 | |a cytochrome P450 | |
| 650 | 4 | |a drug interactions | |
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| 700 | 1 | |a Yazdani, Parto |e verfasserin |4 aut | |
| 700 | 1 | |a Zhan, Joyce |e verfasserin |4 aut | |
| 700 | 1 | |a Wen, Bo |e verfasserin |4 aut | |
| 700 | 1 | |a Bainbridge, Veronica |e verfasserin |4 aut | |
| 700 | 1 | |a Ballesteros-Perez, Alex |e verfasserin |4 aut | |
| 700 | 1 | |a Gartland, Martin |e verfasserin |4 aut | |
| 700 | 1 | |a Lataillade, Max |e verfasserin |4 aut | |
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