Clinical Pharmacokinetics and Safety of Orally Administered VH4011499, a New HIV-1 Capsid Inhibitor, in Adults Without HIV
Abstract Introduction This first-time-in-human study describes the pharmacokinetics, drug–drug interaction potential, and safety of VH4011499 (VH-499), a new HIV-1 capsid inhibitor. Methods This double-blind, randomized, placebo-controlled, phase 1 study evaluated VH-499 in adults without HIV admini...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Adis, Springer Healthcare
2025-04-01
|
| Series: | Infectious Diseases and Therapy |
| Subjects: | |
| Online Access: | https://doi.org/10.1007/s40121-025-01129-y |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849734140537077760 |
|---|---|
| author | Nilay Thakkar Rulan Griesel Amy Pierce Veronica Bainbridge Bronagh Shepherd Konstantinos Angelis Andrew Tomlinson Yash Gandhi Darin Brimhall Brian Spears Daijha Anderson Emma Pinnick Carolina Acuipil Cynthia McCoig Mark Baker Paul Benn |
| author_facet | Nilay Thakkar Rulan Griesel Amy Pierce Veronica Bainbridge Bronagh Shepherd Konstantinos Angelis Andrew Tomlinson Yash Gandhi Darin Brimhall Brian Spears Daijha Anderson Emma Pinnick Carolina Acuipil Cynthia McCoig Mark Baker Paul Benn |
| author_sort | Nilay Thakkar |
| collection | DOAJ |
| description | Abstract Introduction This first-time-in-human study describes the pharmacokinetics, drug–drug interaction potential, and safety of VH4011499 (VH-499), a new HIV-1 capsid inhibitor. Methods This double-blind, randomized, placebo-controlled, phase 1 study evaluated VH-499 in adults without HIV administered orally as single ascending doses as powder-in-bottle (PiB; part 1) and tablet (part 3) formulations and as multiple ascending doses as PiB formulation dosed once daily for 14 days (part 2). Midazolam was used to evaluate the effect of VH-499 on cytochrome P450 3A (CYP3A) activity (part 2). Results Overall, 73 participants were included (VH-499, n = 56; placebo, n = 17). VH-499 plasma exposures were less than dose-proportional, with median time to maximum observed concentration of 8.0–12.0 h for the PiB formulation and 24.0 h for the tablet formulation. Geometric mean terminal half-life was 51.2–66.5 h (2–3 days). The tablet formulation resulted in 45–63% lower exposures compared with PiB. Concomitant midazolam administration after single and multiple VH-499 doses did not lead to clinically significant changes in midazolam or 1-hydroxymidazolam exposures; therefore, VH-499 is not expected to inhibit or induce CYP3A4. VH-499 was well tolerated. Adverse event (AE) frequency was comparable between placebo and VH-499 groups. VH-499-related AEs were predominantly grade 1. No serious AEs across VH-499 groups, AEs leading to withdrawal from drug/study, or deaths occurred. There were no trends in vital signs, electrocardiograms, or laboratory hematology parameters and no clinically relevant changes in chemistry parameters. Conclusion First-time-in-human data further characterize the pharmacokinetics of orally administered VH-499 and provide support for development of VH-499 as part of a complete long-acting regimen for HIV-1 treatment and prevention. Clinical Trial Registration ClinicalTrials.gov, NCT05393271. |
| format | Article |
| id | doaj-art-8f48e12cdee240ec8128b1a36a1a0217 |
| institution | DOAJ |
| issn | 2193-8229 2193-6382 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Adis, Springer Healthcare |
| record_format | Article |
| series | Infectious Diseases and Therapy |
| spelling | doaj-art-8f48e12cdee240ec8128b1a36a1a02172025-08-20T03:07:51ZengAdis, Springer HealthcareInfectious Diseases and Therapy2193-82292193-63822025-04-011451011102510.1007/s40121-025-01129-yClinical Pharmacokinetics and Safety of Orally Administered VH4011499, a New HIV-1 Capsid Inhibitor, in Adults Without HIVNilay Thakkar0Rulan Griesel1Amy Pierce2Veronica Bainbridge3Bronagh Shepherd4Konstantinos Angelis5Andrew Tomlinson6Yash Gandhi7Darin Brimhall8Brian Spears9Daijha Anderson10Emma Pinnick11Carolina Acuipil12Cynthia McCoig13Mark Baker14Paul Benn15GSKViiV HealthcareViiV HealthcareGSKGSKGSKGSKGSKPPD-Thermo Fisher ScientificPPD-Thermo Fisher ScientificViiV HealthcareGSKViiV HealthcareViiV Healthcare, P.T.M.ViiV HealthcareViiV HealthcareAbstract Introduction This first-time-in-human study describes the pharmacokinetics, drug–drug interaction potential, and safety of VH4011499 (VH-499), a new HIV-1 capsid inhibitor. Methods This double-blind, randomized, placebo-controlled, phase 1 study evaluated VH-499 in adults without HIV administered orally as single ascending doses as powder-in-bottle (PiB; part 1) and tablet (part 3) formulations and as multiple ascending doses as PiB formulation dosed once daily for 14 days (part 2). Midazolam was used to evaluate the effect of VH-499 on cytochrome P450 3A (CYP3A) activity (part 2). Results Overall, 73 participants were included (VH-499, n = 56; placebo, n = 17). VH-499 plasma exposures were less than dose-proportional, with median time to maximum observed concentration of 8.0–12.0 h for the PiB formulation and 24.0 h for the tablet formulation. Geometric mean terminal half-life was 51.2–66.5 h (2–3 days). The tablet formulation resulted in 45–63% lower exposures compared with PiB. Concomitant midazolam administration after single and multiple VH-499 doses did not lead to clinically significant changes in midazolam or 1-hydroxymidazolam exposures; therefore, VH-499 is not expected to inhibit or induce CYP3A4. VH-499 was well tolerated. Adverse event (AE) frequency was comparable between placebo and VH-499 groups. VH-499-related AEs were predominantly grade 1. No serious AEs across VH-499 groups, AEs leading to withdrawal from drug/study, or deaths occurred. There were no trends in vital signs, electrocardiograms, or laboratory hematology parameters and no clinically relevant changes in chemistry parameters. Conclusion First-time-in-human data further characterize the pharmacokinetics of orally administered VH-499 and provide support for development of VH-499 as part of a complete long-acting regimen for HIV-1 treatment and prevention. Clinical Trial Registration ClinicalTrials.gov, NCT05393271.https://doi.org/10.1007/s40121-025-01129-yCapsid inhibitorFirst-time-in-humanPharmacokineticsSafety |
| spellingShingle | Nilay Thakkar Rulan Griesel Amy Pierce Veronica Bainbridge Bronagh Shepherd Konstantinos Angelis Andrew Tomlinson Yash Gandhi Darin Brimhall Brian Spears Daijha Anderson Emma Pinnick Carolina Acuipil Cynthia McCoig Mark Baker Paul Benn Clinical Pharmacokinetics and Safety of Orally Administered VH4011499, a New HIV-1 Capsid Inhibitor, in Adults Without HIV Infectious Diseases and Therapy Capsid inhibitor First-time-in-human Pharmacokinetics Safety |
| title | Clinical Pharmacokinetics and Safety of Orally Administered VH4011499, a New HIV-1 Capsid Inhibitor, in Adults Without HIV |
| title_full | Clinical Pharmacokinetics and Safety of Orally Administered VH4011499, a New HIV-1 Capsid Inhibitor, in Adults Without HIV |
| title_fullStr | Clinical Pharmacokinetics and Safety of Orally Administered VH4011499, a New HIV-1 Capsid Inhibitor, in Adults Without HIV |
| title_full_unstemmed | Clinical Pharmacokinetics and Safety of Orally Administered VH4011499, a New HIV-1 Capsid Inhibitor, in Adults Without HIV |
| title_short | Clinical Pharmacokinetics and Safety of Orally Administered VH4011499, a New HIV-1 Capsid Inhibitor, in Adults Without HIV |
| title_sort | clinical pharmacokinetics and safety of orally administered vh4011499 a new hiv 1 capsid inhibitor in adults without hiv |
| topic | Capsid inhibitor First-time-in-human Pharmacokinetics Safety |
| url | https://doi.org/10.1007/s40121-025-01129-y |
| work_keys_str_mv | AT nilaythakkar clinicalpharmacokineticsandsafetyoforallyadministeredvh4011499anewhiv1capsidinhibitorinadultswithouthiv AT rulangriesel clinicalpharmacokineticsandsafetyoforallyadministeredvh4011499anewhiv1capsidinhibitorinadultswithouthiv AT amypierce clinicalpharmacokineticsandsafetyoforallyadministeredvh4011499anewhiv1capsidinhibitorinadultswithouthiv AT veronicabainbridge clinicalpharmacokineticsandsafetyoforallyadministeredvh4011499anewhiv1capsidinhibitorinadultswithouthiv AT bronaghshepherd clinicalpharmacokineticsandsafetyoforallyadministeredvh4011499anewhiv1capsidinhibitorinadultswithouthiv AT konstantinosangelis clinicalpharmacokineticsandsafetyoforallyadministeredvh4011499anewhiv1capsidinhibitorinadultswithouthiv AT andrewtomlinson clinicalpharmacokineticsandsafetyoforallyadministeredvh4011499anewhiv1capsidinhibitorinadultswithouthiv AT yashgandhi clinicalpharmacokineticsandsafetyoforallyadministeredvh4011499anewhiv1capsidinhibitorinadultswithouthiv AT darinbrimhall clinicalpharmacokineticsandsafetyoforallyadministeredvh4011499anewhiv1capsidinhibitorinadultswithouthiv AT brianspears clinicalpharmacokineticsandsafetyoforallyadministeredvh4011499anewhiv1capsidinhibitorinadultswithouthiv AT daijhaanderson clinicalpharmacokineticsandsafetyoforallyadministeredvh4011499anewhiv1capsidinhibitorinadultswithouthiv AT emmapinnick clinicalpharmacokineticsandsafetyoforallyadministeredvh4011499anewhiv1capsidinhibitorinadultswithouthiv AT carolinaacuipil clinicalpharmacokineticsandsafetyoforallyadministeredvh4011499anewhiv1capsidinhibitorinadultswithouthiv AT cynthiamccoig clinicalpharmacokineticsandsafetyoforallyadministeredvh4011499anewhiv1capsidinhibitorinadultswithouthiv AT markbaker clinicalpharmacokineticsandsafetyoforallyadministeredvh4011499anewhiv1capsidinhibitorinadultswithouthiv AT paulbenn clinicalpharmacokineticsandsafetyoforallyadministeredvh4011499anewhiv1capsidinhibitorinadultswithouthiv |