Simultaneous pharmacokinetic modeling of unbound and total darunavir with ritonavir in adolescents : a substudy of the SMILE trial
Darunavir (DRV) is an HIV protease inhibitor commonly used as part of antiretroviral treatment regimens globally for children and adolescents. It requires a pharmacological booster, such as ritonavir (RTV) or cobicistat. To better understand the pharmacokinetics (PK) of DRV in this younger population and the importance of the RTV boosting effect, a population PK substudy was conducted within SMILE trial, where the maintenance of HIV suppression with once daily integrate inhibitor + darunavir/ritonavir in children and adolescents is evaluated. A joint population PK model that simultaneously used total DRV, unbound DRV, and total RTV concentrations was developed. Competitive and non-competitive models were examined to define RTV's influence on DRV pharmacokinetics. Linear and non-linear equations were tested to assess DRV protein binding. A total of 443 plasma samples from 152 adolescents were included in this analysis. Darunavir PK was best described by a one-compartment model first-order absorption and elimination. The influence of RTV on DRV pharmacokinetics was best characterized by ritonavir area under the curve on DRV clearance using a power function. The association of non-linear and linear equations was used to describe DRV protein binding to alpha-1 glycoprotein and albumin, respectively. In our population, simulations indicate that 86.8% of total and unbound DRV trough concentrations were above 0.55 mg/L [10 times protein binding-adjusted EC50 for wild-type (WT) HIV-1] and 0.0243 mg/L (10 times EC90 for WT HIV-1) targets, respectively. Predictions were also in agreement with observed outcomes from adults receiving 800/100 mg DRV/r once a day. Administration of 800/100 mg of DRV/r once daily provides satisfactory concentrations and exposures for adolescents aged 12 years and older.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2024 |
|---|---|
| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:68 |
|---|---|
| Enthalten in: |
Antimicrobial agents and chemotherapy - 68(2024), 2 vom: 07. Feb., Seite e0100423 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Abdalla, Seef [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
Adolescent |
|---|
| Anmerkungen: |
Date Completed 08.02.2024 Date Revised 10.02.2024 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1128/aac.01004-23 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM365833681 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM365833681 | ||
| 003 | DE-627 | ||
| 005 | 20240210232955.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231226s2024 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1128/aac.01004-23 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1287.xml |
| 035 | |a (DE-627)NLM365833681 | ||
| 035 | |a (NLM)38092664 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Abdalla, Seef |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Simultaneous pharmacokinetic modeling of unbound and total darunavir with ritonavir in adolescents |b a substudy of the SMILE trial |
| 264 | 1 | |c 2024 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 08.02.2024 | ||
| 500 | |a Date Revised 10.02.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Darunavir (DRV) is an HIV protease inhibitor commonly used as part of antiretroviral treatment regimens globally for children and adolescents. It requires a pharmacological booster, such as ritonavir (RTV) or cobicistat. To better understand the pharmacokinetics (PK) of DRV in this younger population and the importance of the RTV boosting effect, a population PK substudy was conducted within SMILE trial, where the maintenance of HIV suppression with once daily integrate inhibitor + darunavir/ritonavir in children and adolescents is evaluated. A joint population PK model that simultaneously used total DRV, unbound DRV, and total RTV concentrations was developed. Competitive and non-competitive models were examined to define RTV's influence on DRV pharmacokinetics. Linear and non-linear equations were tested to assess DRV protein binding. A total of 443 plasma samples from 152 adolescents were included in this analysis. Darunavir PK was best described by a one-compartment model first-order absorption and elimination. The influence of RTV on DRV pharmacokinetics was best characterized by ritonavir area under the curve on DRV clearance using a power function. The association of non-linear and linear equations was used to describe DRV protein binding to alpha-1 glycoprotein and albumin, respectively. In our population, simulations indicate that 86.8% of total and unbound DRV trough concentrations were above 0.55 mg/L [10 times protein binding-adjusted EC50 for wild-type (WT) HIV-1] and 0.0243 mg/L (10 times EC90 for WT HIV-1) targets, respectively. Predictions were also in agreement with observed outcomes from adults receiving 800/100 mg DRV/r once a day. Administration of 800/100 mg of DRV/r once daily provides satisfactory concentrations and exposures for adolescents aged 12 years and older | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a adolescent | |
| 650 | 4 | |a children | |
| 650 | 4 | |a darunavir | |
| 650 | 4 | |a free fraction | |
| 650 | 4 | |a population pharmacokinetics | |
| 650 | 4 | |a ritonavir | |
| 650 | 4 | |a unbound | |
| 650 | 7 | |a Darunavir |2 NLM | |
| 650 | 7 | |a YO603Y8113 |2 NLM | |
| 650 | 7 | |a Ritonavir |2 NLM | |
| 650 | 7 | |a O3J8G9O825 |2 NLM | |
| 650 | 7 | |a Anti-HIV Agents |2 NLM | |
| 650 | 7 | |a Sulfonamides |2 NLM | |
| 650 | 7 | |a HIV Protease Inhibitors |2 NLM | |
| 700 | 1 | |a Compagnucci, Alexandra |e verfasserin |4 aut | |
| 700 | 1 | |a Riault, Yoann |e verfasserin |4 aut | |
| 700 | 1 | |a Chan, Man K |e verfasserin |4 aut | |
| 700 | 1 | |a Bamford, Alasdair |e verfasserin |4 aut | |
| 700 | 1 | |a Nolan, Aoife |e verfasserin |4 aut | |
| 700 | 1 | |a Ramos, José T |e verfasserin |4 aut | |
| 700 | 1 | |a Constant, Valentin |e verfasserin |4 aut | |
| 700 | 1 | |a Nguyen, Thao-Nguyen |e verfasserin |4 aut | |
| 700 | 1 | |a Zheng, Yi |e verfasserin |4 aut | |
| 700 | 1 | |a Tréluyer, Jean-Marc |e verfasserin |4 aut | |
| 700 | 1 | |a Froelicher-Bournaud, Léo |e verfasserin |4 aut | |
| 700 | 1 | |a Neveux, Nathalie |e verfasserin |4 aut | |
| 700 | 1 | |a Saidi, Yacine |e verfasserin |4 aut | |
| 700 | 1 | |a Cressey, Tim R |e verfasserin |4 aut | |
| 700 | 1 | |a Hirt, Déborah |e verfasserin |4 aut | |
| 700 | 0 | |a SMILE study group |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Antimicrobial agents and chemotherapy |d 1972 |g 68(2024), 2 vom: 07. Feb., Seite e0100423 |w (DE-627)NLM000026506 |x 1098-6596 |7 nnns |
| 773 | 1 | 8 | |g volume:68 |g year:2024 |g number:2 |g day:07 |g month:02 |g pages:e0100423 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1128/aac.01004-23 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 68 |j 2024 |e 2 |b 07 |c 02 |h e0100423 | ||