Impact of Obesity on the Drug-Drug Interaction Between Dolutegravir and Rifampicin or Any Other Strong Inducers.
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State: Public
Version: Final published version
License: CC BY-NC-ND 4.0
State: Public
Version: Final published version
License: CC BY-NC-ND 4.0
Serval ID
serval:BIB_7B67BF5F2315
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Impact of Obesity on the Drug-Drug Interaction Between Dolutegravir and Rifampicin or Any Other Strong Inducers.
Journal
Open forum infectious diseases
ISSN
2328-8957 (Print)
ISSN-L
2328-8957
Publication state
Published
Issued date
07/2023
Peer-reviewed
Oui
Volume
10
Number
7
Pages
ofad361
Language
english
Notes
Publication types: Journal Article
Publication Status: epublish
Publication Status: epublish
Abstract
Obesity is increasingly prevalent among people with HIV. Obesity can impact drug pharmacokinetics and consequently the magnitude of drug-drug interactions (DDIs) and, thus, the related recommendations for dose adjustment. Virtual clinical DDI studies were conducted using physiologically based pharmacokinetic (PBPK) modeling to compare the magnitude of the DDI between dolutegravir and rifampicin in nonobese, obese, and morbidly obese individuals.
Each DDI scenario included a cohort of virtual individuals (50% female) between 20 and 50 years of age. Drug models for dolutegravir and rifampicin were verified against clinical observed data. The verified models were used to simulate the concurrent administration of rifampicin (600 mg) at steady state with dolutegravir (50 mg) administered twice daily in normal-weight (BMI 18.5-30 kg/m <sup>2</sup> ), obese (BMI 30-40 kg/m <sup>2</sup> ), and morbidly obese (BMI 40-50 kg/m <sup>2</sup> ) individuals.
Rifampicin was predicted to decrease dolutegravir area under the curve (AUC) by 72% in obese and 77% in morbidly obese vs 68% in nonobese individuals; however, dolutegravir trough concentrations were reduced to a similar extent (83% and 85% vs 85%). Twice-daily dolutegravir with rifampicin resulted in trough concentrations always above the protein-adjusted 90% inhibitory concentration for all BMI groups and above the 300 ng/mL threshold in a similar proportion for all BMI groups.
The combined effect of obesity and induction by rifampicin was predicted to further decrease dolutegravir exposure but not the minimal concentration at the end of the dosing interval. Thus, dolutegravir 50 mg twice daily with rifampicin can be used in individuals with a high BMI up to 50 kg/m <sup>2</sup> .
Each DDI scenario included a cohort of virtual individuals (50% female) between 20 and 50 years of age. Drug models for dolutegravir and rifampicin were verified against clinical observed data. The verified models were used to simulate the concurrent administration of rifampicin (600 mg) at steady state with dolutegravir (50 mg) administered twice daily in normal-weight (BMI 18.5-30 kg/m <sup>2</sup> ), obese (BMI 30-40 kg/m <sup>2</sup> ), and morbidly obese (BMI 40-50 kg/m <sup>2</sup> ) individuals.
Rifampicin was predicted to decrease dolutegravir area under the curve (AUC) by 72% in obese and 77% in morbidly obese vs 68% in nonobese individuals; however, dolutegravir trough concentrations were reduced to a similar extent (83% and 85% vs 85%). Twice-daily dolutegravir with rifampicin resulted in trough concentrations always above the protein-adjusted 90% inhibitory concentration for all BMI groups and above the 300 ng/mL threshold in a similar proportion for all BMI groups.
The combined effect of obesity and induction by rifampicin was predicted to further decrease dolutegravir exposure but not the minimal concentration at the end of the dosing interval. Thus, dolutegravir 50 mg twice daily with rifampicin can be used in individuals with a high BMI up to 50 kg/m <sup>2</sup> .
Keywords
PBPK modeling, dolutegravir, drug-drug interaction, obesity, rifampicin, ViiV unrelated to this work. All other authors report no potential conflicts of, interest., drug–drug interaction
Pubmed
Web of science
Open Access
Yes
Funding(s)
Swiss National Science Foundation / Projects / 188504
Create date
25/08/2023 5:17
Last modification date
06/08/2024 6:02