| Title: |
Matrix Approach Assessment of Cabotegravir Drug–Drug Interactions with OAT1/OAT3 Substrates and UGT1A1/UGT1A9 Inhibitors Using Physiologically-Based Pharmacokinetic Modeling |
| Authors: |
Helen Tracey; Simon T. Bate; Susan Ford; Parul Patel; Jackie Bloomer; Aarti Patel; Kunal S. Taskar |
| Source: |
Pharmaceutics ; Volume 17 ; Issue 4 ; Pages: 531 |
| Publisher Information: |
Multidisciplinary Digital Publishing Institute |
| Publication Year: |
2025 |
| Collection: |
MDPI Open Access Publishing |
| Subject Terms: |
PBPK modeling; cabotegravir; OAT1; OAT3; UGT1A1; UGT1A9; drug–drug interactions; HIV |
| Description: |
Background/Objective: Cabotegravir (CAB), available as an oral tablet and as a long-acting (LA) nanosuspension for intramuscular injection, is approved as a combination therapy for the treatment, and as a monotherapy for the prevention, of HIV-1 infection. People living with HIV may receive multiple concomitant medications, with the associated risk of drug–drug interactions (DDIs). CAB is an inhibitor of OAT1/OAT3 renal transporters and a substrate of the UDP-glucuronosyltransferase enzymes UGT1A1 and 1A9, in vitro. While the effect of induction of UGT1A1/UGT1A9 on CAB exposure had been investigated in the clinic, the effect of the risk of DDIs with CAB via inhibition of these enzymes, or as an inhibitor of OAT1/OAT3 transporters, had not been evaluated. Methods: A physiologically-based pharmacokinetic (PBPK) model was developed and verified for orally dosed CAB to investigate the DDI risks associated with CAB, using a matrix approach to extensively qualify the PBPK platform and the substrates and/or inhibitors of either OAT1/OAT3 or UGT1A1/UGT1A9. The effect of uncertainties in in vitro inhibition values for OAT1/OAT3 was assessed via sensitivity analysis. Results: A mean increase of less than 25% in systemic exposure for OAT1/OAT3 substrates was predicted, with the potential for an increase of up to 80% based on the sensitivity analysis. On co-dosing with UGT1A1/UGT1A9 inhibitors, the predicted mean increase in CAB exposure was within 11%. Conclusions: PBPK modelling indicated that clinically relevant DDIs are not anticipated with OAT1/3 substrates or UGT1A1/1A9 inhibitors and CAB. With maximal exposure of the LA formulation of CAB being lower than the oral, the results of these simulations can be extrapolated to LA injectable dosing. |
| Document Type: |
text |
| File Description: |
application/pdf |
| Language: |
English |
| Relation: |
Pharmacokinetics and Pharmacodynamics; https://dx.doi.org/10.3390/pharmaceutics17040531 |
| DOI: |
10.3390/pharmaceutics17040531 |
| Availability: |
https://doi.org/10.3390/pharmaceutics17040531 |
| Rights: |
https://creativecommons.org/licenses/by/4.0/ |
| Accession Number: |
edsbas.458E2348 |
| Database: |
BASE |