In vitro assessment of the potential for dolutegravir to affect hepatic clearance of levonorgestrel

Roberts, Owain, Kinvig, Hannah ORCID: 0000-0002-0061-1683, Owen, Andrew ORCID: 0000-0002-9819-7651, Lamorde, Mohammed, Siccardi, Marco ORCID: 0000-0002-3539-7867 and Scarsi, Kimberly K
(2021) In vitro assessment of the potential for dolutegravir to affect hepatic clearance of levonorgestrel. HIV MEDICINE, 22 (10). pp. 898-906.

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<h4>Objectives</h4>The World Health Organization recommends that all countries adopt dolutegravir-based antiretroviral therapy as the preferred regimen for all individuals living with HIV. Levonorgestrel is a commonly used hormonal contraceptive, which undergoes drug-drug interactions with some antiretrovirals, but the potential interaction between dolutegravir and levonorgestrel has not been examined. We aimed to evaluate cytochrome P450 (CYP)-mediated levonorgestrel metabolism and quantify the effects of dolutegravir on levonorgestrel apparent intrinsic clearance (CL<sub></sub> ) and CYP gene expression.<h4>Methods</h4>In vitro CYP-mediated CL<sub></sub> of levonorgestrel was quantified using a recombinant human CYP (rhCYP) enzyme system. A primary human hepatocyte model of drug metabolism was used to assess the effects of dolutegravir on (1) levonorgestrel CL<sub></sub> , using liquid chromatography-tandem mass spectrometry, and (2) the expression of specific CYP enzymes, using quantitative real-time polymerase chain reaction.<h4>Results</h4>Levonorgestrel clearance was mediated by multiple rhCYPs, including rhCYP3A4. Under control conditions, levonorgestrel CL<sub></sub> was 22.4 ± 5.0 μL/min/10<sup>6</sup>  hepatocytes. Incubation with 43.1 nM of unbound dolutegravir elevated levonorgestrel CL<sub></sub> to 31.4 ± 7.8 µL/min/10<sup>6</sup>  hepatocytes (P = 0.168), while 142.23 nM increased levonorgestrel CL<sub></sub> to 37.0 ± 2.9 µL/min/10<sup>6</sup>  hepatocytes (P = 0.012). Unbound dolutegravir ≥ 431 nM induced expression of CYP3A4 (≥ two-fold) in a dose-dependent manner, while 1.44 μM of unbound dolutegravir induced CYP2B6 expression 2.2 ± 0.3-fold (P = 0.0004).<h4>Conclusions</h4>In summary, this in vitro study suggests that dolutegravir has the potential to increase hepatic clearance of levonorgestrel by inducing both CYP3A and non-CYP3A enzymes. The observed in vitro dolutegravir-levonorgestrel drug-drug interaction should be further examined in clinical studies.

Item Type: Article
Uncontrolled Keywords: contraceptives, DMPK, drug-drug interactions, pharmacokinetics
Divisions: Faculty of Health and Life Sciences
Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology
Depositing User: Symplectic Admin
Date Deposited: 27 Jan 2022 09:15
Last Modified: 18 Jan 2023 21:14
DOI: 10.1111/hiv.13136
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