In vitro assessment of the potential for dolutegravir to affect hepatic clearance of levonorgestrel. Issue 10 (30th July 2021)

• Record Type: Journal Article
• Authors: Roberts, Owain; Kinvig, Hannah; Owen, Andrew; Lamorde, Mohammed; Siccardi, Marco; Scarsi, Kimberly K.
• Is Part Of: HIV medicine. Volume 22:Issue 10(2021)
• Page Start: 898
• Page End: 906
• Publication Date: 2021-07-30
• Subjects: contraceptives -- DMPK -- drug–drug interactions -- pharmacokinetics; HIV infections -- Treatment -- Periodicals; HIV-positive persons -- Periodicals; HIV infections -- Treatment -- Decision making -- Periodicals; 616.9792
• DOI: 10.1111/hiv.13136
• Languages: English
• ISSNs: 1464-2662

Abstract

Abstract: Objectives: 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 (CLint.app. ) and CYP gene expression. Methods: In vitro CYP‐mediated CLint.app. 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 CLint.app., using liquid chromatography‐tandem mass spectrometry, and (2) the expression of specific CYP enzymes, using quantitative real‐time polymerase chain reaction. Results: Levonorgestrel clearance was mediated by multiple rhCYPs, including rhCYP3A4. Under control conditions, levonorgestrel CLint.app. was 22.4 ± 5.0 μL/min/10 6 hepatocytes. Incubation with 43.1 nM of unbound dolutegravir elevated levonorgestrel CLint.app. to 31.4 ± 7.8 µL/min/10 6 hepatocytes ( P = 0.168), while 142.23 nM increased levonorgestrel CLint.app. to 37.0 ± 2.9 µL/min/10 6 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). Conclusions: 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.