 |
|
|
| |
Proposed Fostemsavir Precautions With HCV Meds
|
| |
| |
International Workshop on Clinical Pharmacology of HIV, Hepatitis and Other Antiviral Drugs, September 20-22, 2021
By Mark Mascolini for NATAP and Virology Education
Although fostemsavir, the antiretroviral licensed for people with heavy HIV treatment experience, may be given with most anti-HCV direct-acting antivirals (DAAs), alternatives should be sought for grazoprevir and voxilaprevir [1]. GlaxoSmithKline and ViiV Healthcare researchers detailed the reasoning behind this advice in fostemsavir (Rukobia) prescribing information [2]. They also noted that fostemsavir may boost plasma levels of all HCV DAAs.
Fostemsavir is a novel attachment inhibitor that shields cells from HIV by binding to the viral envelope gp120 protein [3]. The twice-daily antiretroviral is licensed for use with other antiretrovirals "in heavily treatment-experienced adults with multidrug-resistant HIV-1 infection failing their current antiretroviral regimen due to resistance, intolerance, or safety considerations" [2].
Temsavir, the active form of fostemsavir, is metabolized mainly by esterase-mediated hydrolysis and cytochrome P450 (CYP) 3A4. Temsavir does not inhibit or induce major CYP enzymes, but fostemsavir prescribing information warns that the drug should not be given with strong CYP3A inducers, "including but not limited to enzalutamide, carbamazepine, phenytoin, rifampin, mitotane, and St John's wort (Hypericum perforatum)" [2].
Temsavir is a P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) substrate.
And temsavir or its metabolites inhibit BCRP and organic anion transporter protein 1B1/3 (OATP1B1/3). Temsavir does not inhibit or induce uridine diphosphate glucuronosyltransferase (UGT) enzymes.
In this new analysis using victim or perpetrator enzyme or transporter profiles, GlaxoSmithKline investigators further explored whether fostemsavir is likely to have interactions with 12 HCV DAAs. They compared these findings with results of two phase 1 fostemsavir drug-drug interaction studies involving tenofovir disoproxil fumarate (TDF, a BCRP and P-gp substrate) and rosuvastatin (a BCRP and OATP1B1/3 substrate). All of the anti-HCV drug analyzed are substrates of BCRP, OATP1B1/3, and/or P-gp.
When TDF or rosuvastatin was taken with 600 mg of fostemsavir twice daily, tenofovir area under the curve to the end of the dosing interval (AUCtau) rose 19% and rosuvastatin AUCtau climbed 69%. Those increases are similar to gains in AUCtau seen when TDF (11% increase) and rosuvastatin (38% increase) are taken with cobicistat (a BCRP, P-gp, and OATP1B1/3 inhibitor). Other analyses indicated that fostemsavir and cobicistat inhibit OATP1B1/3 with similar potency. Together, the researchers believe, these findings support the conclusion that the inhibitory potency and interaction potential of temsavir with BCRP and OATP1B1/C substrates are in line with those of the benchmark inhibitor cobicistat.
Taking cobicistat with grazoprevir inflates grazoprevir AUC by 536%, while cobicistat boosts voxilaprevir AUC by 271%. Prescribing information for grazoprevir and voxilaprevir points to OATP1B1/3 as the main mechanism behind increased concentrations of these two DAAs in drug-interaction studies, but inhibition of other transporters and metabolizing enzymes may have a minor impact.
On the basis of this reasoning, the researchers proposed that fostemsavir "may increase plasma exposures of all HCV DAAs." Anticipated cobicistat-like increases in grazoprevir levels with temsavir may increase risk of higher alanine aminotransferase (ALT), they added. The investigators do not believe fostemsavir will be a victim of interactions with HCV DAAs.
The GlaxoSmithKline team concluded that "fostemsavir may be administered with most HCV DAAs." But an alternative to grazoprevir or voxilaprevir is recommended, if possible, in HCV regimens including either of those 2 DAAs. Fostemsavir prescribing information notes that dose adjustments are not needed for people with kidney or liver impairment [2].
References
1. Thakkar N, Magee M, Nguyen D, et al. Clinical application for coadministration of fostemsavir and HCV medications. Clinical Pharmacology of HIV, Hepatitis and Other Antiviral Drugs 2021. September 20-22, 2021. Abstract 25.
2. Rukobia (fostemsavir) prescribing information. https://www.rukobiahcp.com/
3. Kozal M, Aberg J, Pialoux G, et al. Fostemsavir in adults with multidrug-resistant HIV-1 infection. N Engl J Med. 2020;382:1232-1243. DOI: 10.1056/NEJMoa1902493.
|
| |
|
|
|
|
|
