 |
|
|
| |
Sofosbuvir exposure higher in opioid users, lower with darunavir
|
| |
| |
20th International Workshop on Clinical Pharmacology of HIV, Hepatitis & Other Antiviral Drugs. May 14-16, 2019. Noordwijk, the Netherlands
Mark Mascolini
Levels of sofosbuvir proved higher in opioid users but lower with darunavir in a cross-sectional study of current drug users with HCV infection [1]. But overall sofosbuvir plasma concentrations in this 47-person group of active drug users proved similar to historic data.
Use of direct-acting antivirals (DAAs) to treat HCV in drug users is complicated by the scarcity of pharmacokinetic (PK) data on DAAs in this population. University of Colorado researchers who conducted this study noted that active drug use may affect DAA PKs by modulating drug-metabolizing enzymes or transporters or by altering the immune system. To begin addressing these issues, the open-label INCLUD study aims to assess adherence to ledipasvir/sofosbuvir (LDV/SOF) and to define the pharmacology of those DAAs in active drug users with HCV [2].
SOF gets metabolized to its active triphosphate, GS-461203, in cells. Then GS-461203 can be dephosphorylated to GS-331007 (007), an inactive metabolite that can escape cells and return to the circulation. The University of Colorado team proposed that charting PKs of both SOF and 007 is critical to understanding the impact of clinical factors and active drug use on SOF PKs. They aimed to track the PKs of SOF and 007 in plasma on the first day of DAA therapy in active drug users with HCV.
The 47 study participants included 43 with HIV (91%), 39 men (83%), 32 whites (68%), 12 blacks (26%), and 10 Hispanics (21%). Sixteen people (34%) used intravenous drugs, 30 (64%) used THC, and 8 (17%) used opioids acquired by prescription or on the street. Thirty-one people (66%) took an integrase inhibitor for HIV, and 16 (34%) took an HIV protease inhibitor.
All participants took an observed dose of LDV/SOF (90/400 mg) and gave samples for drug-level testing several times over the next 24 hours. Overall SOF and 007 first-dose PKs were similar to historic data: geometric mean area under the concentration-time curve (AUC) 2779 and 10,290 ng • h/mL, maximum concentration 1433 and 770 ng/mL, apparent oral clearance 144 and 25 L/h, and terminal half-life 0.7 and 15.0 h.
Multivariate analysis identified five independent predictors of SOF or 007 AUClast at the following %change (and 95% confidence interval):
SOF AUClast
-- Darunavir use (yes vs no): -40% (-46% to -33%), P < 0.0001
-- Opioid use (yes vs no): 43% (27% to 62%), P = 0.0054
007 AUClast
-- Every 10-mL/min higher eGFR: -5% (-7% to -4%)¸ P = 0.0003
-- Every 10-kg higher weight: -7% (-10% to -4%), P = 0.008
-- Opioid use (yes vs no): 21% (11% to 32%), P = 0.03
The researchers noted that the link between darunavir use and lower SOF exposure is consistent with a previous study [3]. But this is the first study to find higher SOF and 007 concentrations with opioid use. They stressed that the mechanisms and clinical relevance of these findings remain to be determined.
References
1. Brooks K, Castillo-Mancilla J, Morrow M, et al. Sofosbuvir and 007 pharmacokinetics among persons with HCV and active drug use. 20th International Workshop on Clinical Pharmacology of HIV, Hepatitis & Other Antiviral Drugs. May 14-16, 2019. Noordwijk, the Netherlands. Abstract 36.
2. ClinicalTrials.gov. Antiviral pharmacology and adherence in drug users. ClinicalTrials.gov identifier NCT02573376.
https://clinicaltrials.gov/ct2/show/NCT02573376
3. German P, Garrison K, Pang PS, et al. Drug-drug interactions between anti-HCV regimen ledipasvir/sofosbuvir and antiretrovirals. Conference on Retroviruses and Opportunistic Infections (CROI). February 23-26, 2015. Seattle. Abstract 82. http://www.croiconference.org/sessions/drug-drug-interactions-between-anti-hcv-regimen-ledipasvirsofosbuvir-and-antiretrovirals
|
| |
|
|
|
|
|
