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No Critical Interactions Between Ledipasvir/Sofosbuvir and Certain Key Antiretrovirals
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15th International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy, May 19- 21, 2014, Washington, DC
Mark Mascolini
Ledipasvir/sofosbuvir, a fixed-dose coformulation of two direct-acting antivirals (DAAs) for HCV infection, did not have a clinically significant impact on five frequently used antiretrovirals--raltegravir, efavirenz, rilpivirine, and tenofovir/emtricitabine (TDF/FTC)--according to results of three studies in healthy volunteers [1]. Atripla had an affect on ledipasvir deemed not clinically relevant by the Gilead team.
Ledipasvir/sofosbuvir is in late-stage development as a once-daily fixed-dose combination for treatment of HCV infection [2]. The tablet contains 90 mg of the NS5A replication complex inhibitor ledipasvir and 400 mg of the NS5B nucleotide polymerase inhibitor sofosbuvir. Gilead Sciences researchers conducted three multidose randomized crossover trials to identify potential drug-drug interactions between the DAAs and (1) raltegravir, (2) Atripla (efavirenz coformulated with TDF/FTC), and (3) Complera (rilpivirine coformulated with TDF/FTC).
Groups 1 and 3 (30 and 32 volunteers) took drugs fed, while group 2 (32 volunteers) took drugs after fasting. Group 1 took ledipasvir alone for 10 days, raltegravir alone for 10 days, and ledipasvir plus raltegravir for 10 days in random sequence. Group 2 took ledipasvir/sofosbuvir alone followed by the DAAs plus Atripla, or Atripla alone followed by Atripla plus the DAAs. Group 3 took ledipasvir/sofosbuvir alone then with Complera, or Complera alone then with ledipasvir/sofosbuvir. Researchers measured levels of all drugs plus GS-331007 (the main circulating nucleoside metabolite of sofosbuvir) on the last day of each dosing interval.
Two people in group 1 and 1 each in groups 2 and 3 stopped treatment because of adverse events. The most frequent problems were constipation in group 1, headache and dizziness in group 2, and nausea in groups 2 and 3. Most adverse events were grade 1.
Raltegravir had no impact on ledipasvir concentrations, and Complera had no impact on ledipasvir, sofosbuvir, or GS-331007 pharmacokinetics. When codosed with Atripla, ledipasvir concentrations were approximately 30% lower than without Atripla, but Atripla had no effect on concentrations of sofosbuvir or GS-331007. Ledipasvir/sofosbuvir lowered raltegravir concentrations less than 20%. The Gilead team deemed none of these changes clinically relevant.
Ledipasvir/sofosbuvir did not affect levels of efavirenz, rilpivirine, or FTC. With ledipasvir/sofosbuvir, tenofovir exposure increased about 1.8- to 2.6-fold in Atripla and about 1.3- to 1.9-fold in Complera. Tenofovir area under the concentration-time curve values with ledipasvir/sofosbuvir were comparable to those seen when people take TDF/FTC with a ritonavir-boosted protease inhibitor, so the researchers concluded no dose adjustment is needed.
The Gilead team concluded that ledipasvir/sofosbuvir may be given with Atripla, Complera, raltegravir, or TDF/FTC without dose adjustments.
Reference
1. German P, Pang P, West S, Han L, Sajwani K, Mathias A. Drug interactions between direct acting anti-HCV antivirals sofosbuvir and ledipasvir and HIV antiretrovirals. 15th International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy. 19-21 May 2014. Washington, DC. Abstract O_06.
2. Mangia A, Marcellin P, Kwo P, et al. All oral fixed-dose combination ledipasvir/sofosbuvir with or without ribavirin for 12 or 24 weeks in treatment-naive genotype 1 HCV-Infected patients: the phase 3 ION-1 study. EASL 49th Annual Meeting. April 9-13, 2014. London. http://www.natap.org/2014/EASL/EASL_28.htm
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