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Impact of Food and Antacids on Levels of Ledipasvir and Sofosbuvir
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15th International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy, May 19- 21, 2014, Washington, DC
Mark Mascolini
Food did not substantially alter concentrations of the direct-acting antivirals (DAAs) ledipasvir and sofosbuvir administered as a once-daily coformulated agent [1]. Standard doses of the H2-receptor antagonist famotidine or the proton pump inhibitor omeprazole had only minor impacts on levels of the coformulated DAAs.
Coformulated ledipasvir/sofosbuvir has yielded high sustained virologic response rates (SVRs) in people with untreated and previously treated HCV genotype 1 infection [2-4], including people coinfected with HIV [5]. Sofosbuvir is a licensed nucleotide polymerase inhibitor, and its major circulating nucleoside metabolite is GS-331007. Ledipasvir is an investigational NS5A replication complex inhibitor.
Gilead Sciences researchers conducted two studies to assess the impact of food and acid-reducing agents on concentrations of these two potent antivirals. The single-dose crossover food study enrolled 30 healthy volunteers who took ledipasvir/sofosbuvir while fasting, with a moderate-fat meal (25% to 30% fat, about 600 kcal), and with a high-calorie/high-fat meal (50% fat, about 1000 kcal), with a 9-day washout between treatments. The Gilead team measured plasma concentrations of ledipasvir, sofosbuvir, and GS-331007 and calculated geometric least-squares means ratios to compare levels of these agents with food versus fasting.
After 2 people withdrew consent, 28 people completed the food study. All adverse events were grade 1. A moderate- or high-fat meal did not change concentrations of ledipasvir. Sofosbuvir area under the concentration-time curve (AUC) increased less than 2-fold with food, while sofosbuvir maximum concentration (Cmax) rose less than 1.3-fold with food. GS-331007 Cmax values were 19% to 30% lower with a medium- or high-fat meal, but food did not affect AUC of the metabolite. The researchers did not consider increases in sofosbuvir levels clinically meaningful.
The acid-agent study included two groups: (1) 12 fed healthy volunteers took ledipasvir/sofosbuvir alone on day 1, ledipasvir/sofosbuvir plus 40 mg of the H2-receptor antagonist famotidine on day 12, and ledipasvir/sofosbuvir 12 hours after famotidine on day 24; (2) 16 fasting volunteers took ledipasvir/sofosbuvir on day 1, 20 mg of the proton pump inhibitor omeprazole on days 12 to 16, then ledipasvir/sofosbuvir plus omeprazole on day 17.
All volunteers completed the famotidine and omeprazole studies. No one in the omeprazole group had an adverse event, and all adverse events in the famotidine group were grade 1.
Famotidine taken with ledipasvir/sofosbuvir did not change ledipasvir or sofosbuvir AUC or GS-331007 AUC or Cmax. Sofosbuvir Cmax was about 15% higher with simultaneous famotidine, while ledipasvir Cmax about 20% lower with simultaneous famotidine; these changes were not judged clinically important. Famotidine taken 12 hours before ledipasvir/sofosbuvir did not alter ledipasvir AUC, sofosbuvir AUC or Cmax, or GS-331007 AUC or Cmax. Ledipasvir Cmax was about 17% lower when famotidine was taken 12 hours earlier.
Simultaneous administration of omeprazole with ledipasvir/sofosbuvir had no impact on the AUC or Cmax of sofosbuvir or GS-331007. Simultaneous omeprazole resulted in about a 4% to 7% lower ledipasvir AUC and about an 11% lower Cmax--neither judged to be clinically relevant.
The Gilead team concluded that ledipasvir/sofosbuvir may be taken without regard to meals. They advised that ledipasvir/sofosbuvir may be taken with an H2-receptor antagonist "at a dose that does not exceed famotidine 40 mg twice daily." A proton pump inhibitor dose comparable to 20 mg of omeprazole can be taken with ledipasvir/sofosbuvir or up to 2 hours after ledipasvir/sofosbuvir.
EASL: 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 - (04/14/14)
EASL: All Oral Fixed-Dose Combination Ledipasvir/Sofosbuvir With or Without Ribavirin for 12 or 24 Weeks in Treatment-Experienced Genotype 1 HCV-Infected Patients: The Phase 3 ION-2 Study - (04/14/14)
EASL: Ledipasvir/Sofosbuvir With and Without Ribavirin for 8 Weeks Compared to Ledipasvir/Sofosbuvir for 12 Weeks in Treatment-Naïve Noncirrhotic Genotype-1 HCV-Infected Patients: The Phase 3 ION-3 Study - (04/11/14)
NEJM Publications:
ION-1 Ledipasvir and Sofosbuvir for Untreated HCV Genotype 1 Infection - (04/14/14)
ION-2 Ledipasvir and Sofosbuvir for Previously Treated HCV Genotype 1 Infection - (04/14/14)
ION-3 Ledipasvir and Sofosbuvir for 8 or 12 Weeks for Chronic HCV without Cirrhosis - (04/11/14)
EASL: New DAA Phase 3 Studies for genotype 1 at EASL - in both Treatment-naives, treatment-experienced; simultaneous publications - (04/21/14)
EASL - The International Liver Congress 2014 49th Annual Meeting of the European Association for the Study of the Liver
London, United Kingdom
April 9-13
References
1. German P, Yang J, West S, Han L, Sajwani K, Mathias A. Effect of food and acid reducing agents on the relative bioavailability and pharmacokinetics of ledipasvir/sofosbuvir fixed dose combination tablet. 15th International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy. May 19-21, 2014. Washington, DC. Abstract P_15.
2. Afdhal N, Zeuzem S, Kwo P, et al. Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection. N Engl J Med. 2014 Apr 11. Epub ahead of print. http://www.nejm.org/doi/full/10.1056/NEJMoa1402454
3. Afdhal N, Reddy KR, Nelson DR, et al. Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection. N Engl J Med. 2014;370:1483-1493.
4. Kowdley KV, Gordon SC, Reddy KR, et al. Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. N Engl J Med. 2014 Apr 10. Epub ahead of print. http://www.nejm.org/doi/full/10.1056/NEJMoa1402355
5. Osinusi A, Townsend K, Nelson A, et al. Use of sofosbuvir/ledipasvir fixed dose combination for treatment of HCV genotype-1 infection in patients coinfected with HIV (interim results). 49th Annual Meeting of the European Association for the Study of the Liver (EASL). April 9-13, 2014. London. http://www.natap.org/2014/EASL/EASL_05.htm
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