Drug products: Harvoni
ATC code: J05AP51
The efficacy of ledipasvir has been shown in both women and men with hepatitis C but published data with analyses of differences based on patient sex are sparse. In a post-hoc analysis, restricted to the patients that completed treatment with ledipasvir and sofosbuvir in a previously published trial, a higher proportion of women had sustained virologic response (SVR). Several randomized and observational trials have not shown a difference in effect based on patient sex.
In pharmacokinetic studies, female sex was associated with a 33% lower apparent oral clearance of ledipasvir compared to males. Based on population PK analyses ledipasvir AUCtau, Cmax, and Ctau were approximately 77%, 58%, and 75% higher in female subjects compared to male subjects. Based on a population PK sensitivity analysis, 49%, 47%, and 29% of the increase in AUCtau, Cmax, and Ctau, respectively, were explained by gender . However, according to the EMA (European Medicines Agency) assessment report and FDA (Food and Drug Administration) clinical pharmacology and biopharmaceutics review both compiled at review of the marketing application for Harvoni (ledipasvir, sofosbuvir) in the EU and the US respectively, the relationship between patient sex and ledipasvir exposure was not considered clinically relevant due to a higher interindividual variability in ledipasvir pharmacokinetics, a favorable safety profile, and high response rates in phase 3 trials [3, 4].
Several studies show no significant differences in effect between men and women [1, 5-10]. A reanalysis of one of these studies, described below, indicated a difference in treatment effect between men and women. The relevance of these findings remains unclear. No studies were designed specifically to detect sex differences with respect to treatment effect. However, in explorative analyses during drug development, male sex among other risk factors was associated with an increased risk of relapse when patients were treated with ledipasvir and sofosbuvir for 8 weeks rather than 12 weeks of therapy according to the EMA (European Medicines Agency) assessment report . A reanalysis restricted to per-protocol data from 423 patients in the ION-3 trial, in which ledipasvir and sofosbuvir were given for 8 or 12 weeks for chronic HCV without cirrhosis, revealed a significant variation in sustained virologic response (SVR) by patient sex. The SVR rates were 98.9% in women and 92.6% in men at 8 weeks of treatment in this analysis. The original study revealed no subgroup differences  and it is important to note that per-protocol analysis is not what is normally used in randomized controlled trials. The authors of the reanalysis argue that since the therapy is highly effective and patients with missing outcome data are treated as treatment failure they will constitute a large part of the patients counted as treatment failures. This practice may, according to the authors, lead to impeded possibilities of detecting subgroup differences .
No studies with a clinically relevant sex analysis regarding adverse effects of ledipasvir have been found.
There is sparse data on the use of ledipasvir in pregnant women; consequentially pregnant women should not use ledipasvir . Regarding teratogenic aspects, please consult Janusmed Drugs and Birth Defects (in Swedish, Janusmed fosterpåverkan).
Date of litterature search: 2016-07-22
Reviewed by: Mia von Euler
Approved by: Karin Schenck-Gustafsson