Kommersiellt obunden läkemedelsinformation riktad till läkare och sjukvårdspersonal

Ledipasvir

Klassificering: A

Preparat: Harvoni

ATC kod: J05AP51

Substanser: ledipasvir

Sammanfattning

Ledipasvir har visats effektivt hos både kvinnor och män med hepatit C men publicerade data med könsjämförelser är mycket begränsat. En post hoc-analys omfattande endast de patienter i en tidigare publicerad studie fullföljt behandling med ledipasvir och sofusbuvir visade att en högre andel kvinnor hade kvarstående virologiskt svar. Flera randomiserade och observationella studier har dock inte visat på någon könsskillnad i behandlingseffekt.

Additional information

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 [3]. 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].

Effects

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 [3]. 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 [1] 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 [2].

Adverse effects

No studies with a clinically relevant sex analysis regarding adverse effects of ledipasvir have been found.

Reproductive health issues

There is sparse data on the use of ledipasvir in pregnant women; consequentially pregnant women should not use ledipasvir [11]. Regarding teratogenic aspects, please consult Janusmed Drugs and Birth Defects (in Swedish, Janusmed fosterpåverkan).

Försäljning på recept

Fler män än kvinnor hämtade ut läkemedel innehållande kombination av sofosbuvir och ledipasvir (ATC-kod J05AX65) på recept i Sverige år 2015, totalt 720 män och 341 kvinnor [12]. Könsfördelningen av hepatit C-fall i Sverige år 2015 var 68 % män och 32 % kvinnor (i 0,3% av fallen var könet okänt) [13].

Uppdaterat: 2019-03-13

Litteratursökningsdatum: 2016-07-22

Referenser

  1. Kowdley KV, Gordon SC, Reddy KR, Rossaro L, Bernstein DE, Lawitz E et al. Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. N Engl J Med. 2014;370:1879-88. PubMed
  2. O'Brien TR, Lang Kuhs KA, Pfeiffer RM. Subgroup differences in response to 8 weeks of ledipasvir/sofosbuvir for chronic hepatitis C. Open Forum Infect Dis. 2014;1:ofu110. PubMed
  3. Committee for Medicinal Products for Human Use (CHMP). Assessment report Harvoni Procedure No EMEA/H/C/003850/0000. European Medicines Agency (EMA) [updated 2014-09-25, cited 2016-07-22]. länk
  4. Food and Drug Administration (FDA). Clinical Pharmacology and Biopharmaceutics Review - HARVONI (ledipasvir/sofosbuvir) [updated 2014-11-03]. länk
  5. Piola P, Nabasumba C, Turyakira E, Dhorda M, Lindegardh N, Nyehangane D et al. Efficacy and safety of artemether-lumefantrine compared with quinine in pregnant women with uncomplicated Plasmodium falciparum malaria: an open-label, randomised, non-inferiority trial. Lancet Infect Dis. 2010;10:762-9. PubMed
  6. Afdhal N, Reddy KR, Nelson DR, Lawitz E, Gordon SC, Schiff E et al. Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection. N Engl J Med. 2014;370:1483-93. PubMed
  7. Afdhal N, Zeuzem S, Kwo P, Chojkier M, Gitlin N, Puoti M et al. Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection. N Engl J Med. 2014;370:1889-98. PubMed
  8. Naggie S, Cooper C, Saag M, Workowski K, Ruane P, Towner WJ et al. Ledipasvir and Sofosbuvir for HCV in Patients Coinfected with HIV-1. N Engl J Med. 2015;373:705-13. PubMed
  9. Walker DR, Pedrosa MC, Manthena SR, Patel N, Marx SE. Early View of the Effectiveness of New Direct-Acting Antiviral (DAA) Regimens in Patients with Hepatitis C Virus (HCV). Adv Ther. 2015;32:1117-27. PubMed
  10. Backus LI, Belperio PS, Shahoumian TA, Loomis TP, Mole LA. Effectiveness of sofosbuvir-based regimens in genotype 1 and 2 hepatitis C virus infection in 4026 US Veterans. Aliment Pharmacol Ther. 2015;42:559-73. PubMed
  11. HARVONI (ledipasvir/sofosbuvir). Summary of Product Characteristics. European Medicines Agency (EMA); 2016.
  12. Läkemedelsstatistik. Stockholm: Socialstyrelsen. 2015 [cited 2016-08-02.] Socialstyrelsens statistikdatabas
  13. Sjukdomsstatistik. Solna: Folkhälsomyndigheten. 2016 [cited 2016-04-04.] länk

Författare: Johan Holm, Linnéa Karlsson Lind

Faktagranskat av: Mia von Euler

Godkänt av: Karin Schenck-Gustafsson