Kommersiellt obunden läkemedelsinformation riktad till läkare och sjukvårdspersonal

Ritonavir

Klassificering: A

Preparat: Kaletra, Lopinavir/Ritonavir Accord, Norvir, Ritonavir Mylan

ATC kod: J05AE03, J05AR10

Substanser: ritonavir

Sammanfattning

Män och kvinnor har varit inkluderade i de pivotala studierna av ritonavir men få analyser av könsskillnader har presenterats. Diarré och allvarlig lipidrubbning tycks vanligare hos män medan lipodystrofi, illamående, njursvikt och leverskador förekommer är vanligare som biverkningar hos kvinnor behandlade med ritonavir.
 
Vår bedömning är att de beskrivna skillnaderna inte motiverar olika dosering eller behandling hos kvinnor och män.

Additional information

Antiretrovirals for treatment of HIV are always given as a combination of at least three medicines. Cobicistat is used to boost the effect of other antiretroviral drugs. As studies on HIV patients always include patients receiving combination therapy it is difficult to know which of the studied medicines that cause changes in effect and/or adverse events.

Pharmacokinetics and dosing

Some studies have shown higher ritonavir exposure in women [1-5] while others show similar results in men and women [6]. The manufacturer does not recommend different dosing in men and women [7].

In a pharmacokinetic analysis of saquinavir with atazanavir or low-dose ritonavir (16 men, 15 women) women had higher exposure for all 3 protease inhibitors (PIs) compared to men after adjusting for weight [8]. As ritonavir is a potent inhibitor of cytochrome P450 3A4 isoenzyme (CYP 3A4) and P-glycoprotein (P-gp) and therefore used to boost other PIs (who are substrates of CYP3A4 and P-gp), the authors speculate that higher exposure of ritonavir in women could be the mechanism behind the higher AUC for the PIs [8].In a study of plasma concentration data from a randomized Phase III study (655 men, 131 women), ritonavir exposure was found to be higher in women [1]. A pharmacokinetic study of lopinavir/ritonavir treated HIV patients (78 men, 76 women) found women to have lower clearance and higher AUC of ritonavir [2]. A randomized open-label study of HIV-positive patients treated with atazanavir+ritonavir or efavirenz combined with abacavir/lamivudine or tenofovir/emtricitabine from the USA (1535 men, 322 women) found that women have lower ritonavir clearance, higher exposure, and higher pre-dose levels of ritonavir compared to men [3].In a South African study in children with HIV randomized to continue ritonavir-boosted lopinavir-based antiretroviral treatment (ART) or switch to nevirapine-based ART (168 boys, 155 girls) girls remaining on ritonavir-boosted lopinavir had higher plasma concentrations of ritonavir than boys during post-randomization visits [4]. A pharmacokinetic study of ritonavir and saquinavir (9 men, 8 women) showed higher concentrations of both drugs in women [5].

In contrast, a study of steady-state concentrations of lopinavir/ritonavir in HIV-patients (9 men, 11 women) found no differences between men and women in pharmacokinetic variables [6]. Using data from Japanese patients with HCV population pharmacokinetic models were developed for paritaprevir, ombitasvir, and ritonavir (100 men, 157 women), and did not find patients’ sex to influence the pharmacokinetic parameters [9]. A Spanish PK study did not find any differences either in PK parameters for ritonavir (n=30) [10]. In a population pharmacokinetic analysis of cobistat or ritonavir boosted Elvitegravir (in all 1046 men, 410 women) patients’ sex did not affect pharmacokinetic variables [11]. A pharmacokinetic study in healthy volunteers measuring plasma drug concentrations after a single oral dose of lopinavir and ritonavir (8 men, 8 women) found no significant sex differences in oral bioavailability and systemic clearance of lopinavir and ritonavir after coprandial administration if weight adjusted doses were used [12]. It is suggested by the authors that food would reduce the gastric physiological differences between men and women [13].

Effects

Both men and women have been included in the pivotal studies but few sex-divided outcome measures have not been presented [7].

In a South African study in children with HIV randomized to continue ritonavir-boosted lopinavir-based antiretroviral treatment (ART) or switch to nevirapine-based ART (168 boys, 155 girls) no sex differences in risk of virological failure were observed within either treatment group [4].

In the US study mentioned above in patients treated with atazananvir+ritonavir or efavirenz combined with abacavir/lamivudine or tenofovir/emtricitabine (1535 men, 322 women) women treated with ritonavir had a higher risk of virologic failure with either nucleoside reverse transcriptase inhibitor backbone than women assigned to efavirenz, or men assigned to atazanavir+ritonavir. In this study, more women than men reported black race which is a possible confounding [3].

Adverse effects

The differences in adverse events which have been described for different antiretroviral regimens are that in general women have been reported to have more nausea and gastrointestinal reactions, more lipodystrophy, a higher risk of developing kidney failure but a lower risk of LDL-level increase compared to men [3, 14-16].

A retrospective cohort study (438 men, 122 women) investigated if particular antiretroviral agents were associated with a higher risk of developing serious liver enzyme elevations in patients with HIV. An increased risk was found in women, use of first-line potent antiretroviral combination regimens in patients without prior NRTI treatment, recent start of nevirapine (HR, 9.6) or ritonavir, and in patients with higher baseline ALT levels, chronic HBV or HCV infection [17].

An American randomized open-label study of HIV-positive patients treated with atazanavir+ritonavir or efavirenz combined with abacavir/lamivudine or tenofovir/emtricitabine (1535 men, 322 women) found no difference between men and women in safety outcome between atazanavir+ritonavir and efavirenz treatment. Self-reported adherence did not differ significantly by sex. In this study, more women than men reported black race which is a possible confounding [3].

In a South African study in children with HIV randomized to continue ritonavir-boosted lopinavir-based antiretroviral treatment (ART) or switch to nevirapine-based ART (168 boys, 155 girls) girls remaining on ritonavir-boosted lopinavir had a higher total cholesterol:HDL ratio and lower mean HDL than boys on that treatments [4].

Reproductive health issues

Ritonavir adversely interacts with oral contraceptives and lowers the dose of both progesterone and estrogen components thus rendering them potentially ineffective [7, 18].  It is recommended that an alternative, effective and safe method of contraception should be used during treatment [7]. Due to ritonavir having a high affinity for several cytochrome P450 isoforms the drug is prone to interaction. Regarding drug-drug interactions aspects, please consult Janusmed Interactions (in Swedish, Janusmed interaktioner).

Regarding teratogenic aspects, please consult Janusmed Drugs and Birth Defects (in Swedish, Janusmed fosterpåverkan).

Other information

Several studies report a higher rate of discontinuation from ART containing ritonavir boosted PI in women [19, 21]. A North American open label phase III study in HIV patients treated with darunavir+ritonavir in addition to an investigator-selected optimized background regimen (142 men, 287 women) found a higher discontinuation rate in women [19]. In the CASTLE study, treatment-naive adult HIV-patients (606 men, 277 women) were randomized to receive either atazanavir/ritonavir or lopinavir/ritonavir with fixed-dose tenofovir/emtricitabin. Discontinuation rates were higher in women than men in each treatment arm (29% and 18%, respectively of women and men on lopinavir/ritonavir) [20]. In a post-hoc analysis of data from a randomised phase-III trial in HIV patients treated with atazanavir  boosted with either cobicistat or ritonavir in combination with emtricitabine/tenofovir disoproxil fumarate (574 men, 118 women) found more discontinuations due to withdrawal of consent and pregnancies in women receiving atazanavir+ritonavir compared to atazanavir+cobicistat [21].

A descriptive retrospective Brasilian study of HIV patients on highly active antiretroviral therapy who modified their treatment within the first year of treatment (52 men, 35 women) found that efavirenz was the most often changed drug, followed by tenofovir, zidovudine and lopinavir/ritonavir [22].

A review has described drug exposure in the genital tract of men and women which is of interest in viral transferal and in effect of pre-exposure prophylactic treatment. In men, concentrations in seminal fluid were described to be highest for nucleoside analogues and lowest for protease inhibitors and efavirenz. Seminal accumulation of raltegravir and maraviroc was defined as moderate. The rank order of accumulation presented in the review is nucleoside/nucleotide reverse transcriptase inhibitors [lamivudine/zidovudine/tenofovir/didanosine > stavudine/abacavir] > raltegravir > indinavir/maraviroc/nevirapine >> efavirenz/protease inhibitors [amprenavir/atazanavir/darunavir > lopinavir/ritonavir > saquinavir] > enfuvirtide. In the female genital tract, the nucleoside analogues also were described as having high accumulation ratios, whereas protease inhibitors have limited penetration; however, substantial variability exists. Second generation non-nucleoside reverse transcriptase inhibitor etravirine, and maraviroc and raltegravir, have been found to demonstrate effective accumulation in cervicovaginal secretions. The rank of accumulation presented in the review is nucleoside/nucleotide reverse transcriptase inhibitor [zidovudine/lamivudine/didanosine > emtricitabine/tenofovir] > indinavir > maraviroc/raltegravir/darunavir/etravirine > nevirapine/abacavir > protease inhibitors [amprenavir/atazanavir/ritonavir] > lopinavir/stavudine/efavirenz > saquinavir [23].

Försäljning på recept

Fler män än kvinnor hämtade ut läkemedel innehållande ritonavir (J05AE03) på recept i Sverige år 2017, totalt 661 män och 576 kvinnor [24].

Uppdaterat: 2018-12-20

Litteratursökningsdatum: 2018-07-18

Referenser

  1. Venuto CS, Mollan K, Ma Q, Daar ES, Sax PE, Fischl M et al. Sex differences in atazanavir pharmacokinetics and associations with time to clinical events: AIDS Clinical Trials Group Study A5202. J Antimicrob Chemother. 2014;69(12):3300-10. PubMed
  2. Smith KY, Tierney C, Mollan K, Venuto CS, Budhathoki C, Ma Q et al. Outcomes by sex following treatment initiation with atazanavir plus ritonavir or efavirenz with abacavir/lamivudine or tenofovir/emtricitabine. Clin Infect Dis. 2014;58(4):555-63. PubMed
  3. Umeh OC, Currier JS, Park JG, Cramer Y, Hermes AE, Fletcher CV. Sex differences in lopinavir and ritonavir pharmacokinetics among HIV-infected women and men. J Clin Pharmacol. 2011;51(12):1665-73. PubMed
  4. Shiau S, Kuhn L, Strehlau R, Martens L, McIlleron H, Meredith S et al. Sex differences in responses to antiretroviral treatment in South African HIV-infected children on ritonavir-boosted lopinavir- and nevirapine-based treatment. BMC Pediatr. 2014;14(1):39. PubMed
  5. Schmitt C, Kaeser B, Riek M, Bech N, Kreuzer C. Effect of saquinavir/ritonavir on P-glycoprotein activity in healthy volunteers using digoxin as a probe. Int J Clin Pharmacol Ther. 2010;48(3):192-9. PubMed
  6. Ofotokun I, Chuck SK, Binongo JN, Palau M, Lennox JL, Acosta EP. Lopinavir/Ritonavir pharmacokinetic profile: impact of sex and other covariates following a change from twice-daily to once-daily therapy. J Clin Pharmacol. 2007;47(8):970-7. PubMed
  7. Norvir (ritonavir). Summary of Product Characteristics. European Medicines Agency (EMA); 2018.
  8. King JR, Kakuda TN, Paul S, Tse MM, Acosta EP, Becker SL. Pharmacokinetics of saquinavir with atazanavir or low-dose ritonavir administered once daily (ASPIRE I) or twice daily (ASPIRE II) in seronegative volunteers. J Clin Pharmacol. 2007;47(2):201-8. PubMed
  9. Gopalakrishnan SM, Polepally AR, Mensing S, Khatri A, Menon RM. Population Pharmacokinetics of Paritaprevir, Ombitasvir, and Ritonavir in Japanese Patients with Hepatitis C Virus Genotype 1b Infection. Clin Pharmacokinet 2016 Jun 17; PubMed
  10. Curran A, Martí R, López RM, Pérez M, Crespo M, Melià MJ et al. Darunavir and ritonavir total and unbound plasmatic concentrations in HIV-HCV-coinfected patients with hepatic cirrhosis compared to those in HIV-monoinfected patients. Antimicrob Agents Chemother. 2015;59(11):6782-90. PubMed
  11. Custodio JM, Gordi T, Zhong L, Ling KH, Ramanathan S. Population Pharmacokinetics of Boosted-Elvitegravir in HIV-Infected Patients. J Clin Pharmacol. 2016;56(6):723-32. PubMed
  12. Ibarra M, Fagiolino P, Vázquez M, Ruiz S, Vega M, Bellocq B et al. Impact of food administration on lopinavir-ritonavir bioequivalence studies. Eur J Pharm Sci. 2012;46(5):516-21. PubMed
  13. Freire AC, Basit AW, Choudhary R, Piong CW, Merchant HA. Does sex matter? The influence of gender on gastrointestinal physiology and drug delivery. Int J Pharm. 2011;415(1):15-28. PubMed
  14. Hodder S, Arasteh K, De Wet J, Gathe J, Gold J, Kumar P et al. Effect of gender and race on the week 48 findings in treatment-naïve, HIV-1-infected patients enrolled in the randomized, phase III trials ECHO and THRIVE. HIV Med. 2012;13(7):406-15. PubMed
  15. Kumar PN, Rodriguez-French A, Thompson MA, Tashima KT, Averitt D, Wannamaker PG et al. A prospective, 96-week study of the impact of Trizivir, Combivir/nelfinavir, and lamivudine/stavudine/nelfinavir on lipids, metabolic parameters and efficacy in antiretroviral-naive patients: effect of sex and ethnicity. HIV Med. 2006;7(2):85-98. PubMed
  16. Mocroft A, Lundgren JD, Ross M, Law M, Reiss P, Kirk O et al. Development and validation of a risk score for chronic kidney disease in HIV infection using prospective cohort data from the D:A:D study. PLoS Med. 2015;12(3):e1001809. PubMed
  17. Wit FW, Weverling GJ, Weel J, Jurriaans S, Lange JM. Incidence of and risk factors for severe hepatotoxicity associated with antiretroviral combination therapy. J Infect Dis. 2002;186(1):23-31. PubMed
  18. Halkes PH, van Gijn J, Kappelle LJ, Koudstaal PJ, Algra A, European/Australasian Stroke Prevention in Reversible Ischaemia Trial Study Group. Risk indicators for development of headache during dipyridamole treatment after cerebral ischaemia of arterial origin. J Neurol Neurosurg Psychiatry. 2009;80:437-9. PubMed
  19. Currier J, Averitt Bridge D, Hagins D, Zorrilla CD, Feinberg J, Ryan R et al. Sex-based outcomes of darunavir-ritonavir therapy: a single-group trial. Ann Intern Med. 2010;153:349-57. PubMed
  20. Squires KE, Johnson M, Yang R, Uy J, Sheppard L, Absalon J et al. Comparative gender analysis of the efficacy and safety of atazanavir/ritonavir and lopinavir/ritonavir at 96 weeks in the CASTLE study. J Antimicrob Chemother. 2011;66(2):363-70. PubMed
  21. Gallant J, Moyle G, Berenguer J, Shalit P, Cao H, Liu YP et al. Atazanavir Plus Cobicistat: Week 48 and Week 144 Subgroup Analyses of a Phase 3, Randomized, Double-Blind, Active-Controlled Trial. Curr HIV Res. 2017;15(3):216-224. PubMed
  22. Bandeira ACPCS, Elias DBD, Cavalcante MG, Lima DGL, Távora LGF. Antiretroviral changes during the first year of therapy. Rev Assoc Med Bras (1992). 2017;63(7):606-612. PubMed
  23. Else LJ, Taylor S, Back DJ, Khoo SH. Pharmacokinetics of antiretroviral drugs in anatomical sanctuary sites: the male and female genital tract. Antivir Ther. 2011;16(8):1149-67. PubMed
  24. Läkemedelsstatistik. Stockholm: Socialstyrelsen. 2017 [cited 2018-07-24.] länk

Författare: Mia von Euler

Faktagranskat av: Jaran Eriksen, Karin Schenck-Gustafsson

Godkänt av: Karin Schenck-Gustafsson