Darunavir

Additional information

Pharmacokinetics and dosing

According to the Prezista® summary of product characteristics, population pharmacokinetic studies have shown a 16.8% higher exposure to darunavir in HIV infected women compared to men, but this difference is not considered clinically relevant [1]. In general, women have been included in the published pharmacokinetic studies, but the majority of subjects are men and results have not been presented separately for men and women [2].

The pharmacokinetics of darunavir have been studied in the male genital tract [3]. In this study, 16 patients provided paired semen and blood samples at baseline and after 48 weeks of treatment. At week 48 the darunavir semen concentration was 13% of that in the blood, and in all but one patients this was above the darunavir EC50 concentrations for wild-type HIV-1 strains [3]. Darunavir pharmacokinetics in cervicovaginal fluid (CVF) of women has also been studied [4]. In the 8 women studied, darunavir was measured in 90% of CVF samples, and darunavir exposure in CVF was 1.5-fold higher than in blood [4].

Effects

In the pivotal studies on which registration of darunavir was based, both men and women were included, although men comprised about 90% of the study subjects [5, 6]. Results were not presented separately for men and women.

One phase IIIb north-American multicenter study (the GRACE study) aimed to assess differences in effect, tolerability and adverse effects of darunavir between men and women [7]. In all, 429 patients (142 men, 287 women) were enrolled and received 600 mg darunavir boosted with 100 mg ritonavir twice daily, in combination with an investigator selected standard backbone treatment. No statistically significant differences in virological response could be seen between men and women after 48 weeks of treatment; 73.5% and 73.0%, respectively, when patients discontinuing treatment for other reasons than virological response were excluded [7]. Increase in CD4+ cells from baseline was significantly higher in women than in men [7].

In another study (the ARTEMIS study) of once daily darunavir 800 mg boosted with 100 mg ritonavir (+ emtricitabine/tenofovir  backbone) (239 men, 104 women) efficacy and safety was assessed [8]. Virological response rates at week 96 were identical (79%) in women and men.

In a pivotal study for the change from twice daily darunavir 600 mg/100 mg ritonavir to once daily 800 mg darunavir/100 mg ritonavir (54 men, 31 women) virological response was excellent (97%) in the whole study but results have not been presented by sex [3].

Adverse effects

Darunavir is generally well tolerated. In the GRACE study (see above, 142 men, 287 women), discontinuation of treatment due to adverse effects did not differ between men and women [7]. Women had a higher prevalence of nausea and vomiting, and men had a higher prevalence of diarrhea; however, these differences were not considered clinically relevant. In the ARTEMIS study, no differences in adverse effects could be seen between men and women [8].

Reproductive health issues

Plasma concentration of estrogen based contraceptives (ethinylestradiol and noretisteron) significantly decreases in co-treatment with darunavir, potentially increasing the risk of unwanted pregnancy [1]. 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

The GRACE study has reported on sex differences for metabolic and anthropometric parameters for persons treated with darunavir 600mg/ritonavir 100mg. Overall, there were few differences between men and women. Regarding fasting lipids, glucose and insulin levels only changes in triglycerides differed where women had a significantly lower increase compared to men at the 48-week follow-up (8 mg/dl in women, 25 mg/dl in men, p=0.006) [9]. Changes from baseline to week 48 in body weight, BMI, waist and hip-circumferences did not occur among men, but all factors significantly increased among women [9].

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 [10].