Other Names

Prezista®: darunavir/ritonavir

Prezcobix®: darunavir/cobicistat

Symtuza®: darunavir/cobicistat/emtricitabine/tenofovir alafenamide (TAF)

Protease inhibitor with potent in vitro activity against both wild-type HIV-1 and a large panel of viruses resistant to currently licensed protease inhibitors.

It is a sulfonamide; according to the manufacturer, no cross-sensitivity was observed in subjects with sulfonamide allergy. However, in one cohort study, the incidence of allergic reaction to darunavir in patients with a history of sulfa allergy was higher (odds ratio 4.29; 95% confidence interval, 1.05–17.56)²⁹³². Use with caution in patients with a known sulfonamide allergy.

Molecular weight: 547.656 (active moiety), 593.724 (TMC114-ethanolate)

Activity

In vitro EC50 4.2 nM (2.5 ng/mL), EC₉₀ 10 nM (5.5 ng/mL). Comparative EC50 values were found against WT-HIV1 and multi-PI-resistant primary isolates. The EC50 value of darunavir increases by a median factor of 5.4 in the presence of human serum. EC50WT is approximately 55 ng/mL.

Prezista ® :
75 mg (white) tablets, DIN 02338432
150 mg (white) tablets, DIN 02369753
400 mg (light orange) tablets, DIN 02324057 (discontinued in Canada)
600 mg (orange) tablets, DIN 02324024
800 mg (dark red) tablets, DIN 02393050

100 mg/mL oral suspension (available in U.S. and Europe)- in Canada via Compassionate Access through Janssen Canada (call Janssen Medical Information at 1-800-567-3331 or submit Compassionate Use for posted on company website https://www.janssenmedicalinformation.ca/login?destination=compassionate-use ;updated Feb 2020). Store at room temperature. Shake well before use.

Store oral suspension at room temperature. Shake well before use.

300 mg (orange) tablets, DIN 02284057 – discontinued

Prezcobix®: fixed dose combination of darunavir 800 mg and cobicistat 150 mg pink oval-shaped, film-coated tablet, DIN 02426501

100 mg/mL oral suspension: (US only or compassionate access through Janssen Canada (call Janssen Medical Information at 1-800-567-3331 or submit Compassionate Use for posted on company website https://www.janssenmedicalinformation.ca/login?destination=compassionate-use ;updated Feb 2020). Store at room temperature. Shake well before use.

See darunavir and ritonavir for other liquid options (substitution of cobicistat with ritonavir may be required).

Prezista®:

No pharmacokinetic data are available on chewing or crushing of Prezista® film-coated tablets. However, since the tablets are not formulated as an extended release formulation, no potential problem is anticipated if the tablets are chewed or crushed for administration through a nasogastric (NG) tube. It is unlikely that chewing or crushing Prezista® tablets would have a significant impact on pharmacokinetics (Data on File, Tibotec, November 2006).

In two patients, one with dysphagia and Candida esophagitis and one with a stomach tube, who received darunavir tablets crushed and dissolved and administered with ritonavir oral solution, adequate plasma darunavir levels were achieved along with good virologic response.²⁹⁵³

A case report describes an intubated 44 year old man on tenofovir/emtricitabine, darunavir, and ritonavir in ICU who was given darunavir tablets via orogastric tube crushed and dissolved in 15-20 mL of water. Viral load did not change significantly and adequate darunavir trough levels were achieved.²⁹⁴¹

An HIV-positive patient on continuous venovenous hemodiafiltration (CVVHDF) received raltegravir 400 mg BID, darunavir 600/100 mg BID, zidovudine 300 mg BID and 3TC 50 mg q24h in suspension via gastric port and simultaneous enteral feeding via the duodenal port of a double-lumen nasogastroduodenal tube. Pharmacokinetic sampling and analysis indicated that darunavir and raltegravir were removed by CVVHDF with approximately the same clearance as provided by a normally functioning kidney. Absorption of both darunavir and raltegravir after suspension and application via the gastric port with continued administration of feed via the duodenal port of the double-lumen tube was good. As such, dose adjustments are not required for patients receiving darunavir and/or raltegravir while undergoing CVVHDF and that absorption of darunavir and raltegravir is not significantly affected by postpyloric enteral feeding.²⁹⁵⁸ 

Prezcobix®:

The chemical stability of crushed Prezcobix (2 tablets crushed and suspended in 20 mL Syrspend® and 1% w/v CMC solution) was evaluated.  Darunavir and cobicistat remained within ±20% of the initial value for 7 days when stored at 4C and at room temperature (~25C).³⁵⁴⁶ 

Tablets are immediate-release formulation; no anticipated absorption issues if the tablets are chewed, split or crushed.³²¹¹

Symtuza®:

Symtuza® should be swallowed whole. The manufacturer does not recommend breaking or crushing Symtuza® to ensure administration of the entire dose. Film-coated tablets.³¹⁰¹ 

The relative bioavailability of darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) single tablet regimen was compared with the tablet administered whole, split or crushed. In the split group there was an 11% decrease in TAF Cmax only (not clinically relevant). In the crushed group there was a 17% decrease in the emtricitabine Cmax and TAF Cmax and AUC were decreased by 29% and 18%, respectively (clinical relevance not assessed, but impact expected to be minimal based on wide therapeutic window for TAF).²⁸⁶⁴

In a case series, three patients on darunavir/ritonavir underwent sleeve gastrectomy. All three patients maintained virologic suppression after gastrectomy. ³³⁹⁴  

In a case report, HIV was diagnosed in a man 11 months following RYGB surgery. When the patient presented for care of his HIV, his HIV-1 RNA was 146 138 copies/mL (5.20 log) and his CD4 T cell count was 320 cells/mm(3) (25%). He was initiated on tenofovir disoproxil fumarate (TDF) 300 mg once daily, emtricitabine (FTC) 200 mg once daily, and darunavir/ritonavir (DRV/r) 600/100 mg twice daily. ARV concentrations were similar to historical data. Six months following ARV initiation, HIV-1 RNA was suppressed. ³³⁹⁶

A case report described a patient who underwent sleeve gastrectomy and was found to have a darunavir trough concentration of 2270 ng/mL (reference trough is 2200 ± 1100 ng/mL) on a dose of 800 mg daily, in combination with ritonavir, raltegravir, abacavir and lamivudine. ³¹⁷⁰

In a case series of 17 patients who underwent sleeve gastrectomy, most of the antiretrovirals, including lamivudine, abacavir, darunavir, tenofovir and emtricitabine exhibited adequate plasma concentrations both at baseline and during follow-up at 3- and 6-month post-surgery.³⁶²⁵ However, raltegravir in 4 patients showed a large inter-individual variability of C_max and AUC at baseline and at 6-month post-surgery. In one patient, the AUC of raltegravir at baseline (4753 μg / h l) and at 6-month post-surgery (5274 μg / h l) were both below literature standards (14,000-26,460 μg / h l). Atazanavir C_max and AUC in 3 patients were also under the literature standard values and worsened post-surgery (n = 2). Ritonavir C_max and AUC were within normal range post-surgery (n =3). Among the 17 patients, 12 (70%) maintained undetectable viral load during follow-up. Those patients were on lamivudine, abacavir, tenofovir, and emtricitabine among other antiretrovirals that were not assayed. Four patients on raltegravir or atazanavir had viral rebound after surgery, requiring treatment modification which led to undetectable viral load. 

A case report described a 43-year-old woman virally suppressed on once-daily darunavir/ritonavir 800/100 mg, emtricitabine 200 mg, and TDF 245 mg. After undergoing Roux-en-Y gastric bypass (RYGB), dosages of emtricitabine and TDF were kept the same, but darunavir/ritonavir was increased to 600/100 mg BID in anticipation of potential change in antiretroviral drug exposure after RYGB. Compared with reference PK, darunavir AUC, Cmax, and Cmin 3 days post-surgery were reduced by 50, 14, and 67%, whereas darunavir exposure 10 weeks post-surgery was comparable with reference. Ritonavir AUC, Cmax, and Cmin 3 days post-surgery were decreased by 67, 67, and 76%, whereas ritonavir PKs were increased by 104, 119, and 135% 10 weeks post-surgery. As a result of normal drug exposures 10 weeks post-surgery, darunavir/ritonavir was changed back to once daily darunavir/ritonavir 800/100 mg. One year post-surgery, TDM showed adequate levels of darunavir/ritonavir, emtricitabine, and tenofovir (changed to tenofovir alafenamide) (3140/298; 147 and 11 ng/mL, 14 hours after administration). Patient maintained viral suppression throughout.^3648 

May be coadministered with omeprazole or ranitidine.

Darunavir is an inhibitor of CYP3A4. Darunavir/r may induce CYP2C9, 2C19. Darunavir/r may possibly inhibit CYP2D6.

Oral Bioavailability:

Absolute oral bioavailability: 37% (alone) and 82% (after coadministration with ritonavir 100 mg BID)

Oral suspension for pediatric use (100 mg/mL) is under development²⁹⁵⁴. When coadministered with low-dose ritonavir, exposures comparable to that of darunavir tablets are noted.

Protein Binding:

95% (humans), primarily alpha-1-acid glycoprotein

Tmax:

2.5-4 hours when given fed with ritonavir 100 mg BID

Serum T½:

~ 15 hours when combined with ritonavir. 10.9-17.2 hours for various dosing regimens; ritonavir did not influence t1/2.

Metabolism:

Substrate and inhibitor of CYP3A4.

Excretion:

After single dose administration of darunavir 400/ritonavir 100 mg, 79.5% and 13.9% of the administered dose of 14C-darunavir was recovered in the feces and urine, respectively.

Note: For more complete information and the most current safety data on antiretrovirals in pregnancy refer to the current US DHHS Perinatal Guidelines. 

Darunavir/Ritonavir:

Summary of Pharmacokinetic study findings of DRV/RTV in pregnancy (DHHS Perinatal Guidelines) 

• compared with postpartum DRV plasma AUC, DRV plasma AUC in third trimester is reduced with both DRV/RTV 600mg/100mg BID (by 17 to 26%) and with DRV/RTV 800mg/100mg daily (by 33 to 39%)
• compared with postpartum DRV plasma trough (Cmin) concentrations, DRV Cmin in the third trimester is reduced with DRV/RTV 600mg/100mg BID (by 8-12%) and with DRV/RTV 800mg/100mg daily (by 42-58%) 
• changes in DRV protein binding during the third trimster have been reported by three studies: one study reported no changes, two studies reported decreased unbound DRV concentrations during pregnancy that were not considered clinically important
• DRV/RTV 800mg/100mg BID did not increase DRV exposure in pregnant women³³⁷² 

Dosing Recommendations in pregnancy (DHSS Perinatal Guidelines)

• DRV/RTV 600mg/100mg PO twice daily is recommended in pregnancy due to low DRV trough levels that occur with DRV/RTV 800mg/100mg once daily dosing
• noted: US FDA recommends DRV/RTV 800mg/100mg PO once daily only for pregnant women who are virally suppressed on a stable, once-daily DRV/RTV regimen prior to pregnancy and whose adherence or ability to tolerate a regimen may be compromised by a switch to twice daily DRV/RTV. US DHHS perinatal guidelines do not recommend once daily dosing.
• DRV/RTV 800mg/100mg PO twice daily is not recommended.

Individual Pharmacokinetic Studies:

In 2 HIV-infected pregnant women receiving darunavir/ritonavir (all VL < 40 copies/mL at delivery), mean darunavir cord:mother  blood concentration ratio was 0.11 (SD +/- 0.01); cord blood concentrations were below cut-off values in both samples.  Mean amniotic fluid:maternal plasma ratio for darunavir was 0.16.  Undetectable viral load was found in amniotic fluid and cord blood.²⁹¹²

In a treatment-naïve pregnant woman, darunavir 800/100 mg QD plus tenofovir/emtricitabine once daily was well-tolerated and resulted in undetectable viral load throughout the pregnancy.  Darunavir concentrations were measured in pregnancy and post-partum.  At week 21, darunavir Ctrough was 1877 ng/ml, and at week 37, darunavir Ctrough was 1407 ng/mL.  Calculated cord blood, amniotic and cervicovaginal fluid to mother plasma ratios were 0.11, 0.24 and 0.09, respectively.²⁹⁴³

In 11 HIV-positive women on cART including darunavir 600 mg/ritonavir 100 mg BID, plasma ART concentrations were measured in the 2nd and 3rd trimesters and post-partum.  Total darunavir and ritonavir pharmacokinetics decreased during pregnancy likely due to pregnancy-related dilution of albumin and/or AAG.  Total darunavir Cmax was 28% and 19% lower while total darunavir Cmin was 43% and 86% higher during the 2nd and 3rd trimesters, respectively, compared with the postpartum period.  AUC12h was 24% and 17% lower in the 2nd and 3rd trimesters compared with the postpartum period.  However, there was no clinically relevant change in unbound darunavir AUC12h and Cmin occurred during pregnancy, and there was no MTCT; therefore no dose adjustment is required for DRV/rtv 600/100mg BID in pregnant women.²⁹⁶²

In 6 HIV-positive women treated with darunavir/ritonavir (600mg/100mg BID or 800mg/100mg QD) throughout pregnancy, darunavir exposures were significantly lower in the 3rd trimester compared to post-partum (GMR:  0.64 (0.47-0.86) for AUCtau; 0.71 (0.49-1.03) for Cmax; 0.45 (0.22-0.91) for Clast).  The cord blood/maternal plasma concentration ratio was < 0.076 for darunavir.²⁹³⁴

In HIV-infected pregnant women receiving darunavir/r 800/100 mg QD with tenofovir/emtricitabine, steady-state PK analysis was performed in the 3rd trimester and at 12 weeks post-partum.  All women had undetectable viral loads throughout pregnancy.  Total darunavir Ctrough ↓ 47%, Cmax ↓ 27%, and AUC ↓ 41% in the 3rd trimester vs. postpartum.  Unnbound darunavir Ctrough ↓ 24%, Cmax ↓ 29%, and AUC ↓ 24% in the 3rd trimester vs. postpartum.  Mean unbound darunavir Ctrough was 66 ng/mL in the 3rd trimester.²⁹³⁸

In a phase IIIb study, HIV-infected women (n=17) in their 2nd trimester received darunavir 800/100 mg QD with other antiretrovirals.  Total darunavir exposures decreased in the 2nd and 3rd trimester compared to postpartum (34% ↓ AUC, 32% ↓ Cmin and 34% ↓ Cmax and 35% ↓ AUC, 50% ↓ Cmin and 31% ↓ Cmax, respectively).  Unbound darunavir exposures decreased in the 2nd and 3rd trimester compared to postpartum (24% ↓ AUC, 132% ↓ Cmin and 34% ↓ Cmax and 20% ↓ AUC, 38% ↓ Cmin and 16% ↓ Cmax, respectively).  Unbound darunavir was >10-fold above the unbound EC50 for wild-type HIV (2.75 ng/mL) in all subjects at all time points and there was no mother-to-child-transmission.  No dose adjustment is required for darunavir/ritonavir 800/100 mg QD in pregnant women.²⁹³⁶ 

Data was reported from a multicentre, nonblinded, prospective, phase IV study (IMPAACT P1026s) which included an arm for pregnant women (n=24) receiving DRV/RTV 800mg/100mg twice daily during pregnancy and reduced to DRV/RTV 600mg/100mg twice daily after delivery. DRV AUC(0-12h) was lower in the second trimester (geometric means ratio GMR 0.62) and third trimester (GMR 0.64) compared to postpartum. RTV AUC(0-12h) was lower in the third trimester (GMR 0.65) compared to postpartum. DRV trough (Cmin) during the second and third trimesters, including postpartum were all greater than 10-fold above the mean DRV protein-adjusted IC₅₀ of 55 ng/mL, 5-fold above the mean DRV protein-adjusted IC₅₀ of 550 ng/mL for resistant virus, and greater than 10-fold above the mean DRV protein-adjusted EC₉₀ of 200 ng/mL for wild-type virus. Although lower in pregnancy compared with postpartum, protein bound DRV concentrations remained above the viral activity of HIV. The percentage of women with a viral load <50 copies/mL in the second trimester, third trimester, at delivery, and postpartum were 66.7%, 87.5%, 80%, and 70.8% respectively. There were no recorded cases of perinatal transmission of HIV.  Authors concluded DRV exposure is reduced in pregnancy, and increasing DRV/RTV dose to 800mg/100mg twice daily during pregnancy failed to significantly increase DRV exposure compared with DRV/RTV 600mg/100mg twice daily.³³⁷² 

Darunavir/Cobicistat:

Prezcobix (darunavir, cobicistat) is not recommended in pregnancy because of substantially lower exposures of darunavir and cobicistat during the second and third trimesters. 

Cobicistat coadministered with darunavir as a fixed dose combination, in combination with a background regimen, was evaluated in a clinical trial of 7 pregnant individuals taking darunavir/cobicistat. Exposure to darunavir and cobicistat as part of an antiretroviral regimen was substantially lower during the second and third trimesters of pregnancy compared to postpartum. One out of 6 individuals who completed the study experience virologic failure with >1000 copies/mL from the third trimester visit through the postpartum period. Five individuals had sustained virologic response (<50 copies/mL) throughout the study period. There are no clinical data on the virologic response when darunavir/cobicistat is initiated during pregnancy. (Gilead Tybost product monograph)

In a Phase 3b, multicentre, open-label pharmacokinetic study (NCT00855335), the PK parameters of darunavir/cobicistat 800/150 mg daily with a meal were evaluated in 7 HIV+ women in the second and third trimester vs. postpartum. Six women completed the study. In the 2nd and 3rd trimester, respectively, the total darunavir AUC was decreased by 56% and 50% and the Cmin decreased by 92% and 89%. For unbound darunavir, the AUC was decreased by 45% and 40% and the Cmin decreased by 92% and 88%. For cobicistat, the AUC was decreased by 63% and 49% and the Cmin by 83% and 83%. In 2 women, the median cord /maternal plasma ratio values were 10% and 7.7%. Viral suppression was achieved in 5/6 (83%) of women in the third trimester and at study completion. One woman was non-adherent and had virologic failure, but no drug resistance. None of the 6 infants were HIV+ infected at 16 weeks post-partum. DRV/cobi was generally well-tolerated in women and their infants.The authors concluded the decrease in darunavir exposure was more pronounced with DRV/cobi than a previous study with DRV/ritonavir (total DRV AUC decreased by 34-35% and unbound DRV AUC 20-24% lower; ritonavir AUC 46-47% lower in pregnancy). The decrease in cobi exposure in this study was similar to that observed with elvitegravir/cobi.³¹⁰⁶  The use of DRV/cobi in pregnancy should be used with caution with close monitoring of adherence, viral suppression and potentially therapeutic drug monitoring. 

Lactation

 No data are available.

Darunavir is a sulfonamide; according to the manufacturer, no cross-sensitivity was observed in subjects with sulfonamide allergy. However, in one cohort study, the incidence of allergic reaction to darunavir in patients with a history of sulfa allergy was higher (odds ratio 4.29; 95% confidence interval, 1.05–17.56)²⁹³². Use with caution in patients with a known sulfonamide allergy.

Drug-induced hepatitis (e.g., acute hepatitis, cytolytic hepatitis) has been reported with darunavir/rtv (0.5% in clinical development program, n=3063). Patients with preexisting liver dysfunction, including chronic active hepatitis B or C, have an increased risk for liver function abnormalities including severe hepatic adverse events.



Postmarketing cases of liver injury, including some fatalities, have been reported. These have generally occurred in patients with advanced HIV1 disease taking multiple concomitant medications, having comorbidities including hepatitis B or C coinfection, and/or developing immune reconstitution syndrome. A causal relationship with darunavir/rtv therapy has not been established. 



If there is evidence of new or worsening liver dysfunction (including clinically significant elevation of liver enzymes and/or symptoms such as fatigue, anorexia, nausea, jaundice, dark urine, liver tenderness, hepatomegaly) in patients on darunavir/rtv, interruption or discontinuation of treatment must be considered.

Baseline Assessment

Appropriate laboratory testing of hepatic parameters should be conducted prior to initiating therapy with Prezista © or Prezcobix © and patients should be monitored during treatment.

Routine Labs

Increased AST/ALT monitoring should be considered in patients with underlying chronic hepatitis, cirrhosis, or in patients who have pretreatment elevations of transaminases, especially during the first several months of treatment.

Tablets: Store between 15-30C.

Oral suspension: Store at room temperature. Shake well before use

Janssen Inc.