Immunodeficiency Clinic > Drug Interaction Guide

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Prezcobix®(Darunavir/Cobicistat) & Alfentanil (Alfenta®) [class:yellow]

Summary/Recommendation:

Consider a pre-emptive dose reduction of alfentanil; monitor closely for increased effect/toxicity and titrate dose accordingly.

Data:

Potential ↑ alfentanil concentrations secondary to CYP3A4 inhibition by darunavir/cobicistat. Based on interaction data with voriconazole (described below), may wish to consider a pre-emptive dose reduction of alfentanil with close monitoring and dose titration when coadministering with darunavir/cobicistat.

In healthy volunteers given 20 ug/kg intravenous alfentanil, administration of oral voriconazole 400 mg twice on the first day and 200 mg twice on the second day led to a 6-fold increase in alfentanil AUC (p<0.001), with 5 subjects experiencing nausea and 2 experiencing vomiting. The study authors suggest that alfentanil doses may need to be reduced by 70-90% when coadministered with voriconazole.³³⁸²

Prezcobix®(Darunavir/Cobicistat) (Selected Pharmacokinetic Properties)

Metabolism:

Substrate and inhibitor of CYP3A4.

Drug Interaction Characteristics:

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.

Dosing (Adult):

Prezista®:

For treatment-experienced patients: 600/100 mg ritonavir po BID with food.

For treatment naïve patients or those with no darunavir resistance-associated mutations (RAMS): 800/100mg ritonavir po once daily with food.

In a multicentre open-label study (n=100) patients virally suppressed on darunavir 800/100 mg QD plus 2 NRTIs were randomized to continue on darunavir 800/100 mg QD or switched to darunavir 600/100 mg QD. At week 48, darunavir Ctrough levels were similar between treatment arms and the reduced darunavir dose showed non-inferior virologic efficacy to the standard dose arm. CD4 cell counts remained stable in both groups.²⁹⁵⁰

Prezcobix®: 1 tablet daily with food.

Symtuza®: 1 tablet daily with food.

Drug Concentrations:

Adult population PK (HIV-positive subjects):

800/100 mg QD: median C0h: 1896-2041 ng/mL, AUC 87788-87854 ng.h/mL (studies TMC114-C211 and C229)
600/100 mg BID: median C0h: 3197-3307 ng/mL, AUC 109401-123336 ng.h/mL (studies TMC114-C202, C213, C214, C229)

Pediatric population PK:

800/100 mg QD (12 to
20 mg/kg darunavir with ritonavir 3 mg/kg BID (10 to
380 mg darunavir/48 mg ritonavir BID (15 to

Darunavir 800mg/100mg daily for 7 days: conc remained above the protein-binding corrected in-vitro EC50 55ng/ml for ≥ 48 hours in healthy volunteers after last dose was administered.²⁹³¹

Based on PK sampling data from the GRACE study, exposure to darunavir was not influenced by age, body weight, hepatitis B co-infection status, or use of etravirine or tenofovir. There were no clinically relevant differences in exposure to darunavir according to race or gender²⁹⁴⁵. In healthy volunteers (n=23) who had previously participated in a pravastatin-darunavir/ritonavir interaction study, CYP3A5 and ABCB1 polymorphisms were not associated with variability in darunavir/ritonavir pharmacokinetics.²⁹⁶¹

Darunavir concentrations were compared in 34 time-matched blood plasma and seminal plasma samples from 18 HIV-positive men. Good penetration of darunavir into the seminal fluid was observed, with concentrations approximately 10-20% of blood plasma levels. All seminal plasma darunavir were above the protein-corrected EC50 values for wild-type HIV-1 (55 ng/mL), and a third of all seminal plasma darunavir levels exceeded the protein-corrected EC50 required to inhibit protease inhibitor resistant HIV-1 (550 ng/mL).²⁹⁵⁹

Intracellular darunavir concentrations are approximately 5-times higher than plasma concentrations, and are significantly correlated with plasma ritonavir exposures²⁹³⁹. In healthy volunteers who received either darunavir 900/100 mg QD or efavirenz 600 mg QD alone or in combination, intracellular concentrations of both darunavir and efavirenz were significantly increased when the drugs were coadministered: intracellular darunavir AUC ↑ 124% and Cmax ↑ 163% and intracellular efavirenz C24h ↑ 139%.²⁹⁵⁷

In a cross-sectional TDM database review of non-pregnant HIV-infected adults taking darunavir 800/100 mg QD, darunavir C24h obtained after morning dosing were significantly higher than those after evening dosing (1632 vs 1433 ng/mL, respectively, p < 0.0001). The difference was more pronounced in women vs. men. Findings may represent Circadian variation in hepatic CYP3A4, intestinal P-gp and gastrointestinal mobility.²⁹⁵²

Bioequivalence demonstrated with 800 mg darunavir tablet to two 400 mg darunavir tablets, both given with ritonavir 100 mg.²⁹⁴⁶

Bioequivalence demonstrated with darunavir 800/cobicistat 150 mg fixed dose tablet to darunavir and cobicistat administered as single agents under fasted and fed conditions.²⁹⁴⁸

View all Prezcobix®(Darunavir/Cobicistat) Properties

Alfentanil (Alfenta®) (Pharmacokinetic Properties)

Substrate of CYP3A4.

Alternative Options: Interaction Check with Drugs from Similar Classes

HIV Protease Inhibitor with alfentanil [yellow] 5

Atazanavir (Reyataz®) & alfentanil (Alfenta®)[class:yellow]
Lopinavir/Ritonavir (Lopinavir/Ritonavir) & alfentanil (Alfenta®)[class:yellow]
Evotaz® (Atazanavir/Cobicistat) (Atazanavir/Cobicistat) & alfentanil (Alfenta®)[class:yellow]
Atazanavir/Ritonavir (Reyataz®, Norvir® ) & alfentanil (Alfenta®)[class:yellow]
Darunavir/Ritonavir (Prezista®, Norvir®) & alfentanil (Alfenta®)[class:yellow]

Prezcobix ® with Opioid [red] 2[yellow] 10[green] 4

Prezcobix ® (Darunavir/Cobicistat) & codeine (Codeine Contin®)[class:yellow]
Prezcobix ® (Darunavir/Cobicistat) & diphenoxylate (Lomotil®)[class:green]
Prezcobix ® (Darunavir/Cobicistat) & fentanyl (prescribed) (Duragesic®)[class:red]
Prezcobix ® (Darunavir/Cobicistat) & heroin [class:yellow]
Prezcobix ® (Darunavir/Cobicistat) & hydrocodone (Hycodan®)[class:yellow]
Prezcobix ® (Darunavir/Cobicistat) & hydromorphone (Dilaudid, Jurnista®)[class:green]
Prezcobix ® (Darunavir/Cobicistat) & levomethadyl (LAAM) (Orlaam®)[class:red]
Prezcobix ® (Darunavir/Cobicistat) & loperamide (Imodium®)[class:green]
Prezcobix ® (Darunavir/Cobicistat) & meperidine (Demerol®)[class:yellow]
Prezcobix ® (Darunavir/Cobicistat) & Methadone (Metadol, Metadol-D, Methadose®)[class:yellow]
Prezcobix ® (Darunavir/Cobicistat) & morphine (MS Contin, MS-IR, M-Eslon, Kadian, M.O.S., Statex®)[class:yellow]
Prezcobix ® (Darunavir/Cobicistat) & oxycodone (Oxycontin, OxyNEO, Supeudol®)[class:yellow]
Prezcobix ® (Darunavir/Cobicistat) & propoxyphene (Darvon-N®)[class:yellow]
Prezcobix ® (Darunavir/Cobicistat) & tramadol (Ralivia, Tridural, Ultram, Zytram XL®)[class:yellow]
Prezcobix ® (Darunavir/Cobicistat) & sufentanil (Sufenta®)[class:yellow]
Prezcobix ® (Darunavir/Cobicistat) & remifentanil (Ultiva®)[class:green]

Interaction Classification

These Drugs should not be coadministered[class:red]
Potential interaction - may require close monitoring, alteration of drug dosage or timing of administration[class:yellow]
No clinically significant interaction expected[class:green]

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The Toronto General Hospital website has been in operation since 2000. The main objectives of the drug information portion of the website/app are to provide a comprehensive and centralized repository of current data on HIV/HCV drug therapy for health care professionals with a main focus on drug interactions, and to promote safe and rational prescribing of antiretrovirals and directly acting antivirals. The website/app content is updated regularly, and includes information from key international HIV/HCV conferences and recent publications in the medical/pharmacy literature.

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