PREZCOBIX
Clinical safety rating: caution
Comprehensive clinical and safety monograph for PREZCOBIX (PREZCOBIX).
PREZCOBIX is a fixed-dose combination of darunavir, a HIV-1 protease inhibitor, and cobicistat, a CYP3A inhibitor. Darunavir selectively inhibits the cleavage of HIV-encoded Gag-Pol polyproteins in infected cells, preventing the formation of mature infectious virions. Cobicistat increases systemic exposure of darunavir by inhibiting CYP3A-mediated metabolism.
| Metabolism | Darunavir is primarily metabolized by CYP3A. Cobicistat is a CYP3A inhibitor and is metabolized by CYP3A and to a minor extent by CYP2D6. |
| Excretion | Darunavir: approximately 79.5% in feces (41% as unchanged drug) and 13.9% in urine (7.7% as unchanged drug). Cobicistat: 86% in feces and 8.2% in urine. |
| Half-life | Darunavir: terminal half-life of approximately 15 hours when coadministered with cobicistat, supporting once-daily dosing. Cobicistat: terminal half-life of approximately 3-4 hours, but its inhibitory effect on CYP3A4 persists for 24 hours. |
| Protein binding | Darunavir: approximately 95% bound to plasma proteins (primarily alpha-1-acid glycoprotein). Cobicistat: 97-98% bound to plasma proteins. |
| Volume of Distribution | Darunavir: apparent Vd of 0.54 L/kg (based on a 70 kg adult, approximately 38 L), indicating distribution into total body water. Cobicistat: apparent Vd of 0.42 L/kg (approximately 29 L). |
| Bioavailability | Darunavir: absolute bioavailability is approximately 37% without a boosting agent; when coadministered with cobicistat, bioavailability is enhanced due to inhibition of CYP3A4-mediated first-pass metabolism, but the exact boosted bioavailability is not separately reported. Cobicistat: absolute bioavailability is not determined; it is used as a pharmacokinetic enhancer. |
| Onset of Action | Oral administration: time to peak plasma concentration (Tmax) is 2.5-4 hours for darunavir and 3-4 hours for cobicistat; clinical antiviral effect begins within hours but maximal suppression requires steady-state (4-5 days). |
| Duration of Action | The pharmacokinetic boosting by cobicistat maintains darunavir plasma concentrations above protein-binding-adjusted IC50 for HIV-1 over 24 hours, allowing once-daily dosing. |
| Molecular Weight | 547.73 Da (darunavir); 776.0 Da (cobicistat) |
Darunavir 800 mg (as two 400 mg tablets) plus cobicistat 150 mg (as one 150 mg tablet) orally once daily with food.
| Dosage form | TABLET |
| Renal impairment | No dose adjustment required in renal impairment including end-stage renal disease on hemodialysis. Cobicistat may decrease estimated creatinine clearance due to tubular secretion inhibition, but actual renal function is preserved. |
| Liver impairment | Child-Pugh A: No adjustment. Child-Pugh B or C: Contraindicated (darunavir metabolism may be impaired, no data for safety/efficacy). |
| Pediatric use | Approved for patients weighing ≥40 kg: Darunavir 800 mg plus cobicistat 150 mg orally once daily with food. For <40 kg, alternative formulations (e.g., darunavir boosted with ritonavir) should be used. |
| Geriatric use | No specific dose adjustment. Use with caution due to higher risk of comorbidities, polypharmacy, and potential renal/hepatic impairment; monitor renal function and drug interactions closely. |
| 1st trimester | Limited data; no evidence of increased risk of major birth defects based on small studies. Use if benefit outweighs risk. |
| 2nd trimester | Limited data; no evidence of fetal harm in animal studies. Consider use with caution. |
| 3rd trimester | Limited data; no evidence of adverse fetal outcomes. Use if clearly needed. |
Clinical note
Comprehensive clinical and safety monograph for PREZCOBIX (PREZCOBIX).
| Placental transfer | Darunavir and cobicistat cross the placenta in humans; transfer is low to moderate based on cord blood concentrations. |
| Breastfeeding | It is not known whether darunavir or cobicistat are excreted in human milk. Due to potential for HIV transmission and adverse effects in nursing infants, breastfeeding is not recommended for women with HIV. If used, exercise caution. |
■ FDA Black Box Warning
No FDA boxed warnings reported.
| Serious Effects |
Coadministration with drugs highly dependent on CYP3A for clearance and for which elevated plasma levels are associated with serious adverse events (e.g., alfuzosin, amiodarone, simvastatin, etc.)Severe hepatic impairment (Child-Pugh Class C)
| Precautions | Hepatotoxicity: Drug-induced hepatitis has been reported; monitor liver function before and during therapy., Severe skin reactions: Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms (DRESS) have occurred; discontinue if severe rash or symptoms develop., Risk of QT prolongation: Use with caution in patients with pre-existing conduction abnormalities or on other QT-prolonging drugs., Sulfonamide allergy: Darunavir contains a sulfonamide moiety; use with caution in patients with known sulfonamide allergy., Co-administration with certain drugs: Do not use with drugs highly dependent on CYP3A for clearance or that strongly induce CYP3A (e.g., rifampin)., Diabetes mellitus/hemophilia: May exacerbate existing conditions; monitor accordingly. |
| Food/Dietary |
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| Lactation Rating |
| L4 |
| Teratogenic Risk | First trimester: Limited human data; animal studies show no teratogenicity at clinically relevant exposures. Second and third trimesters: No evidence of fetal harm; however, use only if clearly needed. |
| Fetal Monitoring | Monitor maternal liver function, renal function, and complete blood counts. Perform fetal ultrasound if clinically indicated. |
| Fertility Effects | No human data on fertility. Animal studies at high doses showed reduced fertility; relevance to humans unknown. |
| Take with food to increase absorption. Avoid grapefruit juice as it may increase drug levels. No other specific food restrictions. |
| Clinical Pearls | PREZCOBIX is a fixed-dose combination of darunavir (800 mg) and cobicistat (150 mg). Cobicistat is a potent CYP3A4 inhibitor; therefore, contraindicated with drugs highly dependent on CYP3A4 clearance. Darunavir requires boosting; cobicistat serves as pharmacoenhancer. No dose adjustment needed for mild-to-moderate hepatic impairment; contraindicated in severe hepatic impairment. Monitor for hepatotoxicity, especially in patients with hepatitis B or C coinfection. Cobicistat increases serum creatinine by inhibiting tubular secretion, but does not affect renal function; eGFR decline typically 10-15 mL/min/1.73m2 within 2-4 weeks and then stabilizes. Do not use in patients requiring ritonavir-boosted darunavir if they are also on tenofovir disoproxil fumarate (more renal toxicity). Administer with food to enhance absorption. |
| Patient Advice | Take PREZCOBIX with food, as food improves absorption. · Do not skip doses; missing doses can lead to drug resistance. · Inform your doctor of all other medications, including over-the-counter drugs, as serious interactions can occur. · Do not take with St. John's wort, certain seizure medications, or certain statins. · PREZCOBIX may increase creatinine levels in blood tests, but this does not mean your kidneys are damaged. · Report any signs of liver problems: yellowing of skin or eyes, dark urine, pale stools, abdominal pain, nausea, vomiting. · Use effective contraception as this drug may reduce effectiveness of hormonal contraceptives (except progestin-only injections). |