Mechanism of effect
Darunavir is a HIV protease inhibitor which prevents HIV replication by binding to the enzyme's active site, thereby preventing the dimerization and the catalytic activity of the HIV-1 protease. Darunavir selectively inhibits the cleavage of HIV encoded Gag-Pol polyproteins in virus-infected cells, which prevents the formation of mature infectious virus particles.
Structual analyses suggests that the close contact that darunavir has with the main chains of the protease active site amino acids (Asp-29 and Asp-30) is an important contributing factor to its potency and wide spectrum of activity against multi-protease inhibitor resistant HIV-1 variants.
Darunavir can also adapt to the changing shape of a protease enzyme because of its molecular flexibility. Darunavir is known to bind to two distinct sites on the enzyme: the active site cavity and the surface of one of the flexible flaps in the protease dimer.
Pharmacodynamic
Darunavir is an inhibitor of the human immunodeficiency virus (HIV) protease. In studies, the drug, co-administered with ritonavir in combination therapy, significantly reduced viral load and increased CD4 cell counts in this treatment-experienced patient population. Darunavir is used as an adjunct therapy with low dose ritonavir, which inhibits cytochrome P450 3A (CYP3A) which increases the bioavailability and half life of darunavir.
Pharmacokinetics
- Bioavailability: with ritonavir: 82%; without ritonavir: 37%
- Peak Plasma Time: 2.5-4 hr
- Protein Bound: 95%
- Metabolism: CYP3A4
- Half-life, elimination: 15 hr
- Excretion: Urine (14%) feces (80%)
Dosage
adult
Therapy-naive Patients and Therapy-experienced Patients with No Darunavir Resistance Associated Substitutions:
Darunavir 800 mg plus ritonavir 100 mg orally once a day with food
Therapy-experienced Patients with At Least 1 Darunavir Resistance Associated Substitution :
Darunavir 600 mg plus ritonavir 100 mg orally twice a day with food
Pediatric
3 to less than 18 years:
Therapy-naive Patients and Therapy-experienced Patients with No Darunavir Resistance Associated Substitutions:
Oral suspension:
10 to less than 15 kg: Darunavir 35 mg/kg plus ritonavir 7 mg/kg orally once a day with food
Tablets and oral suspension:
15 to less than 30 kg: Darunavir 600 mg plus ritonavir 100 mg orally once a day with food
30 to less than 40 kg: Darunavir 675 mg plus ritonavir 100 mg orally once a day with food
40 kg or more: Darunavir 800 mg plus ritonavir 100 mg orally once a day with food
Therapy-experienced Patients with At Least 1 Darunavir Resistance Associated Substitution:
Oral suspension:
10 to less than 15 kg: Darunavir 20 mg/kg plus ritonavir 3 mg/kg orally twice a day with food
Tablets and oral suspension:
15 to less than 30 kg: Darunavir 375 mg plus ritonavir 48 mg orally twice a day with food
30 to less than 40 kg: Darunavir 450 mg plus ritonavir 60 mg orally twice a day with food
40 kg or more: Darunavir 600 mg plus ritonavir 100 mg orally twice a day with food
Drug contraindications
hypersensitivity to this drugInteractions
Drospirenone , Rifampin , Medroxyprogesterone , Rosuvastatin , Rifapentine , Ranolazine , Everolimus , Primidone , Pimozide , Dihydroergotamine , Salmeterol , Sildenafil , teriflunomide , Alfentanil , Hydrocodone , Terfenadine , st. john's wort , Midazolam , Colchicine , ergotamine , fentanyl , ergonovine , Oxycodone , Simvastatin , Cyclosporine , Phenobarbital , Phenytoin , Lovastatin , Methylergonovin , Axitinib , saquinavir , Zileuton , Apixaban , Mefloquine , brigatinib , nasal Mometasone , Efavirenz , Copanlisib , Etravirine , Dabrafenib , Netilmicin , Acalabrutinib , Maraviroc , Halofantrine , Alfuzosin , Pazopanib , Palbociclib , Ixazomib , Tasimelteon , Dexbrompheniramine , Flibanserin , Avanafil , Edoxaban , Entrectinib , Lopinavir and Ritonavir , ELBASVIR/GRAZOPREVIR , Abemaciclib , Triphasic , Eliglustat , Ruxolitinib , riociguat , Gefitinib , Dasatinib , Remdesivir , Cannabidiol , vemurafenib , AvapritinibAlerts
Severe skin reactions, accompanied by fever and/or elevations of transaminases reported (0.4%); Stevens-Johnson Syndrome (<0.1%), toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms, and acute generalized exanthematous pustulosis also reported
Caution with elderly patients
Caution with hepatic impairment (not recommended if severe)
Contains a sulfa moiety; monitor patients with a known sulfonamide allergy
Increase in total cholesterol and triglycerides reported; screen before therapy and throughout treatment
Pancreatitis reported; use caution in patients at risk for pancreatitis (those with elevated triglycerids, history of pancreatitis, or advanced HIV disease
Risk of immune reconstitution syndrome
Redistribution/accumulation of body fat, including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving antiretroviral therapy
Patients may develop new onset diabetes mellitus or hyperglycemia; initiation or dose adjustments of insulin or oral hypoglycemic agents may be required
Patients with hemophilia may develop increased bleeding events
Hepatoxicity
- Risk of hepatotoxicity including drug induced hepatitis: acute hepatitis, cytolytic hepatitis
- Especially with preexisting liver dysfunction (chronic hepatitis B or C)
- Interrupt or discontinue treatment if new/worsening liver dysfunction develops
Points of recommendation
Darunavir must be taken together with another medication called ritonavir. Take the medicines together at the same time every day.
Take darunavir tablets with a full glass (8 ounces) of water or milk. Swallow the darunavir tablet whole. Do not break or chew.
Darunavir works best if you take it with food, at the same time each day.
Shake the oral suspension (liquid) well just before you measure a dose. Measure the liquid with the oral dosing syringe provided with this medicine. If you did not receive an oral syringe with your medication, ask your pharmacist for one.
While using darunavir, you may need frequent blood tests.
Use darunavir regularly to get the most benefit. Get your prescription refilled before you run out of medicine completely.
Take the missed dose of darunavir and ritonavir as soon as you remember and take your next dose at the regularly scheduled time.
Ask a Pharmacist