Drug Profile: Darunavir (Prezista, DRV, formerly TMC-114)

Important note: Information in this article was accurate in July 2006. The state of the art may have changed since the publication date.

Drug Profile: Darunavir (Prezista, DRV, formerly TMC-114)

Hopkins HIV Report 2006 Jul; 18(4):1,6-7

Paul A. Pham, Pharm.D.
Johns Hopkins

Manufacturer: Tibotec Therapeutics

Class: Protease inhibitor

Formulation/Storage: 300 mg tablet/Store at room temperature

Price: Wholesale acquisition cost: $6.25/tablet

Indication: DRV, co-administered with ritonavir (RTV), is indicated for use as part of combination antiretroviral treatment of HIV-1-infected adult patients who are highly treatment-experienced or have virus resistant to multiple protease inhibitors.

Dose: DRV 600 mg (two 300 mg tablets) + RTV 100 mg bid with food.

Since RTV increases DRV AUC by approximately 14-fold; RTV coadministration with DRV is required in order to achieve the desired DRV levels.

Dosing with renal impairment (with/without dialysis): Limited data; usual dose likely.

Dosing with hepatic impairment: No data; use with close monitoring.

Pregnancy Risk: Category B: No human data. Darunavir has shown no embryotoxicity or teratogenicity in mice, rats and rabbits.

Pharmacokinetics: With RTV co-administration, DRV is well absorbed with an absolute bioavailability of 82%. Food (a light snack or a full meal) increases DRV AUC by 30%. At steady-state, the geometric mean DRV AUC and C_min was 62.35 mcg/mL·hr and 3.54 mcg/mL, respectively. DRV trough was 6-fold higher than the EC₅₀ for resistant virus and 18-fold higher than the EC₉₀ for wild type virus. DRV undergoes extensive oxidative metabolism via CYP3A4 to weakly active oxidative metabolites that are primarily excreted in the feces with a terminal half-life of 15 hours.

Drug Interactions: DRV is a substrate and inhibitor of CYP3A4. With RTV co-administration, the net effect of DRV/r on CYP3A4 is generally inhibitory. Drugs that inhibit or induce CYP3A4 may increase or decrease DRV serum concentrations, respectively.

Contraindicated with DRV: terfenadine, astemizole, cisapride, ergot alkaloid, midazolam, triazolam, and pimozide.
Avoid co-administration: simvastatin, lovastatin due to increased statin concentrations
Avoid co-administration: rifampin, carbamazepine, phenobarbital, phenytoin, and St. John’s Wort due to decreased DRV concentration.
Avoid or use with dose adjustment and close monitoring: DRV/r may significantly increase the serum concentrations of these CYP3A4 substrate drugs: amiodarone, bepridil, quinidine, lidocaine, propafenone, trazodone, itraconazole, rifabutin (dose adjust to 150 mg qod), calcium channel blockers (felodipine, nifedipine, and nicardipine), fluticasone, prednisone, cyclosporine, tacrolimus, sirolimus, PDE-5 inhibitors (sildenafil, tadalafil, and vardenafil).
Use with caution: DRV/r may decrease voriconazole, warfarin, methadone, and ethinyl estradiol/norethindrone serum concentration.
The following table summarizes established drug interaction data to date:

Co-administered Drug	Effect of Interaction	Comments/Recommendations
Atazanavir	No interactions	Dose: ATV 300 mg qd plus DRV/r 600/100 mg bid
Efavirenz	DRV C_min decreased by 31%. EFV AUC and C_min increased 21% and 17%, respectively.	Dose not established. Consider: DRV/r 600/100 mg bid plus EFV 600 mg qd
Enfuvirtide	No interactions	Use standard dose
Indinavir	IDV AUC and C_min increased 23% and 125%, respectively. DRV AUC and C_min increased 24% and 44%, respectively.	Dose not established. May increase risk of nephrolithiasis.
Lopinavir/r	DRV AUC and C_min decreased 53% and 65%, respectively. LPV AUC and C_min increased 37% and 72%, respectively.	Avoid co-administration
Nevirapine	No significant change in DRV AUC and C_min. NVP AUC and C_min increased 27% and 47%, respectively.	Limited data (historical control comparison). Consider: DRV/r 600/100 mg bid plus NVP 200 mg bid
Saquinavir	DRV AUC and C_min decreased 25% and 42%, respectively. No change in SQV serum concentration.	Avoid co-administration
Tenofovir	DF DRV: no change. TDF AUC and C_min increased 22% and 37% respectively.	Use standard dose
Acid reducing agents (PPIs, H-2 blocker)	No interactions	Use standard dose
Atorvastatin	Increased atorvastatin exposure by approximately 4-fold.	Dose: Start with atorvastatin 10 mg qd and titrate slowly
Clarithromycin	DRV: no change. Clarithromycin AUC increased 57%.	Dose: clarithromycin with renal impairment. CrCl 30-60 mL/min=250 mg bid, CrCl <30 mL/min = 250 mg qd. Avoid with QTc prolongation
Ketoconazole	DRV AUC increased 42%. Ketoconazole AUC increased 212%.	Do not exceed ketoconazole 200 mg qd or use alternative agent
Paroxetine	Paroxetine AUC decreased by 39%. DRV: no change	Titrate paroxetine to therapeutic effect
Pravastatin	Pravastatin AUC increased 81%	Dose: Start with 10 mg qd and titrate slowly
Sertraline	Sertraline AUC decreased by 49%. DRV: no change	Titrate sertraline to therapeutic effect
Sildenafil	No significant change in sildenafil AUC.	Use with caution. Do not exceed 25 mg in 48h

Clinical Studies Results: The approval of DRV/r is based on the 24-week pooled analyses of two ongoing randomized trials (POWER 1 and 2) involving highly treatment-experienced patients. All patients were 3-class (NRTI, NNRTI, PI) treatment-experienced and had at least one primary PI mutation at screening. Baseline characteristics of the 131 patients randomized to DRV/r plus OBR were: VL=4.52 log₁₀ c/mL, CD4= 153, 8 IAS PI mutations associated with resistance (with ≥3 primary mutations in 54%), and phenotypic resistance to all approved PIs (with the exception of TPV/r due to availability) in 64% of patients. After the initial dose finding part of the study, patients were randomized to receive an optimized background regimen (2 or more NRTIs ± enfuvirtide [ENF]) with DRV/r 600/100 mg bid OR investigator choice of PIs, including boosted or dual-boosted PIs (control group). The primary efficacy endpoint was defined as a decrease in plasma HIV RNA of ≥1 log₁₀ c/mL versus baseline. In an ITT analysis, 69.5% of DRV/r-treated patients and 21% of control patients achieved at least a 1 log₁₀ c/mL reduction in HIV RNA though week 24. An undetectable (<50 c/mL) viral load was achieved in 45% and 12% of DRV/r and control patients, respectively. Virologic response was strongly associated with a DRV phenotypic FC of less than 10-fold, less than 10 IAS PI mutations, and a good baseline phenotypic susceptibility score of the background regimen [Vangeneugden T, et al. Antivir Ther. 2006, 11:S36 (abstract no. 31) and De Meyer, et al. Antivir Ther. 2006, 11:S83 (abstract no. 73)]. Adverse events were comparable between groups.

Adverse Drug Reactions: Adverse reactions were comparable between DRV/r and comparator PIs in the POWER studies. Rates of discontinuation of therapy due to adverse events were 9% and 5% in the DRV/r and comparator PI treated groups, respectively. The most commonly reported adverse reactions were GI intolerance (nausea, vomiting, and/or diarrhea) in approximately 20%, headache in 15%, and nasopharyngitis in 14%. Other PI class adverse effects, including lipodystrophy, hyperglycemia, hyperlipidemia, and transaminase elevation, were comparable between groups. DRV contains a sulfonamide isostere moiety and should be used with caution in patients with severe sulfa allergy. Rash was observed in 7% of subjects with a 0.3% discontinuation rate.

Resistance: Baseline phenotypic DRV fold-change (FC) was the strongest predictor of virologic response. At week 24, 50%, 25%, and 13% of patients with FC ≤10, 10-40, and >40, respectively, achieved HIV RNA <50 c/mL. FCs of ≤10, 10-40, and >40 were associated with <10, 10 or 11, and ≥12 IAS PI mutations. However, the following mutations were more predictive of virologic outcome than IAS PI mutations: 11I, 32I, 33F, 47V, 50V, 54L/M, 73S, 76V, 84V, and 89V [De Meyer, et al. Antivir Ther. 2006, 11:S83 (abstract no. 73)]. With 0-2, 3, or ≥4 of these mutations at baseline, the virologic response (VL <50 c/mL at Week 24) was 50%, 22%, and 10% respectively. In vitro, the pathway to DRV resistance appears to be different from other PIs. Among amino acid substitutions during virologic failure (patients with virologic rebound or never suppressed) in the POWER studies, the most common substitutions developed at position V32 (in 30% of isolates), I54 (in 20% isolates), and I15, L33, I47, G73, and L89 (in 10-20% of isolates). In these isolates, the median DRV phenotypic FC increased from 21-fold at baseline to 94-fold at failure.

In vitro, 77% and 70% of clinical isolates (n=2682) that have decreased susceptibility to LPV and TPV, respectively, were susceptible (FC <10) to DRV [De Meyer, et al. Antivir Ther. 2006, 11:S83 (abstract no. 73)]. Using Virco’s lower DRV FC cutoff of 3.4, other investigators reported higher cross-resistance rates. Analyses of over 50,000 isolates found that only 42% and 28% of isolates with resistance to LPV and TPV will have predicted response to DRV [Staes M, et al. Antivir Ther. 2006, 11:S33 (abstract no. 28)]. On the other hand, clinical isolates (n=586) that have decrease susceptibility to DRV retained susceptibility to LPV and TPV in only 0.5% and 53% of the cases, respectively [De Meyer, et al. Antivir Ther. 2006, 11:S83 (abstract no. 73)].

Package Insert: http://www.fda.gov/cder/foi/label/2006/021976lbl.pdf

2006-07-10
HHR-2006-07-01

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