Darunavir
Darunavir. HIV protease inhibitor with the highest genetic barrier to resistance among current-era PIs — designed to retain potency against… Oral half-life 15 h.
HIV protease inhibitor with the highest genetic barrier to resistance among current-era PIs — designed to retain potency against viruses with multiple PI-resistance mutations. Mechanism: competitive HIV-1 aspartyl protease inhibition. Always coadministered with a CYP3A4 booster (cobicistat as DRV/c in Prezcobix/Symtuza; ritonavir as DRV/r). Substrate of CYP3A4 — own clearance is dominated by oxidative metabolism. The DRV component of the Symtuza single-tablet regimen (DRV 800 / cobi 150 / FTC 200 / TAF 10 mg). Common AE: rash (sulfa moiety; rare SJS), GI intolerance. PK (Prezista label, boosted 800/100 mg PO qd with RTV at SS): Cmax ~6973 ng/mL, AUC(0-24) ~78,410 ng·h/mL, t½ 15 h supporting once-daily dosing. CL/F ≈ 10.2 L/h, V/F ≈ 221 L. Must be taken with food (F drops ~30% fasted).
PK: THIS IS THE LOPINAVIR CASE, NOT THE ATAZANAVIR CASE, AND THE REASONING IS RECORDED SO IT IS NOT RE-LITIGATED. Atazanavir was flagged because its dose range straddles two APPROVED regimens with different exposure regimes; darunavir has NEVER had an approved or marketed unboosted regimen at any dose — "The approved dosage of darunavir is 600 mg in combination with ritonavir 100mg twice daily" — and both ends of this record dose range are boosted. There is no clinical unboosted state for the schema to be ambiguous between, so a boosted-only parameterisation is unambiguous rather than incomplete. A DOUBLE-COUNTING CHECK WAS RUN AND IS CLEAN: darunavir appears in no interactions block as a victim anywhere in this catalog, so nothing currently applies ritonavir inhibition twice — but a future edge would, since these parameters already embed it. The label-only classification is confirmed: eight papers were chased and every one reports ratios, geometric mean ratios or percentage changes, with only the half-life escaping, verbatim twice. The clearance test passes to 0.1%. The absorption rate was the one unambiguous defect, implying a 5.25 h peak against a verbatim "reaching peak plasma concentrations after 2.5-4 hours". A LIMIT IS RECORDED AS A CHOICE RATHER THAN AN ERROR: the record preserves exposure and under-predicts the steady-state peak 1.58x, because a 15 h TERMINAL half-life in one compartment spreads the dose too thin — and the paper says so, naming "a fast distribution/elimination phase" before it.
Pharmacokinetics
- Oral — t½ 15 h · F 100% · ka 1.1 h⁻¹ · Vd 221 L
Sources: PMID:17713972