Itraconazole

Category: pharmacological

Aliases: Sporanox

Pharmacological Mechanism

Triazole antifungal — fungal CYP51 inhibitor. Strong CYP3A4 inhibitor + P-glycoprotein inhibitor — major DDI perpetrator (statin myopathy, ergot crisis, sedative oversedation). Highly lipophilic; absorption requires gastric acid + food (capsule) but solution form is enhanced.

Half-Life (t½)

PO: 21h, IV: 21h

Dosing Guidelines

PO: Typical 200 mg (Range: 100–400 mg)

Target Organ Systems

nervous
cardiovascular
digestive
immune-hematologic

Interactions

Simvastatin (contraindicated): CYP3A4 inhibition. Neuvonen 1998 (PMID:9542477): itraconazole 200 mg/d × 4 d raised simvastatin AUC ≥10× and simvastatin acid AUC 19× (n=10 crossover). Statin myopathy / rhabdomyolysis risk — combination contraindicated.
Cyclosporine (major): CYP3A4 inhibition. Florea 2003 (PMID:14697925): itraconazole 200 mg BID required ~48% cyclosporine dose reduction in renal transplant patients to maintain target trough (n=8). Implies ~2× AUC at fixed dose.
Midazolam (major): CYP3A4 inhibition. Olkkola 1994 (PMID:8181191): itraconazole 200 mg/d × 4 d raised midazolam AUC 10-15× and Cmax 3-4× (same study as ketoconazole arm). Avoid combination.
Triazolam (contraindicated): CYP3A4 inhibition. Varhe 1994 (PMID:7995001) verbatim: "ketoconazole and itraconazole increased the area under the triazolam concentration-time curve [AUC(0-infinity)] 22-fold and 27-fold (p < 0.001)". 9 healthy volunteers, double-blind 3-phase crossover, itraconazole 200 mg/d × 4d + single 0.25 mg PO triazolam d4. AUC 27×; Ki ≈ 0.5/26 = 0.019 µM. PD profoundly impaired; pair is label-contraindicated.
Alprazolam (caution): CYP3A4 inhibition. Yasui 1998 (PMID:9784084) verbatim: itraconazole "increased the area under the concentration-time curves from 0 h to infinity (252 +/- 47 versus 671 +/- 205 ng h/ml)". 10 healthy male, double-blind randomized crossover, itra 200 mg/d × 6d + 0.8 mg PO alprazolam. AUC ratio 671/252 = 2.66×; Ki ≈ 0.5/1.66 = 0.30 µM.
Atorvastatin (caution): CYP3A4 inhibition. Mazzu 2000 (PMID:11061579) verbatim: "itraconazole dramatically increased atorvastatin AUC (150%)" / "elevated atorvastatin plasma levels (2.5-fold) after 20 mg dosing". 18 healthy, single-site randomized 3-way open-label crossover, itra 200 mg + atorvastatin 20 mg. AUC ratio 2.5×; Ki ≈ 0.5/1.5 = 0.33 µM. Statin myopathy risk.
Lovastatin (contraindicated): CYP3A4 inhibition. Neuvonen 1996 (PMID:8689812) verbatim: "itraconazole increased the peak concentration (Cmax) of lovastatin and the area under the lovastatin concentration-time curve (AUC) more than twentyfold (p < 0.001)". 12 healthy, double-blind 2-phase crossover, itra 200 mg/d × 4d + single 40 mg PO lovastatin. AUC ≥20× (conservative lower bound); Ki ≈ 0.5/19 = 0.026 µM. Rhabdomyolysis risk; pair is label-contraindicated.
Oxycodone (caution): CYP3A4 inhibition (N-demethylation to noroxycodone). Saari 2010 (PMID:20076952) verbatim: itraconazole "increased the AUC(0-infinity) of orally administrated oxycodone by 144% (P<0.001)". 12 healthy, 4-session paired crossover, itra 200 mg × 5d + 10 mg PO oxycodone (oral arm; separate IV arm +51%). PO AUC ratio 2.44×; Ki ≈ 0.5/1.44 = 0.35 µM. Respiratory depression risk.

Pathways It Modulates

Fungal ergosterol biosynthesis (inhibitor) — fungal CYP51 (+ mammalian CYP3A4 strong)
Hedgehog / Smoothened signaling (inhibitor) — SMO (off-target, independent of antifungal CYP51 action)

Chemical Identifiers

PubChem CID: 55283
Formula: C35H38Cl2N8O4
Molecular weight: 705.63 g/mol
InChIKey: VHVPQPYKVGDNFY-ZPGVKDDISA-N
SMILES: CCC(C)N1C(=O)N(C=N1)C2=CC=C(C=C2)N3CCN(CC3)C4=CC=C(C=C4)OC[C@H]5CO[C@](O5)(CN6C=NC=N6)C7=C(C=C(C=C7)Cl)Cl