CYP3A4 inhibitors Aprepitant

Aprepitant is a moderate CYP3A4 inhibitor. Aprepitant should not be used concurrently with pimozide or cisapride. Inhibition of cytochrome P450 isoenzyme 3A4 (CYP3A4) by aprepitant could result in elevated plasma concentrations of these drugs, potentially causing serious or life-threatening reactions. Aprepitant is contraindicated in patients who are hypersensitive to any component of the product. 

Although the effect of these increases has not been assessed, such marked increases in levels could increase adverse effects. The manufacturers recommend caution when aprepitant is given with ketoconazole and other drugs that are strong inhibitors of CYP3A4. They specifically name ritonavir, clarithromycin, telithromycin, itraconazole, ne-fazodone, troleandomycin, and nelfinavir. For the effect of diltiazem (a moderate CYP3A4 inhibitor), see Calcium-channel blockers + Aprepi-tanf, p. 861. Other inhibitors of CYP3A4 are listed in Table 1.4 , (p.6). 

When aprepitant is used concomitantly with another CYP3A4 inhibitor, aprepitant plasma concentrations can also be elevated... 

Aprepitant is a substrate, a moderate inhibitor, and an inducer of CYP3A4. Aprepitant is also an inducer of CYP2C9. Use aprepitant with caution in patients receiving concomitant medicinal products, including chemotherapy agents that are primarily metabolized through CYP3A4 (docetaxel, paclitaxel, etoposide, irinotecan, ifosfamide, imatinib, vinorelbine, vinblastine, and vincristine). 

Drugs that may affect aprepitant include CYP 3A4 inhibitors (eg, clarithromycin, diltiazem, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, troleandomycin), CYP3A4 inducers (eg, carbamazepine, phenytoin, rifampin), and paroxetine. 

APREPITANT ANTIVIRALS-PROTEASE INHIBITORS t aprepitant levels with nelfinavir and ritonavir (with or without lopinavir) Inhibition of CYP3A4-mediated metabolism of aprepitant Use with caution clinical significance unclear monitor closely... 

In the short-term, aprepitant is an inhibitor of the cytochrome P450 isoenzyme CYP3A4, and might therefore reduce the activation of antineoplastics activated by this isoenzyme (cyclophosphamide, thiotepa), or increase the toxicity of antineoplastics metabolised by this enzyme (docetaxel, irinotecan). 

Based on the way midazolam interaets with similarly potent inhibitors of CYP3A4, aprepitant may be expeeted to increased the drowsiness and length of sedation and amnesia in patients given midazolam. Consider re-dueing the midazolam dose in patients given aprepitant and monitor the outeome of eoneurrent use earefully. The manufaeturer notes that the potential effeets of inereased levels of other benzodiazepines metabolised via CYP3A4, sueh as alprazolam and triazolam, should be eonsidered if... 

Both aprepitant and diitiazem are substrates and inhibitors of the cytochrome P450 isoenzyme CYP3A4, therefore they eaeh inhibit the other drugs metabolism. The clinical relevance of this interaction is uncertain, but the manufacturers recommend caution with diitiazem and other moderate inhibitors of CYP3A4. ... 

Ketoconazole markedly increases aprepitant levels. The manufacturer recommends caution when aprepitant is used with ketoconazole or other strong inhibitors of CYP3A4. 

Ketoconazole is an inhibitor of the cytochrome P450 isoenzyme CYP3A4, by which aprepitant is metabolised. Concurrent use therefore raises aprepitant levels. 

In the first few days of use, aprepitant 125/80 mg markedly increased levels of midazolam, a probe drug subsfrafe for fhe cyfoehrome P450 isoenzyme CYP3A4. Then, within 2 weeks, a reduction in levels was seen, see Benzodiazepines + Aprepitant , p.721. This effect was not seen with the 40/25 mg dose regimen. Aprepitant is therefore both a dose-dependent inhibitor and an inducer of CYraA4. 

Aprepitant is a dose-dependent inhibitor of CYP3A4, and should be used with caution in... 

Ketoconazole, a strong inhibitor of CYP3A4, increases the effective half-life of aprepitant three fold. 

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