Nelfinavir markedly increases terfenadine levels, which is expected to increase risk of QT prolongation and torsade de pointesarrhythmias. Other protease inhibitors are predicted to interactsimilarly with both terfenadine and astemizole,and concurrentuse is contraindicated. Ritonavir modestly increases cetirizinelevels,and in vitro data suggests that saquinavir will have a similar effect, but this is not considered to be clinically relevant. Basedon in vitro data,ritonavir is predicted to markedly raise fexofenadine levels, but this may not be of any clinical relevance.
Clinical evidence,mechanism, importance and management
Protease inhibitors are inhibitors of cytochrome P450 isoenzyme CYP3A4, by which astemizole is metabolised. On basis of interaction of astemizole with other CYP3A4 inhibitors, such as azoles, , concurrent use of astemizole with any protease inhibitor is contraindicated (See reference number 1). This seems a sensible precaution.
In a study in 16 healthy subjects concurrent use of cetirizine 10mg daily and ritonavir 600mg twice daily for 4 days (after reaching steady-state ritonavir levels), increased AUC of cetirizine by 42 % with a slight 9 % increase in maximum plasma levels. It was suggested that ritonavir may have decreased renal excretion of cetirizine. The increase in cetirizine levels was not considered to be clinically relevant. Ritonavir pharmacokinetics were minimally affected by cetirizine (See reference number 2).
An in vitro study showed that ritonavir markedly reduced transport of fexofenadine, thought to be via inhibition of P-glycoprotein (See reference number 3). This would be predicted to markedly increase bioavailability of fexofenadine, as occurs with verapamil, see Calcium-channel blockers + Antihistamines interaction,
. However, similar marked increases in fexofenadine levels that occurred with erythromycin, and ketoconazole, did not increase adverse effects and were not associated with any prolongation of QT interval. This suggests that a clinically relevant interaction between ritonavir and fexofenadine is not expected.
Nelfinavir 750mg every 8 hrs for 5 days raised levels of a single 60mg dose of terfenadine from less than 5 nanograms/mL to a range of 5 to 15 nanograms/mL. The pharmacokinetics of nelfinavir were unaffected.(See reference number 4) This rise in terfenadine levels is predicted to prolong QT interval, and to increase risk of torsade de pointes arrhythmias. In an in vitro study, saquinavir was a potent inhibitor of metabolism of terfenadine.(See reference number 5) Note that saquinavir is least potent CYP3A4 inhibitor of protease inhibitors. On basis of in vitro study, and what is known about interactions with other inhibitors of CYP3A4 such as azoles, , all protease inhibitors are predicted to raise terfenadine levels and consequently concurrent use is contraindicated.(See reference number 6) Because of seriousness of this reaction, and fact that it is not possible to predict which individuals will be affected, this seems a sensible precaution.
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