Itraconazole as an alternative for ritonavir liquid formulation when combined with saquinavir

Saquinavir belongs to the class of HIV protease inhibitors, and is a potent inhibitor of HIV-1 replication in vitro and in vivo. Saquinavir (Invirase) displays a limited and variable oral bioavailability of approximately 4%[1] The affinity of saquinavir for P-glycoprotein may play a significant role in this respect [2] Saquinavir must be taken with food, because its oral bioavailability when administered on an empty stomach is substantially lower [1] Because of its limited oral bioavailability and the extensive metabolism of the drug by the cytochrome P450 enzyme system (CYP450), some patients exhibit low exposure to saquinavir, putatively leading to an increased risk of virological failure [3] The addition of ritonavir (an inhibitor of CYP450 and P-glycoprotein) to a saquinavir-containing regimen is a widely applied strategy to increase the exposure to saquinavir. The increase in the concentration of saquinavir by the concomitant use of ritonavir is in the range of 20-fold or more. This allows for a reduced dose and dosing frequency of saquinavir (e.g. 400 mg twice a day of both saquinavir and ritonavir), while a high exposure to saquinavir is achieved [4] Currently, ritonavir is temporarily only available as a liquid formulation (because of stability problems with the capsule formulation), which is generally not well tolerated because of its taste. Many patients using ritonavir (including those who also use saquinavir) are thus confronted with a serious problem that has a negative influence on compliance. During our routine therapeutic drug monitoring programme of antiretroviral drugs, we noted that two patients had a greater than five-fold higher exposure to saquinavir than anticipated. Their antiretroviral regimen consisted of two nucleoside reverse transcriptase inhibitors (NRTI) and saquinavir. Further investigation ascertained that these patients concomitantly used itraconazole, an antifungal drug and an inhibitor of CYP450 and P-glycoprotein [5] This prompted us to perform a pilot pharmacokinetic study to investigate in more detail the effect of the addition of itraconazole on the exposure to saquinavir as part of a triple antiretroviral drug regimen with two NRTI. In three HIV-1-infected male patients who used saquinavir (Invirase 1200 mg three times a day) for at least 3 months in combination with two NRTI, but without the concomitant use of other drugs, the pharmacokinetics of saquinavir were determined. Patients were admitted to the hospital after an overnight fast and ingested their drugs during a meal. Over an 8 h interval a total of 12 venous blood samples were drawn, plasma was isolated by centrifugation and immediately stored at −30°C until analysis. Itraconazole was subsequently added to the regimen (200 mg a day, after a loading dose of 200 mg twice a day for 3 days), and the patients returned to the hospital after 14 days and underwent the same procedure to assess the pharmacokinetics of saquinavir, itraconazole and its active metabolite, hydroxyitraconazole. Plasma concentrations of saquinavir, itraconazole and hydroxyitraconazole were quantified using validated high-performance liquid chromatography assays [6,7] Pharmacokinetic parameters were calculated using non-compartmental methods. This analysis revealed that the saquinavir area under the plasma concentration versus time curve (AUC) showed a median five-fold increase (range 2.5–6.9) after the addition of itraconazole. For the maximum and trough concentration, the median increases were 4.8-fold (range 2.0–5.4) and 3.1-fold (range 1.6–16.8), respectively. The individual saquinavir plasma concentration versus time curves before and after the addition of itraconazole are shown in Fig. 1. Saquinavir exposure was comparable to that observed when combined with ritonavir (using a dosage of 400 mg twice a day for saquinavir and ritonavir) [4]Fig. 1.: Steady-state saquinavir plasma concentration versus time curves with (•) and without (○) the co-administration of 200 mg itraconazole a day. Values for the area under the plasma concentration versus time curve (AUC)0–8 h] (in h*mg/l) with and without the co-administration of itraconazole were 8.72 and 1.27 for patient 1, 15.36 and 6.15 for patient 2, and 7.40 and 1.48 for patient 3, respectively.Itraconazole and hydroxyitraconazole pharmacokinetics were in agreement with those previously reported (the median extrapolated AUC[0–24 h] for itraconazole and hydroxyitraconazole was 13.3 and 17.1 h*mg/l, respectively) [8] The combination of itraconazole and saquinavir was well tolerated during the 2 week period. Interestingly, in patient 3 the plasma HIV-1 RNA concentration became undetectable (< 400 copies/ml) during this period for the first time after years of antiretroviral therapy. The currently reported pharmacokinetic interaction may have been caused by the inhibition of P-glycoprotein activity by itraconazole (leading to an increased absorption of saquinavir) or a decreased metabolism as a result of the inhibition of CYP450 by itraconazole (and a decreased elimination of saquinavir). It was recently reported that the combination of itraconazole and indinavir, or the combination of ritonavir and saquinavir was not tolerated because of high exposure to itraconazole and, putatively, the protease inhibitors. The use of itraconazole in combination with a pro-tease inhibitor should therefore be limited to saquinavir [9] The putatively enhanced virological effect and the safety of saquinavir when combined with itraconazole is currently being explored in a large randomized study. Although these results are not yet available, physicians may consider itraconazole as an alternative for ritonavir when combined with saquinavir, if the liquid formulation of ritonavir cannot be tolerated and further treatment with saquinavir is desired. It should be realized, however, that the antiretroviral effect of ritonavir or any synergism is lacking in this case. Furthermore, if low exposure to saquinavir is observed (or anticipated), itraconazole may be used to increase its oral bioavailability. Because the reported pharmacokinetic interaction with itraconazole appears to be smaller compared with ritonavir, the dosage of saquinavir should not be reduced when combined with itraconazole. Cornelis H.W. Koksa Rolf P.G. Van Heeswijka Agnes I. Veldkampa Pieter L. Meenhorstb Jan-Willem Mulderb J.T.M. van der Meerc Jos H. Beijnena Richard M.W. Hoetelmansa