Atazanavir shown to boost amprenavir levels

Even before the 400% US price rise of ritonavir announced last month by Abbott, and the growing movement to boycott Abbott products both in US and here in Europe, there was good reason to look at alternative ways of boosting protease inhibitors, other than by adding a small dose (usually 100-400 mg/day) of Abbott’s Norvir, since it has been known for some time that ritonavir is not a perfect long-term boosting solution. This is because, more than any other protease inhibitor, ritonavir is associated with raised blood lipids that can lead to a higher cardiovascular disease risk, even at the lower doses used for boosting.

A study published in a recent issue of AIDS looking at boosting amprenavir with the newest protease inhibitor, atazanavir – currently available in the EU on expanded access prior to full approval, which is likely at the end of February – comes at an opportune moment.

This small Italian study examined the pharmacokinetics of once- and twice-daily amprenavir/atazanavir in seven heavily treatment-experienced patients, all but one of whom were male. Four were given 600 mg amprenavir twice a day with 400 mg atazanavir once daily. The other three took 1200 mg amprenavir/400 mg atazanavir once daily. Atazanavir and amprenavir were taken at the same time in the morning.

The usual recommended dose for amprenavir is 1200 mg twice daily, or for patients with prior experience of PIs, 700 mg twice daily together with 100 mg of ritonavir. Atazanavir has been approved for once daily dosing at 400 mg/day in the US only, whereas in Europe it will be licensed to be used only with ritonavir boosting: 300 mg atazanavir boosted with 100 mg ritonavir once daily.

Unsurprisingly, the lowest blood levels of amprenavir (C_trough) were seen in the once-daily arm, with a median of 0.32 µg/ml (0.26-0.85 µg/ml); the twice-daily arm had higher trough levels with a median of 1.49 µg/ml (0.72-2.45 µg/ml).

The highest blood levels of amprenavir (C_max) were again seen in the once-daily arm, with a mean of 12.34 µg/ml (7.27-17.5 µg/ml); the twice-daily arm had a mean C_max of 9.63 µg/ml (6.59-12.26 µg/ml).

The median total amount (AUC) of amprenavir that the patients in the twice-daily arm were exposed to per hour, over a 12-hour dosing period, was 51.3 µg.h/ml (31.1-54.5) µg.h/ml. In the once-daily arm, the median amount of total amprenavir exposure per hour, over a 24-hour dosing period, was 93.9 µg.h/ml (61.4-128.7 µg.h/ml).

These levels compare favourably with 600 mg amprenavir twice daily boosted with 100 mg ritonavir twice daily, as reported by Wood and others. In that study, Ctrough, Cmax and AUC values were 1.32 µg/ml, 5.59 µg/ml, and 27.3 µg.h/ml, respectively.

Given these results, the authors suggest that either once- or twice-daily dosing of amprenavir with a once-daily dose of 400 mg atazanavir is comparable or even more effective than boosting 600 mg amprenavir twice daily with 100 mg ritonavir twice daily. There is now a new formulation of amprenavir available - fosamprenavir - and so pharmacokinetic studies need to be completed on this combination as soon as possible.

There are some major limitations to this study, however. Background nucleoside analogues used by the seven patients included tenofovir alone, tenofovir/stavudine, lamivudine/stavudine, and didanosine. Tenofovir has since been shown to reduce blood levels of atazanavir by around 25% when that protease inhibitor is unboosted by ritonavir, although the study authors appear to have been unaware of this interaction at the time of the study. This is especially unfortunate since only blood plasma levels of amprenavir were measured.

Since the study did not examine plasma levels of atazanavir, nor report on the clinical outcome of this combination, it is impossible to tell if drug levels of the 400 mg atazanavir used in this study reached high enough levels to be considered a second active PI, and whether amprenavir exerts a positive effect on atazanavir levels.

It is important to remember that the science of pharmacokinetics reports on complex interactions not only of drugs, but also the effects of the body’s own metabolism and other ingested substances such as food, drink, non-prescription medicines, vitamins and supplements. Age, genetics, gender and weight also play a role. Therefore, these seven individuals may not represent the maximum or minimum levels actually obtainable. Too high maximum exposure can lead to more adverse effects; too low to the emergence of resistance; too much total drug could be more harmful in the long term. Therefore, the latest BHIVA guidelines recommend that individual therapeutic drug level monitoring be carried out when boosting PIs unconventionally.

Still, it appears that there is some interesting potential for using atazanavir as an alternative boosting agent to ritonavir when using amprenavir; it means avoiding the raised lipids associated with ritonavir and still allows for once-daily dosing. Last year, a study by Haas and others found that 400 mg atazanavir boosted 1200 mg saquinavir well enough to dose the drugs once daily (although subsequent research found this combination to be less effective than ritonavir-boosted atazanavir). Additional larger-scale trials - and complete pharmacokinetic information on combinations with all PIs currently approved or in development - would be necessary before atazanavir is commonly used as a boosting agent, however.

Further information on this website

Ritonavir price increase: what are the consequences in 2004? - news story

Atazanavir: positive opinion in EU, but only for treatment-experienced and only when boosted - news story

Testing drug levels - Menu of information