50mg of ritonavir may be an effective booster for some protease inhibitors

The amount of ritonavir needed to boost levels of other protease inhibitors differs between individual drugs, a meta-analysis published in the online edition of AIDS suggests.

Ritonavir (Norvir) doses of between 50 and 100mg were as effective as higher doses of the drug at boosting saquinavir (Invirase), fosamprenavir (Telzir) and darunavir (Prezista).

However, indinavir (Crixivan), lopinavir and tipranavir (Aptivus) were more effectively boosted by higher doses of ritonavir.

The researchers suggest that a 50mg dose of ritonavir may prove to be an effective boosting agent for some widely used protease inhibitors and call for clinical trials to evaluate this.

Ritonavir is an anti-HIV protease inhibitor. At its full dose, it is associated with unpleasant side-effects, most notably nausea, vomiting and diarrhoea. Because of these side-effects, it is no longer recommended for use at its full dose.

However, the drug is recommended as an agent to boost other protease inhibitors. This is because ritonavir blocks the CYP3A4 pathway in the liver, which is involved in the metabolising of other protease inhibitors. This leads to higher blood concentrations of these drugs and their slower clearance from the body.

All the protease inhibitors recommended for use today are licensed for use with a ritonavir booster.

However, even at doses of 100 or 200mg a day ritonavir can cause increases in lipids and side-effects such as nausea and diarrhoea. Therefore reducing the dose of ritonavir could improve tolerability whilst reducing pill burden and cost.

A British-led team of investigators therefore conducted a meta-analysis that included 17 dose-ranging studies exploring the pharmacokinetic impact of ritonavir on saquinavir, fosamprenavir, darunavir, atazanavir, indinavir and tipranavir. Five studies were included that analysed dosing of lopinavir and ritonavir.

Saquinavir/ritonavir

Ritonavir doses of between 50 and 400mg twice daily have been investigated as a booster for saquinavir.

100mg of ritonavir was as effective as higher doses of the drug at boosting saquinavir levels.

However, a recent Thai study found that a once-daily dose of 50mg of ritonavir was as effective as the standard 100mg dose at boosting 1500mg of saquinavir once daily.

Fosamprenavir/ritonavir

When taken twice-daily in combination with 700 mg of fosamprenavir, a 100 mg dose of ritonavir was as effective a booster as a 200 mg dose, the investigators found.

Darunavir/ritonavir

A 100mg dose of ritonavir in combination with darunavir once or twice daily was shown to be an effective booster.

Atazanavir/ritonavir

The approved dose of atazanavir/ritonavir is 300/100mg once daily. The investigators found one study looking at drug concentrations when the ritonavir dose was increased to 200mg. This showed that there was no benefit from using the higher ritonavir dose.

Indinavir/ritonavir

One study showed that a 200mg dose of ritonavir was associated with slower clearance of indinavir compared to a 100mg ritonavir dose.

Tipranavir/ritonavir

The approved dose of tipranavir/ritonavir is 500/200mg twice daily. Studies showed that using a 200mg ritonavir booster increased levels of tipranavir compared to a 100mg dose of ritonavir.

Lopinavir/ritonavir

A meta-analysis of five studies looking at lopinavir/ritonavir dosing showed that a higher dose of ritonavir could compensate for a lower dose of lopinavir.

One study showed that when taken twice daily, a 200mg dose of lopinavir had a similar area under the curve (below therapeutic levels) and achieved similar minimum blood levels as the standard 400mg dose when taken in combination with 150mg of ritonavir rather than 100mg.

“The present systematic review of 17 clinical pharmacology trials shows that ritonavir boosts the protease inhibitors in different ways,” comment the investigators.

“For saquinavir, fosamprenavir and darunavir, there was no correlation between higher ritonavir doses and higher protease inhibitor concentrations…for lopinavir, indinavir and tipranavir, use of higher doses of ritonavir led to higher concentrations of the boosted protease inhibitor.”

The investigators calls for clinical trials to evaluate the safety and efficacy of a 50 mg dose of ritonavir to boost saquinavir, atazanavir, fosamprenavir and darunavir.