Triple PI interactions: fosamprenavir and Kaletra interaction is difficult to overcome
Simon Collins, HIV i-Base
Previous reports have highlighted that the interactions between fosamprenavir and Kaletra are problematic, including a study from last year’s ICAAC conference. [1, 2] Normally, two pills of fosamprenavir are combined with ritonavir either once or twice daily for boosting; lopinavir/ritonavir (Kaletra) is normally dosed as three pills twice daily.
Two studies at this meeting reported that the interaction is not overcome by increased doses of either drug or of additional ritonavir. Even when increased doses of Kaletra were tolerated, fosamprenavir levels remained lower than those used without lopinavir, and most patients using dual-boosted-PI combinations are also likely to be looking for higher levels to overcome earlier levels of resistance.
Corbett and colleagues from the University of North Carolina looked at whether separating each PI by four or 12 hours improved the pharmacokinetics compared to giving all three drugs together. Patients with separated doses used an additional 200mg ritonavir. This strategy corrected the drug levels of lopinavir, but did not improve the levels of amprenavir. 
The second study from Wire and colleagues at GSK looked at pharmacokinetics of both fosamprenavir and lopinavir in two different dosing strategies in two crossover studies in HIV-negative subjects. 
The first regimen increased the dose of Kaletra, using 1400mg fosamprenavir (two pills) with 533/133 mg of lopinavir/ritonavir (four pills) all taken twice a day. The second added an additional dose of ritonavir to standard doses of each drug: 1400mg fosamprenavir (two pills) with 400/100 mg of lopinavir/ritonavir (three pills) with an additional 100mg of ritonavir (one pill), all taken twice a day.
The discontinuation rate due to toxicity was high with 13/36 and 16/36 subjects discontinuing in the first and second study respectively and elevations in cholesterol and triglyceride levels were frequent in all study arms. Both of the increased dosing strategies increased amprenavir levels, but not to the levels seen in other boosted-amprenavir studies. Based on the PK results the study could make specific recommendations about the dosing of fosamprenavir and lopinavir/ritonavir.
These results are in good agreement with the previous findings for amprenavir, the parent drug. In the UK, individualising drug dosing with therapeutic drug monitoring (TDM) is recommended for interactions for which there are insufficient data to recommend a particular dosing strategy. TDM appears warranted to determine the safest approach to any dual-boosted or triple-PI combination.
Although GSK covers the cost of TDM for interactions involving fosamprenavir,  in this particular example it seems likely that gastrointestinal toxicity as well as the huge interindividual variation in plasma levels limit the utility of this combination, and that co-administration should only used in exceptional circumstances.
- Kashuba A, Tierney C, Downey G et al. Combining GW433908 (fosamprenavir; 908) with lopinavir/ritonavir (LPV/R) in HIV-1 infected adults results in substantial reductions in amprenavir (APV) and LPV concentrations: pharmacokinetic (PK) results from adult ACTG protocol A5143. 43rd ICAAC, September, 2003; Abstract H-855a.
- Corbett AH, Davidson L, Park JJ. Dose separation strategies to overcome the pharmacokinetic interaction of a triple protease inhibitor regimen containing fosamprenavir, lopinavir, and ritonavir. 11th CROI 2004, Abstract 611.
- Wire MB, Naderer OJ, Masterman AL et al. The pharmacokinetic interaction between GW433908 and lopinavir/ritonavir (APV10011 and APV10012). 11th CROI 2004, Abstract 612.
- For details of individual TDM programmes see
- Blanchard P. Combinations of lopinavir/r and amprenavir in heavily treatment experienced patients. HTB Vol2 No9.
- Mauss S, Scholten S, Wolf E et al. A prospective, controlled study assessing the effect of lopinavir on amprenavir concentrations boosted by ritonavir. HIV Med. 2004 Jan;5(1):15-7.