Combinations of lopinavir/r and amprenavir in heavily treatment experienced patients

2 November 2001. Related: Conference reports, PK and drug interactions, EACS 8th Athens 2001.

Paul Blanchard, HIV i-Base

Both lopinavir and amprenavir are good candidates for pharmacokinetic (PK) enhancement by coadministration of ritonavir. The combination of both drugs in a ritonavir boosted combination may also be attractive in salvage settings based on the resistance profile of each agent.

However, data on the use of ritonavir boosted lopinavir and amprenavir in the same combination regimen are scarce. In addition the pharmacokinetic interaction between this combination is not well described and its clinical significance is unclear.

Four presentations on this combination were made in the poster sessions of the 8th ECCATH providing more information on PK interactions as well as mixed results in terms of virological and immunological response.

Lopinavir and amprenavir in combination may lower each others trough levels

Preliminary PK data from Stefan Mauss, Duesseldorf, highlighted the complex interactions of this combination [1]. A pharmacokinetic analysis was carried out in ten heavily pre-treated patients receiving the combination of lopinavir/r and amprenavir. No concomitant use of NNRTI’s was allowed and patients were on stable treatment for 6 months before the analysis. Lopinavir trough levels in these patients were found to be 45% of historical controls and trough levels of amprenavir 42% of historical controls. Mauss concluded that amprenavir and lopinavir in combination may lower each others concentrations. A possible explanation may be a synergistic inducing effect on the metabolism of ritonavir by both amprenavir and lopinavir. In addition a high interpatient variability particularly of the plasma trough concentrations of both drugs was observed. Therapeutic drug monitoring (TDM) in patients receiving this combination would seem prudent to prevent treatment failure due to low exposure. Mauss also called for a controlled study to further assess PK and safety.

Moderate antiretroviral effect, but adverse PK interaction

In a prospective study performed by Cingolani and colleagues from the Catholic University, Rome, 22 treatment experienced patients took part in a pilot study of this combination [2]. All 3 classes of antiretrovirals had failed in these patients including a minimum of 2 PI’s. Amprenavir was dosed at 600mg BID and lopinavir/r at 400/100mg BID. At 24 weeks a median decline of −1.13 log copies/mL was seen in plasma viral load and a median increase of 88 cells/mm3 in CD4 count. A PK analysis revealed that amprenavir trough concentrations were 37% lower than historical controls and that week 2 lopinavir levels were predictive of virological response.

Resistance testing and TDM recommended

De Wit and colleagues from the Saint-Pierre University hospital, Brussels presented data on 28 patients receiving the combination of lopinavir/r + amprenavir in the ABT378/r early access programme [3]. All patients were NNRTI experienced and showed genotypic resistance to all the four PI’s which were available at the time (SQV, RTV, IDV, NLF). Lopinavir/r was dosed at 400mg BID or 533 mg BID if an NNRTI was included in the regimen. Amprenavir was dosed at 750mg BID. Other nucleoside analogues made up the rest of the combinations. Median viral load at month 12 showed a decline of −0.5 log copies/mL and there was a fall in median CD4+ T-cell count of 12 cells/mm3. The authors concluded that in this setting the combination showed transient virological benefit and may have been hampered by a PK interaction between lopinavir and amprenavir. They go on to recommend both resistance testing and therapeutic drug monitoring (TDM) to individualise dosing if these agents are used together.

Contribution of amprenavir in less heavily treated patients unclear

In another retrospective cohort study Loutfy and colleagues of the University of Toronto analysed the response of patients who were either treated with the combination of lopinavir/r and amprenavir or lopinavir/r alone along with other NA’s and NNRTI’s [4]. 33 patients received the PI combination and 35 patients lopinavir/r. All patients were PI experienced but perhaps less so than in the cohorts discussed previously. It should also be noted that there was a significant difference in NNRTI experience between the groups with only 6.1% of those in the PI combination group receiving an NNRTI for the first time as part of this regimen versus 22.9% in the lopinavir/r alone group (p=0.05). Amprenavir was dosed at 750-1250 mg BID and lopinavir/r at 400/100 BID or 533/133 mg BID if it was the sole PI or if an NNRTI was part of the regimen. No difference was seen between the lopinavir/r + amprenavir group compared to the lopinavir/r group in terms of both virological and immunological response. Over 11 months the % of subjects who were <50 copies/mL for viral load ranged from 16.7 to 46.1%. The mean change in viral load at 6-12 months was −2.05 log copies/mL and the CD4+ count was between +55 and +90 cells/mm3. The group concluded that the combination of lopinavir/r with amprenavir at these dosages and in these patients had neither an advantage nor a disadvantage over lopinavir/r alone. They acknowledged the need for further studies to assess the effect of PK interactions.

Lopinavir/r + saquinavir without nucleosides

Saquinavir is a protease inhibitor which also benefits from PK enhancement through coadministration with ritonavir. Doses of 400/400 mg of saquinavir/ritonavir were first used over 4 years ago to explore the utility of dual PI only regimens. Poor absorption of saquinavir, probably hampered by cytochrome p450 expression in the gut, also encouraged the coadminstration of ritonavir, a powerful p450 inhibitor. More recently, studies have suggested doses of 1200mg of saquinavir combined with 100mg ritonavir BID may be optimum as opinion shifted away from considerations that the ritonavir should be administered at doses where it may have an antiretroviral effect. In many of the PI combinations used today ritonavir is unlikely to be providing any antiretroviral support and should, in fact, be considered purely as a PK enhancer. As such ritonavir boosted single PI’s should not be considered as “dual PI” combinations, but as single PI’s with enhanced (adequate) pharmacokinetics. It is only when we more into the arena of administration of two PI’s in combination that are both PK enhanced by ritonavir that we can consider them as dual PI’s. The most promising candidates for this approach so far are the lopinavir/r + amprenavir combinations considered above and the lopinavir/r + saquinavir combination explored in the study below.

Another interesting candidate for this approach, as yet unexplored, would be the combination of lopinavir/r and tipranavir. Again, both lopinavir and tipranavir are enhanced by ritonavir coadministration. In addition the combination of protease inhibitors of structurally different classes (one peptidic, one non-peptidic) and resistance profiles may hold the promise of synergistic action. In vitro studies and PK investigation in healthy volunteers should be fast tracked for this combination as treatment options for many patients are already bleak.

Stefan Christoph and colleagues from the Goethe University Hospital, Frankfurt presented their data on the combination of lopinavir/r and saquinavir during the late breaker poster session at ECCATH [5]. The rationale for the study was the avoidance of nucleoside analogue drugs as part of combination therapy for those patients who were either heavily resistant or had experienced toxicities with this class of drugs. Nine pre-treated patients with documented multi-reverse transcriptase inhibitor resistance or nucleoside toxicity received saquinavir-sgc (Fortovase) 1000mg BID combined with varying dosages of lopinavir/r from 266/66mg to 532/132mg (dosage was fixed in each patient). PK comparison was made to saquinavir levels observed in 15 patients using conventional low dose ritonavir (100mg BID) coadministration in the QUAD study. The analysis revealed that saquinavir levels were comparable to conventional boosting with 100mg BID ritonavir and, importantly, that lopinavir levels were not negatively affected by saquinavir coadministration. A viral load decrease of > 2 log copies/mL at a mean of 6.4 months of follow-up was observed in 7 patients while 2 patients failed virologically. The group concluded that for patients with reverse transcriptase inhibitor resistance or toxicity an RTI sparing boosted double PI regimen of lopinavir/r + saquinavir may be a potential option. Remaining PI sensitivity would likely impact the utility of such an approach. Again, further investigation is warranted.

Comment

Standard dosages for the combination of lopinavir/r and amprenavir are not yet established, TDM guidance would appear warranted for all patients being prescribed this combination. The Loutfy study does not detect a difference in response between the combination PI group and lopinavir/r alone. It is unclear if it is sufficiently powered to detect such a difference. In addition it could be postulated that the combination may show advantage in those patients who are the most heavily experienced, patients in the Loufty study appeared to have less antiretroviral exposure than those in the other studies discussed here. The inclusion of more NNRTI sensitive patients in the lopinavir/r only group also biased the response in favour of this group.

Further PK studies and prospective studies determining virologic and immunologic response are warranted, likewise for the lopinavir/r plus saquinavir combination.

References:

1. Mauss S et al. Unfavourable interaction of lopinavir and amprenavir in combination with ritonavir. 8th ECCATH, Athens 2001. Abstract P170.
2. Cingolani A et al. Salvage therapy with amprenavir plus lopinavir/r plus NRTIs in heavily three class experienced patients: A prospective study. 8th ECCATH, Athens 2001. Abstract P252.
3. De Wit S et al. Efficacy and tolerability of the combination of lopinavir/ritonavir (LPV/RTV) and amprenavir (APV) in patients (P) with multiple protease inhibitors (PI) resistant HIV strains: Results at week 24. 8th ECCATH, Athens 2001. Abstract P63.
4. Loutfy M et al. Amprenavir (APV) plus lopinavir/ritonavir (LPV/r) versus LPV/r as the sole PI in salvage antiretroviral (ARV) therapy. 8th ECCATH, Athens 2001. Abstract P66.
5. Stefan C et al. Lopinavir/r – saquinavir without RTI in pre-treated patients with NUC associated resistance or toxicity. 8th ECCATH, Athens 2001. Abstract LB/P8.