Large reductions in plasma PK levels of saquinavir, amprenavir and lopinavir/r levels when given with tipranavir/ritonavir

One of the most important studies presented at the workshop was the first analysis of interaction between tipranavir and other protease inhibitors, from the BI 1182.51 trial. The results have important implications for people currently using tipranavir in regimens that also contain saquinavir, amprenavir or lopinavir/r.

Tipranavir is used at a dose of 500mg boosted by 200mg ritonavir, both twice daily. This study was designed to look at the pharmacokinetic interaction with a second protease inhibitor (saquinavir, amprenavir or lopinavir/r). Ritonavir is a potent CYP3A4 inhibitor and tipranavir is a CYP3A4 inducer.

Patients were enrolled who were too heavily resistant for the registrational RESIST phase-3 tipranavir trials. Enrolment criteria included triple-class experience and three or more universal protease-associated mutations from codons 33, 82, 84 and 90 (UPAMs). Tipranavir/r was added after two weeks to steady-state optimised background (OB) including each boosted-PI and compared to a tipranavir/r-only + OB regimen.

Results from 296 patients were included in this analysis: 296 in the safety data set, 290 in the PK trough data set and 86 patients (out of 134 patients in the intensive PK substudy) had evaluable data at two visits to be included in the intensive PK data set reported here.

The addition of tipranavir/r at week two sent the levels of each of the original PIs through the floor to barely detectable in many patients and to less that the previous median levels in > 80% of patients.

No dosing recommendation can even be made for these second protease inhibitors when used with tipranavir. Concentrations fell well below target for the majority of patients although a small number of people did achieve therapeutic levels. This can only be supported by individual drug level monitoring.

Table 1. Median trough concentrations of concomitant protease inhibitors (µg/mL) before and after tipranavir:

Tipranavir concentrations appeared similar in patients using saquinavir and there appeared to be a trend for slightly higher levels in the amprenavir and lopinavir/r groups.

Side effects were similar in each arm with 55-60% of patients in each arm reporting at least one side effect. Of these, diarrhoea and nausea were the most common. Incidence of laboratory abnormalities was similar in all arms, with raised triglycerides being the most commonly reported lab event.

Virological efficacy in the study was clearly driven by tipranavir with patients in all groups achieving median change of >1log reductions by week 4, once tipranavir was included in the combination. In this highly experienced group, this unfortunately only provided a short-term effect and by week 8 median viral load was rebounding to approximately -0.5 log below. Whether this trend continues further will be shown in the next analysis from 24-week data from this study due to be presented in Bangkok in July.

Curry K, Samuels C, Leith J et al – Pharmacokinetics and safety of tipranavir/ritonavir (TPV/r) alone or in combination with saquinavir (SQV), amprenavir (APV), or lopinavir (LPV): interim analysis of BI 1182.51. Abstract 5.1.

	TPV/r	APV/r	SQV/r	LPV/r
n	66	76	75	79
Week 0		1.9	0.4	5.5
Week 2		1.9	0.5	5.5
Tipranavir added at week 2:
Week 3		0.8	<0.1	3.0
Week 4		0.8	<0.1	3.0
% reduction		50%	>80%	45%
VL reduction
Week 2	-1.2	-0.2	-0.3	-0.4
Week 4	-1.2	-1.2	-1.2	-1.2
Week 8	-0.5	-0.8	-0.7	-0.7