Unexpected Drug-Drug Interaction between Tipranavir/Ritonavir and Enfuvirtide
D Gonzalez De Requena, Andrea Calcagno*, S Bonora, L Ladetto, A D'Avolio, M Sciandra, M Siccardi, O Bargiacchi, A Sinicco, and G Di Perri
Univ of Turin, Italy
compounds should be evaluated for drug interactions. Association of tipranavir (TPV) and enfuvirtide
(T20) has become an option in the salvage setting. Aim of our study was to
investigate the effect of T20 co-administration on both TPV and ritonavir (RTV) plasma concentrations.
Patients placed on a TPV/RTV-based regimen (500/200 mg twice daily) at
our department underwent TPV and RTV concentrations measurement by high-performance
liquid chromatography (HPLC). Record of last dose intake and sampling timing
and no concomitant interacting drug were criteria of selection. TPV and RTV
concentrations were averaged at each time post dose point for each subject.
Samples obtained from 11 to 13 hours after last TPV/RTV dose intake were considered
as Ctrough. Modeling of sparse plasma
samples was made by using a first order absorption and elimination monocompartmental model without Tlag.
Time averaged plasma concentrations from each patient were modelled as naïve
pooled data according to T20 administration. Student’s t-test was use as needed;values
were given as ng/mL.
Results: A total
of 321 samples from 39 subjects (20 with T20, group A, and 19 without, group B)
were considered. No differences in sex, weight, height, or HCV co-infection were
seen between groups. We considered 133 Ctrough (71 from A and 62
from B). Higher mean TPV Ctrough was observed in group A (40,666 ng/mL ±20,230 vs 26,522 ng/mL ±16,907, p =
0.024), as well as higher mean RTV Ctrough (410 ng/mL
±379 vs 265 ng/mL ±144, p = 0.012). Modeling
of all TPV concentrations gave a correlation coefficient R = 0.47 for group A and R =
0.65 for group B. Higher Vd/F (9.83 L vs 4.19 L), but lower Kel value
(0.07 h1 vs 0.17 h1) were
observed in A as compared to B, whereas Ka was similar in both groups.
Half-life elimination of A was 9.57 h vs 4.1 h of B.
Higher Cmin were predicted in A (42770 ng/mL vs 28195 ng/mL), without differences on Cmax
(69,106 ng/mL vs 80,954 ng/mL), or AUC (701,770 ng*h/mL vs 697,781 ng*h/mL). Modeling of RTV concentrations
gave similar results, being differences more pronounced in elimination half
life (4.32 h in A vs 2.65 h in B), and in Cmin (400 ng/mL in A vs 138 ng/mL). No appreciable
difference in TPV and RTV CL/F was found.
TPV and RTV Ctrough were found in patients administered with T20.
Mechanism of interaction is unknown, potentially affecting Vd (higher with T20) and elimination half-life
(higher in T20 group) of TPV and RTV. Further studies are warranted to define
the clinical significance of this finding.