Switch from Enfuvirtide to Raltegravir Lowers Plasma Concentrations of Darunavir and Tipranavir: a Pharmacokinetic Substudy of the EASIER-ANRS 138 Tria

1. ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, July 2011, p. 3613–3615 Vol. 55, No. 7
0066-4804/11/$12.00 doi:10.1128/AAC.01827-10
Copyright © 2011, American Society for Microbiology. All Rights Reserved.
Switch from Enfuvirtide to Raltegravir Lowers Plasma Concentrations
of Darunavir and Tipranavir: a Pharmacokinetic Substudy of the
EASIER-ANRS 138 Trial
Lauriane Goldwirt,1 Josephine Braun,2 Nathalie de Castro,3 Isabelle Charreau,2 Aurelie Barrail-Tran,1
´ ´
Constance Delaugerre,4 Francois Raffi,5 Caroline Lascoux-Combe,6 Jean-Pierre Aboulker,2
¸
Anne-Marie Taburet,1* and Jean-Michel Molina3
Department of Clinical Pharmacy, Bicetre Hospital, Assistance Publique Hopitaux de Paris, and University Paris 11, Le
ˆ ˆ
Kremlin-Bicetre, France1; INSERM SC10, Villejuif, France2; Department of Infectious Diseases, Saint-Louis Hospital,
ˆ
Assistance Publique Hopitaux de Paris, and University Paris Diderot—Paris 7, Paris, France3; Virology Department,
ˆ
Saint-Louis Hospital, Assistance Publique Hopitaux de Paris, Paris, France4; CISIH, CHU Hotel Dieu,
ˆ
Nantes, France5; and Department of Internal Medicine, Saint-Louis Hospital,
Assistance Publique Hopitaux de Paris, Paris, France6
ˆ
Received 29 December 2010/Returned for modification 6 April 2011/Accepted 30 April 2011
We compared tipranavir and darunavir concentrations measured at steady state in 20 human immunodeficiency
virus (HIV)-infected patients enrolled in the EASIER-ANRS 138 clinical trial who switched from enfuvirtide to
raltegravir while maintaining the same background regimen. The geometric mean ratios of the observed predose
concentration (Ctrough), maximum concentration of drug observed in plasma (Cmax), and area under the plasma
concentration-time curve (AUC) before (day 0) and after (week 24) the switch were 0.49, 0.76, and 0.67 and 0.82,
0.68, and 0.64 for tipranavir and darunavir, respectively. The virologic consequences of these drug interactions have
yet to be determined.
Among patients with multidrug-resistant human immunode- plasma HIV-1 RNA below 400 copies/ml under the enfu-
ficiency virus type 1 (HIV-1) infection, salvage antiretroviral virtide-based regimen (4). The twenty patients enrolled in this
regimens, including enfuvirtide, have demonstrated sustained trial gave their written informed consent to participate in the
efficacy. Nowadays, reluctance to use subcutaneous injections pharmacokinetic study. Nine patients were receiving ritonavir-
supports the replacement of enfuvirtide with newly available boosted tipranavir (500/200 mg twice a day [BID]), and 11
antiretrovirals, such as raltegravir, an integrase inhibitor ad- patients were receiving ritonavir-boosted darunavir (600/100
ministered orally. The EASIER-ANRS 138 clinical trial dem- mg BID) as part of their optimized background regimens.
onstrated that a switch to raltegravir was safe, well tolerated, Blood samples were drawn prior to the morning drug intake
and virologically noninferior to the maintenance of enfuvirtide with a light continental breakfast and at 1 h, 3 h, 5 h, and 9 h
in patients infected with multidrug-resistant HIV-1 infection postdosing when darunavir or tipranavir was combined with
who were receiving suppressive antiretroviral therapy (4). Al- enfuvirtide (period 1), as well as at 24 weeks after the switch
though enfuvirtide is a peptide with no in vitro effect on drug- from enfuvirtide to raltegravir (period 2).
metabolizing enzymes or transporters, increases in saquinavir, Tipranavir, darunavir, and ritonavir were assayed by vali-
lopinavir, and tipranavir concentrations when these protease dated high-performance liquid chromatography methods with
inhibitors (PIs) were combined with enfuvirtide have been UV detection, according to a previously described method that
reported (6, 11). Raltegravir is biotransformed mainly via was modified (8). The lower limits of quantification of tiprana-
glucuronidation and has been reported to not alter the phar- vir, darunavir, and ritonavir were 400, 40, and 25 ng/ml, re-
macokinetics of coadministered antiretrovirals (3). A pharma- spectively. The coefficient of variation of quality control sam-
cokinetic substudy was designed in the ANRS 138 trial in order ples included in each analytical run was below 8%.
to assess a potential decrease in exposure of two protease Pharmacokinetic parameters were calculated by a noncom-
inhibitors, tipranavir and darunavir, following the switch from partmental method (WinNonlin; Pharsight Corporation,
enfuvirtide to raltegravir. Mountain View, CA). The area under the plasma concentra-
EASIER-ANRS 138 was an open-label, multicenter, ran- tion-time curve from 0 h to the last sampling time (9 h post-
domized clinical trial that demonstrated noninferior antiviral dosing) (AUC0–9) was determined at steady state and calcu-
efficacy at 24 weeks of a switch from enfuvirtide to raltegravir lated according to the linear up/log down trapezoidal rule
among treatment-experienced patients with suppression of (WinNonlin; Pharsight, CA). The maximum concentration of
drug observed in plasma (Cmax), the observed predose concen-
tration (Ctrough or C0), and the time to Cmax (Tmax) were
* Corresponding author. Mailing address: Clinical Pharmacy De- obtained from the plasma concentration-time curves. For each
partment, Bicetre Hospital, 78 rue du General Leclerc, 94275 Le
ˆ ´ ´
Kremlin-Bicetre, France. Phone: 33-145212964. Fax: 33-145212860.
ˆ
drug, 90% confidence intervals (90% CIs) for the geometric
E-mail: anne-marie.taburet@bct.aphp.fr. mean ratios (GMRs) (with enfuvirtide/with raltegravir) of C0,
Published ahead of print on 16 May 2011. Cmax, and AUC0–9 were constructed and analyzed using a
3613

2. 3614 GOLDWIRT ET AL. ANTIMICROB. AGENTS CHEMOTHER.
TABLE 1. Pharmacokinetic parameters
Median concn (range) for indicated parametera
Parameter Tipranavir Ritonavir-tipranavir
Period 1, week 0 Period 2, week 24 GMR 90% CI Period 1, week 0 Period 2, week 24 GMR 90% CI
C0 (ng/ml) 42,201 (17,417–109,792) 15,321 (10,740–49,991) 0.49 0.42–0.56 514 (98–2,031) 291 (176–542) 0.76 0.40–1.44
Cmax (ng/ml) 71,329 (35,837–138,808) 50,501 (30,516–102,642) 0.76 0.63–0.92 1,431 (342–3,234) 1,093 (356–2,033) 0.73 0.40–1.34
Tmax (h) 3.0 (1.0–5.0) 3.0 (2.5–5.0) 3.2 (0.0–6.0) 4.5 (0.0–5.0)
AUC0–9 437,014 (212,973–1,165,190) 330,315 (171,030–706,218) 0.67 0.55–0.82 6,728 (1,708–14,412) 4,687 (1,580–11,070) 0.76 0.44–1.34
(ng h/ml)
a
Parameters were compared by GMRs and 90% CIs (shown in brackets).
bioequivalence approach after log transformation (Statgraph- and saquinavir-ritonavir (6, 11). In the RESIST study, it has
ics version 5.1; Manugistics, Inc., Rockville, MD). been reported that patients who were on enfuvirtide-based
Twenty patients were included in this pharmacokinetic regimens had higher tipranavir concentrations than those who
study. Baseline characteristics of the 9 patients (8 males) on were not (11). Reasons for the observed decrease are presently
tipranavir and the 11 patients (9 males) on darunavir were the unknown. An inhibitory effect of enfuvirtide or an inductive
following: median ages, 47 and 49 years; median CD4 levels, effect of raltegravir on cytochrome P 450 3A (CYP3A) is
475 and 252 cells/ l; median durations of antiretroviral ther- unlikely, since on one hand, protease inhibitors were coadmin-
apy, 13 years; percentages of viral loads below 50 copies/ml, istered with ritonavir, a very potent CYP3A inhibitor, and on
89% and 91%; and median weights, 60 and 79 kg, respectively. the other hand, no inductive effect for raltegravir has ever been
All but one patient also received nucleos(t)ide analog reverse reported (7). The effect of enfuvirtide or raltegravir on trans-
transcriptase inhibitors [N(t)RTIs] in combination with PIs. A porters cannot be ruled out, as there is increasing evidence that
single patient in each PI group was on proton pump inhibitors. protease inhibitors are substrates of ABC or solute carrier
The pharmacokinetic parameters calculated for darunavir, (SLC) transporters (9, 10, 13). Garvey and collaborators re-
tipranavir, and ritonavir at period 1 with enfuvirtide (day 0) ported that addition of raltegravir to a darunavir-ritonavir-
and period 2 after 24 weeks of raltegravir are compared in tenofovir-emtricitabine regimen did not affect the darunavir
Table 1. Both tipranavir and darunavir concentrations de- concentration (5), which suggests that enfuvirtide increases
creased when enfuvirtide was switched to raltegravir (Fig. 1). protease inhibitor concentrations. Further studies should be
The 90% CI of the GMR was lower than the bioequivalence conducted to assess whether enfuvirtide or raltegravir can af-
range (0.80 to 1.25) for most parameters. Ritonavir concentra- fect the activity of such transporters, especially those expressed
tions were also higher when combined with enfuvirtide, al- in enterocytes or hepatocytes. Unfortunately, low and variable
though the decrease observed after the switch to raltegravir rates of absorption do not allow comparison of terminal half-
was modest, with a wide range of the 90% CI. lives during a 12-h dosing interval, and therefore, there is no
Darunavir and tipranavir exposure and interindividual vari- evidence showing whether the bioavailability, clearance, or
ability were in agreement with previous pharmacokinetic data possibly volume of distribution of protease inhibitors is im-
obtained from HIV-infected patients (1, 2, 12, 14). After paired by enfuvirtide and/or raltegravir. Food effect is unlikely
switching from enfuvirtide to raltegravir, the concentrations of since protease inhibitors were taken with a light meal as a
both of the protease inhibitors were significantly reduced. Such continental breakfast the day of the sampling for the pharma-
drug-drug interaction, although unexpected, has been ob- cokinetic study.
served previously for tipranavir-ritonavir, lopinavir-ritonavir, Despite this decrease in PI concentrations following the
FIG. 1. Mean plasma concentrations (and standard deviations) of tipranavir (n 9) (A) or darunavir (n 11) (B) when combined with enfuvirtide
(open diamonds and solid lines) or raltegravir (closed squares and dotted lines).

3. VOL. 55, 2011 DARUNAVIR OR TIPRANAVIR AND ENFUVIRTIDE OR RALTEGRAVIR 3615
TABLE 1—Continued
Median concn (range) for indicated parametera
Darunavir Ritonavir-darunavir
Period 1, week 0 Period 2, week 24 GMR 90% CI Period 1, week 0 Period 2, week 24 GMR 90% CI
7,033 (1,737–15,237) 4,641 (1,905–13,351) 0.82 0.61–1.10 418 (52–1,145) 319 (54–996) 0.78 0.59–1.02
10,699 (8,412–16,995) 7,369 (4,629–13,351) 0.68 0.59–0.79 1,225 (294–2,128) 785 (306–1,015) 0.67 0.49–0.91
3.0 (1.0–5.1) 1.4 (0.0–8.3) 4.8 (0.9–8.9) 3.0 (0.0–8.3)
68,094 (47,357–122,824) 48,483 (21,130–85,290) 0.64 0.53–0.77 5,491 (1,632–11,395) 4,472 (2,139–7,583) 0.73 0.54–0.98
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