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Raltegravir Levels Down With Tipranavir and Up With Atazanavir
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9th International Workshop on Clinical Pharmacology of HIV Therapy
April 7-9, 2008
New Orleans
Mark Mascolini
Trough concentrations of the integrase inhibitor raltegravir were lower than normal with tipranavir/ritonavir and higher than normal with atazanavir/ritonavir, according to analysis of the French raltegravir expanded-access program [1]. Darunavir/ritonavir had little impact on raltegravir levels. The study author noted that at this point neither the FDA nor European drug regulators see a need for dose adjustment when giving raltegravir with tipranavir/ritonavir
Gilles Peytavin and colleagues measured raltegravir trough concentrations approximately 12 hours after dosing in people who took their raltegravir regimen for at least 1 month. Median age measured 47 years and ranged from 42 to 54 years, and 18% of study participants were women. The researchers determined 276 raltegravir troughs in 175 people divided into three groups:
· Group A: With darunavir/ritonavir: 189 troughs in 125 people
· Group B: With atazanavir/darunavir/ritonavir: 36 troughs in 18 people
· Group C: With tipranavir/ritonavir: 51 troughs in 32 people
Patients also took two nucleosides and could take the nonnucleoside etravirine (64% did) and/or the fusion inhibitor enfuvirtide. Everyone took 400 mg of raltegravir twice daily and standard doses of the other antiretrovirals.
Median raltegravir troughs with darunavir/ritonavir matched previously reported raltegravir levels. Adding atazanavir to the mix boosted raltegravir troughs, while tipranavir/ritonavir lowered raltegravir troughs:
· Group A: Median raltegravir trough 96 ng/mL (interquartile range [IQR] 38 to 259 ng/mL)
· Group B: Median raltegravir trough 182 ng/mL (IQR 76 to 452 ng/mL), P = 0.034 versus group A, P < 0.0001 versus group C
· Group C: Median raltegravir trough 52 ng/mL (IQR 30 to 244 ng/mL), P = 0.002 versus group A
While 9% in darunavir group A and 3% in atazanavir/darunavir group B had a raltegravir trough below the 95% inhibitory concentration of 15 ng/mL, 25% in tipranavir group C had a raltegravir trough below that threshold. Peytavin suggested that higher raltegravir troughs with atazanavir reflect atazanavir's inhibition of UGT 1A1, an enzyme critical to raltegravir metabolism.
Another study presented at this workshop and reviewed separately by NATAP found 30% lower raltegravir troughs with versus without darunavir/ritonavir in healthy volunteers [2]. But the investigators concluded that drop probably does not justify a dose adjustment.
As in earlier studies, the French expanded-access analysis found high patient-to-patient variability in raltegravir troughs--113% in group B, 145% in group C, and 158% in group A. In group A the median darunavir trough stood at 3036 ng/mL (IQR 1994 to 4483 ng/mL) and in group B at 2496 ng/mL (IQR 2081 to 3750 ng/mL). In group B the median atazanavir 12-hour concentration (+/- 2 hours) measured 958 ng/mL (IQR 474 to 1391 ng/mL). The group C median tipranavir trough was 21,055 ng/mL (IQR 10,614 to 33,546 ng/mL). Peytavin listed the target tipranavir trough as approximately 20,000 ng/mL, so a substantial number of tipranavir takers fell below that cutoff.
The clinical import of low raltegravir troughs with tipranavir remains unclear, Peytavin stressed. In the two BENCHMRK trials of raltegravir salvage regimens, 70% of people taking raltegravir with tipranavir--and having a tipranavir-sensitive genotype--had a week-24 viral load below 50 copies, compared with 66% taking raltegravir without tipranavir [3,4]. So at least in heavily treatment-experienced people like those in the BENCHMRK studies, tipranavir does not seem to rob raltegravir of its punch, as long as those people have tipranavir-susceptible virus.
Peytavin noted that at this point neither the FDA nor European drug regulators see a need for dose adjustment when giving raltegravir with tipranavir/ritonavir. But both agencies urge caution when giving raltegravir with the anti-TB drug rifampin and other "strong inducers" of the UGT 1A1 metabolizing enzyme. As noted, atazanavir is a UGT 1A1 inhibitor. The impact of tipranavir on raltegravir levels, Peytavin suggested, could reflect induction of UGT 1A1 or P-glycoprotein.
(Many complete slide sets and posters from this workshop will be available at www.hivpresentation.com shortly after the meeting ends.)
References
1. Rahal A, Soulie C, Schneider L, et al. Therapeutic drug monitoring of raltegravir (MK-0518) in experienced HIV-infected patients. 9th International Workshop on Clinical Pharmacology of HIV Therapy. April 7-9, 2008. New Orleans. Abstract O25.
2. Rhame F, Long M, Acosta E. RAL-KAL: pharmacokinetics of coadministered raltegravir and lopinavir-ritonavir in healthy adults. 9th International Workshop on Clinical Pharmacology of HIV Therapy. April 7-9, 2008. New Orleans. Abstract O19.
3. Cooper D, Gatell J, Rockstroh J, et al. Results of BENCHMRK-1, a phase III study evaluating the efficacy and safety of MK-0518, a novel HIV-1 integrase inhibitor, in patients with triple-class resistant virus. 14th Conference on Retroviruses and Opportunistic Infections. February 25-28, 2007. Los Angeles. Abstract 105aLB.
4. Steigbigel R, Kumar P, Eron J, et al. Results of BENCHMRK-2, a phase III study
evaluating the efficacy and safety of MK-0518, a novel HIV-1 integrase inhibitor, in patients with triple-class resistant virus. 14th Conference on Retroviruses and Opportunistic Infections. February 25-28, 2007. Los Angeles. Abstract 105bLB.
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