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Pharmacokinetic Boosting of Atazanavir with the
Pharmacoenhancer GS-9350 versus Ritonavir
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Reported by Jules Levin
ICAAC Sept 11-15 2009 San Francisco
S Ramanathan, D Warren, L Wei, and BP Kearney
Gilead Sciences, Inc., Foster City, CA, USA
AUTHOR CONCLUSIONS
ATV/GS-9350 300/150 mg provides bioequivalent ATV exposures to ATV/r
ATV/GS-9350 administration is safe and well tolerated
The pharmacoenhancer GS-9350 may be a suitable alternative to RTV for boosting of ATV
A fully enrolled Phase II clinical trial comparing ATV/GS-9350 300/150 mg versus ATV/r 300/100 mg, each in combination with emtricitabine/tenofovir disoproxil fumarate, in treatment-naive HIV patients is ongoing
INTRODUCTION
GS-9350 is a specific, potent, mechanism-based inhibitor of human cytochrome P450 3A (CYP3A) enzymes without antiviral activity
GS-9350 increases (boosts) plasma exposures of the CYP3A4 probe midazolam and the HIV integrase inhibitor elvitegravir comparably to ritonavir (RTV)1
Boosted-atazanavir (ATV) is an HIV protease inhibitor preferred for first line treatment of patients in HIV treatment guidelines
BACKGROUND
ATV is a substrate and inhibitor of CYP3A4 and is coadministered with RTV, a CYP3A4 inhibitor, (ATV/r) to achieve high trough concentrations
ATV-associated adverse effects include hyperbilirubinemia due to UGT1A1 inhibition and modest PR interval prolongation
RTV-associated safety and tolerability issues include hyperlipidemia, gastrointestinal disorders, and risk for developing cardiac conduction abnormalities2-4
GS-9350 may offer an alternative to RTV to boost ATV with the potential for reduced adverse biochemical effects
REFERENCES
1. Mathias, A et al. GS-9350: A pharmacoenhancer without antiviral
activity. 16th Conference on Retrovirus and Opportunistic Infections,
2009 Montreal, CA
2. Shafran, SD et al. The effect of low-dose ritonavir monotherapy on
fasting serum lipid concentrations. HIV Medicine (2005) 6:6, 421-425
3. Collot-Teixeira, S et al. Impact of Different Low-Dose Ritonavir
Regimens on Lipids, CD36, and Adipophilin Expression. Clin.
Pharmacol. Ther. (2009) 85:4, 375-378
4. Norvir, US Prescribing Information, October 2008.
5. Agarwala, S et al. Pharmacokinetic (PK) effect of Omeprazole (OMP) on
atazanavir (ATV) with ritonavir (RTV) in healthy subjects [poster #658].
12th Conference on Retroviruses and Opportunistic Infections 2005,
Boston, MA.
6. Zhu, L et al. Pharmacokinetics, safety and tolerability of atazanavir 200,
300, and 400 mg twice-daily in healthy subjects [poster #A-952]. 48th
Annual ICAAC/IDSA Meeting 2008, Washington, DC.
7. Reyataz US Prescribing Information, April 2009.
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