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Further Information on the Administration of H2-Receptor Antagonists With Atazanavir
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[Letters to the Editor]
JAIDS Journal of Acquired Immune Deficiency Syndromes: Volume 42(4) 1 August 2006 p 516
Agarwala, Sangeeta PhD*; Thal, Gary MD ; Nettles, Richard MD*; Bertz, Richard PhD*
*Bristol-Myers Squibb Co, Princeton, NJ and Bristol-Myers Squibb Co, Plainsboro, NJ sangeeta.agarwala@bms.com
To the Editor:
Further data on the use of atazanavir (ATV) with H2-receptor antagonists and proton pump inhibitors (PPIs) have become available since the letter published by Drs. Homayoun Khanlou and Charles Farthing.1 Previously, ATV and PPI interaction studies demonstrated that ATV exposures were reduced by more than 70%, leading to a recommendation that PPIs should not be used concomitantly with ATV.2,3 Studies to evaluate other dosing strategies with ATV and PPIs are planned. More recently, data have become available on the interaction between ATV and H2-receptor antagonists, indicating that reduced exposures to ATV resulting from an interaction with H2-receptor antagonists may be attenuated by concurrent use of low-dose ritonavir (RTV) or by temporal separation from an H2-receptor antagonist.4
In 2 drug interaction studies of 108 HIV-negative subjects, the effect of the commonly used H2-receptor antagonist famotidine at 40 mg twice daily on ATV at 400 mg and ATV/RTV at 300/100 mg was evaluated.4 Relative to a control arm of ATV at 400 mg alone, coadministration of famotidine at 40 mg twice daily decreased ATV exposures by approximately 40%. Temporal separation (dosing ATV 10 hours after and 2 hours before the famotidine dose) attenuated the reduction in ATV exposures. Furthermore, ATV at 300 mg coadministered with RTV at 100 mg led to a 79% and 4.5-fold increase in area under the curve and Cmin, respectively, with Cmax values similar to ATV at 400 mg alone.
Relative to a control arm of ATV/RTV at 300/100 mg alone, coadministration with famotidine at 40 mg twice daily modestly reduced ATV exposures by 18%, 14%, and 28% for area under the curve, Cmax, and Cmin, respectively. These exposures were similar to an antiretroviral regimen of ATV/RTV with 2 nucleosides including tenofovir, the efficacy of which has been established in a well-controlled study in HIV-infected subjects relative to a standard of care regimen.5 Thus, ATV/RTV at 300/100 mg may be given concomitantly in combination with H2-receptor antagonists. Atazanavir/RTV at 300/100 mg is recommended with H2-receptor antagonists, although the reductions in ATV exposures with maximal doses of famotidine could be overcome by increasing the dose of ATV to 400 mg while keeping the dose of RTV steady at 100 mg. Atazanavir/RTV at 400/100 mg is not recommended because there is a potential for increased risk of ATV intolerability, resulting from increased ATV exposures that could occur with less potent, lower doses, or sporadic dosing of H2-receptor antagonists in combination with higher doses of ATV. To further minimize any reduction in ATV exposures, an alternative to simultaneous dosing of H2-receptor antagonists with ATV/RTV at 300/100 mg is temporal separation, which may be attained by administering ATV/RTV at 300/100 mg at least 10 hours after and at least 2 hours before an H2-receptor antagonist; temporal separation should be considered in treatment-experienced patients.
In summary, although H2-receptor antagonists increase intragastric pH and have been shown to reduce ATV absorption, H2-receptor antagonists are less potent than PPIs in suppressing intragastric acid secretion and may be used with ATV. Atazanavir/RTV at 300/100 mg may be administered concomitantly with H2-receptor antagonists. Alternatively, ATV at 400 mg or ATV/RTV at 300/100 mg may be temporally separated by administering ATV at least 10 hours after and at least 2 hours before an H2-receptor antagonist to minimize the interaction; temporal separation of ATV/RTV at 300/100 mg should be considered in treatment-experienced patients. Local prescribing information may vary; therefore, clinicians using ATV with H2-receptor antagonists should consult their local package inserts for specific information. Additional studies to evaluate alternative dosing strategies with ATV and H2-receptor antagonists are ongoing.
Sangeeta Agarwala, PhD*
Gary Thal, MD
Richard Nettles, MD*
Richard Bertz, PhD*
*Bristol-Myers Squibb Co,
Princeton, NJ
and Bristol-Myers Squibb Co,
Plainsboro, NJ
REFERENCES
1. Khanlou H, Farthing C. Co-Administration of atazanavir with proton-pump inhibitors and H2 blockers. J Acquir Immune Defic Syndr. 2005;39:503.
2. Agarwala S, Gray K, Eley T, et al. Pharmacokinetic interaction between atazanavir and omeprazole in healthy subjects. Presented at: 3rd IAS Conference on HIV Pathogenesis and Treatment; July 24-27, 2005; Rio de Janeiro, Brazil. Abstract WePe3-3C08. Available at: http://ww2.aegis.org/conferences/iashivpt/2005/WePe3-3C08.html . Accessed February 24, 1006.
3. Agarwala S, Gray K, Wang Y, et al. Pharmacokinetic effect of omeprazole on atazanavir co-administered with ritonavir in healthy subjects. Presented at: 12th Conference on Retroviruses and Opportunistic Infections; February 22-25, 2005; Boston, MA. Abstract 658. Available at: http://www.retroconference.org/2005/CD/Abstracts/24122.htm . Accessed February 24, 2006.
4. Agarwala S, Eley T, Child M, et al. Pharmacokinetic effect of famotidine on atazanavir with and without ritonavir in healthy subjects. Presented at: 6th International Workshop on Clinical Pharmacology of HIV Therapy; April 28-30, 2005; Quebec City, Quebec, Canada. Abstract 11.
5. Johnson M, Grinsztejn B, Rodriguez C, et al. Atazanavir plus ritonavir or saquinavir, and lopinavir/ritonavir in patients experiencing multiple virological failures. AIDS. 2005;19:685-694.
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