The Body Covers: The 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy
Pharmacokinetic Interactions of 908
September 16, 2003
All the pieces are falling into place before the expected FDA approval of GW433908, better known as "908," later this year. There were several presentations at this ICAAC clarifying several issues regarding the pharmacokinetic (PK) parameters and interactions of 908 with other compounds.Reference Abstract: Comparison of GW433908 (908) Single and Steady State Pharmacokinetics (PK): Induction Potential and AAG Changes (APV10013) (Poster A-1607)
In another presentation I also covered at ICAAC (see Abstract H-855A), I summarized the PK interactions between 908 and lopinavir/ritonavir (LPV/r, Kaletra), essentially concluding that combining these two drugs together is not a good idea due to the low drug exposure observed in that study.
Two other posters presented today also described the PK interactions of 908 when co-administered with antacids (Maalox), ranitidine (Zantac) (see Abstract A-1606) and atorvastatin (Liptor) (see Abstract A-1622) in healthy volunteers. The first of these studies concluded that the co-administration of antacids or ranitidine with 908 has a moderate decrease in the area under the curve (AUC) that is unlikely to result in any clinical relevance. In the second poster, atorvastatin was found not to have a clinically significant effect on the amprenavir (APV, Agenerase) PK, but the co-administration of 908, with or without ritonavir (RTV or r, Norvir), significantly increased the atorvastatin exposure. Therefore, the author concluded that when 908 and atorvastatin are co-administered, the atorvastatin dose should be less than or equal to 20 mg/day.
Previous studies have documented a time-variant plasma amprenavir PK, meaning that a reduction in amprenavir AUC values was observed after the amprenavir concentration reached steady state. For this reason, investigators from GlaxoSmithKline aimed at determining the time-variance in plasma amprenavir PK and correlating these values with 6-beta-hydroxycortisol and cortisol measurements. A 6-beta-hydroxycortisol/cortisol ratio above one will indicate the presence of CYP3A4 induction.
This study was designed as part of another study looking for the PK interactions between amprenavir and atorvastatin in healthy volunteers (see above). In order to gain a better understanding of the mechanism resulting in time-variant plasma amprenavir PK, patients underwent AUC measurements after they received a single dose of 908, and after reaching plasma steady state.
The investigator found a small reduction (less than 13 percent) in plasma amprenavir AUC over 14 days (after steady state), and no evidence of induction of the CYP3A4, as documented by a 14 percent decrease in the 24-hour urinary 6-beta-hydroxycortisol/cortisol ratio.
So this study once again confirms a time-variant plasma amprenavir PK after concentrations reached steady state. A possible explanation postulated by the author is the reduction in plasma alpha-1-acid glycoprotein, an enzyme that is needed for amprenavir binding during absorption. It is known that this enzyme is reduced in HIV patients after initiation of antiretroviral therapy. What was not clear to me is that the patients who participated in this PK study were all healthy volunteers, and so they should not have had alterations in the alpha-1-acid glycoside at baseline.
It is difficult to come up with any significant and practical applications for the data that was collected and the conclusions reached in this study. This information is just a reminder of the high degree of variability in plasma concentrations, the high inter-patient variability and the multiple factors playing a role in the PK behavior of the drugs that we give our patients.
Read the poster of the abstract covered in this article.
Authored by: M. B. Wire, K. L. Baker, Y. Lou, S. Weller, D. S. Stein
Affiliations: GlaxoSmithKline, Research Triangle Park, NC
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