567
Effects of Minocycline and Valproic Acid Co-administration on Atazanavir Plasma Concentrations
Robert DiCenzo*1,2, Robert DiCenzo*1,2, D Peterson1, and G Schifitto1
1Univ of Rochester, NY, US and 2Univ of Buffalo, NY, US
Background: There is interest in studying the effects of
both valproic acid (VA) and minocycline
(MC) as adjunctive therapy for the treatment of HIV-associated cognitive
impairment. The purpose of the study was to determine whether MC alone or in
combination with VA influenced atazanavir (ATV)
plasma concentrations in patients receiving ATV plus ritonavir (ATV/r).
Methods: We enrolled 12 adult HIV-infected subjects whose
regimen included ATV/r 300/100 mg daily for at least 4 weeks. Each subject
received ATV/r on day 1, ATV/r + MC 100 mg twice daily on days 2 to 15, and ATV/r
+ VA 250 mg and MC 100 mg twice daily on days 16 to 30 with meals. Study drugs were
administered with a standardized breakfast and subjects had 11 plasma samples
drawn over a 24-hour dosing interval at steady state on days 1, 15, and 30. Standard
noncompartmental pharmacokinetic methods were used. Log transforms of pharmacokinetic
parameters were used to compare ATV with and without study drug administration.
Results: MC and VA coadministration was well tolerated
in all 12 subjects (6 male, mean (SD) age, 43.1 (8.2) years). MC co-administration
resulted in a 33% decrease in ATV area under the concentration-time curve at
steady state (AUC24h) (p =
0.014), a 50% decrease in the concentration at the end of the dosing interval (Cmin)
(p = 0.022), and a 25% decrease in maximum
concentration (Cmax) (p = 0.024). The geometric mean ratio (GMR; 95%CI) for ATV AUC24h,
Cmin and Cmax with and
without MC was 0.67 (0.50 to 0.90), 0.50 (0.28 to 0.89) and 0.75
(0.58 to 0.95), respectively. Similar decreases in ATV exposure were seen after
the addition of VA. The GMR (95% CI) for ATV AUC24h, Cmin
and Cmax with and without MC + VA was 0.68
(0.43 to 1.06), 0.50 (0.24 to 1.06) and 0.66 (0.41 to 1.06), respectively. GMR (95%CI) for ATV AUC24h, Cmin and Cmax when comparing ATV/r + MC to ATV/r + MC and
VA was 1.00 (0.57 to 1.77), 1.01 (0.37 to 2.8) and 0.89 (0.53 to 1.48),
respectively.
Conclusions: MC co-administration resulted in decreased ATV
exposure, and there was no evidence that the addition of VA mediated this
affect.
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