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The Effect of Atazanavir and Atazanavir/Ritonavir on UGT1A4 Using Lamotrigine as a Phenotypic Probe
David Burger*1,2, David Burger*1,2, A Huisman1,2, A Huisman1,2, N van Ewijk1,2, N van Ewijk1,2, H Neisingh1, G Rongen1, P Koopmans1,2, P Koopmans1,2, and R Bertz3
1Radboud Univ Med Ctr, Nijmegen, The Netherlands; 2Nijmegen Univ Ctr for Infectious Diseases, The Netherlands; and 3Bristol-Myers Squibb, Princeton, NJ, US
Background: ART agents are well-known for their effects on
cytochrome P450 enzymes leading to various drug–drug interactions. Some agents
also influence other metabolizing enzymes such as UDP-glucuronosyl-transferases
(UGT). We have recently shown that lopinavir/ritonavir induces glucuronidation
using lamotrigine (LTG) as phenotypic probe for UGT1A4 (reduction in AUC of
55%). Atazanavir (ATV) is known to inhibit glucuronidation through UGT1A1,
leading to asymptomatic hyperbilirubinemia. The objective of this study was to
evaluate the effect of ATV and atazanavir/ritonavir (ATV/r) on UGT1A4 using LTG
as phenotypic probe.
Methods: We administered to 21 healthy male volunteers
a single 100-mg dose of LTG on 3 occasions (days 1, 13, and 27); on each
occasion blood was sampled predose and through 120 hours post ingestion (13
samples). From day 8 to 17 subjects took ATV 400 mg once daily. From day 18 to 30
subjects took ATV 300 mg + ritonavir 100 mg once daily. Pharmacokinetic
parameters were calculated using WinNonlin software version 4.1. Geometric mean
ratios (GMR) and 90% confidence interval (CI) of LTG AUC and Cmax in
the 2 test periods (ATV or ATV/rtv) vs in the reference period (LTG alone) were
calculated. The absence of an interaction corresponds to the 90%CI of the GMR
falling completely within 0.80 to 1.25.
Results: Of the total, 17 subjects completed the trial; 4
were withdrawn from the study (protocol violation 1; personal reasons 1;
nonadherence 1; rash and neurological symptoms 1). GMR (+90%CI) of LTG AUC0-inf
and Cmax when taken with ATV vs LTG alone were 0.88 (0.86 to 0.91)
and 0.99 (0.95 to 1.02), respectively, indicating no relevant interaction between
ATV and LTG occurred. GMR (+90%CI) of LTG AUC0-inf and Cmax
when taken with ATV/r vs LTG alone were 0.68 (0.65 tot 0.70) and 0.94 (0.90 to 0.97),
indicating an interaction between ATV/r and LTG was observed. In agreement with
these observation, the mean (+SD) ratio of LTG-2N-glucuronide and LTG AUC0-inf
increased from 0.45 (0.09) when LTG was taken alone to 0.52 (0.13) when
LTG was taken with ATV, and to 0.71 (0.11) when LTG was taken with ATV/r (both p <0.001; paired-samples t-test). ATV and RTV plasma
concentrations were comparable to historical controls.
Conclusions: ATV alone does not significantly influence
glucuronidation of single-dose LTG. In contrast, ATV/r resulted in moderately
decreased exposure (32% decrease in AUC0-inf) to LTG.
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