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Two-way
Interaction Seen Between Phenytoin and Lopinavir/Ritonavir
Use
of the anticonvulsant phenytoin in HIV patients may reduce concentrations
of the combination protease
inhibitor lopinavir/ritonavir/ LPV/RTV (Kaletra),
according to findings in healthy volunteers. Furthermore, LPT/RTV
seems to increase phenytoin clearance.
As
senior investigator Dr. Angela D. M. Kashuba told Reuters Health,
"This study demonstrates the vulnerability of protease
inhibitors to drug
interactions due to induction of drug metabolizing
enzyme activity, even in the presence of ritonavir (Norvir)."
In
the August issue of the Journal of Acquired Immune Deficiency
Syndromes, Dr. Kashuba and colleagues describe their study of
24 healthy subjects who were given various daily doses of LPV/RTV
400/100 mg with and without phenytoin 300 mg over the course of
22 days.
In
short, the researchers established that concomitant LPV/RTV and
phenytoin results in a two-way drug reaction. Phenytoin increases
lopinavir clearance via CYP3A4
induction, which is not offset by low-dose ritonavir.
As
well as being a CYP3A inducer, phenytoin is also a CYP2C9/CYP2C19
substrate. "This is the first study to demonstrate LPV/RTV's
effects on CYP2C activity," Dr. Kashuba continued. "We
have subsequently investigated this phenomenon more closely and
find that LPV/RTV does indeed induce CYP2C9 and CYP2C19 enzyme activity."
Hence, LPV/RTV may increase clearance of phenytoin via CYP2C induction.
These
data, she added, "may have dosing
implications for other compounds metabolized by these
enzymes--warfarin, omeprazole, etc."
Once
again, she concluded, "this study demonstrates the complexity
of drug interaction issues in HIV-infected patients. Close monitoring
of patients on combinations of medications not previously studied
is warranted."
09/22/04
J
Acquir Immune Defic Syndr 2004; 36:1034-1040.
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