MAJOR ARTICLE

A Potentially Significant Interaction

between Efavirenz and Phenytoin:
A Case Report and Review of the Literature

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Sarah M. Robertson,1 Scott R. Penzak,1 Jason Lane,2 Alice K. Pau,2 and JoAnn M. Mican2
1
Clinical Pharmacokinetics Research Laboratory, Clinical Center Pharmacy Department, and 2Office of Clinical Research,
National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland

Although it has not been demonstrated yet, phenytoin is expected to reduce efavirenz exposure through
coinduction of cytochrome P450 (CYP) 3A4 and CYP2B6. Conversely, efavirenz has been shown in vitro to
inhibit the enzymes responsible for phenytoin metabolism, CYP2C9 and CYP2C19. We report a case in which
a potential bidirectional drug interaction between phenytoin and efavirenz resulted in lower-than-expected
efavirenz concentrations and elevated phenytoin levels. Therapeutic drug monitoring was used in this case to
ensure adequate efavirenz exposure.

Antiretrovirals are widely known for their pharmaco-
kinetic drug interactions. Most of the attention has been
focused on the role of cytochrome P450 (CYP) iso-
enzyme modulation in interactions involving protease
inhibitors and nonnucleoside reverse-transcriptase in-
hibitors (NNRTIs). Like protease inhibitors, NNRTIs
are metabolized by CYP3A4. However, their effects on
the isoenzyme differ—delavirdine is a potent inhibitor,
nevirapine is a potent inducer, and efavirenz (EFV) is
a mixed inhibitor and inducer of CYP3A4. As a mixed
inducer and inhibitor, the effect of EFV on coadmin-
istered CYP3A4 substrates is unpredictable. In addition
to its modulation of CYP3A4, EFV has been shown to
inhibit CYP2C9 and CYP2C19 in vitro [1, 2]. EFV is
metabolized principally by CYP2B6 and, to a lesser de-
gree, by CYP3A4 [1, 3]. Concurrent use of medications
that alter these metabolic pathways may affect EFV
exposure.
As an inducer of CYP3A4, phenytoin may cause sig-
nificant reductions in protease inhibitor and NNRTI
Received 21 January 2005; accepted 3 March 2005; electronically published 7
June 2005.
Reprints or correspondence: Dr. Sarah M. Robertson, NIH Clinical Center,
Pharmacy Dept., Bldg. 10, Rm. 1 N 257, Bethesda, MD 20892 (robertsonsa
@cc.nih.gov).
Clinical Infectious Diseases 2005; 41:e15–8
This article is in the public domain, and no copyright is claimed.
1058-4838/2005/4102-00E1
concentrations during coadministration. Results from
a pharmacokinetic study conducted in healthy volun-
teers who received lopinavir in combination with ri-
tonavir revealed a 2-way interaction in which the area
under the concentration-time curves (AUCs) for both
phenytoin and lopinavir were decreased by ∼30% [4].
Although it has not been demonstrated yet, phenytoin
is expected to reduce EFV concentrations as well.
We report a case in which a potential drug interaction
resulted in lower-than-expected EFV concentrations af-
ter initiation of an antiretroviral treatment regimen in
a patient who was receiving phenytoin. Therapeutic
drug monitoring was used in this case to ensure ade-
quate EFV exposure.
CASE REPORT
In July 2004, a 39-year-old Ethiopian man was admitted
to a hospital (not ours) with new-onset seizures. The
medical evaluation included MRI, the findings of which
showed multiple contrast-enhancing lesions in the cer-
ebrum and cerebellum. The patient was also found to
have serum anti-toxoplasma IgG antibodies and a CD4
cell count of 49 cells/mm3 (CD4 cell percentage, 5.5%).
A presumed diagnosis of toxoplasmic encephalitis was
made, and therapy with pyrimethamine and sufadiazine
was started. Prophylaxis with trimethoprim-sulfameth-
oxazole and azithromycin was initiated presumptively
for prevention of Pneumocystis jiroveci pneumonia and

Efavirenz and Phenytoin Drug Interaction • CID 2005:41 (15 July) • e15
Mycobacterium avium complex, respectively. Phenytoin therapy
was initiated and ultimately reached the therapeutic range (10–
20 mg/dL) at a dosage of 300 mg twice daily. The patient was
discharged from the hospital with the above medications.
On 14 September 2004, the patient was evaluated at a local
outpatient clinic. He reported completion of the prescribed
course of medications several weeks prior and was not currently
taking any medications. He complained of a 2-week history of
blurred vision in his right eye. An ophthalmologist diagnosed
cytomegalovirus (CMV) retinitis and referred the patient to
our institution for further treatment.
On 16 September, the patient was admitted to our institution.
At the time of admission, the results of an HIV ELISA and a
Western blot were positive, and the patient had a plasma HIV
RNA load of 1,816,200 copies/mL and a CD4 cell count of 14
cells/mm3 (CD4 cell percentage, 3%). Diagnoses included ad-
vanced HIV infection, CMV retinitis, and probable toxoplasmic
encephalitis. Sulfadiazine (1 g every 6 h) and pyrimethamine
(75 mg daily) were started again for treatment of toxoplasmic
encephalitis, in addition to leucovorin (25 mg twice daily).
Phenytoin was resumed at a dosage of 300 mg daily. The patient
initially received intravenous ganciclovir (5 mg/kg twice daily)
followed by oral valganciclovir (900 mg twice daily) for treat-
ment of CMV retinitis. Azithromycin therapy (1200 mg once
weekly) was also initiated. The patient experienced a witnessed
tonic-clonic seizure on 17 September and was given a loading
dose of 1000 mg of intravenous fosphenytoin. Oral phenytoin
was increased to 300 mg twice daily on 19 September. Anti-
retroviral therapy with EFV (600 mg daily at bedtime), emtri-
citabine (200 mg daily), and tenofovir (300 mg daily) was
started on 22 September. A plan was made to monitor both
phenytoin and EFV plasma concentrations to ensure adequate
safety and therapeutic efficacy.
On 30 September, while the patient was still hospitalized, the
first sample for measurement of EFV level was obtained 12 h
after dosing, and the test result, returned 10 days later, was an
EFV concentration of 0.34 mg/mL. Although it was recognized
that the sample may have been obtained prior to a steady state,
there was concern that phenytoin was inducing the metabolism
of EFV, resulting in the lower-than-expected concentration (12-
h concentration, !1 mg/mL). Despite an early virologic response
(the HIV RNA load decreased to 30,863 copies/mL after 13
days of antiretroviral therapy), it was thought that persistent
inadequate EFV exposure might put the patient at risk for
treatment failure. After consultation with the neurology service,
the decision was made to rapidly taper the phenytoin dosage
and to commence therapy with levetiracetam—an anticonvul-
sant without CYP modulation potential. The EFV dosage was
increased to 800 mg/day under the assumption that CYP in-
duction would continue for 7–14 days after discontinuation of
phenytoin therapy.
e16 • CID 2005:41 (15 July) • Robertson et al.
Prior to implementation of the EFV dosage increase on 12
October, an additional sample was obtained 12-h after dosing,
and the test result was an EFV concentration of 0.58 mg/mL.
The patient received his last dose of phenytoin on 22 October,
after a rapid titration of levetiracetam to 1000 mg twice daily.
Obtainment of a sample for a third measurement of EFV level
was planned for 9 November, after what was predicted to be
sufficient time for reversal of phenytoin’s enzyme induction.
The result for the 9 November sample returned 2 weeks later
and was an EFV concentration of 2.5 mg/mL. At that time, it
was decided that the EFV dosage could be safely reduced to
600 mg/day. On 16 November, the patient had an HIV RNA
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level of 189 copies/mL and a CD4 cell count of 100 cells/mm3
(CD4 cell percentage, 12%), which indicated continued viro-
logic response to antiretroviral therapy. The patient’s latest mea-
sured EFV level, after 3 weeks at a dosage of 600 mg/day, was
1.96 mg/mL.
Phenytoin levels measured after EFV therapy initiation
showed a gradual increase, despite a stable phenytoin dosage
and no additional changes in medications. After a steady state
was achieved, phenytoin plasma concentrations continued to
increase after 24 September, gradually increasing to 17 mg/L
(on 28 September), 16.7 mg/L (on 29 September), and 23.5
mg/L (on 12 October) (table 1).
DISCUSSION
EFV exhibits linear pharmacokinetics, with concentrations in-
creasing in proportion to increases in dose [1]. It has a long
plasma half-life that ranges from 40 to 55 h at steady state [1].
Since EFV is typically taken at bedtime, blood sampling is usu-
ally performed 10–16 h after dosing. Because of its long elim-
ination half-life, EFV levels measured around the mid-interval
are minimally influenced by sampling time, which contributes
only 3% to total concentration variance [5]. Variability in EFV
concentrations is largely due to its high interpatient variability
(coefficient of variation [CV], 118%) [5]. In contrast, its in-
trapatient variability is significantly lower (CV, 30%) [5]. EFV
14-h plasma concentrations range from 0.13 to 15.2 mg/mL
(median, 2.19 mg/mL) [5].
Data have demonstrated a potential relationship between
EFV exposure and virologic response, although there is dis-
agreement in the literature regarding the relationship between
EFV concentrations and CNS toxicity [5–9]. Results from a
study of the association between 14-h EFV levels with viral
suppression and CNS toxicity suggest a potential target con-
centration range of 1–4 mg/mL [5]. Similarly, results from a
retrospective analysis indicate a significant relationship between
treatment failure and minimum plasma concentrations of !1.1
mg/mL [6]. Another group of investigators has proposed a
higher target concentration of 2.2 mg/mL on the basis of their
 Table 1. Results of drug monitoring for a patient who received efavirenz and phenytoin.

Efavirenz Efavirenz Phenytoin Phenytoin Albumin

a
Date in 2004 dosage level, mg/mL dosagea level, mg/Lb level, g/dLc
16 Sep … … 300 mg q.d. 4.1 3.6
17 Sep … … 300 mg po q.d.d … …
19 Sep … … F 300 mg b.i.d. 11 …
22 Sep 600 mg q.d. … 300 mg b.i.d. 11.5 3.6
23 Sep 600 mg q.d. … 300 mg b.i.d. 13.7 3.5
24 Sep 600 mg q.d. … 300 mg b.i.d. 14.2 3.6
28 Sep 600 mg q.d. … 300 mg b.i.d. 17 3.6
29 Sep 600 mg q.d. … 300 mg b.i.d. 16.7 …
30 Sep 600 mg q.d. 0.34 300 mg b.i.d. … …
F 800 mg q.d.

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12 Oct 0.58 300 mg b.i.d. 23.5 …
22 Oct 800 mg q.d. … …e … …
9 Nov 800 mg q.d. 2.5 … … …
23 Nov f 600 mg q.d. … … … …
14 Dec 600 mg q.d. 1.96 … … …
a
The up arrows indicate increases in dosages; the down arrow indicates a decrease in dosage.
b
Therapeutic range for phenytoin level, 10–20 mg/L.
c
Normal range for albumin level, 3.7–4.7 g/dL.
d
Plus fosphenytoin iv.
e
Therapy discontinued.

finding that patients with 10- to 24-h postdose EFV levels above
this limit had at least an 80% response rate [9].
As mentioned above, EFV is extensively metabolized by
CYP2B6 and CYP3A4. Drugs that significantly inhibit or induce
either of these enzymes are expected to alter EFV concentra-
tions. Voriconazole, for instance, has been shown to increase
EFV levels by 44% as a result of CYP3A4 inhibition [1]. Con-
versely, concurrent administration of rifampin, a potent inducer
of CYP3A4 and CYP2B6 was found to reduce the AUC of EFV
by 26% [1].
Induction of CYP3A4 by phenytoin is not as strong as in-
duction by rifampin, as demonstrated in vitro. Recent evidence,
however, suggests that CYP2B6 induction may play a contrib-
utory role in phenytoin interactions [10]. Several studies have
found a large degree of cross-regulation between CYP2B6 and
CYP3A4 expression, and increases in CYP2B6 activity have been
demonstrated with the use of several drugs that are known
inducers of CYP3A4 [11–13]. A recent investigation using hu-
man hepatocyte cultures characterized phenytoin as a strong
inducer of CYP2B6 expression, along with rifampin, clotri-
mazole, and phenobarbital [13]. Although it has not been re-
ported yet in vivo, coinduction of CYP2B6 and CYP3A4 is
expected to result in a reduction in EFV exposure during con-
current use of phenytoin.
Evaluation of drug interactions and studies of individual
cases must be done with an awareness of the potential contri-
bution of pharmacogenetics. Patients homozygous for the
CYP2B6 T/T genotype at position 516 have greater EFV ex-
posure and an increased incidence of CNS symptoms during
their first week of therapy, compared with those of individuals
with the G/G or G/T genotype [14, 15]. Likewise, the allelic
variants CYP2C9*2 and CYP2C9*3 are associated with phen-
ytoin toxicity and lower dosage requirements [16]. The CYP2B6
T/T genotype is more common among African Americans
(prevalence, 20%) than among whites (prevalence, 3%) [14].
In contrast, the CYP2C9*2 and CYP2C9*3 variants are more
common among white populations (prevalence, 8%–19% and
3.3%–16%, respectively) than among African American or
Ethiopian populations (prevalence, 3.2% and 1.3%, respec-
tively) [17]. At this time, it is not entirely clear the extent to
which pharmacogenetics contribute to cases of significant drug
interactions. In this case, however, it is likely that the patient
had neither CYP2B6 nor CYP2C9 polymorphisms, as evidenced
by his dosages and plasma concentrations of phenytoin and
EFV.
The increase in phenytoin plasma concentrations in this case
was possibly the result of inhibition of CYP2C9 and CYP2C19
by EFV. With a half-life of ∼22 h, phenytoin levels measured
after 24 September likely reflect steady-state conditions (⭓5
days after the bolus and dose increase) [18]. As discussed pre-
viously, in vitro studies have shown that EFV inhibits CYP2C9
and CYP2C19 isoenzymes, with Ki values in the range of ob-
served EFV plasma concentrations (2.7–5.4 mg/mL) [1]. Inter-
pretation of this interaction may be complicated by the con-
current use of sulfadiazine, which has been shown elsewhere
to decrease phenytoin clearance by 45%, prolonging its half-
life by 80% [19]. However, because sulfadiazine therapy was
initiated on 16 September and remained unaltered throughout
the duration of events, it is unlikely that it was responsible for

Efavirenz and Phenytoin Drug Interaction • CID 2005:41 (15 July) • e17
the increase in phenytoin levels that occurred after 24
September.
Further data on potential EFV target concentrations are
needed before therapeutic drug monitoring of EFV becomes
standard practice. Nevertheless, EFV concentration monitoring
may be helpful in situations in which potential drug interac-
tions, drug toxicity, or the patient’s clinical condition warrants
its use. Although a full pharmacokinetic study is needed to
confirm or disprove the hypothesis generated by this case re-
port, the events outlined above suggest the potential for a clin-
ically significant 2-way interaction between EFV and phenytoin.
Until more data become available, both phenytoin and EFV
levels should be monitored closely when the drugs are given
concurrently, to avoid potential toxicity or treatment failure.
Acknowledgments
We thank Chad W. Koratich for his care of the patient.
Potential conflicts of interest. All authors: no conflicts.
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