- InfezMed

Le Infezioni in Medicina, n. 4, 367-369, 2015
Caso clinico / Case report
367
A probable drug-to-drug interaction
between voriconazole and haloperidol
in a slow metabolizer of CYP2C19
Caso clinico di una probabile interazione farmacologica tra voriconazolo
e aloperidolo in un metabolizzatore lento del CYP2C19
Ilaria Motta, Andrea Calcagno, Lorena Baietto, Antonio D’Avolio,
Francesco Giuseppe De Rosa, Stefano Bonora
Unit of Infectious Diseases, Department of Medical Sciences, University of Torino, Torino, Italy
nINTRODUCTION
V
oriconazole (VOR) pharmacokinetics is characterized by a high interpatient variability
and a relatively narrow therapeutic index between 1000 ng/mL and 5500 ng/mL, thus supporting the use of therapeutic drug monitoring
[1-3]. VOR is metabolized in the liver through cytochrome P450 isoenzyme 2C19 (CYP2C19) and to
a lesser extent by CYP2C9 and CYP3A4 [4]. Several drug-to-drug interactions (DDIs) have been reported and they may vary according to CYP2C19
genotype. CYP2C19*2 loss of function allele indicates a poor metabolizing cytochrome leading
to voriconazole higher exposure and potentially
to drug-to drug interactions through CYP3A4 or
CYP2C9 isoenzymes; this might increase the risk
of drug-related adverse events [6, 7].
n CASE REPORT
We here report the case of a HIV-positive 43-yearold male patient born in Sub-Saharan Africa with
several opportunistic infections (neurotoxoplasmosis, disseminated Kaposi’s sarcoma) that developed an Aspergillus fumigatus renal abscess five
Corresponding author
Ilaria Motta
E-mail: [email protected]
months after receiving six cycles of vinblastine
and etoposide. He was admitted while receiving
tenofovir/emtricitabine, raltegravir, atovaquone
and azithromycin (as secondary prophylaxis for
neurotoxoplasmosis), pantoprazole, tramadol
and pregabalin (for peripheral neuropathy). Intravenous weight-based VOR was started (450
mg on the first day followed by 300 mg twice-daily, patient’s weight was 75 kg). At day 8 (D8)
oral haloperidol (1 mg three times/day) and oral
delorazepam (1 mg/day) were prescribed for
recurrent auditory hallucinations; at D13 VOR
was orally administered and reduced to 250 mg
twice-daily. Figure 1 represents the time course of
liver function tests (LFTs, namely AST and ALT),
VOR dose and trough concentrations measured
with validated methods: after haloperidol introduction VOR trough levels increased steeply
(from 3931 ng/mL at D6 to 11063 ng/mL at D18)
as well as liver function tests despite its dose-reduction (250 mg twice-daily) [8].
Reducing VOR dose to 250 mg (D13) and 200
mg twice-daily (D20) a further slight increase in
exposure (12055 ng/mL at D21) was observed
as well as AST and ALT elevation (205/172 UI/
mL and 84/75 UI/mL, respectively). Given the
persistence of hepatotoxicity and high plasma
concentrations, VOR was reduced to 100 mg
twice-daily at D21 and haloperidol withdrawn
(and replaced with paliperidone and promazine).
Six days later (D25) VOR Ctrough was 2188 ng/mL
but it was stopped due to the persistence of mild
368 I. Motta, et al.
Figure 1 - Time course of voriconazole administration, dose, plasma exposure, haloperidol administration and
liver function test (HALOP, Haloperidol, VOR, Voriconazole; AST, Aspartate aminotransferase; ALT Alanine aminotransferase. VOR dose is depicted by the height of the circles (on the right axis in mg and twice daily).
liver impairment [102 UI/mL (AST) and 52 UI/
mL (ALT)]; intravenous liposomal amphotericin
B (3 mg/kg) was started and patient’s symptoms
and LFTs slowly normalized. CYP2C19 genotype was investigated: he was carrying the AA
loss of function allele in CYP2C19 encoding gene
(CYP2C19*2, rs4244285).
nDISCUSSION
This case describes a clinically significant DDI in
a patient receiving VOR and several other drugs;
HIV-positive subjects have high risk of DDIs since
they often receive multiple medications for several comorbidities [9]. Surprisingly when VOR was
orally administered its exposure increased approximately three times and he developed grade
3 hepatotoxicity. When revising this patient multiple medications, haloperidol was found to be a
weak inhibitor of CYP2D6 and CYP3A4, pantoprazole a weak inhibitor of CYP2C19/1A2, tramadol inhibitor of CYP2D6, atovaquone a weak
inhibitor of CYP3A4 and tenofovir disoproxil fumarate inhibits OAT1 whereas raltegravir has not
major DDIs [10, 11]. After the loading dose VOR
reaches its steady state at D3; at D6 our patient
presented VOR Ctrough 3931 ng/mL thus possibly
suggesting that the increase of concentration ob-
served at D18 (Ctrough 11063 ng/mL) was associated with haloperidol introduction at D8 [12]. The
time course of VOR exposure, LFTs elevation and
patient’s CYP2C19 genotype (poor metabolizer
status) support this hypothesis; the Drug Interaction Probability Scale define this as “probable”
with a total score of 5 considering the known interactive properties of VOR, the reasonable time
course, the high VOR plasma concentrations, the
symptoms and confirmed liver toxicity and that
no reasonable alternative causes are present [13,
14]. However haloperidol weak CYP3A4 inhibition, unknown patient’s CYP3A4 genotype and
the absence of VOR re-challenge may question
this association. Therapeutic drug monitoring and
CYP2C19 genotyping may be suggested when administering voriconazole to complex patients.
Declaration of interests
No funding was received for this work.
Authors report no conflict of interest. However
they declare that received funding, outside this
work, from drug companies as detailed below.
A.C., S.B. have received grants, travel grants, consultancy fees from Pfizer and ViiV. I.M., L.B. and
A.D. have nothing to declare.
Keywords: voriconazole, haloperidol, pharmacokinetics, CYP2C19, CYP3A4, pharmacogenetics.
A probable drug-to-drug interaction between voriconazole and haloperidol in a slow metabolizer of CYP2C19 369
SummaRY
We present a case of Aspergillus fumigatus renal abscess
treated with voriconazole of a HIV-positive 43-year-old
male patient. Following haloperidol treatment we observed an unexpected increase in voriconazole through
concentrations and liver function tests. CYP2C19*2
loss of function allele was stated, an interaction probably explained by the introduction of haloperidol, a
weak CYP3A4 inhibitor. Therapeutic drug monitoring
and CYP2C19 genotyping may be suggested when administering voriconazole to complex patients.
RIASSUNTO
Viene discusso un caso di ascesso renale da Aspergillus
fumigatus; dopo l’introduzione di aloperidolo si è osservato un inaspettato aumento delle concentrazioni di valle di
voriconazolo e degli enzimi di citolisi epatica. Il paziente è
risultato portatore della variante genetica CYP2C19*2 e la
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