Drug Interactions

Dosing Recommendations for Quetiapine The Journal of Clinical Pharmacology

2019, 59(4) 500–509
When Coadministered With HIV Protease 
C Published 2018. This article is a U.S.

Government work and is in the public

domain in the USA
Inhibitors DOI: 10.1002/jcph.1345

Mario R. Sampson, PharmD1 , Kelly Y. Cao, PharmD2 , Paula L. Gish, PharmD2 ,

Kyong Hyon, MA3 , Poonam Mishra, MD3 , William Tauber, MD3 , Ping Zhao, PhD1 ,
Esther H. Zhou, PhD2 , and Islam R. Younis, PhD1

Abstract
Although current quetiapine labeling recommends that its dosage should be lowered 6-fold when coadministered with strong cytochrome P450
(CYP)3A inhibitors, a reported case of coma in a patient receiving quetiapine with lopinavir and ritonavir prompted the reevaluation of labeling
recommendations for the dosing of quetiapine when coadministered with human immunodeficiency virus (HIV) protease inhibitors. Literature and
database (FDA Adverse Event Reporting System and United States Symphony Health Solutions’ Integrated Dataverse Database) searches allowed us
to identify cases of coma and related adverse events involving the coadministration of quetiapine and HIV protease inhibitors and to estimate the
frequency of concomitant use. Literature review and physiologically based pharmacokinetic modeling allowed us to estimate the potential for CYP3A
inhibition to contribute to adverse events related to HIV protease inhibitor–quetiapine coadministration. We identified excess sedation following
coadministration of quetiapine and an HIV protease inhibitor in 3 reports without obvious confounders. In prescription claims data, 0.4% of quetiapine
patients were dispensed a concurrent ritonavir prescription. The quetiapine dose was not reduced on ritonavir initiation in 90% of therapy episodes.
Available data indicate to us that all HIV protease inhibitors combined with ritonavir are likely to be strong CYP3A inhibitors. We predicted that
ritonavir would increase quetiapine exposure comparable to the strong CYP3A inhibitor ketoconazole. The current dosing recommendations for use
of quetiapine with strong CYP3A inhibitors (ie, 6-fold lower quetiapine dose) are appropriate and should be followed when quetiapine is coadministered
with HIV protease inhibitors.

Keywords
drug interactions, quetiapine, HIV protease inhibitors, coma, pharmacoepidemiology, US Food and Drug Administration

Quetiapine is indicated for the treatment of schizophre-
nia and bipolar disorder. The approved dose range
is 50-800 mg daily. Quetiapine is eliminated mainly
via cytochrome P-450 (CYP)3A-mediated metabolism.
CYP3A inhibitors increase the exposure of quetiapine,
potentially resulting in adverse events. One of the most
common adverse events reported in clinical trials of
quetiapine is somnolence.1
The index case involved a French policewoman who
became comatose 2 days after being prescribed the
HIV protease inhibitor combination lopinavir/ritonavir
200/50 mg following a needlestick injury. Before starting
lopinavir/ritonavir, she had been taking extended-
release quetiapine 150 mg daily. The temporal relation-
ship between the initiation of lopinavir/ritonavir and
coma suggested increased quetiapine exposure as the
cause of coma. However, lack of information on queti-
apine concentrations in the patient’s blood, pill counts
to rule out overdose, or use of concomitant medications
limit the assessment of causality. The patient’s outcome
was not reported.2
Before the index case, the European Medicines
Agency’s (EMA) summary of product characteristics
for quetiapine contraindicated the use of quetiapine
with protease inhibitors. Following the index case, in
2013 the EMA recommended that the contraindica-
tion for quetiapine use be added to the summary of
product characteristics for protease inhibitors.3 Before
the coma case, the United States quetiapine label-
ing recommended reducing the quetiapine dose 6-fold
when coadministered with strong CYP3A inhibitors
such as ritonavir; however, this recommendation was
1 Office of Clinical Pharmacology, Office of Translational Sciences, Center
for Drug Evaluation and Review, Food and Drug Administration, Silver
Spring, MD, USA
2 Office of Pharmacovigilance and Epidemiology, Office of Surveillance
and Epidemiology, Center for Drug Evaluation and Research, Food and
Drug Administration, Silver Spring, MD, USA
3 Division of Antiviral Products, Office of Antimicrobial Products, Office
of New Drugs, Center for Drug Evaluation and Research, Food and Drug
Administration, Silver Spring, MD, USA
Submitted for publication 5 July 2018; accepted 31 October 2018.
Corresponding Author:
Mario Sampson, PharmD, 10903 New Hampshire Ave, Silver Spring, MD
20993.
Email: mario.sampson@fda.hhs.gov
Sampson et al
not present in the United States protease inhibitors’
labeling. The recommendation for a 6-fold dose re-
duction was based on a drug interaction study in
which coadministration with ketoconazole resulted in
a quetiapine area under the curve (AUC) increase
of 6-fold.4 Following the index case and the EMA’s
request to revise the summary of product characteris-
tics for protease inhibitors, several protease inhibitor
manufacturers submitted labeling supplements to the
United States Food and Drug Administration (FDA)
to add clinical recommendations for coadministration
of protease inhibitors with quetiapine.
This article describes the regulatory considerations
and review approach utilized to reevaluate labeling
recommendations for concomitant use of quetiapine
with protease inhibitors. We evaluated the relationship
between quetiapine exposure and coma, quetiapine–
protease inhibitor interactions as a causal factor for
sedation or coma, the role of transporters in quetiap-
ine disposition, CYP3A inhibition magnitude across
protease inhibitors in comparison to ketoconazole, and
physiologically based pharmacokinetic (PBPK) predic-
tions of the effect of protease inhibitors on quetiapine
exposure.
Methods
Database and Literature Searches for Coma and Related
Cases
To identify the number of coma cases reported among
patients taking quetiapine with or without protease
inhibitors, we searched Pubmed in 2014 for cases of
coma among patients using quetiapine. Separately, we
searched Pubmed, Embase, and the FDA Adverse
Event Reporting System (12/06/1995-10/28/2014) for
cases in which patients were coadministered quetiapine
and protease inhibitors and experienced sedation, som-
nolence, respiratory depression, loss of consciousness,
or coma.
Data Source and Design for Concomitant Dispensing
Patterns
We used the Symphony Health Solutions’ anonymous
patient-level longitudinal claims database to estimate
concomitant use of quetiapine and ritonavir. We iden-
tified patients with a prescription claim for quetiapine
or ritonavir between March 2010 and July 2014. Riton-
avir was used as a surrogate for use of any protease
inhibitor because during this period most protease
inhibitors were used in combination with ritonavir,
and ritonavir was not used without protease inhibitors.
Treatment episodes were constructed using prescription
dispensing dates and number of days dispensed. Each
episode started on the date of the first dispensing and
ended with a treatment gap of >7 days or July 2014.
Concomitant dispensing was defined as an overlap of
501
1 day between an episode of quetiapine dispensing
and an episode of ritonavir dispensing.
We investigated whether the quetiapine dose was
changed before or during concomitant use with ri-
tonavir. Our analysis was restricted to patients with
2 quetiapine prescriptions during the concomitant
episode period. Dose was estimated based on the
strength, quantity, and days’ supply.
Literature Search for Drug Interaction Information
Prior evaluations of quetiapine and drug interactions
focused on CYP3A and did not consider transporters.
In 2014 we searched Pubmed, quetiapine United States
labeling, FDA clinical pharmacology reviews, and
Pharmapendium for studies of quetiapine as a substrate
for transporters.
To evaluate the degree of CYP3A inhibition across
the class of 9 approved HIV protease inhibitors and
relative to the prototype strong CYP3A inhibitor ke-
toconazole, we searched Pubmed and the University
of Washington Drug Interaction Database5 to identify
in vivo drug interaction studies of protease inhibitors
or ketoconazole and selected sensitive CYP3A sub-
strates, including maraviroc, midazolam, quetiapine,
and saquinavir.
Physiologically Based Pharmacokinetic Analysis
We conducted PBPK analyses using Simcyp (Sheffield,
UK) 13.2 to predict the effect of ritonavir alone or
ritonavir plus a strong CYP3A inhibitor on quetiapine
exposure. Built-in Simcyp compound files were used
for ketoconazole, midazolam, and saquinavir. Starting
with the built-in ritonavir compound file, we used
internal data for calibration to obtain parameters for
mechanism-based inhibition and induction of CYP3A4
(Table S1). The quetiapine compound file was created
from a published quetiapine PBPK model that included
first-order absorption and CYP3A4, CYP2C9, and
CYP2D6 fraction-metabolized values of 95%, 4%, and
1%, respectively. Simulated results of a ketoconazole-
quetiapine interaction study were consistent with ob-
served quetiapine maximum concentration and AUC
ratios (see PBPK analysis in the Results section),
supporting the use of a quetiapine CYP3A4 fraction
metabolized value of 95%.6 Our simulations were of 10
trials with 12 subjects per trial and utilized the minimal
PBPK model.
Results
Database and Literature Searches for Coma Cases
In Pubmed we identified 107 coma cases involving
quetiapine use; all involved an acute quetiapine over-
dose (Table 1).7–12 Other risk factors for excess se-
dation in these cases included use of sedating drugs
(benzodiazepines and opiates). Two of the 107 cases
502 The Journal of Clinical Pharmacology / Vol 59 No 4 2019

Table 1. Literature Reports of Overdose, Coma, and/or Excess Sedation in Patients Taking Quetiapine

Concomitant CYP3A
Inhibitor and/or Number of
QTP Dose and Respiratory Depressant Coma Cases Serum QTP
Case(s) and Reference Duration Medications Coma (Total = 107) Concentration

34-year-old woman r 36-g acute overdose r LPV/RTV 100/25 mg/d r Severe coma 1 NR
with a history of r Usual dose of r Lorazepam 2.5 mg/d r Unknown time between
schizophrenia, HIV, 600 mg XR/d r Addicted to heroin and ingestion and coma
HCV, and substance r Urinalysis positive other drugs (LSD, r Breathing recovered
abuse7 only for QTP cocaine, and crack) after 36 hours
r Patient’s mother r Same quantity of other
noted 120 fewer prescription
QTP tablets medications remaining
18 overdose cases Median 3.5 g, range NR In 6 cases where the 1 Median 2.59 mg/L, range
where QTP 0.5-24 g overdose was with QTP 0.22-20.48 mg/L
concentrations alone, 1 had a severe
were obtaineda8 coma, and 3 had delirium
19-year-old womanb8 Acute overdose NR r Severe coma at 1 20.48 mg/L 1.5 hours
presentation 1.5 hours after ingestion
after ingestion
r Discharged after
40 hours
34-year-old woman r Estimated 24-g r No substance abuse r Found unconscious 1 r 22 mg/L 2 hours after
with a history of acute overdose according to family 90 min before admission (3.5 hours
depression and r Empty bottle of r Only other drug in hospitalization after dose)
schizophrenia9 QTP found next to urine was cannabis r Severe coma within r 1 mg/L 42 hours after
patient (100 tabs of 2-4 hours after ingestion admission
300 mg) r Recovered within 2 days
945 QTP overdose r QTP amount r Reported coingestion r 96/945 (10%) QTP 96 NR
cases from a 5-year available for 22/945 cases were excluded overdose cases resulted
case series charts; range was r Other drugs in urine in coma
(2002-2006) in a 400 mg to 24 g toxicology screen were r Death in 3/945 cases
poison control r Intentional BZDs (56 cases) and
database10 overdose in 86% of opiates (38 cases)
cases
47-year-old woman r 8-g acute overdose r Atazanavir 350 mg/d r Found in severe coma at 1 r 2.3 mg/L at admission
with HIV11 r QTP started 3 wk r Ritonavir 100 mg/d home 6 h after r 1.5 mg/L 44 hours
before overdose overdose after admission
r Discharged on day 4
14 intentional r Median 2.6 g r QTP alone ingested in r 6 severe coma cases 6 r Range: 1.1-8.8 mg/L
overdose cases r Range 1.2-18 g 1/14 cases r Time of sampling:
where QTP amount r BZDs coingested in 1-26 hours after
was known12 12/14 cases ingestion
r Concentration not
associated with QTP
amount reported
ingested

BZD indicates benzodiazepines; HCV, hepatitis C virus; HIV, human immunodeficiency virus; LPV, lopinavir; NR, not reported; QTP, quetiapine; RTV, ritonavir.
a
This article reported 45 overdose cases; however, results were presented for the subset of 18 patients with measured quetiapine concentrations.
b
Among the 18 patients with reported quetiapine concentrations in the study, additional detail was provided for only this 19-year-old woman.

reported concomitant use of protease inhibitors. Where
reported, the outcomes of the 107 cases ranged from
recovery to death. Recovery from coma was reported in
4 cases.7–9,11 In a report of 18 quetiapine overdose cases,
the outcome was not reported with the exception of 1
patient who recovered.8 In a report of 945 quetiapine
overdose cases, death was reported in 3 cases and coma
in 96 cases; it is unclear if the 3 deaths were among the
coma patients.10 In a report of 920 fatalities associated
with poison/medication exposure, quetiapine use was
reported in 10 cases; occurrence of coma before death
was not reported.13
Our FDA Adverse Event Reporting System search
identified 10 cases in whom sedation, somnolence, res-
piratory depression, loss of consciousness, or coma was
reported following coadministration of quetiapine and
a protease inhibitor. Protease inhibitors coadministered
with quetiapine were lopinavir/ritonavir (n = 3),
atazanavir/ritonavir (n = 3), and darunavir/ritonavir
(n = 3). In 1 case, ritonavir was the only protease
Sampson et al 503

Figure 1. Oral midazolam AUC ratios in the presence and absence of protease inhibitors in drug-drug interactions studies. Only studies in which
RTV dosing was 100 mg once daily or twice daily were included in this figure. Studies were in healthy subjects except for a study in HIV-infected
subjects17 and another in HCV-infected subjects.22 Midazolam was administered simultaneously with the protease inhibitor in most studies; exceptions
were where coadministration was staggered by 10 minutes,19 30 minutes,21 or 2 hours.24 Where GMR was not reported, we calculated the ratio of
reported mean AUC values.19,20,23,24 AUC indicates area under the concentration-time curve; CI, confidence interval; GMR, geometric mean ratio; LPV,
lopinavir; NFV, nelfinavir; Ref, reference; RTV, ritonavir; SQV, saquinavir; TPV, tipranavir.

inhibitor reported; however, the patient was likely on
another protease inhibitor in addition to ritonavir.
Of the 10 cases, the index case and 2 others lacked ob-
vious confounders, and the onset of sedation or coma
occurred soon after protease inhibitor initiation. Case 2
was a 32-year-old woman on a stable dose of quetiapine
600 mg once daily with sedation and confusion several
days after beginning atazanavir/ritonavir (300/100 mg),
emtricitabine, and tenofovir. Symptoms rapidly abated
after discontinuation of quetiapine.14 The third case
was a 41-year-old woman on a stable dose of quetiapine
100 mg once daily with increased sedation and dizziness
2 weeks after starting lopinavir/ritonavir (200/50 mg
twice daily), emtricitabine, and tenofovir, whose symp-
toms worsened after an increase in quetiapine dose
and initiation of paroxetine. The quetiapine dose was
not reported to have been reduced on coadministration
with protease inhibitors in these 3 cases. No additional
cases were identified in the medical literature.
Concomitant Dispensing of Quetiapine and Ritonavir
In Symphony Health Solutions claims data, 3 600 000
and 276 000 patients were dispensed quetiapine and
ritonavir, respectively. Both quetiapine and ritonavir
were dispensed to 13 609 patients (0.4% of quetiapine
patients and 4.9% of ritonavir patients). The fraction
of patients with >30 days estimated concurrent use was
73%. The dose change analysis included 8044 patients.
When concomitant ritonavir was initiated, there was no
change in quetiapine dose in 90% of treatment episodes.
Quetiapine as a Substrate of Drug Transporters
On the basis of measurements of the quetiapine flux
ratio in polarized cells (FDA-recommended approach),
quetiapine is not considered a P-glycoprotein (Pgp)
substrate; however, in an ATPase assay, quetiapine
is considered a Pgp substrate.4,15 Quetiapine appears
to be a Pgp inhibitor, which could limit the role
of Pgp in its disposition.16 We did not identify
studies evaluating quetiapine as a substrate of other
transporters.
Effect of Protease Inhibitors on the PK of CYP3A
Substrates
In the presence versus absence of a protease inhibitor
in clinical drug interaction studies, midazolam AUC
was increased >5-fold (Figure 1).17–26 We did not
identify midazolam–protease inhibitor interaction
studies of atazanavir, darunavir, fosamprenavir, or
indinavir with or without coadministered ritonavir.
Across several studies, in the presence versus absence
of ritonavir 100 mg (various dosage regimens),
the median (range) of midazolam AUC ratios in these
studies was 12.6 (6.5-25.6) (Figure 1). In the presence
versus absence of ketoconazole 400 mg once daily for
2 days, the median (range) midazolam AUC ratio was
13.4 (7.5-19.5) (Figure 2).27–32 In the presence versus
absence of ketoconazole 400 mg once daily for 9 days,
maraviroc AUC ratio (90% confidence interval [CI])
was 5.0-fold (4.0-6.3).33 Except for saquinavir/ritonavir,
in the presence versus absence of protease inhibitors
maraviroc AUC was increased <5-fold (Figure 3).33–36
The effects of ketoconazole and ritonavir on CYP3A
substrates triazolam, alfentanil, and avanafil were
similar, with substrate AUC increased >9-fold
(Table 2).37–41
PBPK Analysis
In the presence versus absence of ketoconazole 200 mg
daily, PBPK analysis predicted a quetiapine geometric
mean AUC ratio of 4.8 (95%CI 4.5-5.2) compared to
504 The Journal of Clinical Pharmacology / Vol 59 No 4 2019

Figure 2. Effect of ketoconazole on oral midazolam exposure in drug-drug interaction studies. Where GMR was not reported, we calculated the
ratio of reported mean AUC values.30 AUC indicates area under the concentration-time curve; CI, confidence interval; GMR, geometric mean ratio;
QD, once daily; Ref, reference.

Figure 3. Human drug-drug interaction studies between ketoconazole or protease inhibitors and maraviroc. A indicates simultaneous coadminis-
tration of maraviroc and inhibitor, and B indicates inhibitor administered 1.5 hours after maraviroc. ATV indicates atazanavir; AUC, area under the
concentration-time curve; BID, twice daily; CI, confidence interval; DRV, darunavir; FPV, fosamprenavir; GMR, geometric mean ratio; LPV, lopinavir; QD,
daily; Ref, reference; RTV, ritonavir; SQV, saquinavir; TID, 3 times a day; TPV, tipranavir.

an observed mean AUC ratio of 6.2 (90%CI 4.9-7.8)
(Figure 4).4 The analysis underpredicted the effect of
ritonavir on the PK of midazolam and predicted the
effect of saquinavir/ritonavir on the PK of midazolam
(Table 3). Finally, the analysis predicted a 9-fold
increase in quetiapine AUC when coadministered with
ritonavir. The addition of ketoconazole is not expected
to cause an additional increase in quetiapine AUC
(Table 4).
Discussion
Following a report of coma in a policewoman pre-
scribed concomitant quetiapine and lopinavir/ritonavir,
we reevaluated labeling recommendations for the do-
sage of quetiapine when given with protease inhibitors.
We evaluated the relationship between quetiapine ex-
posure and coma, quetiapine–protease inhibitor inter-
actions as a causal factor for sedation or coma, the
role of transporters in quetiapine disposition, CYP3A
inhibition magnitude across protease inhibitors in com-
parison to ketoconazole, and PBPK predictions of the
effect of protease inhibitors on quetiapine exposure.
Quetiapine acute overdose, often with ingestion of
respiratory depressants, appears to be associated with
coma. A study of quetiapine acute overdose (n =
945 cases) reported 96 comas and 3 deaths (10%
and 0.3% of cases, respectively).10 In addition, several
case reports of quetiapine overdose describe reversible
comas.7–9,11 In the index coma case the possibility of
overdose of quetiapine or other substances was not
mentioned, and the outcome was not reported.
We identified 3 FDA Adverse Event Reporting
System cases without obvious confounders of pa-
tients prescribed concomitant quetiapine and protease
Sampson et al 505

Table 2. Effect of Ketoconazole and Ritonavir on Selected CYP3A Substrates

Substrate Fold
Substrate (Dose and Route) BDDCS Class Pgp Substrate Precipitant (Dose) Change (90%CI) Ref

Triazolam (0.25 mg PO) I Ketoconazole (400 mg QD × 4 days) 22.4a 37

Triazolam (0.1875 mg PO) Unknown Ritonavir (200 mg BID × 10 days) 21.1a 38

Avanafil (50 mg PO) Unknown Ketoconazole (400 mg QD × 5 d) 12.8a 39

Avanafil (50 mg PO) No Ritonavir (300 mg BID on day 2, 400 mg BID on 12.2a 39

day 3, then 600 mg BID on days 4-8)

Alfentanil (4 mg PO) I No Ketoconazole (400 mg QD × 4 d) 12.0 (6.2-23.3) 40

Alfentanil (43 and 4.3 μg/kg) Ritonavir (BID, starting with 200 mg TID on day 1, 10.0 (6.7-15.1) 41

then 300 mg BID for the following 7 d, then

400 mg BID for the remaining days (7 AM)

BDDCS indicates Biopharmaceutical Drug Disposition Classification System42 ; BID, twice daily; CI, confidence interval; Pgp, P-glycoprotein; PO, by mouth; QD,
once daily; Ref, reference; TID, 3 times daily.
a
CI not reported.
300

300
A B
Quetiapine plasma concentration (ng/mL)
200

200
100

100
0

0 10 20 30 0 10 20 30
Time (hours) Time (hours)
Figure 4. PBPK prediction of quetiapine plasma concentration-time profiles alone (A) and with coadministration of ketoconazole (B).In the quetiapine-
ketoconazole drug interaction study4 and the PBPK simulations, quetiapine dosing was 25 mg on days 1 and 6, and ketoconazole dosing was 200 mg
daily on days 3-6. Observed data were digitized using PlotDigitizer (Sourceforge, San Diego, California). Solid circles show observed data; solid lines
show mean prediction; dashed lines indicate 5th and 95th percentiles of predictions. PBPK indicates physiologically based pharmacokinetics.

inhibitors who experienced excess sedation (n = 2) or even before the index case, the index case could have
coma (n = 1). Evidence supporting a drug interaction been avoided if recommendations had been followed.
as the causal factor for quetiapine toxicity in these cases The other 2 cases occurred in the United States, and it
includes onset of sedation or coma soon after protease is unknown whether the quetiapine dose was reduced
inhibitor initiation, rapid abatement of symptoms fol- 6-fold on coadministration with protease inhibitors as
lowing quetiapine discontinuation in 1 case, worsen- recommended in quetiapine United States labeling.
ing of symptoms after quetiapine dose was increased Our analysis of concomitant dispensing suggests
in 1 case, and biological plausibility (quetiapine is a that quetiapine and protease inhibitors were not com-
CYP3A substrate and protease inhibitors are CYP3A monly coadministered. However, when quetiapine and
inhibitors). Because concomitant use of quetiapine and protease inhibitors were coadministered before 2015,
protease inhibitors was contraindicated in the Euro- it appears that most healthcare professionals did not
pean quetiapine summary of product characteristics reduce the quetiapine dose. They may not have been
506
Table 3. Observed Results and Physiologically Based Pharmacokinetic Predictions of Ritonavir–Oral Midazolam Drug-Drug Interaction Studies
Oral Midazolam Dosing Inhibitor Dosing
5 mg on days 1 and 14 RTV 100 mg QD on days 1-14
3 mg on day 1 RTV 100 mg on day 1
3 mg on day 1 RTV 300 mg on day 1
7.5 mg on days 1 and 16 RTV 100 mg BID on days 3-17;
SQV 1000 mg BID on days 3-17
AUC indicates area under the concentration-time curve; BID, twice daily; CI, confidence interval; GMR, geometric mean ratio; QD, once daily; Ref, reference; RTV,
ritonavir; SQV, saquinavir.
a
CI not reported.
Table 4. Physiologically Based Pharmacokinetic Predictions of the
Ritonavir-Quetiapine Drug-Drug Interaction Based on a Single Queti-
apine Dose of 25 mg
GMR AUC Ratio
Inhibitor Dosing and 95%CI
RTV 100 mg QD on days 1-14 8.8 (8.0-9.6)
RTV 100 mg BID on days 1-14 9.2 (8.4-10.1)
RTV 200 mg BID on days 1-14 9.5 (8.6-10.4)
RTV 100 mg QD + KTZ 200 mg 9.2 (8.4-10.2)
BID on days 1-14
AUC indicates area under the concentration-time curve; BID, twice daily;
CI, confidence interval; GMR, geometric mean ratio; KTZ, ketoconazole; QD,
once daily; RTV, ritonavir.
aware of, or chose not to adhere to, recommenda-
tions in quetiapine United States labeling that em-
phasize the need for quetiapine dose reduction when
it is coadministered with strong CYP3A inhibitors.
Physicians who manage HIV care may not have been
aware of the quetiapine interaction because it was
not included in the United States labeling of protease
inhibitors until 2015. Given the widespread use of drug
interaction software in pharmacies, it is unclear why
quetiapine dose reduction did not occur when patients
were first coprescribed quetiapine and ritonavir. For
example, the clinical decision support software program
Micromedex (Truven Analytics, IBM, Armonk, New
York) classifies the quetiapine-ritonavir interaction as
having major severity. However, if patients routinely
receive quetiapine and HIV medications from sepa-
rate pharmacies, this may partly explain why dose
reductions were infrequent. There are limitations to
the analysis of concomitant dispensing of quetiapine
and ritonavir: the claims database captures dispensing
and not actual use, the database may not capture all
prescriptions for the patients, and the results are not
generalizable to an uninsured population.
Based on literature evaluation, quetiapine disposi-
tion is unlikely to be significantly affected by drug
transporters. There are conflicting data regarding the
role of Pgp in quetiapine disposition. In PBPK model-
The Journal of Clinical Pharmacology / Vol 59 No 4 2019
Midazolam AUC GMR
Simulated Observed Simulated/
(95%CI) (90%CI) [Ref] Observed
17.4 (14.0-21.6) 23.9a23 0.73
2.75 (2.56-2.96) 6.5a19 0.42
3.6 (3.3-3.9) 9.0a19 0.40
12.6 (11.1-14.3) 12.4 (10.8-14.4)25 1.02
ing, incorporation of Pgp was not needed to describe
the PK of quetiapine with and without ketoconazole.6
Additionally, we predict minimal effects of gut and liver
transporters on quetiapine disposition because it is a
Biopharmaceutics Drug Disposition Classification Sys-
tem class I compound.42 Quetiapine is a cationic drug,
and all known organic anion-transporting polypeptide
substrates are anions; thus, quetiapine is unlikely to be a
substrate of organic anion-transporting polypeptide.43
Renal transporters are not of concern because que-
tiapine is extensively metabolized with <1% of the
quetiapine dose excreted as parent drug.
At the time of our review in 2014-2015, the FDA-
approved labeling for protease inhibitors (except for
tipranavir/ritonavir) included no clinical recommenda-
tions for coadministration with quetiapine. Quetiapine
has not been studied in interaction studies with any
protease inhibitor. The only reported interaction study
of quetiapine with a strong CYP3A inhibitor is with
ketoconazole, where quetiapine AUC was increased
6-fold.4 Before the index case, quetiapine United
States labeling stated that the quetiapine dose should
be reduced 6-fold when coadministered with strong
CYP3A inhibitors.
We examined whether all protease inhibitors can be
classified as strong CYP3A inhibitors. CYP enzyme
inhibitors that increase the AUC of a probe substrate
by <2-fold, 2- to 5-fold, and >5-fold are defined
in FDA guidance as weak, moderate, and strong
CYP3A inhibitors, respectively.44 Drugs metabolized
by CYP3A and whose AUC is increased >5-fold when
coadministered with a strong CYP3A inhibitor are
defined as sensitive CYP3A substrates.44 There are
many reports of interaction studies between protease
inhibitors and sensitive CYP3A substrates such as
midazolam and maraviroc. However, although the
AUC ratio of midazolam is consistently above 5-fold
when coadministered with strong CYP3A inhibitors
(Figures 1 and 2), this is not the case for maraviroc
(Figure 3). One limitation of the comparison of mida-
zolam and maraviroc is that midazolam was generally
Sampson et al
coadministered with inhibitors simultaneously in the
cited drug interaction studies, whereas in most of the
maraviroc studies maraviroc was given fasted, and
the inhibitor was given following a meal 1.5 hours
after maraviroc. It is unclear what effect staggered
administration had on the magnitude of interactions.
The effect of nonsimultaneous administration was
evaluated in an oral midazolam-ritonavir interaction
study in which midazolam was coadministered with
ritonavir either simultaneously or 12 hours after the
last ritonavir dose; the midazolam AUC ratio was
20% lower under staggered conditions relative to
simultaneous coadministration.18 If the observed
maraviroc AUC ratios derived from protease inhibitor
interaction studies with staggered coadministration
were increased by 20%, the maraviroc AUC ratios
would still be lower than the midazolam AUC ratios
in midazolam–protease inhibitor interaction studies.
When the midazolam versus maraviroc comparison
is limited to the same strong inhibitors (and dosing)
and to simultaneous administration, AUC ratios
were higher for midazolam versus maraviroc in both
cases: 13.4-fold across multiple studies versus 5.0-fold,
respectively, for ketoconazole and 12.4-fold versus
9.8-fold, respectively, for saquinavir/ritonavir. Due to
our concerns about maraviroc meeting the definition
of a sensitive substrate of CYP3A based on AUC ratio
and evidence that pathways other than CYP3A are
important in the disposition of maraviroc (discussed
below), the focus of our analysis was on midazolam.
Lopinavir/ritonavir, nelfinavir, ritonavir, saquinavir,
saquinavir/ritonavir, and tipranavir/ritonavir are con-
sidered strong CYP3A inhibitors on the basis of the re-
sults of interaction studies with midazolam (Figure 1).
Atazanavir, atazanavir/ritonavir, darunavir/ritonavir,
and fosamprenavir/ritonavir have been studied in in-
teraction studies with maraviroc but not midazolam.
Based on the fold change of maraviroc, each of these
protease inhibitors would be classified as a moderate
CYP3A inhibitor (Figure 3). However, because both
ketoconazole and ritonavir increase the exposure of
midazolam significantly more than that of maraviroc,
our hypothesis is that if studied with midazolam as
a substrate, these protease inhibitors would likely be
classified as strong CYP3A inhibitors.
It is noteworthy that tipranavir/ritonavir had dra-
matically different results when studied with midazo-
lam (10- to 27-fold AUC increase) versus maraviroc
(no AUC change) (Figures 1 and 3). The effect of
tipranavir/ritonavir on midazolam was consistent with
the effect of ritonavir on midazolam (Figure 1). In
contrast, the lack of effect of tipranavir/ritonavir on
maraviroc was markedly different from the effects of
other protease inhibitors on maraviroc, suggesting that
mechanisms other than CYP3A (such as Pgp induction
507
by tipranavir) may be important in the disposition of
maraviroc.
Data are lacking regarding the effect of some
protease inhibitors on midazolam or other sensitive
CYP3A substrates. There are no data for fosamprenavir
or indinavir with either midazolam or maraviroc. In-
dinavir increases the exposure of saquinavir by 6-fold,
and in our drug usage analysis, indinavir was 1 of the
least commonly used protease inhibitors. Most patients
prescribed fosamprenavir will likely also be prescribed
ritonavir because current HIV treatment guidelines for
treatment-naive patients recommend coadministration
of ritonavir when a protease inhibitor is prescribed.45
For purposes of labeling, we considered all protease
inhibitors regardless of coadministration with ritonavir
to be strong CYP3A inhibitors because this is the most
conservative option. If the 6-fold dose reduction is
excessive for certain protease inhibitors, quetiapine can
be up-titrated to effect.
Because quetiapine has been studied with only 1
strong CYP3A inhibitor (ketoconazole), ketoconazole-
midazolam and ritonavir-midazolam interaction stud-
ies were compared to determine whether ritonavir has
a similar effect on CYP3A to that of ketoconazole
and to inform the prediction of whether ritonavir and
ketoconazole have a similar effect on the exposure
of quetiapine. Midazolam AUC ratios across studies
when coadministered with ketoconazole or ritonavir
were similar. However, considerable variability was
observed for studies in which ketoconazole dosing was
consistent, and even more variability was observed for
ritonavir-midazolam studies in which ritonavir 100 mg
dosing frequencies varied. The effect of ketoconzole
and ritonavir on 3 other CYP3A substrates (avanafil,
alfentanil, and triazolam) was similar. Taken together,
the interaction data with midazolam, avanafil, alfen-
tanil, and triazolam suggest that ketoconazole and
ritonavir are both strong CYP3A inhibitors with a
similar effect on respective CYP3A substrates.
Physiologically based PK modeling was used to
predict the effect of ritonavir on quetiapine exposure.
We focused on ritonavir because compound files were
not available for all protease inhibitors. We evaluated
the utility of PBPK by checking the ability of the model
to predict results from prior interaction studies. The
model underpredicted the results of the quetiapine-
ketoconazole interaction and multiple-dose ritonavir-
midazolam interaction studies (single-dose studies were
significantly underpredicted) but was considered ad-
equate for prediction of the steady-state ritonavir-
quetiapine interaction. The PBPK model predicted that
quetiapine AUC would increase by 9-fold when that
drug was coadministered with ritonavir, which seems
reasonable when compared to the 8- to 20-fold range
of midazolam AUC changes observed across studies
508
with ketoconazole 400 mg once daily. Also, the model
predicted that addition of a second strong CYP3A
inhibitor (ketoconazole) to ritonavir would not further
increase quetiapine exposure.
In reevaluating dosing recommendations for the
coadministration of quetiapine and protease inhibitors,
we considered 2 clinical scenarios: 1 when quetiapine
is initiated in a patient on stable protease inhibitor
therapy and the other when a protease inhibitor is
initiated in a patient on stable quetiapine therapy. The
first scenario is less concerning because quetiapine is
recommended to be initiated at the lowest dose of 50 mg
daily, such that there is a 16-fold margin compared
to the highest recommended quetiapine daily dose of
800 mg. The second scenario is a greater safety concern
because a significant increase in quetiapine exposure is
expected on initiating a protease inhibitor–based reg-
imen. Because quetiapine is commonly used, no cases
of excess sedation or coma have been reported in which
the 6-fold quetiapine dose reduction recommendation
was implemented on coadministration with protease
inhibitors, and because the quetiapine dose can be
titrated over a wide range, we consider contraindicating
coadministration of quetiapine and protease inhibitors
to be overly restrictive. The Drug Interactions sec-
tions of the 9 protease inhibitor labels were modi-
fied with the following clinical recommendation for
coadministration with quetiapine: (1) In initiation of
HIV protease inhibitor in patients taking quetiapine,
consider alternative antiretroviral therapy to avoid in-
creases in quetiapine exposures. If coadministration is
necessary, reduce the quetiapine dose to one sixth of
the current dose and monitor for quetiapine-associated
adverse reactions. Refer to the quetiapine labeling
for recommendations on adverse reaction monitoring.
(2) In initiation of quetiapine in patients taking an HIV
protease inhibitor, refer to the quetiapine labeling for
initial dosing and titration of quetiapine.
Conclusion
In conclusion, available data indicate all HIV protease
inhibitors combined with ritonavir are likely to be
strong CYP3A inhibitors. We conclude that current
dosing recommendations for use of quetiapine with
strong CYP3A inhibitors (ie, 6-fold lower quetiapine
dose) are appropriate and should be followed.
Acknowledgments
All authors contributed to the data analysis and to the writing
of this article. Thanks to Elizabeth M. Kang for performing
the concomitant use and dose change analyses.
Data Sharing
Data cannot be shared.
The Journal of Clinical Pharmacology / Vol 59 No 4 2019
Source of Funding
None.
Conflicts of Interest
None.
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Supporting Information
Additional supporting information may be found on-
line in the Supporting Information section at the end
of the article.