Clin Pharmacokinet 2008; 47 (2): 75-89

REVIEW ARTICLE 0312-5963/08/0002-0075/$48.00/0

© 2008 Adis Data Information BV. All rights reserved.

Drug Interactions between HIV Protease

Inhibitors and Acid-Reducing Agents
Ronald W. Falcon1 and Thomas N. Kakuda2
1 Tibotec Therapeutics, Bridgewater, New Jersey, USA
2 Tibotec Inc., Yardley, Pennsylvania, USA

Contents
Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75
1. Gastric Acidity and Drug Absorption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76
2. Interaction of Protease Inhibitors and Acid-Reducing Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77
2.1 Atazanavir . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77
2.1.1 In Combination with Proton Pump Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77
2.1.2 In Combination with Histamine H2-Receptor Antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82
2.2 Darunavir . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83
2.3 Fosamprenavir and Amprenavir . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83
2.4 Indinavir . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84
2.5 Lopinavir . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84
2.6 Nelfinavir . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85
2.7 Ritonavir . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85
2.8 Saquinavir . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86
2.9 Tipranavir . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86
3. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86
4. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87

Abstract Maximal efficacy of protease inhibitor-based antiretroviral therapy for HIV/AIDS requires adequate drug
absorption and bioavailability. However, the use of acid-reducing agents in patients treated with highly active
antiretroviral therapy is common and may induce clinically significant drug-drug interactions that alter plasma
protease inhibitor concentrations, which may lead to inadequate viral suppression or adverse events. As plasma
antiretroviral concentrations are not routinely monitored in patients, it is important to understand the risk of these
interactions and counsel patients appropriately, thereby maximizing antiviral potential and preventing the
development of antiretroviral resistance. We therefore reviewed the literature to assess the current understanding
of the effect of various acid-reducing agents on the pharmacokinetics of protease inhibitors.
The bioavailability of fosamprenavir, indinavir, lopinavir, nelfinavir and tipranavir has been reported to be
negatively affected to varying degrees by certain acid-reducing agents. The negative effect on atazanavir
concentrations observed in healthy subjects was more attenuated in HIV-infected patients and warrants further
investigation. While the plasma concentration of saquinavir increased, short-term studies in healthy subjects did
not indicate an increased risk of adverse events. No clinically relevant changes in plasma concentrations of
darunavir occurred when combined with acid-reducing agents. The individual effect of acid-reducing agents on
protease inhibitor concentrations is difficult to predict because of the large interpatient variability of plasma
concentrations with some protease inhibitors. Studies suggest that some of the interactions between protease
inhibitors and acid-reducing agents may be mitigated by temporal separation of dose administration. Educating
patients about the importance of reporting the use of any acid-reducing agents, whether prescription or over-the-
counter, is essential to optimizing the treatment of HIV disease, as is the need for care providers and patients to
76
agree upon strategies for managing gastric symptoms and HIV disease simultaneously. Clinicians should be
aware of the potential drug-drug interactions between some protease inhibitors and acid-reducing agents.
Highly active antiretroviral therapy (HAART) has become the
mainstay of treatment for HIV disease because of the significant
declines in morbidity and mortality demonstrated with its use.[1,2]
The success of treatment with HAART may be limited by regi-
men-related adverse effects, drug-drug interactions and develop-
ment of drug resistance.[3] A significant impediment to effective
therapy is the potential for negative drug-drug interactions, partic-
ularly those caused by acid-reducing agents, which may reduce the
bioavailability of certain protease inhibitors. While some treat-
ment guidelines suggest minimum target concentrations for partic-
ular antiretrovirals in patients with wild-type virus,[3,4] antiretrovi-
ral blood concentrations are not routinely monitored in the US.
With limited pharmacokinetic data available in antiretroviral-
experienced patients, minimum protease inhibitor trough concen-
tration targets are not as clearly defined but are expected to be
higher. Understanding the likelihood of drug-drug interactions,
exploring regimens that minimize that likelihood, and educating
patients about how best to manage their gastric symptoms and HIV
disease simultaneously are all essential to optimize the treatment
for HIV/AIDS. This review surveys studies of protease inhibitors
and their bioavailability in the presence of acid-reducing agents.
Literature reviews were conducted from November 2005 to June
2007 to assess the current understanding of the effect of various
acid-reducing agents on the pharmacokinetics of frequently pre-
scribed protease inhibitors. Published peer-reviewed pharmaco-
kinetic studies with HIV-infected patients and/or healthy subjects
were identified for review through PubMed, mainly by searching
each protease inhibitor for the term ‘interaction’. Other data
sources included major HIV/AIDS scientific conferences
(2002–7) and current product prescribing information. The main
outcome measures were the area under the plasma concentration-
time curve (AUC), maximum plasma concentration (Cmax) and
minimum plasma concentration (Cmin) during the dosing interval
(either 12 or 24 hours) of protease inhibitors coadministered with
acid-reducing agents in HIV-infected patients and healthy sub-
jects. In studies with HIV-infected patients, the virological res-
ponse, clinical outcome and adverse events/safety were examined,
if reported.
1. Gastric Acidity and Drug Absorption
The efficacy of protease inhibitor therapy requires adequate
and sustained drug concentrations in the blood and ultimately in
virally infected cells, which are contingent upon adequate drug
solubility, absorption and bioavailability. A major determinant of
© 2008 Adis Data Information BV. All rights reserved.
Falcon & Kakuda
drug dissolution and absorption is gastric acidity.[5] Additional
physiological factors influencing drug absorption include the rate
of gastric emptying, gastric blood flow and the presence or ab-
sence of food in the stomach. Drug-specific characteristics that
influence absorption include product solubility, ionisability and
lipophilicity.[5] Gastric acidity is modulated by commonly used
acid-reducing agents, including histamine H2-receptor antagon-
ists, proton pump inhibitors (PPIs), antacids and buffered medica-
tions (table I).
Patients undergoing treatment with HAART for HIV infection
frequently use ancillary medications to reduce gastric acidity for
symptomatic relief and treatment of heartburn, gastroesophageal
reflux disease (GERD) and gastrointestinal tract ulceration. Pa-
tients also often use over-the-counter (OTC) agents that affect
gastric acid, such as calcium carbonate, to treat HAART-related
diarrhoea.[6] Gastrointestinal adverse events may also prompt pa-
tients to interrupt or discontinue antiretroviral therapy. Nausea,
vomiting and diarrhoea were the most common reasons for
HAART discontinuation in a retrospective cohort study of
antiretroviral-naive patients.[7] Luber et al.[8] evaluated sympto-
matic treatment of gastrointestinal adverse events in an Internet
survey of 200 patients undergoing treatment with HAART. In this
survey, the incidence of self-reported heartburn, GERD and gas-
trointestinal ulceration was 62.0%, 29.5% and 13.0%, respective-
ly. Over half (56.2%) of the patients used only OTC medications
for management of gastrointestinal adverse events, while 38.8% of
Table I. Commonly prescribed agents that suppress gastric acidity
Proton pump inhibitors
Esomeprazole
Lansoprazole
Omeprazole
Pantoprazole
Rabeprazole
Histamine H2-receptor antagonists
Cimetidine
Famotidine
Nizatidine
Ranitidine
Other agents
Antacids, e.g. aluminum hydroxide/carbonate, calcium hydroxide/
carbonate, bismuth subsalicylate
Buffered medications, e.g. didanosine
Clin Pharmacokinet 2008; 47 (2)
HIV Protease Inhibitor Interactions
patients used both OTC and prescription medications, and 5% of
patients reported using only prescription acid-reducing agents.
Specifically, 51% reported using OTC PPIs or H2-receptor ant-
agonists, 39% used prescription PPIs and 77% used antacids. The
investigators found that use of acid-reducing agents by patients
taking a protease inhibitor was similar to that of the entire study
population (46% OTC PPIs or H2-receptor antagonists, 42% pre-
scription PPIs and 73% antacids). In this study, 88% of patients
taking PPIs continued acid-reduction therapy for a period of
6 weeks or more.[8] Similar results have been reported from other
clinics in Germany,[9] Italy,[10] Spain,[11] Switzerland[12] and the
US.[13] Optimal absorption of some protease inhibitors requires
increased gastric acidity (a low gastric pH), e.g. atazanavir,[14]
fosamprenavir[15] and indinavir. [16] However, the acid-reducing
agents widely used by HIV patients effectively decrease gastroin-
testinal adverse events by reducing gastric acidity and increasing
the gastric pH. Decreased gastric acidity may impair protease
inhibitor absorption, leading to decreased drug concentrations,
which can reduce antiviral activity and increase the likelihood of
viral resistance.
2. Interaction of Protease Inhibitors and
Acid-Reducing Agents
Reduced protease inhibitor bioavailability attributed to nega-
tive drug-drug interactions with acid-reducing agents has been
documented with atazanavir,[14] fosamprenavir,[17] indinavir,[18]
nelfinavir,[19] tipranavir[20] and, possibly, lopinavir.[21] Table II
summarizes the results of formal drug-drug interaction studies
between protease inhibitors and acid-reducing agents. It should be
noted that formal drug-drug interaction studies of protease medi-
cations are almost invariably conducted on healthy subjects, so as
not to unnecessarily jeopardize the complex medication regimens
used by people with HIV and also to eliminate the confounding
factors resulting from their obligatory multidrug regimens.
2.1 Atazanavir
The aqueous solubility of atazanavir decreases with an increas-
ing pH.[14] Consequently, the concomitant use of PPIs, H2-receptor
antagonists, antacids or buffered medications might be expected to
reduce the absorption and bioavailability of atazanavir. Pharmaco-
kinetic analyses conducted in healthy subjects and HIV-infected
patients have demonstrated that plasma atazanavir concentrations
can be significantly altered when acid-reducing agents are
coadministered. Concerning PPIs, conflicting data among studies
in healthy subjects and HIV-infected patients have led to consider-
able confusion regarding the clinical implications of this drug-
drug interaction. While there appear to be no published reports on
© 2008 Adis Data Information BV. All rights reserved.
77
the concurrent use of atazanavir and antacids, an interaction would
be expected given the finding that buffered didanosine significant-
ly reduces atazanavir exposure (see section 2.1.1).
2.1.1 In Combination with Proton Pump Inhibitors
Healthy Subjects
Pharmacokinetic analyses in healthy subjects have shown that
concurrent use of the PPI omeprazole with ritonavir-boosted or
unboosted doses of atazanavir significantly reduces plasma
atazanavir concentrations. In one study,[24] healthy subjects
(n = 48) received atazanavir/ritonavir 300 mg/100 mg once daily,
the dose indicated for use in antiretroviral-experienced patients,
for 10 days followed by atazanavir/ritonavir 300 mg/100 mg plus
omeprazole 40 mg once daily coadministered with (n = 16) or
without (n = 16) a carbonated beverage (8 oz cola), or atazanavir/
ritonavir 400 mg/100 mg once daily plus omeprazole 40 mg once
daily (n = 16) for 10 days. Omeprazole was administered in the
fasted state 2 hours before atazanavir/ritonavir was taken with
food. There were significant reductions in the mean AUC from
0 to 24 hours (AUC24) [76%], Cmax (72%) and Cmin (79%) for
atazanavir when using the standard atazanavir/ritonavir dose in
combination with omeprazole (table II). Neither coadministration
with a carbonated beverage nor the use of a higher dose of
atazanavir (400 mg) helped to mitigate the negative effect of this
drug-drug interaction.
In a subsequent study,[25] the atazanavir 400 mg once-daily dose
indicated for use in antiretroviral-naive patients was administered
to healthy subjects (n = 48) for 6 days, followed by atazanavir
400 mg plus omeprazole 40 mg once daily coadministered with
(n = 16) or without (n = 16) a carbonated beverage (8 oz cola) on
days 7–12, or atazanavir/ritonavir 300 mg/100 mg once daily
(n = 16) on days 7–16. Omeprazole was administered in the fasted
state 2 hours before atazanavir was taken with food. Omeprazole
coadministration, with or without a carbonated beverage, signifi-
cantly reduced the mean atazanavir AUC24, Cmax and Cmin by
>93% (table II). In subjects receiving atazanavir/ritonavir, reduced
mean AUC24 (50%) and Cmax (73%) values were observed for
atazanavir, although the mean Cmin increased by 23%. Increased
mean AUC24 (45%) and Cmax values (24%) for omeprazole were
also reported during coadministration with atazanavir. Given that
omeprazole is metabolized by cytochrome P450 (CYP) 2C19 and
CYP3A,[39,40] the increases in omeprazole concentrations suggest
that atazanavir may be an inhibitor of CYP2C19 and/or CYP3A.
Tomilo et al.[26] conducted a single-dose study on the inter-
action between atazanavir 400 mg and lansoprazole 600 mg in
nine healthy subjects (table II). Coadministration of lansoprazole
significantly (p < 0.01) decreased the mean atazanavir AUC24
(98%) and Cmax (94%). Taken together, the results for similar
Clin Pharmacokinet 2008; 47 (2)
 78
Table II. Bioavailability of commonly used protease inhibitors in the presence of acid-reducing agentsa

Drug and dosage Acid-reducing agent Mean changeb Comments

Cmax (%) Cmin (%) AUC (%)
ATVc
ATV/RTV 300 mg/100 mg od FAM 40 mg bid (n = 16) ↓ 14 ↓ 28 ↓ 18 Addition of 8 oz carbonated beverage did not
compensate for interaction[22]
ATV 400 mg od FAM 40 mg bid (n = 16) ↓ 47 ↓ 42 ↓ 41 Addition of 8 oz carbonated beverage did not
compensate for interaction
Administer ATV 2 h prior to evening dose of FAM or
use ATV/RTV 300–400 mg/100 mg od[22]

© 2008 Adis Data Information BV. All rights reserved.

ATV/RTV 300 mg/100 mg + TDF 300 mg od FAM 40 mg bid (n = 20) ↓ 11 ↓ 33 ↓ 12 Temporal separation does not compensate for
2 h after ATV/RTV + TDF decreased ATV Cmin[23]
ATV/RTV 300 mg/100 mg + TDF 300 mg od FAM 40 mg od (n = 20) ↓ 26 ↓ 23 ↓ 22 Temporal separation does not compensate for
12 h after ATV/RTV + TDF decreased ATV Cmin[23]
ATV/RTV 300 mg/100 mg + TDF 300 mg od FAM 20 mg bid (n = 20) ↓9 ↓ 19 ↓ 10 FAM decreases ATV Cmin during concurrent
concurrent with ATV/RTV + TDF administration with ATV/RTV and TDF[23]
ATV/RTV 300 mg/100 mg + TDF 300 mg od FAM 20 mg bid 2 h after ↓4 ↓ 18 ↓4 Temporal separation does not compensate for
ATV/RTV + TDF (n = 20) decreased ATV Cmin[23]
ATV/RTV 300 mg/100 mg od OME 40 mg od (n = 16) ↓ 72 ↓ 79 ↓ 76 Addition of 8 oz carbonated beverage or increasing
ATV dose to 400 mg did not compensate for
interaction; contraindicated[24]
ATV 400 mg od OME 40 mg od (n = 16) ↓ 96 ↓ 95 ↓ 94 Addition of 8 oz carbonated beverage did not
compensate for interaction; contraindicated[25]
ATV 400 mg LAN 60 mg (n = 9) ↓ 94 ND ↓ 98 Single-dose study[26]

DRV
DRV/RTV 400 mg/100 mg bid RAN 150 mg bid (n = 18) ↓3 ↓6 ↓4 No significant interaction[27]
DRV/RTV 400 mg/100 mg bid OME 20 mg od (n = 18) ↑1 ↑7 ↑4 No significant interaction[27]

FPVd,e
FPV 1400 mg Maalox® TC 30 mL (n = 26) ↓ 35 ↑ 14 ↓ 18 Single-dose study[17]
FPV 1400 mg RAN 300 mg (n = 26) ↓ 51 ↓1 ↓ 30 Single-dose study; use RAN with caution[17]
FPV 1400 mg bid ESO 20 mg od (n = 25) ↓3 ↑3 ↓2 No significant interaction (but possible at higher
ESO doses); ESO AUC increased 55%[28]
FPV/RTV 700 mg/100 mg bid ESO 20 mg od (n = 23) ↓5 ↓7 ↓9 No significant interaction (but possible at higher
ESO doses); ESO AUC unchanged[28]

Continued next page

Clin Pharmacokinet 2008; 47 (2)

Falcon & Kakuda
 Table II. Contd

Drug and dosage Acid-reducing agent Mean changeb Comments

Cmax (%) Cmin (%) AUC (%)
IDVf
IDV 400 mg CIM 600 mg bid (n = 12) ↑7 ↓ 18 ↓2 Single-dose study[18]
IDV 800 mg OME 40 mg od (n = 8) ND ND ↓ 10 Single-dose study[29]
IDV 800 mg OME 40 mg od (n = 14) ND ↓ 55 ↓ 47 Single-dose study; compensated with the addition of
RTV 200 mg[30]
HIV Protease Inhibitor Interactions

LPVg
LPV/RTV SGC 400 mg/100 mg bid Antacid, PPI or H2RA (n = 4) ND ↑ 18h ND HIV-infected patients. No apparent effect on LPV

© 2008 Adis Data Information BV. All rights reserved.

trough concentrations. Not a formal interaction
study[31]
LPV/RTV SGC 800 mg/200 mg od Antacid, PPI or H2RA (n = 10) ND ↑ 73h ND HIV-infected patients. Increased LPV trough
concentration. Not a formal interaction study[31]
LPV/RTV tablet 400 mg/100 mg bid RAN 150 mg (n = 12) ↓2 ↓3 ↓2 Single dose of RAN. No significant interaction[21]
LPV/RTV tablet 800 mg/200 mg od RAN 150 mg (n = 11) ↓2 ↓ 20 ↓4 Single dose of RAN. Significant (p < 0.05) decrease
in Cmin[21]
LPV/RTV tablet 400 mg/100 mg bid OME 40 mg od (n = 11) ↑8 ↓1 ↑7 No significant interaction[21]
LPV/RTV tablet 800 mg/200 mg od OME 40 mg od (n = 12) ↑ 11 ↓ 19 ↑7 Significant (p < 0.05) decrease in Cmin[21]

NFV
NFV 1250 mg bid OME 40 mg od (n = 20) ↓ 37 ↓ 39 ↓ 36 Significant interaction.[19] Coadministration not
recommended[32]

RTV
LPV/RTV 400/100 mg bid
LPV/RTV 800 mg/200 mg od
LPV/RTV 400 mg/100 mg bid
LPV/RTV 800 mg/200 mg od
LPV/RTV 400 mg/100 mg bid
LPV/RTV 800 mg/200 mg od
Antacid, PPI or H2RA (n = 4) ND ↑ 33h ND HIV-infected patients. Increase not statistically
significant. Not a formal interaction study[31]
Antacid, PPI or H2RA (n = 10) ND ↑ 64h ND HIV-infected patients treated. Increase not
statistically significant. Not a formal interaction
study[31]
RAN 150 mg (n = 12) ↔ ↔ ↔ Single dose of RAN. No significant interaction for
RTV[21]
RAN 150 mg (n = 11) ↔ ↔ ↔ Single dose of RAN. No significant interaction for
RTV[21]
OME 40 mg od (n = 11) ↔ ↔ ↔ No significant interaction for RTV[21]
OME 40 mg od (n = 12) ↔ ↔ ↔ No significant interaction for RTV[21]

Continued next page

79

Clin Pharmacokinet 2008; 47 (2)

 Table II. Contd 80

Drug and dosage Acid-reducing agent Mean changeb Comments

Cmax (%) Cmin (%) AUC (%)
TPV/RTV 500 mg/200 mg OME 40 mg od (n = 15) ↓ 19 ND ↓ 17 Single-dose study.[33] Significant interaction for RTV

SQV

SQV-HGC 600 mg RAN 150 mg (n = 12) ↑ 114 ND ↑ 85 Single-dose study. No correlation between maximum
pH achieved and SQV AUC[34]

SQV-SGC 1200 mg bid CIM 400 mg bid (n = 12) ↑ 179 ↑ 32 ↑ 120 SQV 1200 mg tid for 13 days then 1200 mg bid with
CIM for 12 days[35]

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SQV-FCT/RTV 1000 mg/100 mg bid OME 40 mg od (n = 22) ↑ 75 ↑ 106 ↑ 82 SQV exposure increased significantly[36]

SQV/RTV bid OME 40 mg od (n = 12) ↑ 55 ↑ 73 ↑ 54 HIV-infected patients. SQV exposure increased

concurrent with SQV/RTV significantly.[37] RTV pharmacokinetics not
significantly changed

SQV/RTV bid OME 40 mg od (n = 12) ↑ 65 ↑ 97 ↑ 67 HIV-infected patients. SQV exposure increased

2 h prior to SQV/RTV significantly.[37] RTV pharmacokinetics not
significantly changed

TPV

TPV/RTV 500 mg/200 mg Maalox® plus 20 mL (n = 23) ↓ 25 ↓ 29 ↓ 27 Single-dose study.[38] Consider separating
administration[20]

TPV/RTV 500 mg/200 mg OME 40 mg (n = 15) ↑5 ND 0 Single-dose study.[33] No significant interaction for
TPV

a All studies were performed in healthy subjects and at steady state unless mentioned otherwise.

b Based on least squares geometric means ratio.

c Exhibits pH-dependent absorption.[14]

d Pharmacokinetics measure amprenavir.

e Exhibits pH-dependent absorption.[15]

f Exhibits pH-dependent absorption.[16]

g Does not exhibit pH-dependent absorption.[21]

h Comparing ‘users’ and ‘non-users’ of acid-suppression agents at week 48.

ATV = atazanavir; AUC = area under the plasma concentration versus time curve; bid = twice daily; Cmax = maximum concentration; Cmin = minimum concentration;
CIM = cimetidine; DRV = darunavir; ESO = esomeprazole; FAM = famotidine; FCT = film-coated tablet; FPV = fosamprenavir; H2RA = histamine H2-receptor antagonist;
HGC = hard-gel capsule; IDV = indinavir; LAN = lansoprazole; LPV = lopinavir; ND = no data; NFV = nelfinavir; od = once daily; OME = omeprazole; oz = ounce(s); PPI = proton
pump inhibitor; RAN = ranitidine; RTV = ritonavir; SGC = soft-gel capsule; SQV = saquinavir; TDF = tenofovir disoproxil fumarate; tid = three times daily; TPV = tipranavir;
↑ indicates increase; ↓ indicates decrease; ↔ indicates no change reported (without value given).

Clin Pharmacokinet 2008; 47 (2)

Falcon & Kakuda
HIV Protease Inhibitor Interactions
interaction of lansoprazole and esomeprazole with atazanavir sug-
gest that this drug-drug interaction may be a PPI class effect. Thus,
the manufacturer of atazanavir recommends that omeprazole and
other PPIs not be coadministered with atazanavir, even when used
with low-dose ritonavir.[14]
HIV-Infected Patients
Discordant results from studies of atazanavir in healthy volun-
teers and in HIV-infected patients have led to additional investiga-
tion into this interaction. Across ten HIV clinics in Los Angeles
(CA, USA), a review of electronic medical records identified 50
patients receiving atazanavir, with or without ritonavir, who were
concurrently using PPIs or H2-receptor antagonists.[41] Atazanavir
Cmin values, measured in a central clinical laboratory, were re-
corded for 15 patients using PPIs and 19 patients using H2-
receptor antagonists. Based on a reference Cmin value of 0.27 mg/
L, six of 15 patients (40%) using PPIs had below-reference
atazanavir Cmin values, five of whom were receiving atazanavir/
ritonavir. Four of 19 patients (21%) using an H2-receptor ant-
agonist, two of whom were receiving atazanavir/ritonavir, also had
below-reference atazanavir Cmin values. The mean atazanavir
Cmin was considerably lower in the PPI-treated patients (0.65 mg/
L; range <0.05–1.85 mg/L) than in those who received H2-recep-
tor antagonists (1.12 mg/L; range <0.05–3.17 mg/L). In agreement
with the manufacturer’s warning, the investigators concluded that
PPIs should be avoided and H2-receptor antagonists should be
administered separately in patients treated with atazanavir. It
should be noted that the currently recommended Cmin for
atazanavir in HIV-infected patients is 0.15 mg/L,[3] and the mini-
mum effective concentration for 90% activity (MEC90) in the
wild-type virus is ~6–11 ng/mL (9–15 nmol/L) in vitro.[42]
A prospective study conducted in two HIV clinics in Paris
evaluated and compared atazanavir Cmin values in atazanavir/
ritonavir-treated patients with or without concurrent use of a
PPI.[43] Among 92 patients, 13 reported PPI use (omeprazole
20 mg [n = 9] or 40 mg [n = 1] once daily, and rabeprazole 30 mg
once daily [n = 3]). The median atazanavir Cmin for PPI-treated
patients (0.55 mg/L; range 0.20–1.98 mg/L) was comparable to
that reported in non-PPI-treated patients (0.47 mg/L; range
0.65–1.94 mg/L). In three patients, Cmin values obtained during
concurrent PPI use and after PPI discontinuation were comparable.
Although the investigators concluded that PPI use had no effect on
the atazanavir Cmin in atazanavir/ritonavir-treated patients, the
Cmin ranges reported indicated that some patients may have had
inadequate atazanavir concentrations, although individual patient
concentration data were not shown. In published case reports of
individual patients receiving atazanavir/ritonavir, concurrent es-
omeprazole reduced the atazanavir AUC and Cmin in one pa-
© 2008 Adis Data Information BV. All rights reserved.
81
tient,[44] while another showed no effect on atazanavir exposure
with lansoprazole coadministration.[45] The value of these reports
is limited.
Despite the documented negative pharmacokinetic interaction
between atazanavir and PPIs and H2-receptor antagonists, data
from small studies suggest that the impact on virological outcomes
may not be clinically significant. Although plasma atazanavir
concentrations were not measured, no negative effect on the viral
load was observed in a retrospective case review of 14 atazanavir-
treated, antiretroviral-experienced patients using acid-reducing
agents, PPI (n = 10), H2-receptor antagonists (n = 3) or didan-
osine-buffered tablets (n = 1).[46] Patients used either atazanavir
with low-dose ritonavir (n = 8) or atazanavir without ritonavir
(n = 6) doses for a median of 24 weeks (range 8–76 weeks).
In a retrospective review of pharmacy and medical records,
virological outcomes of patients who received an antiretroviral
regimen that included atazanavir/ritonavir with (n = 10) or without
(n = 66) concomitant PPI use for at least 6 weeks were compared
to assess the clinical relevance of this drug-drug interaction.[47]
PPI-treated patients used rabeprazole 20 mg (n = 8) or 40 mg
(n = 1), or omeprazole 20 mg once daily (n = 1) for a mean
duration of 21.6 weeks (range 6–52 weeks). Virological responses
reported for PPI-treated and non-PPI-treated patients were com-
parable: HIV RNA <50 copies/mL (70% vs 63%) and <500
copies/mL (90% vs 83%). While both virological outcome assess-
ments suggested a lack of effect of this potential drug-drug inter-
action, the small numbers of patients evaluated, the wide range of
follow-up periods and the lack of pharmacokinetic parameters
limit the interpretation of these clinical observations. In another
retrospective review,[48] virological and immunological responses
were determined in HIV-positive patients who were receiving
atazanavir (with or without ritonavir) at recommended doses con-
currently with either omeprazole 20 mg once daily (n = 15) or
pantoprazole 40 mg once daily (n = 17) for a mean duration of 17
and 4 months, respectively. Three patients in each PPI group had a
negative therapeutic outcome defined as a 0.5 log10 increase in the
viral load and/or a CD4 count reduction of >75 cells/mL. Plasma
atazanavir trough concentrations measured in four patients were
above the expected therapeutic minimum concentration. A third
retrospective review consisting of 12 HIV-infected patients indi-
cated no clinically relevant effect of PPI and atazanavir coadmin-
istration.[49] Five of the 12 subjects had a viral load of <400 copies/
mL at initiation of atazanavir, with or without ritonavir, which was
maintained during concurrent atazanavir and PPI therapy. Four
additional subjects initiated atazanavir, with or without ritonavir,
with a PPI and achieved a viral load of <400 copies/mL. The
duration of concurrent therapy was 4–23 months in these nine
subjects. In the three remaining patients who did not achieve a
Clin Pharmacokinet 2008; 47 (2)
82
viral load of <400 copies/mL, poor adherence may have impaired
the response. A recent single case report[50] suggested no loss of
the virological or immunological response in a patient switched to
atazanavir (150 mg twice daily) in combination with omeprazole
(20 mg once daily) for 12 weeks, contrary to recommended
atazanavir administration and coadministration with a PPI.
Several variables may contribute to the inconsistent results and
conclusions of these pharmacokinetic and clinical studies of con-
current atazanavir and PPI use. First, plasma atazanavir concentra-
tions measured in healthy subjects are approximately twice those
measured in HIV-infected patients.[14] Therefore, pharmacokinetic
assessments of atazanavir conducted in healthy subjects may not
be clinically applicable to HIV-infected populations. Moreover,
the broad range of Cmin values reported in the HIV patient co-
horts[41,43] demonstrate a high degree of interpatient variability, an
observation also reported by other investigators.[51] Hence, until
strong correlations between plasma atazanavir concentrations and
the virological or clinical outcome have been established, these
and other protease inhibitor drug concentration data should be
interpreted with caution. The particular PPIs used, the dose and the
timing of administration relative to atazanavir may also have
varying effects on plasma atazanavir concentrations. Formal stud-
ies in healthy subjects used high-dose omeprazole (40 mg once
daily) exclusively, whereas the studies in HIV-infected patients
used mostly low doses of omeprazole and various other PPIs. Both
the timing of drug doses relative to blood collection and the timing
of atazanavir administration relative to PPI administration were
standardized and well controlled in the healthy subject studies,
whereas the studies of HIV-infected patients used variable meth-
ods with less controlled drug administration.
This uncertainty regarding the effect of concurrent PPI use on
plasma atazanavir concentrations is further complicated by drug-
drug interactions between atazanavir and other antiretrovirals such
as tenofovir and didanosine. Because of the negative effect of
tenofovir on plasma atazanavir concentrations,[52] it is recommen-
ded that ritonavir-boosted atazanavir is used when combined
with tenofovir.[14] Although data are limited, the concurrent
use of atazanavir/ritonavir with tenofovir and a PPI in HIV-
infected patients has not been shown to negatively affect the
atazanavir Cmin or virological outcomes.[43,47] When combined
with atazanavir, the buffered tablet formulation of didanosine has
been shown to reduce the mean atazanavir AUC (87%), Cmax
(89%) and Cmin (84%) in healthy subjects.[53] The more commonly
used enteric-coated capsule formulation of didanosine requires
fasted conditions for proper absorption, while atazanavir should be
taken with food for proper absorption. Therefore, dosing recom-
mendations indicate that atazanavir should be taken with food at
© 2008 Adis Data Information BV. All rights reserved.
Falcon & Kakuda
least 2 hours before or 1 hour after taking the enteric-coated
capsule or buffered tablet formulations of didanosine.
2.1.2 In Combination with Histamine H2-Receptor Antagonists
Use of H2-receptor antagonists has also been shown to alter
atazanavir pharmacokinetics in formal drug-drug interaction stud-
ies in healthy subjects (table II). Reductions in plasma atazanavir
concentrations were observed with concurrent use of the
H2-receptor antagonist famotidine in healthy subjects. Relative to
concentrations achieved with atazanavir 400 mg once daily, coad-
ministration of famotidine 40 mg twice daily reduced the mean
atazanavir AUC (41%) and Cmin (42%). However, temporal sepa-
ration of atazanavir and famotidine doses or use of ritonavir-
boosted atazanavir (atazanavir/ritonavir 300 mg/100 mg once
daily) with famotidine resulted in atazanavir exposure comparable
to that achieved with atazanavir 400 mg alone.[22] In an evaluation
of atazanavir/ritonavir 300 mg/100 mg once daily, coadministra-
tion of famotidine 40 mg twice daily reduced the mean atazanavir
AUC (18%) and Cmin (28%).[22] When coadministered with a
higher atazanavir dose (atazanavir/ritonavir 400 mg/100 mg once
daily), atazanavir exposure was comparable with that observed
with the standard atazanavir/ritonavir dosage (300 mg/100 mg
once daily). The investigators also reported that the atazanavir
AUC and Cmax values were highly correlated with the average
6-hour gastric pH (r = –0.7).[22] A recently reported study by the
same group[23] indicated that famotidine (20 mg twice daily and
40 mg once or twice daily) significantly reduced the mean
atazanavir Cmin (18–33% depending on the schedule) regardless of
temporal separation of its dosing (concurrent, 2 hours after and
12 hours after) in relation to coadministration of atazanavir/ritona-
vir 300 mg/100 mg plus tenofovir 300 mg once daily in healthy
subjects. When the dosage of famotidine could be compared
(20 mg vs 40 mg twice daily) using the same temporal dosing
schedule (2 hours after coadministration of atazanavir/ritonavir
with tenofovir), the degree of the reduction in atazanavir exposure
appeared to be related to the famotidine dose (mean Cmax [4% vs
11%], Cmin [18% vs 33%], and AUC [4% vs 12%]), although it
should be noted that this comparison involved separate popula-
tions of healthy subjects.
Based on these data in healthy subjects, different atazanavir
dose recommendations are indicated according to patient type. For
antiretroviral-naive patients, atazanavir 400 mg once daily may be
taken with food at least 2 hours before or at least 10 hours after
taking an H2-receptor antagonist, or ritonavir-boosted atazanavir
(atazanavir/ritonavir 300 mg/100 mg once daily) may be taken
with an H2-receptor antagonist with no regard to the timing of
doses. For antiretroviral-experienced patients, it is recommended
that the atazanavir/ritonavir 300 mg/100 mg once-daily dose is
Clin Pharmacokinet 2008; 47 (2)
HIV Protease Inhibitor Interactions
taken with food either at least 2 hours before or at least 10 hours
after an H2-receptor antagonist. Although pharmacokinetic data in
healthy subjects showed that a higher atazanavir 400 mg dose
boosted with ritonavir achieved atazanavir exposure comparable
with standard atazanavir/ritonavir 300 mg/100 mg once-daily dos-
ing, long-term use of the higher atazanavir dose in antiretroviral-
experienced patients may contribute to increased adverse events or
other pharmacokinetic concerns.
2.2 Darunavir
In a randomized, three-way, crossover study,[27] coadministra-
tion of boosted darunavir with either omeprazole or ranitidine
showed no effect on steady-state plasma darunavir pharmaco-
kinetics. Healthy subjects (n = 18) each received the following:
darunavir/ritonavir 400 mg/100 mg twice daily alone or in combi-
nation with omeprazole 20 mg once daily or ranitidine 150 mg
twice daily for 4 days, followed by one morning dose on day 5.
Each treatment phase was separated by a washout period of at least
7 days. Relative to darunavir/ritonavir alone, concurrent use of
omeprazole or ranitidine had no significant effect (p > 0.05) on the
mean AUC from 0 to 12 hours (AUC12), Cmax and Cmin of
darunavir after multiple dosing. While data in HIV-infected pa-
tients are not available, these results in healthy subjects suggest
that darunavir/ritonavir may be coadministered with either
omeprazole or ranitidine without the need for any dose adjustment.
There appear to be no published studies on the potential for
interaction between darunavir and antacids.
2.3 Fosamprenavir and Amprenavir
The solubility of fosamprenavir, a prodrug of amprenavir, has
been shown to decrease as the pH exceeds 3.3.[15] This pH-
dependant solubility presents a risk of negative drug-drug interac-
tions if fosamprenavir is coadministered with acid-reducing
agents. Also, fosamprenavir contains a phosphate group capable of
binding to the metal cations present in antacids, which may further
affect the solubility of fosamprenavir or its conversion to the
active form, amprenavir.[17]
Pharmacokinetic studies in healthy subjects have shown vary-
ing effects of antacids, H2-receptor antagonists and PPIs when
coadministered with fosamprenavir (measured as plasma am-
prenavir concentrations) [table II]. In a single-dose, cross-
over study,[17] healthy subjects (n = 26) received fosamprenavir
1400 mg simultaneously with 30 mL of an oral antacid (magnesi-
um hydroxide 1800 mg/aluminum hydroxide dried gel 3600 mg,
Maalox® 1 TC). Following a 4- to 7-day washout period, these
1 The use of trade names is for product identification purposes only and does not imply endorsement.
© 2008 Adis Data Information BV. All rights reserved.
83
same subjects received ranitidine 300 mg 1 hour before taking
fosamprenavir 1400 mg. While antacid use reduced the mean
amprenavir AUC24 by 18% and Cmax by 35% and increased the
concentration at 12 hours [C12] by 14%, these changes were not
considered clinically significant by the investigators. Concurrent
ranitidine administration reduced the mean amprenavir AUC24
and Cmax to a greater degree (by 30% and 51%, respectively), and
yet the C12 remained unchanged.[17] Based on these findings, it is
suggested that ranitidine and other H2-receptor antagonists be used
with caution when coadministered with fosamprenavir.
An evaluation of fosamprenavir, with and without ritonavir-
boosting, when coadministered with esomeprazole showed no
effect on steady-state amprenavir pharmacokinetics. Healthy sub-
jects (n = 56) received esomeprazole 20 mg once daily for 7 days
and then added either fosamprenavir 1400 mg twice daily or
fosamprenavir/ritonavir 700 mg/100 mg twice daily for 14 days.
Following a 21- to 28-day washout period, subjects then received
fosamprenavir 1400 mg twice daily or fosamprenavir/ritonavir
700 mg/100 mg twice daily without esomeprazole for another
14 days. With concurrent esomeprazole, the mean amprenavir
AUC12, Cmax and C12 remained unchanged in both fosamprenavir
treatment arms, suggesting that these agents may be safely
coadministered.[28] The only significant effect was an increase
(55%) in the esomeprazole AUC12 after coadministration of es-
omeprazole 20 mg once daily with fosamprenavir 1400 mg twice
daily. It should be noted that fosamprenavir and esomeprazole
were simultaneously administered in a fasted state. Therefore, the
effects of staggered esomeprazole dosing or simultaneous dosing
of esomeprazole and fosamprenavir with food are unknown.
Data from HIV-infected patients are limited to one case report
that showed no drug-drug interaction with concurrent use of
fosamprenavir/ritonavir and esomeprazole.[44] It is not possible to
draw any conclusions from this study. Given that steady-state
amprenavir pharmacokinetics are comparable between HIV-in-
fected patients and healthy subjects,[28] the results of the previous-
ly described acid-reducing agent studies in healthy subjects are
likely to be relevant to HIV-infected populations.
The conflicting observations regarding the impact of the H2-
receptor antagonist ranitidine and the PPI esomeprazole on plasma
amprenavir concentrations are surprising, since both medications
are effective acid-reducing agents. Moreover, these divergent find-
ings cannot be explained by inferring enzyme inhibition, because
ranitidine is not an inhibitor of CYP,[54] unlike esomeprazole,
which inhibits CYP2C19.[55] Other differences in the study design,
e.g. the dose or potency of the acid-reducing treatment, may have
contributed to these conflicting results. One plausible explanation
Clin Pharmacokinet 2008; 47 (2)
84
may be the timing of administration and the amount of time
necessary for esomeprazole activity to occur. If esomeprazole and
fosamprenavir are administered simultaneously, gastric acidity
may remain high long enough for fosamprenavir to be converted to
amprenavir and absorbed effectively. Similarly, acid-reducing
agents that have a shorter duration of effect might also be sched-
uled in a way that does not interfere with fosamprenavir absorp-
tion. Separation of dosing and/or ritonavir-boosting is suggested,
as well as careful monitoring of the antiretroviral treatment res-
ponse.[3]
There is little published information on the potential interaction
between amprenavir and acid-reducing agents. It is advised that
amprenavir is administered at least 1 hour apart from antacids or
the buffered formulation of didanosine, as these medications were
stated to decrease plasma amprenavir concentrations when admin-
istered concurrently, while no information is given concerning
coadministration with H2-receptor antagonists or PPIs.[56] How-
ever, the mean amprenavir AUC12 and C12 were not significantly
affected by concurrent administration in the fasting state of a
single dose of buffered or enteric-coated didanosine (400 mg) with
amprenavir 600 mg twice daily for 4 days in a study of 16 healthy
subjects.[57]
2.4 Indinavir
Animal studies have indicated that the aqueous solubility of
indinavir is highly dependent on the pH.[16] The results of formal
drug-drug interaction studies are summarized in table II. Single-
dose studies with unboosted indinavir (which is currently not used
clinically) in small numbers of healthy subjects indicated no
significant interaction with cimetidine[18] or omeprazole.[29] In a
randomized, placebo-controlled, crossover study in 14 healthy
subjects, Rublein et al.[30] determined the effect of administration
of omeprazole 40 mg once daily for 7 days on the pharmaco-
kinetics of a single dose of indinavir 800 mg or indinavir/ritonavir
800 mg/200 mg. Coadministration of omeprazole 40 mg with
unboosted indinavir decreased the mean indinavir AUC24 and C12
by 47% (p = 0.001) and 55% (p > 0.05), respectively. When rito-
navir plus indinavir was combined with coadministration of
omeprazole, the mean indinavir AUC24 increased by 55%, which
was similar to the value attained without omeprazole coadmin-
istration, and suggests that ritonavir boosting counteracts the ef-
fect of omeprazole on indinavir exposure.
Data regarding the combined use of indinavir and PPIs have
been summarized in a therapeutic drug monitoring database for
nine HIV-infected patients who received indinavir 800 mg three
times daily and omeprazole 20–40 mg once daily.[58] Plasma
indinavir concentrations in these patients were compared with
© 2008 Adis Data Information BV. All rights reserved.
Falcon & Kakuda
those of an average population curve of 15 other patients also
treated with indinavir 800 mg three times daily and were found to
be below, above and within the 95% CI of the population curve in
four, one and four of the nine patients, respectively. While these
results suggested a potential drug-drug interaction between in-
dinavir and omeprazole, interpatient variability of indinavir
pharmacokinetics may partially explain some of the differences in
plasma indinavir concentrations. The small number of patients and
uncontrolled study design also limit the clinical interpretation of
these data.
There appear to be no published studies on the potential for
interaction between indinavir and antacids, although simultaneous
administration would be expected to decrease indinavir exposure
given the effects of buffered didanosine. Simultaneous single-dose
administration of buffered didanosine 200 mg and indinavir
800 mg in 16 subjects has been reported to significantly decrease
the mean indinavir AUC (84%) and Cmax (82%), whereas there
was little effect when buffered didosine was administered 1 hour
after the indinavir dose (the currently recommended temporal
scheduling), as the mean indinavir AUC and Cmax were decreased
by 11% and 4%, respectively.[59] Administration of buffered
didanosine 400 mg 1 hour before indinavir 800 mg had no statisti-
cally significant effect on the mean indinavir AUC and Cmax
(decreases of 5% and 15%, respectively) in a single-dose study of
12 HIV-infected patients.[60]
2.5 Lopinavir
Lopinavir solubility does not appear to be pH dependent.[21]
Therefore, the gastric pH and the effects of acid-reducing agents
would not be expected to influence plasma lopinavir concentra-
tions. In a retrospective analysis of data from a clinical trial
comparing the soft-gel capsule formulation of lopinavir/ritonavir
800 mg/200 mg once daily and 400 mg/100 mg twice daily for
48 weeks in HIV-infected patients (n = 190),[31] patients were
identified as acid-reducing agent ‘users’ (PPIs, H2-receptor ant-
agonists, or antacids) or ‘non-users’. The Cmin values for lopinavir
and ritonavir were available for 8–10 and 4–7 ‘users’ versus 76–95
and 45–48 ‘non-users’ in the once-daily and twice-daily groups,
respectively, at weeks 4, 8, 16, 24 and 48. The patient numbers
varied dependent on how many patients were assessed and had
evaluable data at each timepoint. The mean lopinavir Cmin was
50% (p = 0.01) and 71% (p = 0.06) higher in ‘users’ than in ‘non-
users’ at weeks 24 and 48, respectively, in the group receiving
lopinavir/ritonavir 800 mg/200 mg once daily, whereas there was
no difference in the group receiving lopinavir/ritonavir 400 mg/
100 mg twice daily (table II). The Cmax and AUC values were not
significantly changed. The same group[61] has recently re-analysed
Clin Pharmacokinet 2008; 47 (2)
HIV Protease Inhibitor Interactions
these data with the addition of 38 HIV-infected patients from
another clinical trial that compared the same formulation of lopi-
navir/ritonavir 800 mg/200 mg once daily and 400 mg/100 mg
twice daily for 48 weeks. There was still no significant reduction
in the Cmax, Cmin or AUC values for lopinavir in ‘users’ of acid-
reducing agents, although the Cmin values remained higher in
patients receiving lopinavir/ritonavir once daily.
After the introduction of the new lopinavir/ritonavir tablet
formulation, a more formal assessment of concurrent omeprazole
or ranitidine administration was undertaken in healthy subjects.[21]
In this parallel-group study, healthy subjects (n = 11–12 per treat-
ment) received either lopinavir/ritonavir 800 mg/200 mg once
daily or 400 mg/100 mg twice daily as the new tablet formulation
for 15 days, with the addition of either omeprazole 40 mg once
daily for days 11–15 or a single dose of ranitidine 150 mg on day
11. Relative to either dose of lopinavir/ritonavir alone, coadmin-
istration with either omeprazole or ranitidine did not significant-
ly alter the mean lopinavir AUC and Cmax values (table II),
although the mean lopinavir Cmin values were significantly re-
duced (p < 0.05) during coadministration with lopinavir/ritonavir
800 mg/200 mg once daily (19–20%) but not with lopinavir/
ritonavir 400 mg/100 mg twice daily (1–3%).
The results of the pharmacokinetic observations reported in
HIV-infected clinical trial participants and in formal drug-drug
interaction studies in healthy volunteers suggest that exposure to
lopinavir is not altered to a clinically relevant degree when lopina-
vir/ritonavir twice daily is used in combination with acid-reducing
agents. The decrease in the lopinavir Cmin observed when the new
tablet formulation of lopinavir/ritonavir 800 mg/200 mg was ad-
ministered once daily with ranitidine or omeprazole warrants
further investigation and is difficult to reconcile with earlier obser-
vations that lopinavir Cmin values were increased in HIV patients
receiving long-term lopinavir/ritonavir 800 mg/200 mg once daily
as the older soft-gel formulation when comparing ‘users’ and
‘non-users’ of acid-reducing agents.
There appear to be no published studies on the potential for
interaction between lopinavir and antacids.
2.6 Nelfinavir
In a two-period, fixed-sequence study,[19] 20 healthy subjects
received nelfinavir 1250 mg twice daily alone followed by coad-
ministration with omeprazole 40 mg once daily, each for 4 days,
separated by a 1-week washout period. The mean AUC, Cmax, and
Cmin of nelfinavir were significantly reduced (36–39%) during
coadministration with omeprazole (table II). Furthermore, the
mean AUC, Cmax and Cmin of its active metabolite were decreased
by 92%, 88% and 75%, respectively. The investigators concluded
© 2008 Adis Data Information BV. All rights reserved.
85
that, when coadministered with omeprazole, the systemic expo-
sure of nelfinavir and its active metabolite are reduced significant-
ly, which may result in loss of the virological response and
development of resistance. The major oxidative metabolite of
nelfinavir has in vitro anti-HIV activity comparable with that of
the parent drug, although circulating levels of the active metabolite
are substantially lower than those of the parent drug.[62] It is
therefore unlikely that the reduction in the active metabolite with
omeprazole coadministration is clinically significant. However,
coadministration of omeprazole and nelfinavir is not recommen-
ded.[32] There appear to be no published studies on the potential for
interaction between nelfinavir and antacids or H2-receptor ant-
agonists. On the basis of a single-dose study in ten HIV-infected
patients,[59] the administration of buffered didanosine 200 mg 1
hour after nelfinavir 750 mg (the currently recommended temporal
separation for these agents) increased the mean nelfinavir AUC by
12% and had no effect (or affected it by <10%) on the mean
nelfinavir Cmax.
2.7 Ritonavir
There do not appear to be any published studies on the inter-
action between ritonavir administered as a single agent with
antacids, H2-receptor antagonists or PPIs. It has been reported that
no clinically significant interaction was observed with respect to
the mean ritonavir AUC and Cmax during coadministration of
buffered didanosine 200 mg twice daily and ritonavir 600 mg
twice daily for 4 days in 12 subjects.[59] In studies where ritonavir
was administered in combination with lopinavir (see section 2.5
for details), there has been no evidence that coadministration of
acid-reducing agents decreases the bioavailability of ritonavir
(table II). However, one study[31] reported increases in the mean
ritonavir Cmin values of 63% and 33%, respectively, after receiv-
ing lopinavir/ritonavir 800 mg/200 mg once daily or 400 mg/
100 mg twice daily as the old soft-gel capsule formulation for 48
weeks in HIV patients who were using concurrent acid-reducing
agents compared with those who were not; these increases, al-
though substantial, were not statistically significant, and the num-
bers of patients analysed as ‘users’ on each dosage (ten and four,
respectively, were low). In a recent study,[33] omeprazole 40 mg
once daily for 5 days decreased the mean ritonavir AUC12 (19%)
and Cmax (17%) after oral administration of a single dose of
tipranavir/ritonavir 500 mg/200 mg in 15 healthy subjects. It
should be noted that the Cmin values were not reported in this
single-dose study of tipranavir/ritonavir, and nor was the timing of
omeprazole administration in relation to that of tipranavir/ritona-
vir. There are no warnings or contraindications against use of
ritonavir with acid-reducing agents.[63]
Clin Pharmacokinet 2008; 47 (2)
86
2.8 Saquinavir
Saquinavir has low bioavailability, with 30% of an oral dose
being absorbed and only 4% reaching the systemic circulation.[64]
The absorption of saquinavir is dependent on intestinal
CYP3A4.[65] It is therefore now recommended that saquinavir is
administered in combination with ritonavir to ensure adequate
absorption. Studies using older, unboosted formulations of sa-
quinavir showed that coadministration of ranitidine[34] or cime-
tidine[35] resulted in increased plasma saquinavir concentrations in
healthy subjects, an effect that appeared to be unrelated to the
effects of these H2-receptor antagonists on gastric acidity (table
II).
In a two-sequence study,[36] 18 healthy subjects received the
currently recommended dose for saquinavir film-coated tablets
boosted with ritonavir (saquinavir/ritonavir 1000 mg/100 mg
twice daily) for 15 days, with coadministration of omeprazole
40 mg once daily on days 11–15 (table II). Relative to saquinavir/
ritonavir alone, concurrent administration of omeprazole substan-
tially increased the mean saquinavir AUC12 (82%), Cmax (75%)
and Cmin (106%). The interaction between omeprazole and sa-
quinavir has recently been reported in a crossover study of
12 HIV-infected patients receiving saquinavir/ritonavir twice
daily.[37] Omeprazole 40 mg once daily for 6 days administered
simultaneously or 2 hours before protease inhibitors increased the
saquinavir AUC12 (54% and 67%, respectively), Cmin (73% and
97%, respectively) and Cmax (55% and 65%, respectively), where-
as ritonavir pharmacokinetics were not significantly changed.
Safety data in both studies indicated that the increased saquinavir
exposure did not result in an increased number of adverse events.
Of note, these studies were limited in duration and in healthy
subjects. Among 56 HIV-infected patients treated with saquinavir/
ritonavir 1000 mg/100 mg twice daily for 48 weeks, high plasma
concentrations of saquinavir were significantly associated with
constitutional adverse effects.[66] Whether long-term coadministra-
tion of saquinavir and acid-suppressing agents leads to further
adverse effects has not been formally evaluated.
The potential may therefore exist for increased saquinavir
exposure when it is coadministered with H2-receptor antagonists
or PPIs, probably via mechanisms unrelated to their acid-neutraliz-
ing properties. There are no warnings or contraindications against
saquinavir/ritonavir use in combination with acid-reducing
agents.[67] There do not appear to be any published studies on the
potential for interaction between saquinavir and antacids.
2.9 Tipranavir
Studies have shown differing effects of acid-reducing agents on
the pharmacokinetics of tipranavir (table II). A single-dose phar-
© 2008 Adis Data Information BV. All rights reserved.
Falcon & Kakuda
macokinetic evaluation in 23 healthy subjects showed that antacid
use significantly reduced tipranavir plasma concentrations. The
volunteers received the recommended dose of ritonavir-boosted
tipranavir (tipranavir/ritonavir 500 mg/200 mg twice daily) for
8 days, and then a single dose of tipranavir/ritonavir 500 mg/
200 mg with 20 mL of antacid (magnesium hydroxide 100 mg/
aluminium hydroxide 3600 mg) was coadministered. Concurrent
antacid use reduced the mean tipranavir AUC12, Cmax and C12 by
25–29% (p < 0.01).[38] Accordingly, it is recommended that
tipranavir/ritonavir be administered separately from antacids to
reduce the risk of inadequate tipranavir absorption in patients
treated with tipranavir/ritonavir who use antacids.[20] In a recent
study,[33] omeprazole 40 mg once daily for 5 days had no statisti-
cally significant effect on the tipranavir AUC12 (0%) and Cmax
(5% increase) after oral administration of a single dose of
tipranavir/ritonavir 500 mg/200 mg in 15 healthy subjects. It
should be noted that Cmin values were not reported in this single-
dose study of tipranavir/ritonavir, nor was the timing of
omeprazole administration in relation to that of tipranavir/ritona-
vir. There appear to be no published studies on the potential for
interaction between tipranavir and H2-receptor antagonists.
3. Discussion
The pH dependency of the aqueous solubility of some protease
inhibitors (e.g. atazanavir, fosamprenavir and indinavir) is well
documented. Consequently, the gastric pH can have a marked
effect on the absorption and bioavailability of these agents. How-
ever, this is not a class effect that is applicable to all protease
inhibitors. Coadministration of acid-reducing agents such as
antacids, H2-receptor antagonists or PPIs has a profound effect on
the gastric pH and would therefore be expected to affect the
bioavailability of protease inhibitors that have pH-dependent solu-
bility. There is also the potential for specific drug-drug interaction
between specific protease inhibitors and specific acid-reducing
agents by other mechanisms.
Most patients receiving antiretroviral therapy experience gas-
trointestinal adverse effects at some time and often have to use
acid-reducing therapy to control symptoms. Initially, they may
turn to intermittent use of OTC medications and eventually to
prescription medication. Regardless, it is important to know
whether there are any negative drug-drug interactions between
protease inhibitors and acid-reducing agents. During the develop-
ment of protease inhibitors, formal drug-drug interaction studies
are an essential component of research, and such studies are
usually performed in healthy subjects. However, published infor-
mation on potential interactions between each approved protease
inhibitor and representative agents of each of the three main
Clin Pharmacokinet 2008; 47 (2)
HIV Protease Inhibitor Interactions
classes of acid-reducing therapies (antacids, H2-receptor antagon-
ists and PPIs) has not been systematically recorded. We reviewed
the published literature on these interactions and included infor-
mation on the buffered tablet formulation of didanosine.
Given the frequent use of acid-reducing agents by patients with
HIV, special attention must be paid to concomitant conditions and
medications when selecting a protease inhibitor for antiretroviral
therapy. It is possible that patients with HIV who are seeking
gastrointestinal symptom control may unwittingly sabotage the
efficacy of their antiretroviral therapy by using acid-reducing
agents. Moreover, these negative drug-drug interactions may not
be identified by the usual safety net, because patients do not
consistently report the use of OTC medications to their healthcare
provider. Initial and ongoing patient counselling must include
information on the interactions of OTC and prescription acid-
reducing agents with protease inhibitors and should include ac-
ceptable options for controlling gastrointestinal symptoms that
may be experienced as an adverse effect of HAART. It is critical
for patients to understand these interactions and the associated
risks, because other providers involved in the care of persons with
HIV (e.g. in the contexts of primary care, the emergency room or
urgent care) may not be familiar with the interactions and might
administer these medications without knowing their potential im-
pact. Although this may increase counselling time with patients, it
would help to ensure the maximal antiviral effect by maintaining
optimal drug exposure while maintaining a high barrier to the
development of drug resistance. Identifying potential negative
drug-drug interactions affecting protease inhibitor bioavailability
can help to optimize antiretroviral therapy for patients with HIV
disease, but only if these interactions are generally known.
Clinicians are beginning to use electronic medical records to
assess the potential extent of this problem.
The individual effect of acid-reducing agents on protease inhib-
itor concentrations is difficult to predict because of the large
interpatient variability of plasma concentrations of some protease
inhibitors. Furthermore, we feel that the ability to extrapolate
within a class of acid-reducing agents is limited by differences in
individual drug effects on the gastric pH, specific metabolic path-
ways and dosing schedules, and any generalizations might be
potentially misleading. Studies have suggested that some of the
interactions between protease inhibitors and acid-reducing agents
may be mitigated by temporal separation of dose administration.
Education of patients about the importance of reporting the use of
any acid-reducing agents, whether OTC or prescription, is essen-
tial to optimizing the treatment of HIV, as is the need for care
providers and patients to agree upon strategies for managing
gastric symptoms and HIV disease simultaneously. Clinicians
should be aware of the potential drug-drug interactions between
© 2008 Adis Data Information BV. All rights reserved.
87
some protease inhibitors and acid-reducing agents. Some
clinicians and investigators consider that the clinical significance
of the potential drug-drug interaction between certain protease
inhibitors and acid-reducing agents in HIV-infected patients may
be minimal, and that with careful monitoring, concurrent use may
not be prohibitive in all patients. However, there may well be a
clinically significant impact over the long term for two reasons:
firstly, because adherence may well slip as the timing of drugs
within a regimen become more complex (with or without food, 2
hours after other medications); and secondly, because of the
genetic barrier to resistance. Ritonavir-boosted protease inhibitors
are used specifically to obtain higher drug concentrations and
prevent development of resistance. With lower concentrations, the
likelihood of resistance development may possibly be more simi-
lar to that of an unboosted protease inhibitor, and patients might
fail with protease inhibitor mutations, unlike the general trend
showing no primary protease inhibitor mutations when failing a
ritonavir-boosted protease inhibitor. Further study is needed to
better clarify the potential for clinically significant interaction
between individual protease inhibitors and the major classes of
acid-reducing therapy, particularly with respect to the mainten-
ance of clinically effective minimum protease inhibitor concentra-
tions in practice for HIV-infected individuals and the potential risk
of resistance development.
4. Conclusion
Negative drug-drug interactions occur with fosamprenavir
when it is taken concurrently with H2-receptor antagonists or
antacids, although contradictory data suggest a minimal effect of
low-dose esomeprazole on plasma fosamprenavir concentrations.
Atazanavir bioavailability is also significantly decreased by con-
current use of acid-reducing therapy with H2-receptor antagonists
and PPIs but appears compensated by ritonavir to some extent;
however, it is usually recommended that atazanavir administration
is separated from that of acid-reducing therapy with H2-receptor
antagonists, and concurrent use of atazanavir and PPIs is not
recommended. Plasma concentrations of indinavir, lopinavir and
tipranavir may be decreased by negative interactions with some
products that reduce gastric acidity. Plasma concentrations of
nelfinavir and its active metabolite are significantly decreased by
coadministration with omeprazole, and so coadministration of
nelfinavir and PPIs is contraindicated. In contrast to all other
protease inhibitors, exposure to saquinavir has been shown to
increase when the gastric pH is raised by acid-reducing agents.
No clinically meaningful interaction appears to occur between
darunavir or ritonavir with acid-reducing therapy.
Clin Pharmacokinet 2008; 47 (2)
88
Acknowledgements
Ronald Falcon is the Senior Medical Director at Tibotec Therapeutics and
a former Medical Director of HIV at Roche Labs, and holds stock in Johnson
& Johnson. Thomas Kakuda is the Director of Clinical Pharmacology at
Tibotec Inc. and a former Medical Science Liaison at Roche Labs, and holds
stock in Johnson & Johnson. The authors thank Peter A. Todd, PhD, for
his assistance in manuscript editing and preparation, and acknowledge
Lori DeLaitsch (Clinical Affairs, Tibotec Therapeutics) for her valuable
contribution. Financial support for the preparation of this review was provided
by Tibotec Therapeutics. The authors have no other conflicts of interest that
are directly relevant to the content of this review.
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Correspondence: Dr Ronald W. Falcon, Tibotec Therapeutics, 430 Route 22
East, Bridgewater, NJ 08807, USA.
E-mail: rfalcon@tttus.jnj.com
Clin Pharmacokinet 2008; 47 (2)