Antiviral Therapy 2015; 20:425–432 (doi: 10.
3851/IMP2932)
Original article
A novel ritonavir paediatric powder formulation
is bioequivalent to ritonavir oral solution with a
similar food effect
Ahmed Hamed Salem1,2*, Yi-Lin Chiu1, Joaquin M Valdes3, Angela M Nilius3, Cheri E Klein1
1
Clinical Pharmacology and Pharmacometrics, AbbVie, North Chicago, IL, USA
2
Clinical Pharmacy, Ain Shams University, Cairo, Egypt
3
Infectious Diseases Development, AbbVie, North Chicago, IL, USA
*Corresponding author e-mail: sale0074@umn.edu
Background: A novel ritonavir oral powder formulation
has been developed to eliminate the alcohol and propyl-
ene glycol contents in the current ritonavir oral solution
for paediatric use. Two clinical studies were conducted to
assess the bioequivalence of the powder formulation to
the marketed oral solution and to evaluate the effect of
food and vehicles on bioavailability.
Methods: Study 1 was a randomized, partial-crossover,
4-period study in 48 subjects. Regimens included: oral
solution under moderate-fat conditions, powder formu-
lation in water under fasting, moderate-fat or high-fat
conditions, and powder formulation in chocolate milk
or pudding under moderate-fat conditions. Study 2 was
a randomized, crossover, 4-period study in 24 subjects.
Subjects were randomized to a sequence of the oral solu-
tion and powder formulation in water, infant formula
and apple sauce, all under moderate-fat conditions.
Introduction
Ritonavir is a peptidomimetic inhibitor of HIV-1 and
HIV-2 proteases. Ritonavir (marketed as Norvir®) was
first approved in the United States (US) and the European
Union (EU) in 1996 and is indicated in combination with
other antiretroviral (ARV) agents for the treatment of
HIV-1-infected patients (adults and children older than 1
month of age in the US and 2 years of age and older in the
EU). It is marketed in 159 countries globally.
In recent years, ritonavir has been independently
approved to be administered as a pharmacokinetic
enhancer at doses up to 200 mg once or twice daily for
the adult as well as paediatric populations, according
to the approved labels of the following HIV protease
inhibitors (PIs): amprenavir, atazanavir, darunavir, fosa-
mprenavir, lopinavir, saquinavir and tipranavir. When
©2015 International Medical Press 1359-6535 (print) 2040-2058 (online)
AVT-14-OA-3347_Salem.indd 425
Bioavailability comparisons were assessed by the 90% CIs
for the geometric least-squares mean ratios.
Results: Ritonavir powder formulation in water was
found to be bioequivalent to the marketed oral solution.
Ritonavir powder formulation administered in chocolate
milk, pudding, infant formula or apple sauce was bio-
equivalent to the powder formulation administered in
water. Compared with fasting conditions, moderate-fat
and high-fat meals were associated with approximately
25–40% and 35–50% reduction in ritonavir concentra-
tions, respectively.
Conclusions: The novel ritonavir powder formulation is
bioequivalent to marketed ritonavir oral solution under
moderate-fat conditions with a similar effect of meals.
None of the vehicles tested negatively affected the bioa-
vailability, which suggests the potential for use of a broad
range of vehicles for dose preparation.
used as a pharmacokinetic enhancer, ritonavir blocks
the cytochrome P450 (CYP) 3A-mediated metabolism
of the other drug, leading to increased serum levels and
prolonged half-life of the other drug [1].
Ritonavir is available as 100 mg film-coated tablets,
100 mg soft capsules and as an 80 mg/ml oral solution.
A ritonavir oral powder formulation (AbbVie, North
Chicago, IL, USA) for paediatric use was developed to
eliminate the alcohol and propylene glycol contents in
the marketed ritonavir oral solution. Feasibility stud-
ies initially focused on an improved oral solution by
examining the minimum amount of alcohol and pro-
pylene glycol co-solvent required to solubilize the drug
substance. However, even formulation variations based
on lower ritonavir concentrations of 10 to 20 mg/ml,
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 AH Salem et al.
rather than the current 80 mg/ml, still required rela-
tively high levels of alcohol co-solvents to maintain rito-
navir solubility and would have potentially increased
daily alcohol intake for an equivalent therapeutic dose.
Therefore, an alternative ritonavir oral powder formu-
lation that eliminates alcohol and propylene glycol co-
solvents was explored to better meet the needs of the
paediatric population. The two clinical studies reported
here aimed to assess the bioequivalence of the oral
powder to the marketed ritonavir oral solution, assess
the bioavailability of the new formulation under vari-
ous meal conditions and evaluate the bioavailability of
the oral powder when administered in chocolate milk,
pudding, infant formula or apple sauce.
Methods
Design of the studies
Two studies (studies 1 and 2) were performed to assess
the bioavailability of the ritonavir oral powder (AbbVie)
compared to the marketed Norvir® oral solution (AbbVie)
under moderate-fat conditions. Study 1 also assessed the
bioavailability of the oral powder in water under various
meal conditions (dosing following a 10-h fast or following
a moderate-fat or high-fat meal) and assessed the effect
of two vehicles (chocolate milk and vanilla pudding) on
the bioavailability of the oral powder. Study 2 assessed
the bioavailability of the oral powder in three vehicles
(water, infant formula, apple sauce). The bioequivalence
and vehicle effect assessments were performed on study
drug administered following a moderate-fat meal, as the
marketed oral solution is recommended to be taken with
food. Safety and tolerability were assessed throughout the
studies based on reported adverse events, vital signs, elec-
trocardiograms and clinical laboratory measurements.
In study 1, single doses of 100 mg ritonavir were sepa-
rated by at least 5 days in a 4-period, randomized, par-
tial-crossover, open-label design in 48 healthy subjects. In
period 1 and 2, all 48 subjects received a single 100-mg
dose of marketed ritonavir oral solution and a single 100-
mg dose of ritonavir oral powder in water administered
under moderate-fat conditions in a crossover fashion. In
period 3 and 4, 24 subjects received single 100-mg doses
of ritonavir oral powder in water administered under
high-fat conditions and under fasting conditions, while
the other 24 subjects received single 100-mg doses of rito-
navir oral powder in chocolate milk administered under
moderate-fat conditions and in vanilla pudding adminis-
tered under moderate-fat conditions, in a crossover fash-
ion. Each dose of study drug was administered orally in
the morning on day 1 of each period.
Approximately 240 ml of water was administered
following each dose. For the fasting regimen, study
drug was administered following an approximate 10-h
fast and at least 4 h before lunch. For the moderate- and
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AVT-14-OA-3347_Salem.indd 426
high-fat regimens, study drug was administered
approximately 30 min after the start of the meal. The
moderate-fat breakfast consisted of approximately 600
Kcal, with approximately 30% from fat. The high-fat
breakfast consisted of approximately 900 Kcal, with
approximately 60% from fat. On the other study days,
subjects received a standardized diet during confine-
ment, providing approximately 30% of the daily calo-
ries from fat, 50% from carbohydrates and 20% from
protein (adding up to approximately 2,000 Kcal/day).
In study 2, single doses of 100 mg ritonavir were
separated by at least 5 days in a 4-period, randomized,
complete crossover, open-label design in 24 healthy
subjects according to a complete-crossover design.
The four regimens, all administered under moderate-
fat meal conditions were: ritonavir powder in water,
infant formula and apple sauce, and ritonavir oral solu-
tion. In addition to the respective vehicle, each subject
consumed approximately 240 ml of water. The caloric
intake came primarily from carbohydrates (54%) while
fat and protein accounted for 29% and 17%, respec-
tively, of the calories. The sequences of regimens were
such that each subject was to receive all four regimens
upon completion of the study.
Study subjects were HIV-negative adults in general
good health who did not require any concomitant med-
ication. These studies were performed in accordance
with the Declaration of Helsinki and its amendments,
and in compliance with the guidelines of Good Clini-
cal Practice. The study protocols and informed consent
forms were approved by the Institutional Review Board
of Research Consultants Review Committee (Austin,
TX, USA). Written informed consent was obtained
from all subjects prior to entry into the study.
Sample collection and assay
In each study, blood samples were drawn for pharma-
cokinetic analysis immediately prior to dosing (0 h) and
at approximately 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 18, 24,
30 and 36 h post-dosing. The concentrations of rito-
navir in plasma were analysed using a validated liquid
chromatography method with tandem mass spectrom-
etry (MS/MS) detection [2]. The correlation coefficients
were equal to or greater than 0.990 and 0.995 for the
respective study 1 and study 2 standard curves. The
coefficients of variation ranged from -2.8% to 2.2%
for study 1 and from -1.4% to 3.1% for study 2. The
lower limits of quantitation for study 1 and study 2
were approximately 9.49 and 9.58 ng/ml, respectively.
Values that were less than the lower limit of quantita-
tion for a given run were reported as zero.
Pharmacokinetic and statistical analyses
Ritonavir pharmacokinetic parameters were calculated
with standard non-compartmental analyses using Phoenix
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26/06/2015 16:30:07

WinNonlin version 5.2.1 (Pharsight Corp., Mountain
View, CA, USA). The maximum observed plasma concen-
tration (Cmax), time to Cmax (Tmax), area under the plasma
concentration–time curve (AUC) to the last measured
plasma concentration (AUCt) and extrapolated to infinite
time (AUC∞) were calculated.
All available data were included in the analyses for
both studies. Three types of assessments were per-
formed: bioequivalence assessment (oral powder in
water versus marketed oral solution), vehicle effect
assessment (oral powder in chocolate milk, vanilla
pudding, apple sauce or infant formula versus oral
powder in water) and food effect assessment (oral
powder in water following a moderate-fat or high-fat
breakfast versus oral powder in water under fasting
conditions). For the bioequivalence assessment, bio-
equivalence was declared if the 90% CIs of the ratios
of AUCt, AUC∞ and Cmax for the oral powder relative
to the oral solution were contained within the 0.80 to
1.25 range.
For all three assessments, a mixed effects analysis
was performed for Tmax, and the natural logarithms of
Cmax, AUCt and AUC∞ using the SAS system version 9.2
software (SAS Institute, Cary, NC, USA). The model
included effects for sequence, period and regimen.
Results
Demographic data for the subjects enrolled in these
studies are shown in Table 1. For study 1, all 48 sub-
jects completed study drug administration for all 4
study periods, and all 48 subjects completed all study
procedures. For study 2, 24 subjects were enrolled in
the study and 23 completed all study procedures. One
Table 1. Demographics of the healthy adult subjects enrolled
in the studies
Study 1 (n=48) Study 2 (n=24)
Sex Analyses from study 2
Male, n (%) 30 (63) 15 (63)
Female, n (%) 18 (37) 9 (37)
Ethnicity/race concentration profiles are similar for the oral solution and
White, n (%) 30 (63) 19 (79)
Black, n (%) 13 (27) 5 (21)
Asian, n (%) 2 (4) –
Multi-race, n (%) 2 (4) –
Native Hawaiian or other 1 (2) –
Pacific Islander, n (%) water was bioequivalent to the oral solution under
Mean age, years ±sd 31.6 ±8.4 37.3 ±10.9
(range) (20–53) (19–55)
Mean weight, kg ±sd 75.4 ±11.7 72.2 ±12.0
(range) (53–115) (55–99)
Mean height, cm ±sd 170 ±9.8 170 ±10.0
(range) (152–200) (153–197)
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Ritonavir paediatric powder formulation
subject discontinued due to a positive cotinine test that
was assessed as not related to study drug.
Analyses from study 1
The mean concentration–time profiles for ritonavir
100 mg dosed as the oral powder and oral solution
are shown in Figure 1. The point estimates of relative
bioavailability and the 90% CIs for ritonavir AUC and
Cmax values for the assessments in study 1 are presented
in Table 2.
Bioequivalence assessment for study 1
The oral powder was bioequivalent to the reference
marketed oral solution when administered following
a moderate-fat meal as the 90% CIs of the geometric
mean ratios for Cmax, AUCt and AUC∞ were contained
within the range of 0.80 to 1.25.
Food effect assessment for study 1
For the oral powder under moderate-fat conditions ver-
sus fasting conditions, a moderate-fat meal decreased
the bioavailability with respect to Cmax, AUCt and AUC∞
by approximately 39%, 25% and 23%, respectively.
Likewise, comparing administration under high-fat
conditions with fasting conditions, a high-fat meal
decreased the bioavailability with respect to Cmax, AUCt
and AUC∞ by approximately 49%, 34% and 32%,
respectively. In Table 3, food effect results from study
1 are compared to those observed with currently mar-
keted oral solution and tablets.
Vehicle effect assessment for study 1
Under moderate-fat conditions, administration of the
oral powder in chocolate milk and in pudding demon-
strated bioequivalent peak and total ritonavir expo-
sures when compared with administration in water
as the 90% CIs of the geometric mean ratios for Cmax,
AUCt and AUC∞ were contained within the range of
0.80 to 1.25.
The mean concentration–time profiles for ritonavir 100
mg in each regimen are shown in Figure 2. The overall
the oral powder. The point estimates of relative bioavail-
ability and the 90% CIs for ritonavir AUC and Cmax values
for the assessments in study 2 are presented in Table 4.
Administration of the oral powder formulation in
moderate-fat conditions. Likewise, oral powder formu-
lation in infant formula and apple sauce under moder-
ate-fat conditions met bioequivalence criteria relative
to the oral powder in water because the 90% CIs of
the ratio of central values for AUCs and Cmax were con-
tained within the range of 0.80 to 1.25.
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 AH Salem et al.

Figure 1. Mean (+sd) ritonavir plasma concentration–time profiles from study 1

A 0.6
Marketed ritonavir oral solution, moderate-fat (n=48)
Ritonavir oral powder in water, moderate-fat (n=48)

Ritonavir concentration, µg/ml 0.5

0.4

0.3

0.2

0.1

0.0
0 4 8 12 16 20 24 28 32 36
Time, h
B 1.2
Ritonavir oral powder in water, moderate-fat (n=24)
Ritonavir oral powder in water, high-fat (n=24)
1.0 Ritonavir oral powder in water, fasting (n=24)
Ritonavir concentration, µg/ml

0.8

0.6

0.4

0.2

0.0
0 4 8 12 16 20 24 28 32 36
Time, h
C 0.7
Marketed ritonavir solution, moderate-fat (n=24)
Ritonavir oral powder in water, moderate-fat (n=24)
0.6 Ritonavir oral powder in chocolate milk, moderate-fat (n=24)
Ritonavir oral powder in pudding, moderate-fat (n=24)
Ritonavir concentration, µg/ml

0.5

0.4

0.3

0.2

0.1

0.0
0 4 8 12 16 20 24 28 32 36
Time, h

(A) Bioequivalence assessment. (B) Food effect assessment. (C) Vehicle assessment.

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 Ritonavir paediatric powder formulation

Table 2. Relative bioavailability and 90% CIs for the bioequivalence assessment of ritonavir from study 1

Central valueb Relative bioavailability

Regimens and pharmacokinetic parameters a
Test Reference Point estimatec 90% CI

Bioequivalence assessment (under moderate-fat conditions)

Oral powder versus oral solution
Cmax 0.39 0.39 1.017 0.947, 1.092
AUCt 4.15 4.02 1.032 0.982, 1.084
AUC∞ 4.36 4.19 1.039 0.992, 1.087
Food effect assessment
Oral powder: high-fat versus fasting
Cmax 0.36 0.72 0.506 0.440, 0.581
AUCt 4.11 6.25 0.658 0.608, 0.711
AUC∞ 4.32 6.39 0.677 0.629, 0.728
Oral powder: moderate-fat versus fasting
Cmax 0.43 0.72 0.606 0.535, 0.686
AUCt 4.68 6.25 0.750 0.692, 0.812
AUC∞ 4.90 6.39 0.767 0.709, 0.829
Vehicle effect assessment (under moderate-fat conditions)
Oral powder in chocolate milk versus oral powder in water
Cmax 0.32 0.36 0.897 0.803, 1.001
AUCt 3.62 3.68 0.983 0.899, 1.074
AUC∞ 3.78 3.88 0.976 0.896, 1.063
Oral powder in pudding versus oral powder in water
Cmax 0.38 0.36 1.064 0.953, 1.188
AUCt 4.07 3.68 1.106 1.012, 1.209
AUC∞ 4.24 3.88 1.094 1.004, 1.191
a
Units for maximum observed plasma concentration (Cmax) and area under the plasma concentration–time curve (AUC) are µg/ml and µg•h/ml, respectively. bAnti-
logarithm of the least squares means for logarithms. cAnti-logarithm of the difference (test minus reference) of the least squares means of the logarithms. AUCt, AUC
to the last measured plasma concentration; AUC∞, AUC extrapolated to infinite time.

Table 3. Effect of food on the bioavailability of the marketed tablet, marketed oral solution and oral powder

Marketed tablet [3] (100 mg) Marketed oral solution [4] (600 mg) Oral powder (study 1; 100 mg)
Parametera PEb 90% CIc PEb 90% CI PEb 90% CI

Cmax 0.782d 0.675, 0.907d 0.769e 0.705, 0.838e 0.606f 0.535, 0.686f
AUC∞ 0.795d 0.724, 0.873d 0.930
e
0.847, 1.021e 0.767f 0.709, 0.829f
Cmax 0.766g 0.659, 0.891g – – 0.506h 0.440, 0.581h
AUC∞ 0.775g 0.704, 0.853g – – 0.677h 0.629, 0.728h
a
Units for maximum observed plasma concentration (Cmax) and area under the plasma concentration–time curve extrapolated to infinite time (AUC∞) are µg/ml and
µg•h/ml, respectively. bPoint estimate (PE) for relative bioavailability determined as the anti-logarithm of the difference of least squares means for logarithmically
transformed values, with ‘fasting’ as the reference. cDue to the discreteness of the sign test statistic, the actual confidence level was 94.8% for the marketed
tablet, which was higher than the necessary 90%. dModerate fat (approximately 30% fat of 857 Kcal). eLow fat (approximately 10% fat of 514 Kcal). fModerate fat
(approximately 30% fat of 600 Kcal). gHigh fat (approximately 50% fat of 907 Kcal). hHigh fat (approximately 60% fat of 900 Kcal).

Safety analysis 1 subject each. Seven subjects in study 1 reported only

All treatment-emergent adverse events (TEAE) reported
in both studies were mild in severity. No deaths or dis-
continuations due to adverse events occurred during
the studies. No clinically significant or potentially clini-
cally significant clinical laboratory, vital signs, ECG and
physical examination findings were observed after dos-
ing in either of the two studies.
In study 1, 8 of 48 subjects (16.7%) reported ≥1
TEAE. The most common TEAE was headache reported
by 4 of 48 subjects. All other TEAEs were reported by
AEs that were determined by the investigator as having
no reasonable possibility of relationship to study drug,
while one subject reported events of headache and nau-
sea that were determined as having a reasonable pos-
sibility of a relationship to study drug. In the post-study
period of study 1, one serious adverse event (SAE) of
‘induced abortion’ was reported in a 21-year-old female
subject who underwent an elective abortion. This event
was evaluated by the investigator as having no reason-
able possibility of relationship to the study drug.

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 AH Salem et al.

Figure 2. Mean (+sd) ritonavir plasma concentration–time profiles from study 2 under moderate-fat conditions

0.8
Ritonavir oral powder in water
Ritonavir oral powder in infant formula
Ritonavir oral powder in apple sauce
Marketed ritonavir oral solution

0.6
Ritonavir concentration, µg/ml

0.4

0.2

0.0
0 4 8 12 16 20 24 28 32 36
Time, h

Table 4. Relative bioavailability and 90% CI for the central values of ritonavir pharmacokinetic parameters from study 2
Regimens (test versus reference under moderate-fat Central valueb Relative bioavailability
conditions) and pharmacokinetic parametera Test Reference Point estimatec 90% CI

Oral powder in water versus oral solution

Cmax 0.49 0.49 1.001 0.901, 1.112
AUCt 4.26 4.24 1.005 0.938, 1.077
AUC∞ 4.42 4.43 0.998 0.934, 1.066
Oral powder in infant formula
versus oral powder in water
Cmax 0.51 0.49 1.053 0.947, 1.17
AUCt 4.48 4.26 1.054 0.985, 1.128
AUC∞ 4.66 4.42 1.054 0.988, 1.124
Oral powder in apple sauce versus
oral powder in water
Cmax 0.47 0.49 0.964 0.868, 1.071
AUCt 4.08 4.26 0.959 0.897, 1.026
AUC∞ 4.25 4.42 0.962 0.902, 1.026

a
Units for maximum observed plasma concentration (Cmax) and area under the plasma concentration–time curve (AUC) are µg/ml and µg•h/ml, respectively. bAnti-
logarithm of the least squares means for logarithms. cAnti-logarithm of the difference (test minus reference) of the least squares means for logarithms. AUCt, AUC to
the last measured plasma concentration; AUC∞, AUC extrapolated to infinite time.

In study 2, 5 of 24 subjects (20.8%) reported ≥1 The most common TEAE was headache, reported by
TEAEs. The proportions of subjects reporting ≥1 three subjects (12.5%). All other TEAEs were reported
TEAE summarized by regimen were 3/23 subjects by one subject each. TEAEs of abdominal pain, nau-
(13.0%) in regimen A and 4/23 (17.4%) in regimen D. sea and headache were assessed by the investigator as

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possibly related to study drug. No SAEs were reported
in study 2.
Discussion
Here we describe the bioavailability of a novel ritonavir
formulation for paediatric use. The new formulation is
an oral powder that is to be suspended in liquid vehicles
or sprinkled on food for administration. In comparison
to the marketed ritonavir oral solution, the new pow-
der formulation provides longer expiry dating through
slower degradation and an alcohol and propylene gly-
col-free formulation which may be desired by some
physicians and other health-care providers. In addition,
the new powder formulation would retain the flexibility
of the ritonavir oral solution to accommodate ARV or
pharmacokinetic-enhancing doses, including weight or
body surface area doses as indicated in other approved
package inserts. It will also provide a dosage form for
patients who may have difficulty swallowing a tablet.
Two clinical studies were conducted to assess the bio-
equivalence of the new formulation to the marketed oral
solution and to evaluate the effect of food and adminis-
tration vehicles on its bioavailability. The results of study
1 demonstrated the bioequivalence of the powder for-
mulation to the oral solution. The bioequivalence dem-
onstrated in the study allows the extrapolation of the
existing safety, clinical pharmacology and efficacy data
obtained with the oral solution to the new formulation.
Five different vehicles for administration were
assessed including two soft foods and three liquids. Soft
food options included apple sauce and pudding which
allow for administration of the powder as a sprinkle.
The other tested vehicles were water, infant formula
and chocolate milk which allow for administration as a
liquid. Administration of the new formulation in infant
formula, chocolate milk, apple sauce or pudding was
shown to be bioequivalent to administration in water.
Therefore, the new ritonavir paediatric formulation may
be taken in a variety of vehicles to allow convenience in
various patient settings and to meet patient preference.
In study 1, we also compared the bioavailability of
the new formulation under moderate-fat and high-fat
conditions to that under fasting condition in order
to assess the effect of food on the new formulation.
Results demonstrated that food significantly decreased
both Cmax and AUC of ritonavir by 23% to 49% follow-
ing powder formulation administration under either
moderate-fat or high-fat meal conditions. Tmax was
longer when the formulation was given with food. This
increase in Tmax is consistent with delayed gastric emp-
tying following a meal. Reductions in ritonavir expo-
sures with food have also been reported with currently
marketed oral solution and tablets. For the ritonavir
tablets, ritonavir Cmax and AUC were approximately
Antiviral Therapy 20.4
AVT-14-OA-3347_Salem.indd 431
Ritonavir paediatric powder formulation
20–23% lower when dosed following a meal compared
to administration under fasting conditions [3]. When
the oral solution was given under non-fasting condi-
tions, peak ritonavir concentrations decreased by 23%
and the extent of absorption decreased 7% relative
to fasting conditions [4]. Both tablet and solution are
labelled to be taken with food and hence the new pow-
der formulation is proposed to be taken with food.
Both studies were conducted at a dose of 100 mg.
The 100 mg dose is the most commonly administered
dose of ritonavir as a pharmacokinetic enhancer of
other PIs [5,6]. In addition, the 100 mg dose lies in the
non-linear range of ritonavir pharmacokinetics where
potential differences in exposure between formula-
tions are likely to be magnified. Therefore, the 100 mg
dose is considered to be a sensitive dose to detect dif-
ferences in bioavailability and bioequivalence results
at this dose level can be confidently extrapolated to
other doses.
The effect of food on the ritonavir oral powder bioa-
vailability may be attributed to the change in physiolog-
ical pH of the upper intestinal tract after meals. Due to
the gastric emptying of acidic chime in the postprandial
state, the physiological pH of the upper intestinal tract
is lower, at pH 5, when compared with the pre-prandial
state, pH 6.5 [7,8]. Ritonavir is a weak base and hence
will be ionized to a higher extent in the fed state. Such
ionization may result in slightly lower permeability
and absorption when compared with the fasted state
[9]. When co-administered with other PIs, effect of acid
reducing agents on ritonavir varied according to the co-
administered PI [10,11].
The safety results were consistent with the known
safety profile of ritonavir. Headache and gastrointesti-
nal events were the most frequently reported TEAEs in
these studies. No clinically significant values in clini-
cally laboratory evaluations or ECGs were observed.
In summary, the new ritonavir powder formulation
is bioequivalent to the currently marketed ritonavir
oral solution under moderate-fat conditions. Ritonavir
exposure following administration of the new formu-
lation is decreased by 23% to 49% in the fed condi-
tion, compared with the fasted condition. Consistent
with the recommendation for the marketed tablets
and oral solution, the new powder formulation should
be administered with food. The data from this study
suggest that a variety of vehicles may produce similar
bioavailability as none of the vehicles tested negatively
affected the bioavailability of the ritonavir oral powder.
Acknowledgements
The authors gratefully acknowledge Sonja Kemmis
Causemaker and Mary Woulfe, both from AbbVie
(North Chicago, IL, USA), for their assistance with
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 AH Salem et al.
study conduct, data analysis and manuscript prepara-
tion. The findings reported in this article were presented
in part at the 15th International Workshop on Clinical
Pharmacology of HIV & Hepatitis Therapy in Washing-
ton DC, USA from 19–21 May 2014 (Abstract P_01).
Disclosure statement
The design, study conduct and financial support for the
clinical trials were provided by AbbVie. AbbVie partici-
pated in the interpretation of data, review and approval
of the publication. All authors are employees of AbbVie
and have no additional conflicts of interest to disclose.
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