Pharmacokinetics of lower doses of saquinavir soft-gel caps (800 and 1200 mg twice daily) boosted with itraconazole in HIV-1-positive patients.

Abstract

The pharmacokinetics of 800 mg and 1200 mg of saquinavir soft-gel caps (SQV-SGC) twice daily plus 100 mg itraconazole once daily were compared to 1400 mg SQV-SGC twice daily without itraconazole.
The pharmacokinetics of SQV were determined in 17 randomly selected patients on 1400 mg twice daily SQV-SGC without itraconazole and after 2 weeks with lower SQV-SGC doses plus itraconazole. SQV plasma concentrations were determined by HPLC. Pharmacokinetic parameters were calculated by a non-compartmental model.
Median (+IQR) area under plasma concentration-versus-time curve (AUC0-12h) were 3.33 (1.96-7.34), 4.29 (3.14-7.67) and 4.07 (2.76-4.49) mg/l x h for SQV 1400 mg without itraconazole, SQV 1200 mg with itraconazole and SQV 800 mg with itraconazole, respectively. These differences were not statistically significant. The median Cmin was above the proposed minimum effective concentration of 0.05 mg/l for all three regimens.
SQV-SGC 800 mg or 1200 mg twice daily boosted with 100 mg of itraconazole once daily resulted in adequate SQV pharmacokinetics not significantly different from SQV-SGC 1400 mg twice daily.

Full text

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Antiviral Therapy 8:245-249
©2003 International Medical Press 1359-6535/02/$17.00 245
Objective: The pharmacokinetics of 800 mg and 1200 mg
of saquinavir soft-gel caps (SQV-SGC) twice daily plus
100 mg itraconazole once daily were compared to 1400
mg SQV-SGC twice daily without itraconazole.
Methods: The pharmacokinetics of SQV were determined
in 17 randomly selected patients on 1400 mg twice daily
SQV-SGC without itraconazole and after 2 weeks with
lower SQV-SGC doses plus itraconazole. SQV plasma
concentrations were
Pharmacokinetic parameters were calculated by a non-
compartmental model.
determined by HPLC.
Results: Median (+IQR) area under plasma concentra-
tion-versus-time curve (AUC0–12h) were 3.33 (1.96–7.34),
4.29 (3.14–7.67) and 4.07 (2.76–4.49) mg/l.h for SQV
1400 mg without itraconazole, SQV 1200 mg with itra-
conazole and SQV 800 mg with itraconazole, respectively.
These differences were not statistically significant. The
median Cminwas above the proposed minimum effective
concentration of 0.05 mg/l for all three regimens.
Conclusion: SQV-SGC 800 mg or 1200 mg twice daily
boosted with 100 mg of itraconazole once daily resulted
in adequate SQV pharmacokinetics not significantly
different from SQV-SGC 1400 mg twice daily.
Short Communication
Pharmacokinetics of lower doses of saquinavir
soft-gel caps (800 and 1200 mg twice daily) boosted
with itraconazole in HIV-1-positive patients
Peter G Cardiello1,2, Tarika Samor1, David Burger3*, Richard Hoetelmans4, Apicha Mahanontharit1,
Kiat Ruxrungtham1,5, Joep M Lange2, David A Cooper6and Praphan Phanuphak1,5
1HIVNAT, The Thai Red Cross AIDS Research Centre
2IATEC, Amsterdam, The Nethelands
3Department of Pharmacy, UMC, Nijmegen, The Netherlands
4Department of Pharmacy and Pharmacology, Slotervaart Hospital, Amsterdam, The Netherlands
5Faculty of Medicine, Chulalongkorn University, Thailand
6NCHECR, Sydney, Australia
*Corresponding author: Tel: +31 24 3616405; Fax: +31 24 3540331; E-mail: D.Burger@akf.umcn.nl
Successful management of patients with AIDS often
requires a combination of three drugs from two
different antiretroviral classes [1]. A major obstacle to
treating HIV-1-infected patients in the developing
world has been access to combination regimens due to
their cost. The use of lower doses of antiretroviral
drugs should help to increase access to effective treat-
ments. Saquinavir soft gelatin capsule (SQV-SGC) is
an effective antiretroviral drug but its cost prohibits
widespread use in resource-limited
Maintaining the SQV plasma concentration levels
above 0.05 mg/l, the critical threshold, is difficult
[2,3]. Itraconazole has been shown to boost the levels
of SQV hard gel by fivefold [4].
Saquinavir has an affinity for the P-glycoprotein
multidrug transporter and the oral bioavailabity of
saquinavir is limited by the cytochrome P450 enzyme
system [5]. Itraconazole has been proposed to inhibit
P-glycoprotein activity, allowing increased SQV
settings.
absorption, and inhibit the cytochrome P450 enzyme
system, leading to decreased SQV metabolism [4,6].
While standard recommended daily dosages of SQV-
SGC are 3600 mg (1200 mg three times daily) or
3200 mg (1600 mg twice daily), a lower dosage of
2800 mg (1400 mg twice daily) resulted in adequate
pharmacokinetic parameters both with and without
the addition of itraconazole 100 mg once daily [2].
While others have reported on using lower SQV-SGC
dosages when boosting with ritonavir, the data on the
steady-state pharmacokinetics of lower dosages of
saquinavir when boosted with itraconazole are
lacking [7]. We report the pharmacokinetics of SQV-
SGC in both 800 and 1200 mg dosages twice daily
plus 100 mg itraconazole and dual nucleoside reverse
transcriptase inhibitors (NRTIs) as compared to
unboosted SQV-SGC 1400 mg twice daily in HIV-1-
infected in combination with two NRTIs.
Introduction

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©2003 International Medical Press
246
Materials and methods
Patients and study design
Patients were recruited from the Thai Red Cross
Society’s Anonymous STD/HIV screening clinic and
the HIV outpatient immune clinic of King
Chulalongkorn Memorial Hospital, Bangkok,
Thailand. Prior to enrollment in the current study,
111 out of the 116 randomized patients were
pretreated for 48 weeks with half or full doses of
zidovudine (AZT)/zalcitabine (ddC), as described
previously [8]. This was followed by 18 weeks of
standard doses of AZT/ddC, before starting a triple-
drug regimen consisting of SQV-SGC 1400 mg twice
daily in combination with standard doses of either
Combivir[AZT/lamivudine (3TC)] or didanosine
(ddI)/stavudine (d4T) (1:1) for 110 weeks. The effect of
itraconazole on the safety, efficacy and pharmacoki-
netics of SQV-SGC was evaluated during the last 48
weeks of this period. Patients were randomized to
receive itraconazole in a dose of 0, 100 or 200 mg once
daily (1:1:1) in addition to their previous antiretroviral
regimen [2].
At the start of the current study, itraconazole was
stopped for a 2 week itraconazole washout period in a
subset of 17 randomly selected patients, who
continued the same SQV-SGC dose of 1400 mg twice
daily and their NRTI backbone.
After an overnight fast, patients ingested SQV-SGC
1400 mg with breakfast (10–15 g fat, 400–700 kcal)
on their pharmacokinetic evaluation day. This same
group of patients then took either 800 or 1200 mg
SQV-SGC twice daily and two NRTI backbones plus
itraconazole 100 mg once daily for 2 more weeks.
After an overnight fast, patients ingested SQV-SGC
800 mg or 1200 mg plus itraconazole 100 mg simul-
taneously with breakfast (10–15 g fat, 400–700 kcal),
for their second pharmacokinetic evaluation day. On
both pharmacokinetic days, blood samples were
drawn just before ingestion of the drugs and at 0.5, 1,
1.5, 2, 2.5, 3, 4, 6, 8, 10 and 12 h post-ingestion.
Plasma was isolated by centrifugation (900 G, 10
min) on the same day and stored at –20°C until
analysis. The study was approved by the Ethics
Committee of the
Chulalongkorn University, and written informed
consent was obtained from all patients.
Faculty of Medicine,
Analysis of plasma samples
Plasma concentrations of SQV were analysed with a
sensitive and selective reversed-phase high-perfor-
mance liquid chromatographic assay with ultraviolet
detection at the Department of Clinical Pharmacy of
UMC Nijmegen, The Netherlands [9]. The lower limit
of quantification of SQV was 0.025 mg/l and the assay
is linear up to concentrations of at least 25 mg/l.
Between-day and within-day variation of quality
control samples of SQV in plasma ranges from 0.7 to
7.6%, and the mean accuracy is 103.6 for SQV.
Pharmacokinetic analysis
Plasma concentration (C) versus time (t) data of SQV
were analysed by non-compartmental methods. The
highest observed plasma concentration was defined
Cmax, with the corresponding sampling time as tmax.
The terminal, log-linear period (log C vs t) was defined
by the last data points (n≥3) by visual inspection. The
absolute value of the slope (β/ln10) was calculated by
least squares linear regression analysis. The half-life
(t1/2) was calculated by the equation t1/2=ln2/β. The area
under the plasma concentration versus time curve from
0 to 12 h (AUC0–12h) was estimated using the linear
trapezoidal rule from 0 to 12 h (AUC0–12h). The
apparent oral clearance (CL/F) was calculated by
Dose/AUC; the apparent volume of distribution (Vd/F)
was calculated by CL/β.
Statistical analysis
Statistical calculations were performed using the
Statistical Product and Service Solutions (SPSS) for
Windows, version 9.0 (SPSS, Inc., Chicago, Ill., USA).
Geometric mean ratios (GMRs) were determined
using either 800 mg of SQV+itraconazole or 1200 mg
of SQV+itraconazole as the test group and the
unboosted 1400 mg of SQV as the reference group. A
P-value of ≤0.05 was considered statistically significant
for all tests. This study was powered to detect a 50%
difference in AUC0–12hbetween SQV-SGC in 800 or
1200 mg dosages twice daily plus 100 mg itraconazole
and unboosted SQV-SGC 1400 mg twice daily.
Results
Pharmacokinetics
Seventeen patients completed the pharmacokinetic
substudy [five males and 12 females, median age (IQR)
32 years (28–36), median weight 51 kg (47–58)]. None
had evidence of abnormal liver or kidney function.
Patients did not use any co-medication known to inter-
fere with the metabolism of SQV. The median
pharmacokinetic parameters of SQV are shown in
Table 1. There was a 6.7-, 8.5- and 2.5-fold interpa-
tient variation in the Cminof SQV on the 1400 mg twice
daily dose, the 1200 mg twice daily dose and the 800
mg twice daily dose, respectively. The median Cminin
all regimens was above the minimal effective concen-
tration of 0.05 mg/l as estimated in protease
inhibitor-naive patients treated with two NRTIs
(Figure 1) [3]. One of nine patients (11.1%) on the
1200 mg twice daily dose and one of eight patients
PG Cardiello et al.

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Antiviral Therapy 8:3
247
(12.5%) on the 800 mg twice daily dose have a
Cmin<0.05 mg/l, while the unboosted 1400 mg SQV
dose resulted in five of 17 patients (29.4%) having a
Cmin<0.05 mg/l (Table 1). The GMRs show that there is
neither a significant difference in the pharmacokinetic
parameters (AUC, Cminand Cmax) between the 800 mg
twice daily SQV-SGC dose and the 1400 mg twice
daily SQV-SGC dose (P=0.43, 0.20 and 0.22, respec-
tively), nor for the 1200 mg twice daily SQV-SGC dose
and the 1400 mg twice daily SQV-SGC dose (P=0.28,
0.28 and 0.42, respectively) (Table 2).
Discussion
Lower doses of SQV-SGC (800 or 1200 mg twice daily)
boosted with 100 mg itraconazole once daily resulted in
adequate pharmacokinetic parameters that were not
significantly different from SQV-SGC 1400 mg twice
daily. There were no additional adverse events on these
lower dose regimens. This allows the possibility for
evaluation of new combinations using the less expensive
itraconazole as a protease inhibitor boosting agent.
Despite the median Cmin of SQV being above 0.05
mg/l for all three SQV-SGC dose regimens, the inter-
patient variation revealed that 5/14 patients (29.4%)
Saquinavir levels boosted by itraconazole
Table 1. Median (IQR) pharmacokinetic parameters of saquinavir and itraconazole as measured after simultaneous ingestion of
saquinavir soft-gelatin capsules 1400 mg twice daily without itraconazole versus 800 or 1200 mg twice daily plus itraconazole
100 mg once daily in 17 HIV-1-infected patients
Saquinavir dose
twice daily
Patients AUC0-12
(h*mg/l)
Cmax
(mg/l)
Tmax(h)Cmin(mg/l)t1/2(h)CL/F (l/h)Vd/F (l) # patients with
Cmin<0.05 mg/l
1400 mg 17 3.33
(1.96–7.34)
1.05
(0.69–2.48)
2.0
(1.8–3.0)
0.09
(0.04–0.13) (4.0–6.0)
4.6420
(191–714) (1572–8245)
25905
1200 mg + itraconazole9 4.29
(3.14–7.67)
1.42
(0.60–2.19)
2.0
(1.5–2.5)
0.11
(0.06–0.14) (4.0–7.5)
5.0279
(156–383) (1118–4587)
12101
800 mg + itraconazole84.07
(2.76–4.49)
0.98
(0.84–1.21)
2.6
(1.9–3.3)
0.08
(0.06–0.08) (4.7–6.1)
5.1197
(179–294) (1387–1981)
17891
The median (IQR) steady-state pharmacokinetic parameters for saquinavir are listed along with the number of patients on un-boosted and boosted saquinavir with
Cmin<0.05 mg/l. AUC0-12h, area under the plasma concentration versus time curve from 0 to 12 h; Cmax, maximal concentration; Cmin, minimal concentration at 24 h
post-dose; tmax, time to reach Cmax; t1/2, plasma elimination half-life; CL/F, apparent oral clearance; Vd/F, apparent volume of distribution.
1400 mg twice daily
800 mg twice daily + itraconazole 100 mg
1200 mg twice daily + itraconazole 100 mg
Time after intake (h)
0.00
02468 10 12
0.20
0.40
0.60
0.80
1.00
1.20
1.40
1.60
Saquinavir plasma concentration mg/l
Figure 1. SQV pharmacokinetics HIVNAT 001
The median steady-state plasma concentration versus time curve of saquinavir after simultaneous ingestion of saquinavir soft-gelatin capsules 800 mg plus itracona-
zole 100 mg, or saquinavir soft-gelatin capsules 1200 mg plus itraconazole 100 mg, or saquinavir soft-gelatin capsules 1400 mg twice daily without itraconazole; all
regimens were administered during a breakfast.

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©2003 International Medical Press
248
on the SGV-SGC 1400 mg twice daily dose had a Cmin
below 0.05 mg/l, while only 1/9 patients (11.1%) on
SQV-SGC 1200 twice daily with itraconazole and 1/8
patients (12.5%) on SQV-SGC 800 mg twice daily
with itraconazole had a Cminbelow 0.05 mg/l.
The lower Cmincan be a problem in viral control. It
must be noted, however, that the use of the 0.05 mg/l
threshold is not validated for boosted SQV regimen as
this value was assessed in unboosted three times daily
SQV regimens [3]. Until more data are available
regarding pharmacokinetics–pharmacodynamic rela-
tionships for boosted SQV regimens, it appears
rational to use the 0.05 mg/l threshold for all new SQV
regimens to be developed.
Itraconazole, like ritonavir, is able to boost plasma
SQV levels, so that lower dosages of SQV-SGC can be
used to achieve adequate pharmacokinetic levels.
Itraconazole may have some important advantages
over ritonavir, because itraconazole does not need
refrigeration, has a lower cost and may have less toxi-
city than ritonavir. While SQV-SGC does require
refrigeration, future studies using SQV-hard gel caps
boosted with itraconazole may eliminate this inconve-
nience if adequate levels can be achieved. Ritonavir
contains castor oil, which may be responsible for some
of the gastrointestinal side effects [10,11].
Despite a 50% difference in SQV dose (800 vs 1200
mg) we could not observe more than a 5% difference
in SQV AUC when both SQV doses are boosted by
itraconazole. Apparently, the effect of itraconazole is
already maximal with the 800 mg dose of SQV and
there is no benefit of higher SQV doses. Interpatient
variability in itraconazole plasma (or hepatic) levels
may be an alternative explanation for the absence of a
dose-response effect.
Using itraconazole to boost the lower SQV-SGC
doses of 800 mg twice daily (nine pills daily of SQV-
SGC plus itraconazole) will result in the same or lower
pill burden than other standard SQV-SGC regimens or
ritonavir boosted SQV-SGC combinations. The cost of
ritonavir 100 mg almost doubles that of itraconazole:
US$0.82/capsule vs US$0.44/capsule. A potential
drawback of the use of itraconazole as a pharmacoki-
netic enhancer may be the possible emergence of
resistant organisms.
In conclusion, our pharmacokinetic data suggest
that the use of lower doses of SQV-SGC (800 or 1200
mg twice daily) boosted with 100 mg itraconazole once
daily resulted in adequate SQV pharmacokinetic para-
meters not significantly different from SQV-SGC 1400
mg twice daily. Our data support subsequent Phase III
studies of the use itraconazole 100 mg once daily to
boost 800 mg twice daily of SQV-SGC. By adminis-
tering smaller SQV-SGC doses plus itraconazole, one
can decrease pill burden and the costs of providing
adequate SQV-SGC dosages, making this regimen
somewhat more affordable, an important benefit in the
developing world, where drug access is a major
obstacle in treating patients.
Acknowledgement
The authors would like to thank all the patients in the
trial, the staff of HIVNAT, Chulalongkorn University
Immune Clinic and the Thai Red Cross AIDS
Research Centre. Metta Thongtalung and Suchada
Manotaya are acknowledged for their assistance on
pharmacokinetic days.
Sources of support
Financial support for the conduct of the study was
provided by Roche-Bangkok,Thailand. Combivir
(AZT/3TC) was purchased by Roche-Bangkok,
Thailand and provided by Glaxo Wellcome-Bangkok,
Thailand. ddI (Videx) and d4T (Zerit) were provided
by Bristol-Myers Squibb-Bangkok,
Saquinavir (Fortovase) was supplied by Roche-
Bangkok, Thailand. Itraconazole (Sporal) was
provided by Janssen
Thailand. Ritonavir (Norvir) was purchased by
Roche- Bangkok, Thailand.
Thailand.
Pharmaceutica-Bangkok,
PG Cardiello et al.
Table 2. Geometric mean ratios plus 90% confidence interval and P-values
Saquinvir-soft-gel cap
(SQV-SGC) dose
ParameterGeometric mean ratio (800 mg
dose/1400 mg dose) and 90% CI
P-value
800 mg twice daily
vs
1400 mg twice daily
AUC (h*mg/l)
Cmin(mg/l)
Cmax(mg/l)
0.82 (0.52–1.28)
0.79 (0.57–1.09)
0.71 (0.44–1.16)
0.43
0.20
0.22
ParameterGeometric mean ratio (1200 mg
dose/1400 mg dose) and 90% CI
P-value
1200 mg twice daily
vs
1400 mg twice daily
AUC (h*mg/l)
Cmin(mg/l)
Cmax(mg/l)
1.47 (0.79–2.75)
1.27 (0.86–1.87)
1.24 (0.78–1.99)
0.28
0.28
0.42

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