ORIGINAL ARTICLE
Co-administration of Ritonavir and Primaquine Decreases
Plasma Concentration of Primaquine: Single- and Multipledose Study in the Rats
Melva Louisa, Vivian Soetikno, Nafrialdi, Rianto Setiabudy, Frans D. Suyatna
Department of Pharmacology and Therapeutics, Faculty of Medicine, University of Indonesia. Jl. Salemba Raya
no. 6, Jakarta Pusat 10430, Indonesia. Correspondence mail: [email protected].
ABSTRAK
Tujuan: untuk meneliti pengaruh pemberian ritonavir terhadap kadar primakuin, jika diberikan bersamaan,
dalam dosis tunggal atau berulang. Metode: pada studi dengan pemberian dosis tunggal, 30 tikus Sprague
Dawley jantan secara acak diberikan primakuin 12,5 mg/kgBB atau primakuin 12,5 mg/kgBB + ritonavir 10
mg/kgBB atau primakuin 12,5 mg/kgBB + ketokonazol 10 mg/kgBB. Ketokonazol digunakan sebagai kontrol
positif penghambat metabolisme primakuin. Pada studi dengan pemberian dosis berulang, 30 tikus Spraque
Dawley secara acak diberikan primakuin 12,5 mg/kgBB/hari atau primakuin 12,5 mg/kgBB/hari + ritonavir
10 mg/kgBB/hari atau primakuin 12,5 mg/kgBB/hari + rifampisin 100 mg/kgBB/hari. Rifampisin digunakan
sebagai kontrol positif penginduksi metabolisme primakuin. Hasil: pada pemberian dosis tunggal, ketokonazol
meningkatkan area di bawah kurva kadar plasma (AUC) primakuin (h45,8%, p<0.000), sedangkan ritonavir
menurunkan AUC primakuin (i64,6%, p<0.000). Pemberian dosis berulang menunjukkan bahwa rifampisin
dan ritonavir menurunkan AUC primakuin berturut-turut sebanyak 60,2% (p<0.000) dan 67,7% (p<0.000).
Kesimpulan: pemberian primakuin dan ritonavir bersamaan dapat menurunkan AUC primakuin. Hal ini dapat
menyebabkan konsentrasi primakuin sebagai anti-relaps pada malaria oleh Plasmodium vivax tidak mencukupi,
sehingga dapat menyebabkan kegagalan terapi dengan primakuin.
Kata kunci: primaquine, ritonavir, interaksi obat, metabolisme.
ABSTRACT
Aim: to explore the effects of ritonavir and primaquine combination given as a single-dose or multiple-dose
compared to ritonavir alone on ritonavir plasma concentration in the rats. Methods: in single-dose study, 30
male Spraque Dawley rats were randomly allocated to receive primaquine 12.5 mg/kgBW or primaquine 12.5
mg/kgBW + ritonavir 10 mg/kgBW or primaquine 12.5 mg/kgBW + ketokonazole 10 mg/kgBW. Ketokonazole
was used as positive control for inhibitor of primaquine metabolism. In the multiple-dose study, thirty Spraque
Dawley male rats were randomly allocated to receive primaquine 12.5 mg/kgBW/day or primaquine 12.5 mg/
kgBW/day + ritonavir 10 mg/kgBW/day or primaquine 12.5 mg/kgBW/day + rifampicin 100 mg/kgBW/day.
Rifampicin was used as a positive control for inducer of primaquine metabolism. Results: in the single-dose
study, ketokonazole increases the area under the plasma concentration (AUC) of primaquine (h45.8%, p<0.000),
while the ritonavir decreases the AUC of primaquine (i64.6%, p<0.000). Multiple-dose study shows that
both rifampicin and ritonavir decreases the AUC of primaquine by 60.2% (p<0.000) and 67.7% (p<0.000),
respectively. Conclusion: concomitant administration of primaquine and ritonavir decreases the AUC of ritonavir.
This effect could result in the insufficient concentration of primaquine as anti-relapse therapy in malaria caused
by Plasmodium vivax, which might lead to treatment failure with primaquine.
Key words: primaquine, ritonavir, drug interaction, metabolism.
Acta Medica Indonesiana - The Indonesian Journal of Internal Medicine
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Melva Louisa
INTRODUCTION
Two of the most deadly diseases, HIV and
malaria, have an overlapping geographical
distribution in sub-Saharan Africa and also in
East- and South-East-Asia (India, Thailand,
Myanmar dan Indonesia).1-3 There is a high
likelihood of individuals in the endemic area
like Indonesia being infected with these diseases.
It is often related to the poverty and suitable
environment for the pathogens to spread. Over
90 million people in Indonesia live in the
malaria endemic area. In HIV/AIDS patients,
immunodeficiency can affect the immune
response of the body towards malaria parasites,1
while Hoffman et al., 1999 showed that in HIV
patients with acute malaria, there are tendency
towards higher HIV viral load. HIV infection can
be easily transmitted from a patient with a high
viral load. Therefore, HIV – malaria coinfection
can increase the risk of HIV transmission.4
Hence, intensive intervention in the prevention
and treatment of malaria in HIV/AIDS patients
in endemic area is an effective way to reduce to
risk of morbidity in these patients.
Concomitant treatment with antimalaria and
anti-HIV is a new challange in the management
of co-infection of malaria/HIV. Drug interaction
is an important aspect to consider to reach a
successful clinical cure. Anti-HIV regimen
consists of 3 to 4 drugs. If a patient has to receive
a prophylactic treatment for malaria, then the
patient receives two or three additional drugs.5
Primaquine is one of the drugs used in the
therapy of malaria caused by Plasmodium vivax.
P. vivax is one of the parasites which caused
human malaria in the subtropics. Primaquine is
the only drug available to eliminate hypnozoites
in P.vivax. Regimen of primaquine to eliminate
hypnozoites in the liver range from 14-day course
to eight-week regimen.6,7 The administration
of primaquine in a relatively long period is
unavoidable in the endemic areas.
Interaction between antimalarial drugs and
antiretroviral drug therapy mostly involve protease
inhibitors.5 Ritonavir, is a peptidomimetic HIV
protease inhibitor that is active against HIV-1 and
HIV-2. Despite its activity as anti HIV, ritonavir
is mostly used as a pharmacokinetic enhancer
(CYP3A4 inhibitor).8 In an in vitro study, it was shown that
primaquine is a substrate of cytochrome P4503A4
(CYP3A4),9 while ritonavir is known as substrate
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Acta Med Indones-Indones J Intern Med
and inhibitor of CYP3A4.10 Theoretically, there
is a high likelihood of these two drugs to interact
via cytochrome P450.
In our previous study that investigated the
effect of primaquine to the concentrations of
ritonavir in the rat plasma, we reported that
concomitant administration of ritonavir and
primaquine, single-dose or repeated-dose,
decreased the area under the plasma concentration
curve of ritonavir (>40% reduction). We
suggested that this effect could result in the
insufficient concentration of ritonavir as antiHIV, which might lead to treatment failure with
ritonavir.11 Therefore, further information whether
ritonavir might alter the plasma concentration of
primaquine will add a valuable information in the
treatment of malaria and HIV.
The aim of the present study is to investigate
the effect of ritonavir on the plasma concentration
of primaquine, given in single- or repeated-dose
administration.
METHODS
Experimental Design
The study protocol was approved by the
Ethics Committee of the Faculty of Medicine,
University of Indonesia. The study consisted
of two parts. The first part was designed to
investigate whether ritonavir has inhibitory
effect on the metabolism of primaquine, given
concomitantly as a single dose. Ketokonazole
was used as a positive control for inhibitor of
primaquine metabolism. Thirty male Spraque
Dawley rats weighing ±300 g were randomly
allocated into 3 groups of 10 rats to receive
primaquine 12.5 mg/kgBW or primaquine
12.5 mg/kgBW + ritonavir 10 mg/kgBW or
primaquine 12.5 mg/kgBW + ketokonazole 10
mg/kgBW.
The second part was carried out to investigate
whether ritonavir has inducing effect on the
metabolism of primaquine, given concomitantly
in a repeated fashion for 5 days. Rifampicin
was used as a positive control for inducer of
primaquine metabolism. Thirty male Spraque
Dawley rats weighing ±300 g were randomly
allocated into 3 groups of 10 rats to receive
primaquine 12.5 mg/kgBW/day or primaquine
12.5 mg/kgBW/day + ritonavir 10 mg/kgBW/day
or primaquine 12.5 mg/kgBW/day + rifampicin
100 mg/kgBW/day.
Vol 44 • Number 4 • October 2012
Co-administration of Ritonavir and Primaquine Decreases Plasma
Blood Samples
For single-dose study, serial blood samples
were collected at 0, 1, 2, 3, 4 and 6 h after drug
administration. For repeated-dose, study serial
blood samples were collected at day 0 (before
drug administration), 1, 2, 3, 4 and 5. Blood
samples were centrifuged at 3000 g for 15
minutes at 40C and the separated serum was
assayed on the same day.
Analytical Methods
HPLC methods to determine primaquine
in plasma. The concentration of primaquine
in plasma was analysed by a validated HPLC
method with ultaviolet detector at l=255 nm.
The mobile phase was KH2PO4 buffer pH 5.8
: methanol : acetonitrile = 65 : 15 : 20, pumped
isocratically at flow rate of 1,0 mL/min and
temperature of 350C. We use phenacetine as
internal standard. Retention time of phenacetine
and primaquine were at 5.3 and 6.3 min,
respectively (Figure 1). Ritonavir could not be
detected in this system.
Analytical system validation. The calibration
curve was linear (r = 0.9999, n = 6) in the range
of 0.5 – 6 µg/mL, and the limit of quantitation
was 0.9 µg/mL. Precision, expressed as the
inter- (n=5) and intraday (n=10) coefficient of
variation, was ≤7.84% on the same day and
≤10.45% between days for each quality control
sampel of 1.5; 2.5 and 5 µg/mL, respectively.
Accuracy expressed as the inter- and intraday%
bias was 0.04–1.83% and -2.88–1.56% between
days at each quality control sample.
Statistical Analysis
AUC of ritonavir was calculated using the
trapezoidal rule based on plasma concentrations
obtained at the predetermined sampling time
points as stated in methods.
Since the data obtained showed a normal
and homogeneous distribution, AUC0-t(h) of
primaquine concentration were analyzed using
the related one-way ANOVA followed by Tukey
method for multiple comparisons at a significance
level of α = 0.05. Results are expressed as means
± S.D.
RESULTS
The mean concentration of primaquine in a
single dose study and repeated dose study versus
Absorbance unit
Sample extraction. Plasma sample (0.25 mL)
was spiked with 50 µL phenacetine (internal
standard) and 50 µL NaOH 0.1 N. The mixture
was vortexed for 30 seconds before adding 1,5
mL of dichlormethane. Then, the sample was
centrifuged at 3000 rpm for 5 minutes. The
organic layer was evaporated under a gentle
stream of nitrogen. The residue was reconstituted
in 200 µL of mobile phase and an aliquot of 20 µL
was injected to the HPLC system (WatersTM).
The mixture was separated on a Reverse Phase
C18 Column (SymmetryTM C18 5 µm; 2.6 x
150 mm).
Figure 1. Chromatogram of phenacetine and primaquine
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Melva Louisa
Acta Med Indones-Indones J Intern Med
Primaquine concentration (mcg/mL)
A 1,4
)L
1,2
m
/g
c 1
(m
n 0,8
o
it
ar 0,6
t
n
e
c 0,4
n
co
e 0,2
in
u 0
q
a
im
r -0,2
P
-0,4
primaquine (decreased by 60.2%, p<0.000). This
result was also as expected. Rifampicin is the
known inducer of cytochrome P450, not only
the CYP3A4 but also several other cytochrome
P450 isozymes. It was known from previous
publications that the induction of cytochrome
P450 in the rats might occur 3–5 days after
drug exposure.12 Concomitant administration
of primaquine with ritonavir given repeatedly
for 5 days also significantly lowered the AUC
of primaquine (decreased by 67.7%, p<0.001)
(Figure 3B).
A
4
3,707
3,5
3
2,541
AUC (mcg.h)/mL
time was shown in Figure 2.
In the single dose study, concomitant
administration of primaquine with ketokonazole
showed an increase in the area under the
plasma concentration (AUC) of primaquine
compared to primaquine alone (increased by
45.8%, p<0.000). This result was as expected
before. Ketokonazole is a potent inhibitor of
CYP3A4, an enzyme which also metabolizes
primaquine. Inhibition of metabolizing enzyme
caused a significant increase in the plasma
concentration of primaquine. On the contrary,
concomitant administration of primaquine +
ritonavir significantly lowered the AUC of
primaquine (decreased by 64.6%, p<0.000)
compared to primaquine alone (Figure 3A).
The result of the repeated dose study,
concomitant administration of primaquine with
rifampicin showed a decrease in the AUC of
2,5
2
1,5
0,898
1
0,5
0
Single dose study
0
1
2
3
4
6
Primaquine
Primaquine + Ritonavir
Primaquine + Ketokonazole
Blood sampling time (hours)
Primaquine
Primaquine + Ritonavir
Primaquine + Ketokonazole
Primaquine concentration (mcg/mL)
L)3,5
/m
gc 3
(m
2,5
n
o
it 2
ar
t
n1,5
e
c
n1
co
e
n
i0,5
u
q
a 0
m
ir
P
-0,5
250
200
150
102,348
82,968
100
0
-1
1
2
3
4
5
50
Blood sampling time (days)
Primaquine
Primaquine + Ritonavir
Primaquine + Rifampicin
Figure 2. Mean of ritonavir concentration versus blood
sampling time after. A. Single dose administration of
primaquine 12.5 mg/kgBW or primaquine 12.5 mg/kgBW
+ ritonavir 10 mg/kgBW or primaquine 12.5 mg/kgBW +
ketokonazole 10 mg/kgBW; B. Repeated dose administration
for 5-days of primaquine 12.5 mg/kgBW/day or primaquine
12.5 mg/kgBW/day + ritonavir 10 mg/kgBW/day or primaquine
12.5 mg/kgBW/day + rifampicin 100 mg/kgBW/day
276
300
257,172
4
AUC (mcg.h)/mL
B
B
0
Multiple dose study
Primaquine
Primaquine + Ritonavir
Primaquine + Rifampicin
Figure 3. Mean Area Under the Curve (AUC) of primaquine
concentration after administration of: A. single dose
of primaquine, primaquine + ritonavir, primaquine +
ketokonazole. B. repeated administration of primaquine,
primaquine + ritonavir, primaquine + rifampicin
Vol 44 • Number 4 • October 2012
Co-administration of Ritonavir and Primaquine Decreases Plasma
DISCUSSION
The present study shows that single
concomitant administration of ritonavir and
ketokonazole results in the significant increase of
primaquine plasma concentration, while ritonavir
significantly reduces plasma concentration of
primaquine.
Interaction between primaquine
and ketokonazole was as expected before.
Ketokonazole increases AUC of primaquine by
45.8%. This significant increase could lead to the
higher toxicity of primaquine. Higher doses of
primaquine is known to cause many undesirable
effects, such as mild to moderate cramps and
occasional epigastric distress. These symptoms
are often accompanied by methemoglobinemia
and cyanosis. 13,14 Ketokonazole increases
plasma concentration of primaquine through
the inhibitory mechanism to cytochrome P450,
mainly the CYP3A4 isoform. Primaquine
is a substrate of CYP3A4 and CYP1A2,
while ketokonazole is a potent inhibitor of
CYP3A4.9,15 The capacity of ketokonazole to
impair biotransformation of CYP3A is well
established in in vivo and in vitro models.15,16
Though ketokonazole is commonly utilized as
an index inhibitor of human CYP3A4 isoforms,
but the mechanism of ketokonazole inhibition
of CYP3A is still not clearly established.16,17
Greenblat et al., showed that the mechanism of
ketoconazole inhibition to CYP3A4 appeared to
be a mixed competitive-noncompetitive process,
with the noncompetitive component being
dominant but not exclusive.17 Another research
by Lim et al., showed that inhibition of CYP3A4
by ketokonazole can also be mediated through
the disruption of pregnane X receptor, steroid
receptor coactivator-1 and hepatocyte nuclear
factor 4 [alpha] interaction.18
No direct interaction study between
primaquine and ketokonazole has been done
before, in animals or in human. Therefore, we
could not compare the magnitude of the decrease
in primaquine AUC in our result with those in
other studies.
Single concomitant administration of
ritonavir and primaquine reduced area under the
plasma concentration of primaquine by 64.6%.
Ritonavir was known for its inhibitory properties
to CYP3A4.
A study by von Moltke showed that ritonavir
are a highly potent mechanism-based inhibitors
of human CYP3A isoforms. In their study,
von Moltke et al., showed that ritonavir and
amprenavir inhibitory properties were as potent as
ketokonazole.16 However, in our result, ritonavir
did not act as inhibitor of primaquine metabolism.
On the contrary, ritonavir even reduced the AUC
of primaquine. The possible explanation of this
reduction might be through the interaction in
the absorption site. Our previous study also
showed that concomitant administration of
ritonavir and primaquine also resulted in the
reduction of ritonavir plasma concentrations.
Just as we proposed in our previous study, we
thought that this decrease might be trough the
interaction via transport protein in the intestine.
It is known that both ritonavir and primaquine is a
substrate of P-glycoprotein, an efflux transporter
that is widely expressed in the apical side of
the intestinal epithelia.19,20 However, no direct
study has ever confirmed the involvement of
P-glycoprotein in the interaction of antimalarial
and anti-HIV before.
Our result showed that repeated-dose
concomitant administration of primaquine
+ rifampicin or primaquine + ritonavir, both
significantly decreased the AUC of primaquine.
The significant decrease of primaquine plasma
concentrations could result to the insufficient
concentration of primaquine as anti-relapse in the
treatment of malaria caused by P.vivax.
It is widely known that rifampicin is an
inducer of cytochrome P450. Rifampicin potently
induces CYP1A2, CYP2C9 and CYP3A4. Its
administration in a standard dose often results
in a reduced plasma concentrations and altered
drug efficacy of a large number of compounds,
including antimalarials such as quinine,
chloroquine, mefloquine and artemisinins.
However, no previous data has ever described the
influence of rifampicin to the pharmacokinetics
and pharmacodynamics of primaquine.21
Our results showed that both single- and
repeated-dose concomitant administration of
ritonavir and primaquine reduced the AUC of
primaquine. The decrease is significant, which
lowered of primaquine AUC of 67.7% (in
repeated-dose study), which is somewhat greater
reduction than that caused by rifampicin (60.2%).
This decrease could result to the insufficient
concentration of primaquine as anti-relapse
in the treatment of malaria caused by P.vivax,
which might lead to treatment failure and drug
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Melva Louisa
resistance with primaquine. We suggests that the
reduction of primaquine plasma concentrations
was due to the inducing effect of ritonavir to
metabolizing enzyme, CYP3A4. Despite the
inhibitory properties of ritonavir to CYP3A4,
ritonavir was also known as moderate inducer
of CYP3A4. Foisy in 2008, showed that at both
therapeutic and boosting doses, ritonavir exhibits
a clinically relevant induction effect on numerous
drug metabolizing enzymes. A decrease or loss
of therapeutic effect may be observed when
ritonavir is coadministered with medications that
are substrates for these enzymes.22
Ritonavir is a unique drug that exhibits both
inhibitory and inducing effects on metabolizing
enzymes. Therefore, clinicians should be aware
of the potential of ritonavir in altering plasma
concentrations of many drugs that shared the
same metabolizing enzymes. Primaquine is one
of the drugs that was impacted by ritonavir.
Clinicians shoud be aware of this interactions.
Since primaquine is the only drug available to
prevent relapses in malaria caused by P.vivax,
a decrease efficacy of primaquine due to
concomitant administration with ritonavir is a
serious problem to consider.
However, our study was done in animal
model. This model was limited by species
differences in systemic pharmacokinetics.13 Our
result still needs to be confirmed in clinical trials
that investigated full pharmacokinetic parameters
of primaquine.
CONCLUSION
As a conclusion, this study showed
that single- or repeated-dose concomitant
administration of ritonavir and primaquine
decreased plasma concentration of primaquine
in animal models. This effect could result in
insufficient concentration of primaquine as antirelapse therapy in malaria caused by Plasmodium
vivax, which might lead to treatment failure with
primaquine.
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