Integrase Inhibitor Raltegravir

Selected Properties of Raltegravir
Other names
Isentress, MK-0518
Manufacturer
Merck Canada Inc.
Pharmacology/Mechanism of
Action
Raltegravir is a novel HIV-1 integrase strand transfer inhibitor.

The bulk drug is a potassium salt of raltegravir with a molecular
weight of 482.52.
Activity
Resistance - genotypic
Raltegravir potently inhibits integrase catalyzed strand transfer,

with an IC50 of 10 nM, close to the limit of the sensitivity of the
assay. Inhibition of integrase prevents the covalent insertion, or
integration, of unintegrated linear HIV-1 DNA into the host cell
genome preventing the formation of the HIV-1 provirus.
Raltegravir is selective for strand transfer, having much reduced
activity on either assembly or 3 end processing when analyzed
in staged enzymatic assays.
HIV1: EC95: 31 20 nM (in vitro)
HIV 1 - diverse, primary clinical isolates including isolates

resistant to reverse transcriptase inhibitors & protease
inhibitors: EC95: 6 to 50 nM (in vitro)
HIV 2: EC95 value = 6 nM (in vitro)

Resistance data are preliminary and limited. Raltegravir has a
st
low genetic barrier (similar to the 1 generation NNRTI class).
Resistance is associated with mutations at positions 148
(Q148H/K/R) or 155 (N155H) plus 1 additional substitution
(i.e., L74M/R, E92Q, T97A, E138A/K, G140A/S, V151I, G163R,
H183P,Y226D/F/H, S230R and D232N). Both of the integrase
variants, Q148K and E138A/G140A/Q148K, engender a
substantial loss of susceptibility to raltegravir.
Another resistance pathway involves a mutation at position 143
(Y143C/H/R)
Resistance - phenotypic
Cross-Resistance
Oral Bioavailability
There seems to be cross-resistance between raltegravir and

elvitegravir. Viruses with integrase inhibitor resistance mutations
remain fully sensitive to the effects of non-nucleoside reverse
transcriptase inhibitors as well as nucleosides and protease
inhibitors.
The absolute bioavailability of raltegravir has not been
established.
The pharmacokinetics of raltegravir were compared in 67
patients who swallowed the intact tablet with 13 HIV-infected
patients who chewed the raltegravir tablet due to swallowing
difficulties. HIV-infected patients receiving raltegravir by chewing
the tablet showed higher drug absorption and reduced
pharmacokinetic variability compared with patients swallowing
the intact tablet. Crushed tablets tested in water or in a pH 6.8
buffer exhibited prompt and complete dissolution of
RAL.[Cattaneo et al. AAC 2012]
Academic copyright. A. Tseng, Pharm.D., FCSHP, AAHIVP, Toronto, Ontario. Please note: This chart summarizes
selected properties based on current available data. Please consult a health professional whenever beginning, stopping or
modifying drug therapy. Updated March 2014.
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Effect of Food
The absorption of raltegravir, etravirine, emtricitabine, and

tenofovir was not compromised when the drugs were crushed,
dissolved in 60 mL warm water, and administered by
gastrostomy tube to a 52 year old HIV-positive male with
ulcerative esophagitis.[Sandkovsky et al. 2012]
Film-coated tablets:
A single dose pharmacokinetic study in healthy subjects (n = 20)
showed that a high fat meal affected the rate but not the extent
of absorption of raltegravir. Data from Phase II trials suggest
that the effect of food on C12hr is not clinically important
[Wenning et al. ICAAC 2007]. Raltegravir was administered
without regard to food in Benchmrk-1 and Benchmrk-2 studies.
In healthy volunteers who received raltegravir 400 mg BID for 10
days in conjunction with various meal types, a low-fat meal
appeared to modestly decrease absorption with little effect on
trough concentrations (C12h), a moderate-fat meal had little to
no effect, and a high-fat meal appeared to modestly increase
absorption, although none of these effects appear clinically
meaningful.[Brainard et al. J Clin Pharmacol 2010].
Chewable tablets:
Administration of chewable tablet with a high fat meal led to an
average 6% decrease in AUC, 62% decrease in Cmax and
188% increase in C12hr compared to administration in the fasted
state. Administration of the chewable tablet with a high fat meal
does not affect raltegravir pharmacokinetics to a clinically
meaningful degree and the chewable tablet can be administered
without regard to food.
Protein Binding
Raltegravir may be administered twice daily without regard

to meals.
83% protein bound (over concentration range of 2 to 10 M)
Vd
Tmax
serum T
Drug Concentrations
Raltegravir is rapidly absorbed with median Tmax 3 hours in the

fasted state.
Concentrations declined in a biphasic manner with initial phase
t ~1 hr and terminal phase t ~9 hours.
Raltegravir displays dose proportional pharmacokinetics over the
clinically relevant dose range (100 to 800 mg).
Adults:
In a single dose pharmacokinetic study in healthy subjects (n =
20), AUC 0- & Cmax of raltegravir were dose proportional for the
dose range 100-1600 mg. Raltegravir C12h increased
proportionally from 100-800 mg, and slightly less than
proportionally from 100-1600mg [Wenning et al. ICAAC 2007].
Considerable intersubject and intrasubject variability was
observed in the kinetics.
Subjects who received 400mg BID: AUC 14.3 uMhr, C12hr 142
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Page 2 of 15
nM. Gender, age, body mass index, race, and HIV status had
no clinically meaningful effect on raltegravir pharmacokinetics.
Similarly, in a study of 44 treatment-nave African-American
patients administered RAL 400 mg BID plus tenofovir/FTC,
mean raltegravir AUC 5159 ng.hr/mL (CV 78%), Cmax 1315
nd
ng/mL (CV 109%), C12h after 2 dose was 166 ng/mL (CV
94%); these results were comparable to historical controls,
suggesting no influence of race on raltegravir
pharmacokinetics.[Wohl et al. 2013]
Pediatrics:
Preliminary dose finding study suggest HIV infected adolescents
( 12 and < 19 yrs) receiving RAL 8mg/kg BID achieve systemic
exposure similar to adults receiving 400mg BID. RAL well
tolerated in this preliminary study.(Acosta et al. 2008)
Raltegravir Steady State Pharmacokinetic Parameters in
Pediatric Patients Following Administration of Recommended
Doses:
Body
Weight
25 kg
N*
Geometric
Mean
(%CV)
AUC0-12hr
(Mhr)
Geometric
Mean
(%CV)
C12hr (nM)
Film-coated
tablet
400 mg twice daily 18
14.1 (121%)
233 (157%)
Formulation
Dose
25 kg
Chewable
tablet
Weight based
dosing
22.1 (36%)
113 (80%)
11 to <25 kg
Chewable
tablet
Weight based
dosing
13
18.6 (68%)
82 (123%)
Weight based
dosing
19
24.5 (43%)
113 (69%)
Oral
3 to <20 kg suspension
*Number of patients with intensive pharmacokinetic (PK) results at the final

recommended dose.
Geometric coefficient of variation.
The pharmacokinetics of raltegravir in infants under 4 weeks of

age has not been established.
Chewing vs. swallowing tablets
The pharmacokinetics of raltegravir were compared in 67
patients who swallowed the intact tablet with 13 HIV-infected
patients who chewed the raltegravir tablet due to swallowing
difficulties. HIV-infected patients receiving raltegravir by chewing
the tablet showed higher drug absorption and reduced
pharmacokinetic variability compared with patients swallowing
the intact tablet.[Cattaneo et al. 2012]
In 12 healthy volunteers, the pharmacokinetics of raltegravir 400
mg BID by swallowing was compared to raltegravir 800 mg QD
where the tablets were chewed. While large inter-patient
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variability was observed with the BID dosing, variability was

reduced by 20-1500% when raltegravir tablets were chewed.
Chewing raltegravir also led to significantly higher raltegravir
AUC (40722 14843 vs. 21753 12229 ng*h/mL, p<0.0001)
and no difference in Cmin (36 23 vs. 43 23 ng/mL, p=0.298).
compared to swallowing the tablets.[Cattaneo et al. 2013][Rizk et
al. 2014]
Reformulated 600 mg tablet
In healthy volunteers, the effect of food on single dose
pharmacokinetics of raltegravir 1200 mg, administered as either
3 x 400 mg marketed tablet or 2 x 600 mg reformulated tablet.
For the reformulated tablet, administration with a low fat meal
resulted in 40% AUC, 52% Cmax and 16% C24h, while
administration with a high fat meal resulted in 3% AUC, 28%
Cmax and 12% C24h.[Krishna et al. 2013]
Concentrations in UGT1A1*28/*28 genotype
The pharmacokinetics of single dose raltegravir was studied in
subjects with generally low UGT1A1 activity (UGT1A1*28/*28
genotype) compared to subjects with normal activity
(UGT1A1*1/*1 gentoype). Raltegravir AUC 41%, Cmax 40%
and Cmin 91% in individuals with the UGT1A1*28/*28
genotype relative to the UGT1A1*1/*1 genotype. However,
these differences are not considered to be clinically important,
and the Tmax and t values were similar for both genotypes. No
dose adjustment of raltegravir is required for individuals with the
UGT1A1*28/*28 genotype.[Petry A et al. ICAAC 2008]
Cervicovaginal fluid concentrations
Simultaneous plasma and cervicovaginal fluid (CVF) samples
were obtained in 7 HIV-negative women taking raltegravir for 7
days. Raltegravir was detectable in CVF 6 hours post-dose,
Tmax 12h, CVF t 17 hours (vs. plasma t 7 hours), with
CVF:plasma AUC ratio of 64% on day 1 and 93% on day 7.
Raltegravir CVF concentrations were C12h 607 ng/mL, AUC
th
1677 ng.hr/mL.[Jones A et al. 10 IWCPHT 2009, #O_06]. In 6
HIV-positive women taking raltegravir 400 mg BID for at least 4
weeks, similar raltegravir CVF concentrations were
observed.[Patterson et al. IAC 2010]
Semen concentrations
A total of 96 blood and 96 semen samples were collected within
1 hour of each other in 16 HIV-infected men virally suppressed
on raltegravir-based therapy for a median of 21 months. The
median seminal plasma to blood plasma ratios and AUC0-12h
seminal plasma to blood plasma ratios of raltegravir were 3.25
(interquartile range 1.46 to 5.37) and 2.26 (interquartile range
1.05 to 4.45), respectively. Concentrations of raltegravir in
seminal plasma are several fold-higher than those attained in
blood plasma and those required to inhibit viral replication in this
compartment.[Antoniou et al. 2014]
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Raltegravir concentrations and HIV-1 RNA levels were

measured in simultaneous semen and plasma samples from 10
treatment-experienced patients on 24 weeks of raltegravir-based
therapy. In all samples, semen RNA was <100 copies/mL and
plasma RNA was <50 copies/mL. Median raltegravir
concentration was 345 (83-707) ng/mL in semen and 206 (106986) ng/mL in plasma, yielding a median semen:plasma ratio of
1.42 (0.52-6.66).[Barau et al. AAC 2010].
Intracellular concentrations
Paired plasma and intracellular samples were obtained from 12
HIV-infected adults taking raltegravir BID and after switching to
once daily. With BID dosing, no plasma trough concentrations
were below the IC95, in contrast to 33% for once daily dosing.
Fifty percent of the once daily group had intracellular trough
concentrations below the inhibitory concentration 95 (IC95), 25%
in the b.i.d. group. Lower plasma and intracellular concentrations
may contribute to inferior virologic suppression rates observed
with once daily raltegravir dosing.[Sandkovsky et al. AIDS 2012].
Plasma and intracellular raltegravir concentrations after single
dose raltegravir 400 mg were measured for 48 hours in healthy
subjects. Intracellular raltegravir concentrations were 24% of
plasma concentrations, and intracellular:plasma ratios were
stable without significant time-related trends suggesting no
intracellular accumulation.[Wang et al. ICAAC 2010]
Minimum target trough

concentrations (for wildtype virus)
Gut-associated lymphoid tissue concentrations

Concentrations of raltegravir in gut-associated lymphoid tissue
(GALT) were compared to blood plasma concentrations in
healthy male volunteers who received raltegravir 400 mg BID for
7 days. After multiple doses, raltegravir AUCs in the terminal
ileum, splenic flexure and rectal tissue were 84-fold, 679-fold
and 239-fold higher than blood concentrations, respectively. The
raltegravir accumulation ratio was 0.9 for terminal ileum, 8.4 for
splenic flexure and 5.5 for rectal tissue. These data suggest that
RAL may also have a role in PEP/PrEP and treatment of primary
HIV infection.[Patterson et al. HIV PK 2012, #O_11]
IC95 = 15 ng/mL
In vitro simulations suggest that antiviral effect is consistent with
th
AUC rather than trough [McSharry J et al. 10 IWCPHT 2009,
#O_09].
CSF (% of serum)
Based on data from two healthy volunteer studies, C2h or AUC0-3h

may be used to reliably predict AUC0-12h, which may be a better
PK parameter for raltegravir TDM.[Burger et al. 2010]
In 18 HIV-positive patients, raltegravir concentrations were
measured in matched CSF and plasma samples. Raltegravir
was present in all CSF specimens with a median concentration
of 13.9 ng/mL (IQR 8.9, 24.6). The median CSF-to-plasma ratio
was 7.3% (IQR 2.2%, 17%). CSF concentrations correlated with
plasma concentrations (rho = 0.47, p = 0.03) but not with post-
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Page 5 of 15
dose sampling time. Raltegravir concentrations in CSF exceeded

the IC50 of wild-type HIV in all but 1 specimen by a median of
4.1-fold (IQR 2.6, 7.2).[Letendre S et al. ICAAC 2009]
In 3 HIV-positive patients who started a raltegravir-based
regimen and underwent lumbar punctures for clinical reasons,
raltegravir CSF trough concentrations were above or very close
to in-vitro 95% inhibitory concentration (IC95) (14.6
ng/ml).[Calcagno et al. 2010]
In 27 HIV-positive patients on raltegravir who underwent lumbar
punctures for clinical reasons, the median raltegravir
CSF:plasma ratio was 0.25 (IQR 0.10-0.42). At the end of the
dosing interval, patients on boosted PIs had higher CSF trough
concentrations compared to those on other ARVs (difference not
significant). Patients with altered BBB function had higher
CSF:plasma ratios (0.57 vs. 0.18, p=0.01). In 4 patients on
rifampin (3 on RAL 800 mg BID), CSF:plasma ratio was
0.31.[Calcagno et al. 2012]
Metabolism
Excretion
Dosing Adult
2010 CNS Penetration Effectiveness (CPE) Score: 3

[Letendre S et al. 2010]
Raltegravir is not an inhibitor of cytochrome P450 enzymes,
major UGTs, or P-glycoprotein and does not induce CYP3A.
The major mechanism of clearance of raltegravir in humans is
UGT1A1-mediated glucuronidation.
Feces: 51% (only raltegravir was present, most of which is likely
derived from hydrolysis of raltegravir-glucuronide secreted in
bile).
Urine: 32% (raltegravir + raltegravir glucuronide)
400 mg BID with or without food.
Raltegravir film-coated tablets must be swallowed whole.
Raltegravir chewable tablets may be chewed or swallowed
whole.
Dosing Pediatric
Because the formulations are not bioequivalent, do not

substitute chewable tablets for the 400 mg film-coated
tablet.
If at least 25 kg in weight:
One 400 mg film-coated tablet orally, twice daily OR
Chewable tablets: weight based to maximum dose 300 mg,
twice daily as specified:
Weight (kg)
Dose
# of Chewable Tablets
25 to <28
150 mg BID
1.5* x 100 mg BID
28 to <40
200 mg BID
2 x 100 mg BID
At least 40
300 mg BID
3 x 100 mg BID
*
The weight-based dosing recommendation for the chewable tablet is based on

approximately 6 mg/kg/dose twice daily.
The 100 mg chewable tablet can be divided into equal halves.
At least 4 weeks of age and weighing at least 3 kg to less

than 25 kg:
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Page 6 of 15
Body weight
(kg)
3 to <4
4 to <6
6 to <8
8 to <11
11 to <14
14 to <20
20 to l<25
Volume (Dose) of
Suspension
1 mL (20 mg) BID
1.5 mL (30 mg) BID
2 mL (40 mg) BID
3 mL (60 mg) BID
4 mL (80 mg) BID
5 mL (100 mg) BID
# of Chewable
Tablets
3 x 25 mg BID
1 x 100 mg BID
1.5 x 100 mg BID
*The weight-based dosing recommendation for the chewable tablet and oral
suspension is based on approximately 6 mg/kg/dose twice daily.
For weight between 11 and 20 kg either formulation can be used.

Note: The chewable tablets are available as 25 mg and 100 mg tablets.
The 100 mg chewable tablet can be divided into equal halves.
The maximum dose of chewable tablets is 300 mg twice

daily. The maximum dose of oral suspension is 100 mg
twice daily.
The safety and effectiveness of raltegravir in pediatric patients
less than 4 weeks of age have not been established.
Summary of Raltegravir Dosing in Pediatrics (studies)
RAL Dose
Ref
Age
4 wks<2 yo
2-5 yo
Oral suspension
12-18
400 mg BID (AF)
6 mg/kg BID, max

300 mg BID (OCT)
6-11 yo <25 kg 6 mg/kg BID, max
300 mg BID (OCT)
25 kg 400 mg BID (AF)
IMPAACT P1066
Nachman et al. CROI
2011, #715
Nachman et al. CROI
2010, #161LB
Nachman et al. CROI
2010, #873
ICAAC 2008; Wiznia et
al. CROI 2009; Frenkel
et al. ICAAC 2009.
OCT= oral chewable tablet; AF = adult formulation (400 mg tab)
Special instructions for pediatric

patients
Raltegravir film-coated tablets must be swallowed whole.

Raltegravir chewable tablets may be chewed or swallowed
whole. The 100 mg chewable tablet can be divided into equal
halves. The maximum dose of chewable tablets is 300 mg
twice daily.
Raltegravir chewable tablets contain phenylalanine, a component
of aspartame.
each 25 mg chewable tablet contains approximately 0.05 mg
phenylalanine.
each 100 mg chewable tablet contains approximately 0.10 mg
phenylalanine.
Phenylalanine can be harmful to patients with phenylketonuria.
Each single-use packet for oral suspension contains 100 mg of
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Page 7 of 15
raltegravir which is to be suspended in 5 mL of water giving a

final concentration of 20 mg/mL. Pour packet contents into 5 mL
of water and mix. Once mixed, measure the recommended
volume (dose) of suspension with a syringe and administer the
dose orally. The oral suspension should be administered orally
within 30 minutes of mixing. The maximum dose of oral
suspension is 100 mg twice daily.
Adjust in Liver Dysfunction
Because the formulations are not bioequivalent, do not

substitute chewable tablets or oral suspension for the 400
mg film-coated tablet.
Moderate hepatic insufficiency (Child Pugh score 7 to 9) has no
clinically meaningful effect on raltegravir pharmacokinetics (14%
AUC, 37% Cmax and 26% C12 vs. healthy matched
control subjects).(Iwamoto et al. 2009)
No dosage adjustment is necessary for patients with mild to
moderate hepatic impairment.
The kinetics of raltegravir and darunavir were studied in five HIVHCV co-infected patients with moderate to severe hepatic
impairment (2 with chronic active hepatitis, 3 with cirrhosis).
Plasma Ctrough samples were collected at days 14 and 30 after
this new regimen was initiated; 24 matched HIV-1 patients with
normal liver function treated with raltegravir and darunavir were
used as a control group. Mean raltegravir Ctrough was 637 vs.
221 ng/mL in controls. Patients with cirrhosis had higher mean
raltegravir Ctrough than patients with active non-cirrhotic
hepatitis (665 vs. 581 ng/mL). No differences in
viral/immunologic outcome or safety parameters were found
between cirrhotic and non-cirrhotic patients. Use raltegravir
with caution in patients with moderate to severe liver
impairment because of the risk of additive toxicity.(Tommasi et
al. 2010)
The kinetics of multi-dose raltegravir 400 mg BID were studied in
HIV/HCV coinfected patients with Child-Pugh grade C hepatic
cirrhosis on stable cART (LPVr, FPVr or DRVr) with controlled
viremia (<50 copies/ml) for at least 6 months. Compared to
patients with no histologic liver damage, patients with advanced
cirrhosis (Child-Pugh C) showed higher RAL exposure, with
mean 72% AUC and 6.5-fold C12. No safety issues were
identified and RAL was well tolerated by all patients.(HernandezNovoa et al. CROI 2012).
The kinetics of raltegravir 400 mg BID plus either abacavir/3TC
or tenofovir/FTC were studied in 10 HIV+ patients (80% HCV)
with end-stage liver disease: median age 50 (39-63) yrs, 58 (483
81) kg, CD4 258 (57-604) cells/mm , MELD and CP scores at
screening were 12 [5; 26] and 10 [6; 14], respectively. Median
MELD at M1 was 11 [7; 33]. Albumin concentration at M1 was 27
[24; 36] g/L. Raltegravir was well tolerated in all subjects.
Raltegravir pharmacokinetics exhibited wide variability, but were
within the range historically reported in patients or volunteers
with normal liver function.(Barau et al. CROI 2013)
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Adjust in Renal Failure/Dialysis
Severe renal insufficiency (Clcr<30 mL/min) has no clinically

meaningful effect on pharmacokinetics of 400 mg raltegravir
(15% AUC, 32% Cmax and 28% C12 vs. healthy matched
control subjects). Raltegravir half-life ( t1/2 ~24%, t1/2
~51%) was slightly prolonged in renal insufficiency, but these
changes were not clinically important. No serious adverse
events were observed.(Iwamoto et al. 2009) No dosage
adjustment is necessary in patients with renal insufficiency.
Antiretroviral pharmacokinetics were studied in a 49-year old
HIV-positive man virologically suppressed on darunavir/ritonavir
600/100 mg twice daily, etravirine 200 mg twice daily and
raltegravir 400 mg twice daily while undergoing hemodialysis
three times weekly. The morning dose of the antiretrovirals was
taken after completion of the 4-hour morning hemodialysis
session. After dialysis, darunavir, etravirine, raltegravir and
ritonavir concentrations were decreased by 57%, 29%, 82% and
60%, respectively compared to predialysis levels. A
supplemental dose of 600 mg darunavir administered prior to the
hemodialysis session was successful in restoring darunavir
concentrations approximately equal to expected levels, while
administration of a supplemental dose of raltegravir 400 mg was
not, likely due to wide intra- and inter-patient variability. Dose
supplementation of etravirine was not deemed necessary given
the relatively low amount removed during hemodialysis. After 1
year of therapy, the patient maintained viral
suppression.[Giguere et al. 2009]
Pre- and post-dialysis raltegravir concentrations were measured
in 2 ESRD HIV-infected patients. The hemodialysis extraction
ratio and raltegravir hemodialysis clearance were 5.5% and 9.1
ml/min in patient 1, and 9.5% and 19.1 ml/min in patient 2.
These results suggest minimal raltegravir removal by
hemodialysis with no specific raltegravir dosage adjustments
required.[Molto et al. 2010]
Toxicity
An HIV-positive patient on continuous venovenous

hemodiafiltration (CVVHDF) received raltegravir 400 mg BID,
darunavir 600/100 mg BID, zidovudine 300 mg BID and 3TC 50
mg q24h in suspension via gastric port and simultaneous enteral
feeding via the duodenal port of a double-lumen
nasogastroduodenal tube. Pharmacokinetic sampling and
analysis indicated that darunavir and raltegravir were removed
by CVVHDF with approximately the same clearance as provided
by a normally functioning kidney. Absorption of both drugs after
suspension and application via the gastric port with continued
administration of feed via the duodenal port of the double-lumen
tube was good. As such, dose adjustments are not required
for patients receiving darunavir and/or raltegravir while
undergoing CVVHDF and that absorption of darunavir and
raltegravir is not significantly affected by postpyloric enteral
feeding.[ Taegtmeyer et al. 2011]
Single dose PK study in healthy subjects (n = 20), single doses
of raltegravir up to 1600 mg were generally well tolerated
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Page 9 of 15
[Wenning et al. ICAAC 2007].

In the Benchmrk studies, the rate of side effects was similar for
the raltegravir and placebo treatment groups. The most
common ADRs (>10%) in these studies were: nausea,
headache, diarrhea and pyrexia. CK elevations with myopathy
and rhabdomyolysis have been reported. The relationship of
Raltegravir to these events is not known. No lipid abnormalities
have been reported so far with raltegravir.
Overdose
Pregnancy & Lactation
Severe, potentially life-threatening, and fatal skin reactions,

including Stevens-Johnson syndrome and toxic epidermal
necrolysis have been reported. Hypersensitivity reactions have
also been reported, characterized by rash, constitutional
findings, and sometimes, organ dysfunction, including hepatic
failure. Discontinue raltegravir and other suspect agents
immediately if signs or symptoms of severe skin reactions or
hypersensitivity reactions develop (including, but not limited to,
severe rash or rash accompanied by fever, general malaise,
fatigue, muscle or joint aches, blisters, oral lesions,
conjunctivitis, facial edema, hepatitis, eosinophilia, angioedema).
Clinical status including liver aminotransferases should be
monitored and appropriate therapy initiated.
Doses as high as 1600-mg single dose and 800-mg twicedaily multiple doses were studied in healthy volunteers
without evidence of toxicity.
Occasional doses of up to 1800 mg per day were taken in

the P005/P018 & P019 studies without evidence of toxicity
Pregnancy
Third trimester and postpartum raltegravir pharmacokinetics

were studied in 10 HIV-positive women receiving raltegravir
400 mg BID. Raltegravir kinetics showed extensive
variability (consistent with observations in other populations),
rd
but exposure was not consistently altered during the 3
trimester compared to post-partum and historical data. The
cord blood:maternal plasma ration (n=6) was 0.98 (0.092.26).[Best et al. ICAAC 2010] Similar results were
rd
observed in 3 trimester and post-partum concentrations in
a cohort of 5 HIV-positive women on raltegravir 400 mg
th
BID.[Colbers et al. 12 IWCPHT 2011]
Thus, raltegravir appears to readily cross the placenta and

standard dosing may be used in pregnancy
High raltegravir concentrations were observed in 3 newborns

whose mothers received raltegravir during pregnancy.
Raltegravir concentrations in the neonates were
disproportionately higher (209-3634 ng/mL at 5.5-13 hours
post dose) compared to maternal raltegravir concentrations
(22-493 ng/mL at 7-12 hours post dose), indicating effective
placental transfer and possibly immature neonatal UGT1A1
mediated glucuronidation.[McKeown et al. 2010]
Placenta transfer of drug was demonstrated in both rats and

rabbits.
Treatment related increases in the incidence of

supernumerary ribs were seen in rats (exposures 3 fold the
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Page 10 of 15
exposure at the recommended human dose)

Lactation
It is not know if raltegravir is secreted in human milk.
Raltegravir is secreted in the milk of lactating rats.
It is recommended that HIV infected mothers not breast-feed

their infants to avoid risking postnatal transmission of HIV
Drug Interactions
Use in preventing vertical transmission
Case series of 31 pregnant women: raltegravir was

virologically effective and caused no adverse events in
women or their newborns (France) [Jeantils et al. ICAAC
2013].
Three cases in which raltegravir was used late in pregnancy

to rapidly reduce maternal HIV-1 viral load in women with
multidrug resistant virus. In all three cases, addition of
raltegravir to the mother's regimen was associated with rapid
reduction in maternal viral load. The much higher raltegravir
concentrations in neonates compared with their mothers
suggests effective placental transfer. [Hegazi et al. 2012]
See Drug interaction tables for more details
Effect of Raltegravir on the Kinetics of Other Agents
Does NOT inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9,
CYP2C19, CYP2D6, or CYP3A in vitro
Does NOT induce CYP3A4 in vitro
Baseline Assessment
Effect of Other Agents on the Pharmacokinetics of Raltegravir

Strong inducers of UGT1A1 (ex Rifampin) will reduce
plasma concentrations of Raltegravir
Less strong inducers (e.g., efavirenz, nevirapine, rifabutin,

St. John's wort) may be used without dose adjustment of
Raltegravir.
Strong inhibitors or UGT1A1 (Ex ATV/r) will increase plasma

concentrations of Raltegravir. In trials the combination of
Raltegravir with ATV/r did not result in toxicity concerns.
Therefore may use combination without dose adjustment.
CD4, viral load
Routine Labs
CD4, viral load
Dosage Forms
400 mg tablets, DIN 02301881
Chewable tablets:
o 100 mg, pale orange, oval-shaped, orange-banana
flavoured, DIN 02392437
o 25 mg, pale yellow, round, orange-banana flavoured, DIN
02392429
Storage
Oral suspension (approved in U.S.):

o single-use packet for oral suspension contains 100 mg of
raltegravir which is to be suspended in 5 mL of water giving
a final concentration of 20 mg/mL
Store at room temperature (20-25C); excursions permitted to
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Page 11 of 15
15-30C.
The oral suspension should be administered orally within 30
minutes of mixing.
References:
Acosta E, Wiznia A, Nachman S, Teppler H, Long M, Homony B, et al. Raltegravir pharmacokinetics in
th
adolescents: preliminary results from IMPAACT protocol 1066 [abstract P8]. 9 International Workshop
on Clinical Pharmacology of HIV Therapy. New Orleans, USA, April 7-9, 2008.
Antoniou T, Loutfy MR, Brunetta J, Smith G, Halpenny R, la Porte C. Pharmacokinetics of raltegravir in the
semen of HIV-infected men. Antiviral Therapy 2014; Feb 12.
Barau C, Braun J, Vincent C, et al. Pharmacokinetic study of raltegravir in HIV+ patients with end state
liver disease : LIVERAL ANRS 148 study [abstract 528]. 20th Conference on Retroviruses and
Opportunistic Infections, Atlanta, GA, March 3-6, 2013.
http://www.retroconference.org/2013b/Abstracts/46396.htm
Barau C, Delaugerre C, Braun J, de Castro N, Furlan V Charreau I, et al. High Concentration of
Raltegravir in Semen of HIV-Infected Men: Results from a Substudy of the EASIER-ANRS 138 Trial.
Antimicrob Agents Chemother 2010;54(2):937-9.
Best BM, Capparelli EV, Stek A, et al. Raltegravir pharmacokinetics during pregnancy [abstract H-1668a].
th
th
50th ICAAC, September 12-15 , 2010, Boston, MA.
Brainard DM et al. Effect of low-, moderate-, and high-fat meals on raltegravir pharmacokinetics. J Clin
Pharmacol 2011;51(3):422-7.
Burger D, Colbers EPH, Van Luin M, Koopmans PP. AUC0-3h of raltegravir is correlated to AUC0-12h: a
th
novel approach for therapeutic drug monitoring of raltegravir [abstract 41]. 11 International Workshop on
th
Clinical Pharmacology of HIV Therapy, April 5-7 , 2010, Sorrento, Italy.
Cahn P. Sued O. Raltegravir: a new antiretroviral class for salvage therapy. Lancet. 369(9569):1235-6,
2007 Apr 14.
Calcagno A, Bonora S, D'Avolio A, Siccardi M, Simiele M, Chiesa M, Gonzalez de Requena D, Di Perri G.
Raltegravir penetration in seminal plasma of healthy volunteers. Antimicrob Agents Chemother 2010 Mar
22. [Epub ahead of print]
Calcagno A, Bonora S, Bertucci, R, Lucchini A, DAvolio A, Di Perri G. Raltegravir penetration in the
cerebrospinal fluid of HIV-positive patients. AIDS 2010;24:931-2.

Calcagno A, Simiele M, Rostagno R, Cusato J, Bracchi M, et al. Raltegravir penetration in the
cerebrospinal fluid: impact of coadministered antiretrovirals and rifampin [abstract P_30]. 13th
th
International Workshop on Clinical Pharmacology of HIV Therapy. April 16-18 , 2012, Barcelona, Spain.
Cattaneo D, Baldelli S, Cerea M, Landonio S, Meraviglia P, Simioni E et al. Comparison of the in vivo
pharmacokinetics and in vitro dissolution of raltegravir in HIV patients receiving the drug by swallowing or
by chewing. Antimicrob Agents Chemother 2012;56:6132-6136.
Cattaneo D, Cossu MV, Fucile S et al. Comparison of the pharmacokinetics of raltegravir given at 400 mg
Bid by swallowing versus 800 mg qd by chewing in healthy volunteers: a randomized, open-label, two-
www.hivclinic.ca
Page 12 of 15
th
th
period cross-over phase 1 study [abstract PE7/10]. 14 European AIDS Conference, October 16-19 ,
2013, Brussels.
Colbers A, Molto J, Ivanovic J, et al. A comparison of the pharmacokinetics of raltegravir during
th
preganancy and post-partum [abstract P_18]. 12 International Workshop on Clinical Pharmacology of
HIV Therapy. April 13-15, 2011, Miami.
Cooper D, Gatell JM, Rockstroh J, et al. Results of BENCHMRK-1, a phase III study evaluating the
efficacy and safety of MK-0518, a novel HIV-1 integrase inhibitor, in patients with triple-class resistant
virus. 14th Conference on Retroviruses and Opportunistic Infections, Los Angeles, California, USA, Feb
2528, 2007: 105a LB (abstr).
DeJesusE., et al. First report of raltegravir (RAL, MK-0518) use after virologic rebound on elvitegravir
(EVT, GS 9137). Poster exhibition: 4th IAS Conference on HIV Pathogenesis, Treatment and Prevention:
Abstract no. TUPEB032
Giguere P, la Porte C, Zhang G, Cameron B. Pharmacokinetics of darunavir, etravirine and raltegravir in
an HIV-infected patient on haemodialysis. AIDS 2009;23:740-2.
Grinsztejn B. Nguyen BY. Katlama C. Gatell JM. Lazzarin A. Vittecoq D. Gonzalez CJ. Chen J. Harvey
CM. Isaacs RD. Protocol 005 Team. Safety and efficacy of the HIV-1 integrase inhibitor raltegravir (MK0518) in treatment-experienced patients with multidrug-resistant virus: a phase II randomised controlled
trial. Lancet. 369(9569):1261-9, 2007 Apr 14.
Hegazi A, McKeown D, Doerholt K, Donaghy S, Sadiq ST, Hay P. Raltegravir in the prevention of motherto-child transmission of HIV-1: effective transplacental transfer and delayed plasma clearance observed in
preterm neonates. AIDS. 2012;26:2421-2423.
Hernandez-Novoa et al. Multiple-dose pharmacokinetics of raltegravir in patients co-infected with
th
HIV/HCV with and without advanced (Child-Pugh grade C) hepatic cirrhosis [abstract 609]. 19
Conference on Retroviruses and Opportunistic Infections, Seattle, WA. March 5-8, 2012.
Iwamoto M, Hanley WD, Petry AS, Friedman EJ, Kost JT, Breidinger SA, Lasseter KC, Robson R, Lunde
NM, Wenning LA, Stone JA, Wagner JA. Lack of a clinically important effect of moderate hepatic
insufficiency and severe renal insufficiency on raltegravir pharmacokinetics. Antimicrob Agents Chemother
2009;53(5):1747-52.
Jeantils V, Messaouden H, Carbillon L. Pregnancy and a regimen containing raltegravir: a pilot study on
the materno foetal safety [abstract H-1463]. 53rd ICAAC. September 10-13, 2013. Denver.
Jones A,Talameh J, Patterson K, Rezk N, Prince H, Kashuba A. First-dose and steady-state
th
pharmacokinetics of raltegravir in the genital tract of HIV uninfected women [abstract O_06]. 10
International Workshop on Clinical Pharmacology of HIV Therapy. April 15-17, 2009, Amsterdam.
Kassahun et al. Absorption, Metabolism and Excretion of MK-0518, a Potent HIV-1 Integrase Inhibitor, in
th
Healthy Male Volunteers [abstract A-0372]. 46 ICAAC, September 27-30, 2006, San Francisco.
Krishna R, Rizk ML, Schulz V et al. A single dose food effect study of raltegravir formulations [abstract
th
th
PE10/17]. 14 European AIDS Conference, October 16-19 , 2013, Brussels.
Lentendre S et al. Raltegravir concentrations in CSF exceed the median inhibitory concentration [abstract
th
A1-1311]. 49 ICAAC, September 12-15, 2009, San Francisco.
Letendre S, Ellis RJ, Deutsch R, Clifford DB, Collier AC, Gelman GG, et al. Correlates of time-to-loss-ofAcademic copyright. A. Tseng, Pharm.D., FCSHP, AAHIVP, Toronto, Ontario. Please note: This chart summarizes
www.hivclinic.ca
Page 13 of 15
viral-response in CSF and plasma in the CHARTER Cohort: CPE score predicts CSF suppression
th
[abstract 430]. 17 Conference on Retroviruses and Opportunistic Infections, San Francisco, CA,
February 16-19, 2010.
McKeown DA, Rosenvinge M, Donaghy S, et al. High neonatal concentrations of raltegravir following
transplacental transfer in HIV-1 positive pregnant women. AIDS 2010;24:2416-2418
McSharry J, Weng Q, Kulaway R, Drusano G. Dose range and dose fractionation studies for raltegravir
th
pharmacodynamics in an in vitro hollow fiber infection model system [abstract O_09]. 10 International
Workshop on Clinical Pharmacology of HIV Therapy. April 15-17, 2009, Amsterdam.
Merck Canada Ltd. Isentress Product Monograph. Kirkland, QC. February 10, 2012.
Molto J, Sanz-Moreno J, Valle M, Cedeo S, Bonal J, Bouarich H et al. Minimal removal of raltegravir by
hemodialysis in HIV-infected 1 patients with end stage renal disease. Antimicrob Agents Chemother
rd
2010, epub ahead of print May 3 .
Patterson K, Prince H, White N, Wang R, Jones A, Kashuba A. Pharmacokinetics of raltegravir in the
blood plasma and genital tract in HIV+ and HIV- women [abstract LBPE18]. XVIII International AIDS
Conference, Vienna, Austria, July 18-23, 2010.
Patterson K, Stevens, Prince H, Jennings S, Shaheen N, Madanick R, et al. Antiretrovirals for prevention:
pharmacokinetics of raltegravir in gut-associated lymphoid tissue (GALT) of healthy male volunteers
th
[abstract O_11]. 13 International Workshop on Clinical Pharmacology of HIV Therapy, April 16-18, 2012,
Barcelona.
Petry A, Wenning LA, Kost JT, Jin B, Breidinger S, Delepeleire I et al. Raltegravir pharmacokinetics in
th
individuals with UGT1A1*1/*1 and UGT1A1*28/*28 genotypes [abstract A-961]. 48 ICAAC, October 2528, 2008, Washington, DC.
Petry et al. Safety, Tolerability, and Pharmacokinetics after Single and Multiple Doses of MK-0518 in
th
Healthy Subjects [abstract A-0376]. 46 ICAAC, September 27-30, 2006, San Francisco.
Rizk ML, Krishna R, Schulz V, et al. A multiple dose study of raltegravir formulations [abstract 523].
Conference on Retroviruses and Opportunistic Infections, March 3-6, 2014, Boston, MA.
Sandkovsky U, Swindells S, Moore R, Acosta EP, Fletcher CV. Acceptable plasma concentrations of
raltegravir and etravirine when administered by gastrostomy tube in a patient with advanced multidrugresistant human immunodeficiency virus infection. Pharmacotherapy 2012: 32(2):142147.
Sandkovsky U, Swindells S, Robbins BL, Nelson SR, Acosta EP, Fletcher CV. Measurement of plasma
and intracellular concentrations of raltegravir in patients with HIV infection. AIDS 2012;26:22579.
Steigbigel R, Kumar P, Eron J, et al. Results of BENCHMRK-2, a phase III study evaluating the efficacy
and safety of MK-0518, a novel HIV-1 integrase inhibitor, in patients with triple-class resistant virus. 14th
Conference on Retroviruses and Opportunistic Infections, Los Angeles, California, USA, Feb 2528, 2007:
105b LB (abstr).
Taegtmeyer AB, Mller V, Kovari H, Kullak-Ublick GA, Corti N. Effect of continuous venovenous
hemodiafiltration on darunavir and raltegravir exposure after administration via a gastroduodenal tube.
AIDS 2011;25:1339-41.
Teppler H, Azrolan N, Chen J. Differential effect of MK-0518 and efavirenz on serum lipids and
lipoproteins in antiretroviral therapy (ART)naive patients. 46th Annual Interscience Conference on
www.hivclinic.ca
Page 14 of 15
Antimicrobial Agents and Chemotherapy, San Francisco, California, USA, Sept 2730, 2006: H-256a
(abstr).
Tommasi C, Nicastri E, Gallo AL, Tempestilli M, Bellagamba R, Fezza R et al. Raltegravir and darunavir
th
pharmacokinetics in HIV-1 infected patients with advanced liver disease [abstract 10]. 11 International
th
Workshop on Clinical Pharmacology of HIV Therapy, April 5-7 , 2010, Sorrento, Italy.
Wang L et al. Time-course comparison of intracellular and plasma raltegravir after a single dose in
th
th
healthy volunteers [abstract A1-2012]. 50th ICAAC, September 12-15 , 2010, Boston, MA.
Wenning L, Anderson M, Petry A, Friedman E, Kost J, James S, et al. Raltegravir dose proportionality
th
and effect of food [abstract H-1046]. 47 ICAAC, September 17-20, 2007, Chicago, IL.
Wohl D, Dumond J, Blevins S, Pittard D, Ragan D, Wang R, et al. Raltegravir pharmacokinetics in
treatment-naive patients is not influenced by race: results from the raltegravir early therapy in AfricanAmericans living with HIV (REAL) study. Antimicrob Agents Chemother 2013;57:784-8.
www.hivclinic.ca
Page 15 of 15

Integrase Inhibitor Raltegravir

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Integrase Inhibitor Raltegravir

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Selected Properties of Raltegravir

Merck Canada Inc.

Raltegravir is a novel HIV-1 integrase strand transfer inhibitor.

Raltegravir potently inhibits integrase catalyzed strand transfer,

HIV1: EC95: 31 20 nM (in vitro)

HIV 1 - diverse, primary clinical isolates including isolates

HIV 2: EC95 value = 6 nM (in vitro)

There seems to be cross-resistance between raltegravir and

The absorption of raltegravir, etravirine, emtricitabine, and

Raltegravir may be administered twice daily without regard

Raltegravir is rapidly absorbed with median Tmax 3 hours in the

*Number of patients with intensive pharmacokinetic (PK) results at the final

Geometric coefficient of variation.

The pharmacokinetics of raltegravir in infants under 4 weeks of

variability was observed with the BID dosing, variability was

Raltegravir concentrations and HIV-1 RNA levels were

Minimum target trough

Gut-associated lymphoid tissue concentrations

Based on data from two healthy volunteer studies, C2h or AUC0-3h

dose sampling time. Raltegravir concentrations in CSF exceeded

2010 CNS Penetration Effectiveness (CPE) Score: 3

Because the formulations are not bioequivalent, do not

The weight-based dosing recommendation for the chewable tablet is based on

The 100 mg chewable tablet can be divided into equal halves.

At least 4 weeks of age and weighing at least 3 kg to less

1.5 x 100 mg BID

For weight between 11 and 20 kg either formulation can be used.

The 100 mg chewable tablet can be divided into equal halves.

The maximum dose of chewable tablets is 300 mg twice

400 mg BID (AF)

6 mg/kg BID, max

OCT= oral chewable tablet; AF = adult formulation (400 mg tab)

Special instructions for pediatric

Raltegravir film-coated tablets must be swallowed whole.

raltegravir which is to be suspended in 5 mL of water giving a

Adjust in Liver Dysfunction

Because the formulations are not bioequivalent, do not

Adjust in Renal Failure/Dialysis

Severe renal insufficiency (Clcr<30 mL/min) has no clinically

An HIV-positive patient on continuous venovenous

[Wenning et al. ICAAC 2007].

Pregnancy & Lactation

Severe, potentially life-threatening, and fatal skin reactions,

Occasional doses of up to 1800 mg per day were taken in

Third trimester and postpartum raltegravir pharmacokinetics

Thus, raltegravir appears to readily cross the placenta and

High raltegravir concentrations were observed in 3 newborns

Placenta transfer of drug was demonstrated in both rats and

Treatment related increases in the incidence of

exposure at the recommended human dose)

It is not know if raltegravir is secreted in human milk.

Raltegravir is secreted in the milk of lactating rats.

It is recommended that HIV infected mothers not breast-feed

Use in preventing vertical transmission

Case series of 31 pregnant women: raltegravir was

Three cases in which raltegravir was used late in pregnancy

Does NOT induce CYP3A4 in vitro

Effect of Other Agents on the Pharmacokinetics of Raltegravir

Less strong inducers (e.g., efavirenz, nevirapine, rifabutin,

Strong inhibitors or UGT1A1 (Ex ATV/r) will increase plasma