A new chapter in the clinical use of boosted Invirase

1
A new chapter in the clinical use of boosted
Invirase
Mike YouleDirector of AIDS Research, Royal Free
Hospital, London, UK
The licensed dose of Invirase/r (saquinavir) in
the EU is 1000/100 mg bid. Doses other than
1000/100 mg bid are not licensed in the EU.
2
The evolution of saquinavir/r over a decade of
experience
Fortovase/r 200 mg capsule 1000/100 mg bid
Invirase/r 200 mg capsule 1000/100 mg bid
3
Boosted Invirase a better tolerability profile
than boosted Fortovase
1
Diarrhoea
12
3
Nausea
Invirase/r 1000/100 mg bid
2
Fortovase/r 1000/100 mg bid
4
Abdominal pain
2
n 24
0
Vomiting
3
0
Abdominal distension
4
0
2
4
6
8
10
12
14
Number of patients with events
Kurowski et al. HIV Med 2003 494100
4
Invirase 500right formulation, right dose

• Once-daily dosing a possibility
• SQV/r 2000/100 mg qd

• Invirase now available as a 500 mg film-coated
  tablet
• Approved in EU in May 2005
• Recommended dosage SQV/r 1000/100 mg bid
• Significantly reduced pill burden

Invirase 500/r 1000/100 mg bid
The licensed dose of Invirase/r in the EU is
1000/100mg bid. Doses other than 1000/100mg bid
are not licensed in the EU
5
Invirase 500 mg film-coated tablet bioequivalent
to 200 mg tablet
5000
Invirase 500 mg
Invirase 200 mg
4000
3000
n 94
Saquinavir concentration (ng/ml)
2000
1000
0
0
2
4
6
8
10
12
14
16
18
20
22
24
Time (hours)
When dosed at 1000/100 mg, in fed state
Bittner et al. Antivir Ther 2005 1080310
6
Invirase/r showing its colours
7
Saquinavir/r 1000/100 mg bid efficacy

• 1000/100 mg bid proven potency
• QUAD1
• MaxCmin12
• MaxCmin23

1. Staszewski et al. 9th EACS 2003. Oral F1/1
2. Dragsted et al. J Infect Dis 2003 18863542
3. Dragsted et al. Antivir Ther 2005 1073543
8
Staccato proven potency with Invirase/r qd dosage
lt 400 copies/ml, ITT
100
96
89
80
lt 50 copies/ml ITT
60
Proportion of patients with undetectable HIV RNA
()
n 200 Baseline median CD4, 267 cells/mm3 HIV
RNA, 4.7 log10 copies/ml
40
20
0
0
8
16
24
Time (weeks)
Investigational Invirase/r 1600/100 mg qd dosage
Ananworanich et al. Antivir Ther 2005 107617
The licensed dose of Invirase/r in the EU is
1000/100mg bid. Doses other than 1000/100mg bid
are not licensed in the EU
9
SQV concentration profiles with 1600/100 mg qd
in Thai patients and 2000/100 mg qd in UK
patients
10000
1000
n 20
Median SQV concentration (ng/ml)
n 18
100
10
0
4
8
12
16
20
24
Time (hours)
1. Adapted from Autar et al. J Antimicrob
Chemother 2004 5478590 2. Adapted from
Boffito et al. Antivir Ther 2004 94239
The licensed dose of Invirase/r in the EU is
1000/100mg bid. Doses other than 1000/100mg bid
are not licensed in the EU
10
SQV AUC (median and IQR) for the three evaluated
dosing regimens
60000
50000
40000
AUC24 (ng.h/ml)
30000
20000
10000
0
1000/100 mg bid
1600/100 mg qd
2000/100 mg qd
Adapted from Boffito et al. Antivir Ther 2004
94239
The licensed dose of Invirase/r in the EU is
1000/100mg bid. Doses other than 1000/100mg bid
are not licensed in the EU
11
Switching to saquinavir 500/r-based regimens in
subjects on HAART is not associated with loss of
virological control

• Mahungu T, Ballinger J, Swaden L, Smith C, Youle
  M and Johnson M Royal Free Centre for HIV
  Medicine, Royal Free Hospital, London, UK

Mahungu et al. 10th EACS 2005. Poster PE1.1/5
12
Reviewing the Invirase 500/r cohort at the Royal
Free Centre for HIV Medicine, London

• Retrospective study of 137 patients
• Eligible patients received Invirase 500/r from
  September 2004 as part of special licence sales
• 1000/100 mg bid (n 116)
• 2000/100 mg qd (n 19)
• The proportion of patients remaining on Invirase
  500 after 6, 12 and 24 weeks was calculated
• The levels of plasma HIV-1 RNA, CD4 cells, lipid
  markers and liver enzymes were measured before
  and after treatment

Mahungu et al. 10th EACS 2005. Poster PE1.1/5
The licensed dose of Invirase/r in the EU is
1000/100mg bid. Doses other than 1000/100mg bid
are not licensed in the EU
13
Baseline characteristics
IQR, interquartile range
Mahungu et al. 10th EACS 2005. Poster PE1.1/5
14
The majority (95.6) of patients remained on
Invirase 500 therapy at 24 weeks
97.1
97.1
95.6
100
90
80
70
60
Patients ()
50
40
30
20
10
0
6 week
12 weeks
24 weeks
Mahungu et al. 10th EACS 2005. Poster PE1.1/5
15
Efficacy virological and immunological response
(n 126)

• 73 of patients had lt 50 copies/ml at baseline
• Of these, 84 maintained undetectable viraemia
  throughout follow-up
• Median change in CD4 count from baseline was 17
  cells/mm3
• 27 patients had VL of gt 50 copies/ml at baseline
• Of these, 53 achieved undetectable viraemia
  after initiating Invirase 500 therapy
• Median change in CD4 count from baseline was 25
  cells/mm3

Mahungu et al. 10th EACS 2005. Poster PE1.1/5
16
Seven patients did not complete 24 weeks of
Invirase 500 therapy

• Three patients were lost to follow-up
• One patient chose to discontinue therapy no
  adverse events reported
• One patient switched to ATV therapy qd treating
  physician unaware of SQV/r qd possibility
• One patient switched to FPV/LPV/r therapy for 2
  months, before switching back to Invirase 500
• One patient, who was also receiving ATV,
  experienced nausea and vomiting and was switched
  to FPV therapy

17
Tolerability liver function enzymes and lipid
markers (n gt 68)
Mahungu et al. 10th EACS 2005. Poster PE1.1/5
18
Invirase 500/r cohort summary

• Over 24 weeks
• Clear evidence of the utility of Invirase 500 in
  clinical practice
• Ongoing activity when patients switched from
  Invirase 200 mg formulation to Invirase 500
• Invirase 500 was well tolerated
• No significant changes in lipid profile or liver
  function enzymes
• Lower pill count of Invirase 500 provides
  compelling rationale to use SQV/r in first-line
  PI regimens

Mahungu et al. 10th EACS 2005. Poster PE1.1/5
19
Invirase 500 moving forward
20
ABRIDGED PRESCRIBING INFORMATION (For full
prescribing information refer to the Summary of
Product Characteristics SPC) INVIRASE
(Saquinavir) 500mg Film-Coated Tablet Indication
Treatment of HIV-1 infected adult patients. Only
give in combination with ritonavir and other
antiretrovirals. Dosage and Administration
Adults and adolescents over 16 years 1000mg BID
with ritonavir 100mg BID in combination with
other antiretroviral agents within two hours
following a meal. Take ritonavir at the same time
as Invirase. Dose reduction may be required when
Invirase/ritonavir administered with some other
HIV protease inhibitors (PIs), e.g. nelfinavir,
indinavir, delavirdine. Caution with severe renal
or moderate hepatic impairment. Limited data in
HIV infected patients lt 16 years and adults gt
60 years. Due to the significantly lower
saquinavir plasma levels in children compared to
adults, Invirase should not be used as the sole
PI in children. Contra-indications
Hypersensitivity to saquinavir, ritonavir or
excipients. Patients with severe hepatic
impairment. Invirase/ritonavir should not be
given together with other medicinal products
which may interact and result in potentially life
threatening side effects. Do not administer with
terfenadine, astemizole, pimozide, cisapride,
amiodarone, propafenone, flecainide, midazolam,
triazolam, simvastatin, lovastatin, ergot
alkaloids (e.g. ergotamine, dihydroergotamine,
ergonovine and methylergonovine) and rifampicin
(risk of severe hepatocellular toxicity).
Precautions Do not give as the sole PI. Only use
in combination with ritonavir.  Safety and
efficacy not established in patients with
significant underlying liver disorders. Chronic
hepatitis B or C patients treated with
combination antiretroviral therapy (CART) are at
increased risk for severe and potentially fatal
hepatic adverse events. Patients with
pre-existing liver dysfunction including chronic
active hepatitis have an increased frequency of
liver function abnormalities during CART and
should be monitored. Worsening liver disease
requires interruption or discontinuation of
treatment. Exacerbation of chronic liver
dysfunction, including portal hypertension
reported in patients with underlying hepatitis B
or C, cirrhosis and other underlying liver
abnormalities. Limited data in patients with
chronic diarrhoea or malabsorption. It is unknown
whether these patients could receive
subtherapeutic drug levels. Limited data in
children treated with Fortovase and none for
children treated with Invirase as sole PI.
Fortovase (50mg/kg BID) co-administered with
nelfinavir or ritonavir leads to increased
saquinavir exposures in children and when
combined with ritonavir, may result in saquinavir
exposures up to 2-fold greater than those
achieved with Fortovase 1200mg TID in adults.
Patients with galactose intolerance, the Lapp
lactase deficiency or glucose-galactose
malabsorption should not take this medicine.
Increased bleeding, including spontaneous skin
haematomas and haemarthroses reported in
haemophiliac patients Type A and B treated with
PIs. New onset diabetes mellitus, hyperglycaemia
or exacerbation of existing diabetes mellitus
reported in patients receiving PIs. CART
associated with redistribution of body fat
(lipodystrophy). Risk factors include older age
and duration of antiretroviral treatment and
associated metabolic disturbances. Upon
initiation of CART, an inflammatory reaction to
asymptomatic or residual opportunistic pathogens
may arise in HIV infected patients with severe
immune deficiency causing serious clinical
conditions or aggravation of symptoms. Evaluate
inflammatory symptoms and institute treatment.
Co-administration of saquinavir and ritonavir has
led to severe adverse events, mainly diabetic
ketoacidosis and liver disorders, especially in
patients with pre-existing liver disease. Doses
of ritonavir gt 100mg BID associated with an
increased incidence of adverse events. Caution if
Invirase/ritonavir is used with atorvastatin
(consider a reduced dose of atorvastatin,
treatment with pravastatin/fluvastatin
recommended where a HMG-CoA reductase inhibitor
is indicated). Concentration of ethinyl
oestradiol may be decreased when co-administered
with Invirase/ritonavir - use alternative or
additional contraceptive measures when
oestrogen-based oral contraceptives used.
Concomitant use of boosted saquinavir and
fluticasone or other glucocorticoids that are
metabolised by CYP3A4 not recommended. Drug
Interactions Most data is with unboosted
Invirase and Fortovase limited data with
ritonavir boosted Invirase/Fortovase. Results
from unboosted studies might not be
representative of saquinavir/ritonavir therapy.
Caution when co-administered with inducers or
inhibitors
and/or substrates of CYP3A4 and/or P-gp.
Inhibitors of CYP3A4 may increase saquinavir
blood levels inducers of CYP3A4 may decrease
saquinavir blood levels substrates of CYP3A4 may
be increased by saquinavir. Ritonavir, indinavir,
delavirdine, nelfinavir, nefazodone,
clarithromycin, erythromycin, streptogramin
antibiotics such as quinupristin/dalfopristin,
ketoconazole, itraconazole may increase
saquinavir blood levels. Hepatocellular changes
should be monitored frequently if saquinavir is
given with delavirdine. Saquinavir or
saquinavir/ritonavir may increase indinavir,
nelfinavir, clarithromycin, bepridil, systemic
lidocaine, quinidine, tricyclic antidepressants,
alprazolam, clorazepate, diazepam, flurazepam,
felodipine, nifedipine, nicardipine, diltiazem,
nimodipine, verapamil, amlodipine, nisoldipine,
isradipine, atorvastatin, cyclosporin,
tacrolimus, rapamycin, dapsone, disopyramide,
quinine, fentanyl, alfentanyl, digoxin,
sildenafil, vardenafil, tadalafil blood levels
caution, monitor for adverse events and consider
therapeutic drug monitoring and dose adjustments.
Saquinavir levels may be decreased by
carbamazepine, phenobarbital, phenytoin, garlic
capsules, dexamethasone, St. Johns wort
(Hypericum perforatum), rifampicin, rifabutin,
efavirenz - saquinavir-efavirenz combination
should only be used in association with a booster
such as ritonavir. Concentrations of warfarin may
be affected - monitor INRs. Systemic
corticosteroid effects including Cushing's
syndrome and adrenal suppression reported in
patients receiving ritonavir and inhaled or
intranasally administered fluticasone propionate
this could also occur with other corticosteroids
metabolised via the P450 3A pathway. Consider
dose reduction of the glucocorticoid with close
monitoring of local and systemic effects or
switch to a glucocorticoid which is not a
substrate for CYP3A4. For glucocorticoid
withdrawal, progressive dose reduction may have
to be performed over a longer period. Effects of
high fluticasone systemic exposure on ritonavir
plasma levels unknown. Concentration of methadone
may be decreased when coadministered with
Invirase/ritonavir. Methadone dosage may need to
be increased. Blood levels of ethinyl estradiol
decreased when co-administered with
saquinavir/ritonavir. Effects of medicinal
products which reduce gastrointestinal transit
time on saquinavir plasma concentrations unknown.
Pregnancy and Lactation Only use if the
potential benefit justifies the potential risk to
the foetus. Discontinue breast-feeding prior to
receiving saquinavir. To avoid HIV transmission,
it is recommended that HIV-infected women do not
breast-feed. Side-Effects Clinical trial data.
The most frequently reported adverse events with
Invirase as monotherapy (600mg TID) were
diarrhoea, abdominal discomfort, nausea. Adverse
events (mild, moderate and severe) gt2 at least
remotely related to Invirase Very common (
10) diarrhoea, nausea Common ( 1 and lt
10) Headache, peripheral neuropathy, numbness
extremities, paraesthesia, dizziness, buccal
mucosa ulceration, abdominal discomfort,
vomiting, abdominal pain, flatulence, rash,
pruritus, pain, fatigue, asthenia, fever. At
least possibly related serious adverse reactions
with a frequency of less than 2 Confusion,
ataxia and weakness, acute myeloblastic
leukaemia, haemolytic anaemia, attempted suicide,
Stevens-Johnson syndrome, severe cutaneous
reaction associated with increased liver function
tests, thrombocytopenia and intracranial
haemorrhage, exacerbation of chronic liver
disease with Grade 4 elevated liver function
test, jaundice, ascites, drug fever, bullous skin
eruption and polyarthritis, nephrolithiasis,
pancreatitis, intestinal obstruction, portal
hypertension, peripheral vasoconstriction.
Isolated CPK increase, glucose decrease and
increase, raised transaminases, neutropenia. For
a full listing of adverse events including
post-marketing experience, refer to the SPC.
Legal Category Limited to sale and supply on
prescription only. Presentation Plastic bottles
(HDPE) containing 120 500mg film-coated tablets.
Marketing Authorisation Number EU/1/96/026/002.
Marketing Authorisation Holder Roche
Registration Limited, 40 Broadwater Road, Welwyn
Garden City, Hertfordshire AL7 3AY, United
Kingdom. Further information is available from
Roche Products (Ireland) Limited, 3004 Lake
Drive, Citywest, Naas Road, Dublin 24. Telephone
[phone]. Fax [phone]. Invirase is a
registered trade mark. Date of Preparation 
September 2005.