Expanding the library of pharmacokinetic data for Inviraser

1
Expanding the library of drug interaction data
for Invirase/r
Marta BoffitoAssociate Director of the
Pharmacokinetic Research Unit, Chelsea and
Westminster 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
EFFECT OF OMEPRAZOLE ON THE PHARMACOKINETICS
OFSAQUINAVIR 500 MG FORMULATION WITH RITONAVIR
IN HEALTHYMALE AND FEMALE VOLUNTEERS

• 1Winston A, 2Back D, 1Fletcher C, 2Robinson L,
  2Unsworth J, 1Tolowinska I, 3Schutz M, 1Pozniak
  A, 1Gazzard B and 1Boffito M
• 1Chelsea and Westminster Hospital, London, UK
  2University of Liverpool, Liverpool, UK
  3Hoffmann-La Roche, Basel, Switzerland

3
Trial design Invirase/r 1000/100 mg bid
omeprazole 40 mg qd
Safety and PK sampling (day 10)
Safety and PK sampling (day 15)
Safety analysis (day 1)
Safety analysis (day 7)
Safety analysis (day 29)
Add omeprazole 40 mg qd
Invirase/r 1000/100 mg bid
Follow-up
Screening
?21 to 0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
17
18
20
21
22
29
16
19
Study day
n 18 healthy volunteers Invirase 500 mg
formulation
Winston et al. 10th EACS 2005. Poster LBPE4.3/16
4
Baseline characteristics of study population n
18
Winston et al. 10th EACS 2005. Poster LBPE4.3/16
5
Effect of omeprazole on saquinavir plasma
concentrations
With omeprazole (40 mg qd)
AUC012h 37,511 ng.h/ml
Without omeprazole
AUC012h 20,559 ng.h/ml
Saquinavir (ng/ml)
n 18
Time (h)
Winston et al. 10th EACS 2005. Poster LBPE4.3/16
6
SQV PK parameters (Invirase/r 1000/100 mg bid)
without (day 10) and with (day 15) omeprazole 40
mg qd
GMR geometric mean ratio
n 18 healthy volunteers
Winston et al. 10th EACS 2005. Poster LBPE4.3/16
7
Effect of omeprazole onritonavir plasma
concentrations
2000
With omeprazole (40 mg qd)
AUC012h 10,004 ng.h/ml
1500
Without omeprazole
AUC012h 10,696 ng.h/ml
Ritonavir (ng/ml)
1000
500
n 18
0
0
2
4
6
8
10
12
Time (h)
Winston et al. 10th EACS 2005. Poster LBPE4.3/16
8
Summary effect of omeprazole on the PK of SQV
500 with ritonavir

• Increase in SQV plasma exposure when Invirase/r
  co-administered with omeprazole
• No significant increase in RTV PK parameters
• Exact mechanism of interaction is not known but
  appears to be due to increased absorption as t1/2
  and time to Cmax were not affected
• Despite the increased plasma SQV exposure, no
  clinically significant or grade 3/4 laboratory
  adverse events were recorded

Invirase 500 mg formulation
Winston et al. 10th EACS 2005. Poster LBPE4.3/16
9
Effect of different SQV/r regimens and different
study populations on saquinavir AUC
Mean median for bid regimens, AUC024h is
estimated by doubling AUC012h
1) Winston et al. 10th EACS 2005. Poster
LBPE4.3/16 2) Invirase 500 SmPC 3) Autar et al.
9th EACS 2003 Abstract 4.1/1 4) Cardiello et
al. JAIDS 2003 323759 5) Autar et al. 7th
International Congress on Drug Therapy in HIV
Infection Abstract P285 6) Autar et al. JAC
2004 5478590
10
Effect of different SQV/r regimens and different
study populations on saquinavir AUC
82 increase in SQV AUC with addition of
high-dose OMP
Mean median for bid regimens, AUC024h is
estimated by doubling AUC012h
1) Winston et al. 10th EACS 2005. Poster
LBPE4.3/16 2) Invirase 500 SmPC 3) Autar et al.
9th EACS 2003 Abstract 4.1/1 4) Cardiello et
al. JAIDS 2003 323759 5) Autar et al. 7th
International Congress on Drug Therapy in HIV
Infection Abstract P285 6) Autar et al. JAC
2004 5478590
11
Effect of different SQV/r regimens and different
study populations on saquinavir AUC
Predicted AUC in HIV patients on high-dose OMP
Mean median for bid regimens, AUC024h is
estimated by doubling AUC012h
1) Winston et al. 10th EACS 2005. Poster
LBPE4.3/16 2) Invirase 500 SmPC 3) Autar et al.
9th EACS 2003 Abstract 4.1/1 4) Cardiello et
al. JAIDS 2003 323759 5) Autar et al. 7th
International Congress on Drug Therapy in HIV
Infection Abstract P285 6) Autar et al. JAC
2004 5478590
12
How clinically relevant is an increase in SQV
exposure?

• The SQV AUC0?12h with the approved dose of
  Invirase/r 1000/100 mg bid is described as 14,607
  ng.h/ml in HIV-infected adults1
• Thai patients tend to achieve higher SQV
  exposures than Western patients
• With Invirase/r 1600/100 mg the AUC0?24h is
  reported to be 53,950 ng.h/ml
• An 82 increase in HIV-infected adults with the
  1000/100mg bid dose is expected to result in
  similar exposures as those seen in Thai patients
  on Invirase/r

1. Invirase 500 US Product Information
Investigational Invirase/r 1600/100 mg qd dosage
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
High SQV plasma exposure levels in Thai patients
10000
SQV/r 1600/100 mg qd
AUC(024h) 53,950 ng.h/ml
1000
Median saquinavir conc. (ng/ml)
n 20
100
10
0
4
8
12
16
20
24
Time (h)
Investigational Invirase/r 1600/100 mg qd
dosage
Adapted from Autar et al. J Antimicrob Chemother,
2004 54(4)785790
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
14
Staccato no grade 3/4 adverse events despite
high SQV plasma levels
92 (46) patients reported ARV-related adverse
events, which were mostly mild and self-limiting
100
80
n 200 24 week follow up
54
60
Adverse events over 24 weeks ()
38
40
20
8
0
0
0
Grade 1
Grade 2
Grade 3
Grade 4
No AE
Investigational Invirase/r 1600/100 mg qd
dosage
Ananworanich et al. Antivir Ther 2005 10761767
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
15
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.