|
Sample Drug Profile
Pharmaprojects has researched over 36,000 drug compounds since 1980.
Each profile captures the researched data on the individual product, including
therapies and indications by phase, originator and licensees, chemical data and
structure, clinical trials, pharmacologies, patent data, country information and licensing
opportunities.
In the sample drug profile below, for tacrolimus developed by Astellas, you can identify
all the searchable fields within a drug profile as the headings in bold type.
| Drug Name |
World Status |
Pharma Status |
| tacrolimus |
Launched |
Active |
| FK-506 |
| FR-900506 |
| Prograf |
|
Protopic |
|
Protopy |
| tacrolimus hydrate |
| Updated On |
By |
Latest Change |
| 04 April 2006 |
TS |
Phase III trial for psoriasis reported |
| Originator |
Country |
Development Stage |
| Astellas |
Japan |
Launched |
| Licensee |
|
|
| Hoffmann-La Roche |
Switzerland |
Launched |
| Sucampo Pharmaceuticals |
USA |
Phase III Clinical Trial |
| |
|
|
| Therapy Description |
Code |
Therapy Status |
| Immunosuppressant |
I5 |
Launched |
| Antipruritic/inflamm, allergic |
D4A |
Launched |
| Musculoskeletal |
M5Z |
Launched |
| Antiarthritic, immunological |
M2C |
Launched |
| Ophthalmological |
S1Z |
Phase III Clinical Trial |
| Antipsoriasis |
D5A |
Phase III Clinical Trial |
| Antiasthma |
R8A |
Phase II Clinical Trial |
| Neuroprotective |
N7C |
Phase I Clinical Trial |
| Pharmacology Description |
Code |
| Calcineurin inhibitor |
CALCINE- |
| Interleukin 2 antagonist |
IL-2- |
| Tumour necrosis factor alpha antagonist |
TNF-A- |
| Therapy Code |
Pharmacology Code |
I5
D4A
M5Z
M2C
A16
S1Z
D5A
R8A
N7C |
CALCINE-, IL-2-, TNF-A-
CALCINE-, IL-2-, TNF-A-
CALCINE-, IL-2-, TNF-A-
CALCINE-, IL-2-, TNF-A-
CALCINE-, IL-2-, TNF-A-
CALCINE-, IL-2-, TNF-A-
CALCINE-, IL-2-, TNF-A-
CALCINE-, IL-2-, TNF-A-
CALCINE-, IL-2-, TNF-A- |
| Route of Administration |
Route of Administration Code |
| Parenteral, intravenous |
P-IV |
| Alimentary, po |
A-PO |
| Topical, skin |
T-DM |
| Respiratory, inhaled general |
R-IG |
| Topical, eyes |
T-EY |
| Topical, cream |
T-CR |
| Topical, solution |
T-SO |
| Topical, gel |
T-GL |
| Indication |
Indication Status |
| Transplant rejection, general |
Launched |
| Transplant rejection, bone marrow |
Launched |
| Eczema, atopic |
Launched |
| Myasthenia gravis |
Launched |
| Arthritis, rheumatoid |
Launched |
| Colitis, ulcerative |
Pre-registration |
| Lupus nephritis |
Phase III Clinical Trial |
| Conjunctivitis |
Phase III Clinical Trial |
| Psoriasis |
Phase III Clinical Trial |
| Dry eye syndrome |
Phase II Clinical Trial |
| Asthma |
Phase II Clinical Trial |
| Ischaemia, cerebral |
Phase I Clinical Trial |
| Target Name |
LocusLink/Entrez Gene ID |
| FK506 binding protein 1A, 12kDa |
2280 |
| Human (5mg po) |
| bioavailability - 18%; t1/2 - 34.8hr; Tmax - 1.6hr; Cmax - 29.7ng/ml; AUC - 243nghr/ml;
Vd - 1.94l/kg; Cl - 0.04l/hr/kg |
| Origin of Material |
Code Description |
| NP-B |
Natural product, bacterial |
| CAS Registry Number |
Rotatable Bonds |
Molecular Formula |
| 104987-11-3 |
10 |
C44H69NO12 |
| Hydrogen Bond Acceptors |
Hydrogen Bond Donors |
AlogP |
Molecular Weight |
| 12 |
3 |
6.10 |
804.04 |
| Chemical Name |
| 15,19-Epoxy-3H-pyrido(2,1-c)(1,4)oxaazacyclotricosine-1,7,20,21(4H,23H)-tetrone,
5,6,8,11,12,13,14,15,16,17,18,19,24,25,26,26a-hexadecahydro-5,19-dihydroxy-3-(2-(4-hydroxy-3-methoxycyclohexyl)-1-methylethenyl)-14,16-dimethoxy-4,10,12,18-tetramethyl-8-(2-propenyl)-,
(3S-(3R*(E(1S*,3S*,4S*)),4S*,5R*,8S*,9E,12R*,14R*,15S*,16R*,18S*,19S*,26aR*))-
[CAS] |
| Structure |
 |
| Country |
Number |
Priority Country |
Priority Date |
| EP |
184162 |
GB |
3 December 1984 |
| Country Name |
Country Status |
Year Launched |
Licensing Op. |
| Argentina |
Launched |
1997 |
No |
| Australia |
Launched |
1997 |
No |
| Austria |
Launched |
1997 |
No |
| Belgium |
Launched |
1998 |
No |
| Brazil |
Launched |
1999 |
No |
| Canada |
Launched |
1996 |
No |
| China |
Launched |
1999 |
No |
| Denmark |
Launched |
1996 |
No |
| Finland |
Launched |
2000 |
No |
| France |
Launched |
1996 |
No |
| Germany |
Launched |
1995 |
No |
| Greece |
Launched |
2000 |
No |
| Hong Kong |
Launched |
1997 |
No |
| Ireland |
Launched |
1997 |
No |
| Israel |
Launched |
1998 |
No |
| Italy |
Launched |
1998 |
No |
| Japan |
Launched |
1993 |
No |
| Luxembourg |
Launched |
1998 |
No |
| Malaysia |
Launched |
1999 |
No |
| Mexico |
Launched |
1998 |
No |
| Netherlands |
Launched |
1997 |
No |
| New Zealand |
Launched |
1997 |
No |
| Norway |
Launched |
1998 |
No |
| Philippines |
Launched |
2000 |
No |
| Portugal |
Registered |
|
No |
| South Africa |
Launched |
1999 |
No |
| South Korea |
Launched |
1998 |
No |
| Spain |
Launched |
1996 |
No |
| Sweden |
Launched |
1996 |
No |
| Switzerland |
Launched |
1997 |
No |
| Thailand |
Launched |
1998 |
No |
| Turkey |
Launched |
1999 |
No |
| UK |
Launched |
1994 |
No |
| USA |
Launched |
1994 |
No |
| Event Date |
Act/Est |
Event |
Details |
|
4 April 2006 |
Est |
New Therapeutic Activity |
Antipsoriasis (D5A) |
|
4 April 2006 |
Est |
New Indication |
Psoriasis |
| 23 Jul 2004 |
Est |
Orphan Drug Status Granted |
Japan, Refractory spring catarrh |
| 1 Mar 2004 |
Est |
Pharmacology Identified |
TNF alpha antagonist (TNF-A-) |
| 20 Feb 2004 |
Act |
New Licensees |
Kaneka |
| 27 Jan 2004 |
Act |
New Licensees |
Roche |
| 3 Jun 2003 |
Act |
New Licensees |
GlaxoSmithKline |
| 31 Oct 2002 |
Est |
New Therapeutic Activity |
Antiasthma (R8A) |
| 31 Oct 2002 |
Est |
New Indication |
Asthma |
| 19 Feb 2002 |
Act |
New Licensees |
Sucampo (R-Tech Ueno) |
| 27 Jun 2001 |
Est |
New Therapeutic Activity |
Neuroprotective (N7C) |
| 3 Nov 2000 |
Est |
Additional Launches |
The Philippines |
| 18 Nov 1999 |
Est |
Additional Launches |
Malaysia and Singapore |
| 21 Jul 1999 |
Est |
Additional Launches |
China |
| 15 Jan 1999 |
Est |
Additional Launches |
Belgium and Italy |
| 15 Nov 1998 |
Est |
Additional Registrations |
Mexico |
| 15 Oct 1998 |
Est |
Additional Launches |
Taiwan |
| 15 Jul 1998 |
Est |
New Licensees |
Gador and Teva |
| 15 Jul 1998 |
Est |
Additional Launches |
Israel, Jordan, Norway, S Korea and Thailand |
| 15 Mar 1998 |
Est |
Additional Launches |
Australia |
| 15 Nov 1997 |
Est |
Additional Registrations |
Jordan and the Netherlands |
| 15 Jul 1997 |
Est |
Additional Launches |
Austria, Ireland and Switzerland |
| 15 Dec 1996 |
Est |
Additional Launches |
Spain |
| 15 Oct 1996 |
Est |
Additional Launches |
Sweden |
| 15 Oct 1996 |
Est |
Additional Registrations |
Switzerland |
| 15 Jul 1996 |
Est |
Additional Registrations |
Italy |
| 15 Jun 1996 |
Est |
Additional Launches |
Canada, Denmark and France |
| 15 May 1996 |
Est |
Additional Registrations |
Sweden |
| 15 Dec 1995 |
Est |
Additional Registrations |
France and Spain |
| 15 Jul 1995 |
Est |
New Licensees |
Johnson & Johnson |
| 15 Jun 1995 |
Est |
Additional Launches |
Germany |
| 15 Dec 1994 |
Est |
Additional Launches |
The UK |
| 15 Aug 1994 |
Est |
Additional Launches |
The US |
| 15 Aug 1994 |
Est |
Additional Registrations |
The UK |
| 15 Jun 1994 |
Est |
Additional Registrations |
The US |
| 15 Jul 1993 |
Est |
First Launches |
Japan |
| 15 Jul 1993 |
Est |
First Registrations |
Japan |
| 15 Mar 1992 |
Est |
Names Granted |
FK-506 |
| 15 Feb 1992 |
Est |
Registration Submissions |
Japan |
| 15 May 1991 |
Est |
Licences Discontinued |
Klinge |
| 15 Dec 1990 |
Est |
New Licensees |
Klinge |
| 15 Nov 1990 |
Est |
Change in Status |
Phase III Clinical Trial |
| 15 Sep 1990 |
Est |
Change in Status |
Phase II Clinical Trial |
| 15 Jun 1989 |
Est |
Change in Status |
Phase I Clinical Trial |
| Novelty |
Market Size |
Speed |
Total |
| Leading Compound |
US$ 501-2000 million |
Faster than Average |
12 |
Tacrolimus is a macrolide immunosuppressant, isolated from Streptomyces tsukubaensis
and developed by Fujisawa. It forms a complex which shields the active site of
calcineurin (Scrip, 1995, 2052, 18). It inhibits IL-2 and the expression of IL-2
receptors (23rd ESDR (Amsterdam), 1993, Abs 80). Fujisawa is also developing a
modified-release formulation (qv).
Marketing
It is launched as Prograf for primary and rescue liver and kidney transplantation in
Japan (1993) (also for bone marrow transplantation), the UK, the US (not rescue)
(1994), Germany (1995), Canada, Denmark, France (also other organ transplants),
Spain, Sweden (1996), Argentina (by Gador), Australia (by Janssen-Cilag (Johnson
& Johnson (J&J)), Austria, Hong Kong, Ireland, the Netherlands (also for
heart transplant rescue), New Zealand (by J&J), Switzerland (1997), Belgium
(also for primary and rescue heart transplantation), Israel (by Teva), Italy (also
for rescue heart transplants), Jordan (by Hikma), Luxembourg, Mexico (by J&J),
Norway, S Korea, Taiwan (also for other rescue organ transplantation), Thailand
(by J&J) (1998), Brazil, Malaysia (by J&J), S Africa (by Adcock), Singapore,
Turkey, Uruguay (1999), Bahrain, Brunei, Cyprus, the Czech Republic, Finland,
Greece, Lebanon, Paraguay, the Philippines, Poland, Saudi Arabia, Sudan, and Yemen
(2000) (Press releases, Fujisawa, Oct 1994 & Nov 1998; Direct communication,
Fujisawa, 19 Feb 2001). Technical approval has been granted in Portugal (Ann Rep,
Fujisawa, 1999). It is launched in China (1999) by Fujisawa for primary immunosuppression
in liver and kidney allograft transplants, and organ rejection resistant to conventional
immunosuppression (Scrip Daily Online, 9 Jul 1999). It is additionally approved
for graft-vs-host disease (GvHD) in bone marrow transplantation in Japan (Press
release, Fujisawa, 22 Nov 1999). It is also approved in Japan for heart transplant
and myasthenia gravis (orphan drug status). It is launched in Austria, Canada,
Denmark, Finland, Germany, Ireland, Japan, Norway, Spain, Sweden, Switzerland,
the UK and the US as Protopic, registered in the rest of the EU, Hong Kong and
S Korea, and awaiting registration in China and Taiwan as a 0.03% and 0.1% ointment
formulation for atopic dermatitis (eczema). The 0.03% formulation is additionally
approved for paediatric use (Press release, Fujisawa, 3 Oct 2002). Fujisawa has
signed a co-promotion agreement for Protopic in the US with GlaxoSmithKline (Press
release, Fujisawa, 4 Jun 2003). Roche will distribute and promote Protopic in
Brazil, the Caribbean, C America, Chile, Colombia, Ecuador, Mexico, Peru and Venezuela
(Press release, Fujisawa, 26 Jan 2004). Approval for GvHD in the US was not recommended
and an additional study was requested by the FDA (Press release, Fujisawa, Jan
1999). A granule formulation is launched in Japan and an sNDA has been filed there
for lung, pancreas and small intestine transplants (Ann Rep, Fujisawa, 1999; Scrip
Daily Online, 11 Jun 2001, S00713478). It is awaiting approval for rheumatoid
arthritis (RA) and ulcerative colitis in Japan (Scrip Daily Online, 5 Jun 2003,
S00803618 & 25 Feb 2004, S00834522). It has Japanese orphan drug status for
refractory spring catarrh (Scrip Daily Online, 23 Jul 2004, S00852068). It is
licensed to Sucampo Pharmaceuticals (formerly R-Tech Ueno) for ophthalmic use
(Press release, Sucampo, 19 Feb 2002). An MAA filing for a capsule formulation
for organ rejection in heart transplant is under preparation in the EU (Press
release, Fujisawa, 4 Nov 2004).
Clinical
Phase III
In a 5yr study, survival was 83.2 cf 85.3% for ciclosporin (qv), with graft survival
rates of 70 and 65.2%, respectively. Chronic rejection rates were 5.9 and 17.9%,
respectively (Press release, Fujisawa, 10 Dec 2001). In a 12wk trial in >4000
adults and children with atopic dermatitis, tacrolimus 0.03 and 0.1% ointment
improved or completely cleared disease in >66% of patients (Press release, Fujisawa,
16 Nov 2000). It is in a 5yr study with mycophenolate mofetil +/- steroid withdrawal
in kidney transplant patients (96% survival and 85% rejection-free at 1yr) (Press
release, Fujisawa, 18 May 2004). In 557 kidney transplant patients, nearly 2x
as many of those on microemulsion ciclosporin had experienced a rejection episode
at 6mth cf those on tacrolimus. In 606 liver transplant patients, 6mth rejection
rates were 31 and 19%, respectively. The kidney study indicated a lower incidence
of hypercholesterolaemia and new-onset or worsening hypertension with tacrolimus
(Transplantation, 2000, 69, Abs 8, 198 & 966; Press release, Fujisawa, 19
May 2000). In 314 heart transplant patients receiving tacrolimus or ciclosporin,
reject rates were 54.0 and 66.4%, respectively (Press release, Fujisawa, 14 Sep
2004). In a double-blind, multicentre, randomized, Japanese Phase III trial in
212 patients with DMARD-resistant RA, addition of tacrolimus 3mg/kg x16wk to prednisolone
<5mg/day and/or 1 other NSAID produced an ACR20 response rate of 48.3, cf 14.1%
for placebo (J Rheumatol, 2004, 31, 243, PMID:14760792). It is in Phase III trials
in Japan for lupus nephritis and in Australia for liver/kidney transplants. It
is in Phase III trials in the US for chronic RA (Scrip Daily Online, 27 Feb 2003,
S00791102). A cream formulation is in Phase III trials in Japan and the US for
atopic dermatitis and in the US for psoriasis (Scrip Daily Online, 30 Oct 2003,
S00821736; Press release, Fujisawa, 4 Nov 2004). An eyedrop formulation is in
Phase III trials in Japan for vernal conjunctivitis. An oral capsule formulation
is in Phase III in Japan and the US for organ transplant rejection. A gel formulation
is in Phase III in the US for psoriasis (Company pipeline, Fujisawa, 25 Feb 2004;
1st Qtr Rep, Fujisawa, 2005). Development of the gel and cream formulations has
been discontinued in Europe (Press release, Fujisawa, 4 Nov 2004).
Phase II
In a randomized, double-blind, multicentre Phase II trial in 213 patients with
moderate-to-severe atopic dermatitis, the median decreases in the summary score
for dermatitis on the trunk and extremities after 3wk of treatment with 0.03,
0.1 and 0.3% tacrolimus ointment were 66.7, 83.3 and 75%, respectively cf 22.5%
for placebo. The results for the face and neck were similar. The only significant
adverse event was a burning sensation at the site of application (NEJM, 1997,
337, 816, PMID:9295241). In a 3mth renal transplantation study, it demonstrated
possible synergy with rapamycin (qv) (Press release, Fujisawa, 10 Dec 2001). It
is in a European and US Phase II safety and efficacy study in 160 patients with
dry eye syndrome, conducted by Sucampo (Press release, Sucampo, 15 Jul 2003).
It is in Phase II in Europe for RA (Ann Rep, Fujisawa, 2003). An inhalable formulation
is in Phase II trials for asthma in Europe (Scrip Daily Online, 31 Oct 2002, S00776932).
Phase I
It was in early clinical development for stroke (Direct communication, Fujisawa,
22 Jun 2001). In healthy volunteers, 5mg po had a bioavailability, t1/2, Tmax,
Cmax, AUC, Vd and Cl of 18%, 34.8hr, 1.6hr, 29.7ng/ml, 243nghr/ml, 1.94l/kg and
0.041l/hr/kg, respectively (Product insert, tacrolimus, 2002).
Preclinical
In rats with collagen-induced arthritis, tacrolimus 1.8mg/kg suppressed paw swelling,
histological changes in the knee joint and radiographic changes in the hind paw.
It also recovered the decrease in bone mineral density in the femora. At 3.2mg/kg,
it markedly reduced TNF-alpha expression (Inflamm Res, 2003, 52, 524, PMID:14991082).
In vitro, in combination with an anti-CD25 immunotoxin, it suppressed HIV production
and exerted a strong antiproliferative activity on infected PBMCs. Without prior
addition of the immunotoxin, the amount of suppression was much lower, suggesting
efficacy in latently-infected cells (36th ICAAC (New Orleans), 1996, Abs I64).
In NC/Nga mice, a 0.1-1% ointment formulation suppressed development of dermatitis
and was effective against established dermatitis by suppressing CD4 cells, mast
cells, eosinophils, IL-4, IL-5 and IgE (Jpn J Pharm, 1998, 76, 175). Updated by
IL on 21/12/2004. |
| |
Additional Clinical Information
Post Marketing
In 9 patients with moderate-to-severe steroid-refractory ulcerative colitis given
tacrolimus 0.15mg/kg po daily, all patients responded within 1-2wk. After 12wk,
6 patients (67%) were in complete remission, 2 (22%) had mild-to-moderate disease
activity and 1 patient (11%) underwent colonectomy. At 21mth follow-up, 6/9 patients
(67%) had their colon in situ. 2 patients developed severe side-effects, and mild
side-effects were common (Alimentary Pharmacol Ther, 2003, 18, 415).
In 54 subjects (26 volunteers, 10 end-stage renal disease patients and 18 kidney
transplant patients), there was no significant difference in pharmacokinetics
between blacks and non-blacks. However, bioavailability was significantly lower
in blacks (26th Meet ACCP (Phoenix), 1997, Abs 5).
In 2 investigator-blinded, randomized, parallel-group trials in 650 atopic dermatitis
patients aged 2-15yr, 0.1% Protopic was superior to 1% pimecrolimus cream in moderate
to severe disease, and 0.03% Protopic was comparable or better in mild disease
(Press release, Fujisawa, 8 Jul 2004)
Phase III
In 301 kidney transplant patients who switched treatment from ciclosporin-based
to tacrolimus-based therapy after 6mth, there was a 73% reduction in gingival
hyperplasia, a 72% reduction in hypertrichosis, cholesterol was reduced by 37mg/dl
and diastolic BP dropped from 91 to 86mmHg (Scrip Daily Online, 2002, S00753648).
In a randomized paediatric study in 560 children aged 2-15yr with moderate-to-severe
atopic eczema, tacrolimus 0.03 or 0.1% produced >90% improvement in 38.5 and 48.4%
patients, respectively cf 15.7% of those receiving hydrocortisone acetate (Pharm
J, 2001, 267, 637).
In a randomized trial in 570 adults with moderate-to-severe atopic eczema, tacrolimus
0.1% ointment produced >90% improvement at 3wk in 50% of patients, and was comparable
to hydrocortisone-17-butyrate 0.1% ointment (Pharm J, 2001, 267, 637).
In 7341 adults and children, it was safe and showed no long-term immunosuppressive
effects (Press release, Fujisawa, 22 Mar 2003)
In a randomized trial in 361 kidney transplant patients at 27 US transplantation
centres, patients received tacrolimus + corticosteroids + either sirolimus (qv)
(n=185) or mycophenolate mofetil (n=176) prior to their transplant. Incidence
of acute rejection, the primary endpoint, was 13% for sirolimus cf 11.4% for mycophenolate
mofetil. Patient and graft survival were 97.3 and 93.0%, respectively, on sirolimus
and 97.7 and 95.5%, respectively, on mycophenolate mofetil
In kidney transplant patients, mycophenolate mofetil (qv) + tacrolimus was superior
at 1yr to mycophenolate mofetil + ciclosporin or tacrolimus + azathioprine and
was superior to ciclosporin at 5yr (Press release, Fujisawa, 15 May 2000)
In 181 paediatric liver transplant patients, 1yr survival was 93.4%, cf 92.1%
with ciclosporin, and 55.5 and 40.2% were free of acute rejection, respectively
(Press release, Fujisawa, 17 May 2001).
In 196 paediatric kidney transplant patients, 6mth rejection rates on ciclosporin
and tacrolimus were 59.1% and 36.9%, respectively (Press release, Fujisawa, 15
May 2001)
Phase II
In a multicentre, open-label trial in 80 patients with active RA despite treatment
with methotrexate <20mg/wk po x>1mth, patients were given tacrolimus 3mg/day
po x6mth in addition to their methotrexate regime. Other DMARDs were discontinued,
but patients were permitted to receive NSAIDs and oral corticosteroids. 63 patients
completed the study; 7 withdrew due to adverse events and 4 withdrew due to lack
of efficacy. Mean creatinine level increased from 0.74mg/dl at baseline to 0.81mg/dl
after treatment and the ACR20 response rate was 52.5% at the end of the study
(Arthritis Rheum, 2003, 48, 2763).
In 120 renal transplant patients, acute rejection rates were 14% with tacrolimus
cf 32% with ciclosporin (Scrip, 1997, 2267, 18).
In 12 renal transplant patients on triple immunosuppression including prednisone
and azathioprine converted from ciclosporin A to tacrolimus in an attempt to terminate
acute renal transplant rejection, tacrolimus 5-10mg iv led to an overall graft
survival rate of 91.7%. There was 1 death from lymphoma after 4mth of tacrolimus
therapy (Transplant Proc, 1996, 28, 3165).
In renal transplant patients, tacrolimus gave a 63.8% graft survival rate after
5yr cf 53.8% for ciclosporin. Tacrolimus also showed greater efficacy in the prophylaxis
of transplant rejection after 6mth cf ciclosporin microemulsion formulation (19.9%
vs 38%) (Press release, Fujisawa, 29 Aug 2000).
In a 6mth multicentre study in 37 children <2yr old with moderate-to-severe
atopic dermatitis, tacrolimus 0.03 and 0.1% ointment was effective and adverse
events were uncommon (Press release, Wake Forest University Medical Center, 5
Aug 2002).
|
| |
Additional Clinical References
Drugs, 2003, 63, 1247
J Dermatol Treat, 2003, 14, 86
Transplantation, 2003, 75, 1512
Int J Colorectal Dis, 2003, 18, 271
Clin Transplant, 2003, 17, 249
Scrip, 1994, 1970, 23 |
| 24 February 2005 |
Copyright © T&F Informa UK Ltd 2005 |
Top
|
|
.gif)
