CLOPIDOGREL FORM 1 VS CLOPIDOGREL FORM 2

FROM PERSPECTINES OF BA - BE
TO CLINICAL APPLICATION

H.Achmad Basori
Professor of Pharmacology
Department of Pharmacology and Therapeutic
School of Medicine
Airlangga University
 FAKTA : ATHERO THROMBOSIS
PENYEBAB KEMATIAN NO.1 DIDUNIA
 LAPORAN WHO : Kejadian atherothrombosis (Jantung & Stroke )
merupakan penyebab kematian No 1.

STROKE : Penyebab kematian tertinggi diwilayah perkotaan, jumlahnya

mencapai 15.9 % dari proporsi penyebab kematian di Indonesia

REACH REGISTRY & Literature pada NEJM, Circulation, Journal

Cardiovascular, Arch Neurology:
27 % Atherothrombosis merupakan Polyvascular, pada stroke 40%
 Penderita M I  3 - 4 x beresiko terkena serangan stroke ,TIA
 Penderita stroke  2 – 3 x beresiko terkena M I, ACS, CVD
 PVD  4x MI,ACS,CVD , 2 3 x STROKE , TIA

1. The World Health Report 2001. Geneva: WHO; 2001.

Adult Treatment Panel II. Circulation 1994; 89:1333–63. 2. Kannel WB. J Cardiovasc Risk 1994; 1: 333–9.
3. Wilterdink JI, Easton JD. Arch Neurol1992; 49: 857–63. 4. Criqui MH et al. N Engl J Med 1992; 326: 381–6.
DATA RISET KESEHATAN DASAR 2007- 2008 DI 33 PROVINSI OLEH BALITBANGKES KOMPAS RABU 3 DESEMBER 2008
Clopidogrel Form 2 (PLAVIX, PLACTOGRIX)
Antithrombotic Drug Therapy in CV Disease 2009; Antiplatelet in cardiovascular Disease,2009)

- Clinical Trials: 107.000 pasien, > 900 clinical studies (1996 –

2009): 1st liner drugs (single and combination)
- Prescription: > 90 juta pasien (acute,chronic, very different
profile ( CVS/CBR)
- World's 2nd biggest drug, 2009 ( > 9 Billion / year )
- Dipasarkan ke 110 negara
- Guidelines: NSG, ESO, ACC/AHA,ESC,AUSSIE,ASA (Class IA
- FDA dan EMEA (2000) : Atherothrombosis patients:
ACS (STEMI, NSTEMI, with or without stent), recent MI, recent
stroke,established PAD and CABG

BPOM RI (2009): Recent MI, Recent Stroke, Established PAD, ACS,

(STEMI dan NON STEMI), dan PCI
Antiplatelet in Ischaemic Heart Diseas (2009)
Management Strategic in Antithrombotic Therapy (2007)
Pharmacology in cardiology Intervention (2009)

Randomized Clinical Trials ( Multi Centres) of

Clopidogrel Form 2 (PLAVIX, PLACTOGRIX)
1996 – 2009 :
CAPRIE, CLASSIC, PCI-CURE, CREDO, CURE,
ARMYDA- 2, PCI- CLARITY, COMMIT, CLARITY, ECG
CLARITY-TIMI 28, ISAR-CHOICE, TIMI, CHARISMA,
CLEAR PLATELET, CRES, ALBION, TRITON-TIMI
38,FASTER, ESPRIT, ACTIVE, ACUITY, OASIS-2,
CAMPER, CARESS, COMMIT-CSS-2, MATCH,
GUSTO – V, ASSENT-3, PLATO, REPLACE -2,
ESSENCE, ESPS-2, CURRENT OASIS 7, …
Menurunkan …….
Ischemic events, cardiovascular death, stent thrombosis, late thrombosis
vascular occlusion, recurrent MI, recurrent Stroke, vasc throm pada PAD
CLOPIDOGREL PRASUGREL TICAGRELOR
Medically manage: MI, PCI Only PCI Only
STROKE, TIA
ACS (PCI ,n-PCI), PVD Bleeding risk >>>>> Bleeding risk >>>>>>
(fatal, non fatal) Intracranial bleeding, ICH

History of TIA or Stroke Increased dyspnea,

History of Asthma, COPD
Old patients (>75 yrs)
Drug Interactions ? Serum Cr and uric acid
Lower BW patients (<60 kg) increased  nephrotoxic
Cancer risk Co-administration
With CYP3A4 inhibitor
Drug interaction with ASA
Hepatic impairment
History of ICH
Moderate and severe renal
impairment
Bradycardia, old >75 yr
2 x Day  Compliant
TRITON TIMI 38,PLATO,EMEA PI, Wallentin L et al. N Engl J Med. 2009 361(11):1045-57.
FDA website Cardiovascular and TICA + ARB (GFR< 30
RenalDrugsAdvisoryCommittee/ ucm192863.htm. Accessed on August 23rd, 2010.,
Exp.Opin.Pharmacother (2012): 13,2:175-191, Trilogy-ACS,2012 ml/min Bleeding,Dypsnea
Dinicolantonio & Serebruany,V, Clin. Cardiol. 35, 11, 647–648 (2012) Renal failure, Death
CLOPIDOGREL FORM 2
Better Safety Profile
(CLASSIC Trial,Bertrand eta al, Circulation 2000, 102: 624 – 629)

Fewer side effects

(CLASSIC Trial,Bertrand eta al, Circulation 2000, 102: 624 – 629)
Rapid onset of action with a loading dose
(Cadroy et al: Circulation 2000, 101: 2823-2828)
Better Clinical Outcomes (Triton TIMI 38,Plato)
(Bhatt et al: J.Am.Coll.Cardiol 2002, 39: 9 – 14) The British Journal of
Cardiology ,vol 16, issue 5,Sept-Oct, 2009 )
Relationship between Antithrombotic
effects and safety is optimal
(PRINCIPLE – TIMI 44)
Positive risk benefit profile
(High platelet inhibiting activity/significant
reduction of atherothrombotic (low bleeding
incidence)Balanced Anti Platelet
(TRITON-TIMI 38; Darius et al, 2009)
Lancet,2004,364:1519-1521; ACC/AHA/SCAI Guide Lines 2005;NEJM,10:356,2007; Circulation,2006,113:2803-
2809; www.medscape.org/CME/CE Released: 12/06/2006 J.Am.Coll.Cardiol,2007,49:734-739; JAMA,299:
532-539,2008 ., www.fda.gov/consumer/features/drugsonline0707.html.
 Hazard of death or MI after clopidogrel
discontinuation post-ACS
N = 3137 US Veterans Administration patients

0.001 0.001

0.008 0.008

Instantaneous 0.0006 0.0006

incidence
rate (per
person-day) 0.0004 0.0004

0.0002 0.0002

0 0
0 45 90 180 270 360 450 0 45 90 180 270 360 450
Time since stopping clopidogrel (days)
Medically treated (n = 1568) PCI (n = 1569)
Ho PM et al. JAMA. 2008;299:532-9.
Association between length of clopidogrel
treatment and outcome in stented patients
Retrospective study; N = 749 consecutive patients with DM

Composite of death and MI Death

25

20 P < 0.001 P < 0.001

Cumulative 15
incidence
(%) 10

0
0 90 180 270 360 450 540 630 0 90 180 270 360 450 540 630
Time (days)

<6 months 6-9 months >9 months

DM = diabetes mellitus Brar SS et al. J Am Coll Cardiol. 2008;51:2220-7.

 CLOPIDOGREL

Clopidogrel Form-1 Clopidogrel Form- 2

(RACEMATES) (SINGLE ENANTIOMER)
S = 50% R = 50% S = 99.8% R = 0.2%
PLAVIX (Innovator)
Mee Too
PLATOGRIX (Innovator)
- USA : 2006 - USA: Clopidogrel Form 2
FDA Recall : 2007 1997 – 2011 (SS-BMS)
- German : Agustus 2008 - Indonesia :
EMEA Recall : 2010 Plavix (Clopidogrel Form 2)
1998 – 2018 (SA)
Platogrix (Clopidogrel Form 2)
2013 -- 2019
- European : Clopidogrel
Form-2 : 2008 ~ 2013 (SS)
KEPUTUSAN BADAN POM RI – 2009 : Indikasi
Clopidogrel form 2 ( Plavix, Platogrix)
berbeda dgn me-too nya

Clopidogrel form 1 (Me-too)

Untuk medically manage recent MI, stroke, PVD

Clopidogrel Form-2 (Plavix /Plactogrix)

diterima untuk Indikasi yang lebih luas :
Medically manage of Recent MI, Recent Stroke , TIA
Established PAD, ACS (STEMI dan NON STEMI), PCI,
CABG
 Clopidogrel mana yang memberikan
Clinical efficacy maksimum, side effects
Minimum, dan toxic effects rendah ?
US Patent No.4,847,265 (the ’265 patent), US Patent for Plavix : 1998 – 2011
The distric court identified the limitations stated in claim 3 of the 265 patent as:
(1) The bisulfate salt of (2) the dextrorotatory enantiomer of (3) the compound MATTPCA
(4) Substantially separated from the levorotatory enantiomer
United States Court of Appeals for the Federal Circuit (2007- 1438)

The Plavix issue commenced in January 2006, when :

Apotex launched its clopidogrel 75mg product, a copy of SA - BMS company,
asserted that the original patent [covering both (+)/(-) anantiomers] of
clopidogrel (racemate)(596 patent) http://Patft.uspto.gov

FDA Finds Consumers Continue to Buy Potentially Risky Drugs

Over the Internet, i.e : Anticoagulant or blood thinner is a medication that
requires very close monitoring to prevent stroke/death.
Blood thinner, clopidogrel, may pose increased risk of cardiac events,
such as heart attack if used in sub-optimal doses, which might be found
in generic imported tablets. www.fda.gov/consumer/features/drugsonline0707.html.
MAUDE Adverse Event Report (2001 – 2007)
FDA Home > Medical Devices >Databases
•Ditemukan kejadian thrombotic re-occlusions(SAT/Stent thrombosis /late stent
thrombosis /reinfarction),dan kematian. Diduga akibat penghentian Plavix, dan
penggantian Plavix ke Generic Clopidogrel
 TABLE 2: Examples of intercepted drugs with particular associated risks
Drug Product Common Intended Medical Use
Alendronate sodium Tablets Osteoporosis
Amoxicillin Capsules Antibiotic
Celecoxib Capsules Osteo- and Rheumatoid Arthritis
Clopidogrel Tablets Blood thinner
Isotretinoin Capsules Oral anti-acne
Levothyroxine Tablets Thyroid hormone replacement
Methotrexate Tablets Anti-cancer
Prednisone Tablets Inflammation (steroid)
Phenytoin Capsules Anti-seizure
Warfarin Tablets Blood thinner
Zolpidem Tablets Insomnia

www.fda.gov/consumer/features/drugsonline0707.html.
MAUDE Adverse Event Report
•FDA Home > Medical Devices >Databases
FDA Recall
LAPORAN US FDA :
Ditemukan kejadian Clopidogrel non-reponsiveness a.l,
thrombotic re-occlusions(SAT/Stent Thrombosis
/reinfarction), dan kematian.Diduga akibat penghentian
Plavix, dan penggantian Plavix ke Generic Clopidogrel
Even Date :
 20 / 07 / 2001 Case 1-08-cv-01495-JDB-documen 4-2
 18/ 07 / 2003 US COURT OF APPEALS FOR FEDERAL CIRCUIT
 27 / 07 / 2003 US FDA MELALUI PENGADILAN
 06 / 05 / 2003
18 / 01 / 2006 MENARIK PEREDARAN GENERIC
 16 / 03 / 2006
 08 / 06 / 2006 CLOPIDOGREL DI USA
 20 / 08 / 2006 USA District Court for the Southern
 03 / 11 / 2006 District of New York, 2007
 22 / 01 / 2007
Generic Anticoagulant, Antithrombotic,and
Thrombolytic Agent.Are there any specific guidelines?
(Fareed, et al, 2007)
International Summit on Generic Antithrombotics Drugs
October 12, 2007, New Delhi, India

 Warfarine  Non Linier kinetics, NTI , PB  variability >>>

 LMWH (Enoxaparine,Deltaparine)
 Pharmacological difference despite chemical
equivalence
 Streptokinase  21 sample tested  3 according to label
 Some Aspirin preparations contain high free salicylic acid
and active acid content
• Clopidogrel  have weak antiplatelet  Require
additional dosing
 (Jawed Fareed and Arthur Sasahara ,Loyola Univ.Chicago, USA),
INTERNATIONAL SUMMIT ON GENERIC ANTITHROMBOTIC
DRUGS,2007. 12 October , 2007, New Delhi, India

1.The generic versions of anti-platelet drugs like clopidogrel

have weak anti-platelet activity and require additional dosing

2. S & R ratio of MTPPA in Clopidogrel vary. Higher dosage

are needed to achieve similar effects

3.Ratio of diastereoisomer (S & R) vary in different preparation

Complex drug/compositional variations may occur leading
to safety/efficacy compromise

4.This striking discrepancy between claimed and actual performance of

these critical drug may result in life threatening situations for several
ill patients

5. Until that time the interchange between generic and branded

anticoagulant, anti PLATELET and antithrombotic drugs
should be considered with caution !!!!!
Substituting Generic Drugs for Branded Antithrombotic
Drugs ? Pro-active Thrombosis Prevention Forum,Februari 15, Boston, MA
Jawed Fareed (2007)

 No clear cut guidelines from regulatory bodies

 Complex drugs/compositional variations may occur
leading to safety/efficacy compromise
 Newer guidelines from peer groups and regulatory
bodies are needed to validate the generic
Antithrombotic drugs
 Closed monitoring when patients are switched from
brand name to generic product, or vice verse, or
from one generic to another generic to avoid under
– dosing or over – dosing
 All Antithrombotic are critical Drugs. Small changes
can results pharmacodynamic variation
 ACCF/AHA 2011 Health Policy Statement on
Therapeutic Interchange and Substitution
(Journal of the American College of Cardiology).
Published ahead of print on August 15, 2011, available
at: http://content.onlinejacc.org/cgi/content/full/j.jacc.2011.06.001

Physicochemical Biochemical
Equivalence? Equivalence ?

Anticoagulant,Anti Platelet,
Thrombolytic
GENERIC EQUIVALENCE ?

Pharmacologic Clinical
Equivalence ? Equivalence ?
 EMA Recall
EMEA recommends precautionary recall of batches
of clopidogrel-containing medicines from Acino Pharma
GmbH (26 / 03 / 2010).
The European Medicines Agency recently recommended
a recall of a number of generic clopidogrel besylate products
in European markets over safety concerns :
- Clopidogrel A1 Pharma
- Clopidogrel Acino
- Clopidogrel Acino Pharma
- Clopidogrel Acino Pharma GmbH
- Clopidogrel Hexal
- Clopidogrel Ratiopharm
- Clopidogrel Ratiopharm GmbH
- Clopidogrel Sandoz
2009 : EMA : Generic Clopidogrel FORM I from Glochem
Visakhapatnam, India.
Indication: secondary prevention of MI and
post ischaemic stroke

2010 : EMA Recall of Generic Clopidogrel FORM I due

to GMP failure at active substance manufacturer site
containing MethylChloride (hepatotoxin, Nephrotoxin,
Mutagen, Carcinogenic)
Could Clopidogrel Generic be interchangeable to
Innovator product ?
Cardiac Interventions Today May/june , 25– 26., July/Agustus, 7.,2012
 Pharmacodynamic response,safety, and efficacy of Generic
versions of Clopidopgrel have not been vetted in Clinical Trial

 The lack of longitudinal data on these generic medicines is

Dr. Paul A. Gurbel sobering
is director Of the Center
for Thrombosis
Research
at Sinai Hospital The reability of Clopidogrel Generic has not been tested
in Baltimore.
and there could be variations in potency and consistency from
batch to batch

 The purity of generic after some Clopidogrel pill manufactured

in India were proven to contain significant levels of Methyl
Chloride (Toxin and Carcinogen)
Clinicians should strive to find a Antiplatelet Therapy that achieves the optimal
level of platelet inibition for the patient, regardless of Cost, and no Economic
Pressures
 DRUG DISCOVERY & DEVELOPMENT PROJECT
(INNOVATOR)
Overall cost per marketed compound = US $ 1 billion
Time-scale = 8-12 years ,Total patent lifetime = ~15 years
DRUG EARLY CLINICAL TRIAL
DISCOVERY DEVELOPMENT Phase I Phase II Phase III Phase IV
Target selection Pharmacokinetics Pharmacokinetics,
Lead-finding Short-term tolerability, side
Lead optimisation toxicology effects in healthy
Pharmacological Formulation volunteers
Small-scale trials
profiling Synthesis scale-up in patients to assess
efficacy & dosage
Large-scale
controlled trials
Post-
2-5 years 1 year 5-7 years marketing
(10-20%) (3-5%) (1-2%) surveillance
Drug Development Compound
candidate compound approved for
marketing
HPR
Oct 99
 OBAT PATEN vs OBAT GENERIK ?

Obat Patent (innovator) :

Obat dengan zat aktif pertama kali yang ditemukan oleh suatu
industri farmasi (mis,Plavix). Obat ini dilindungi oleh hak patent sampai
masa paten-nya habis.
Menurut UU No. 14 Tahun 2001 masa berlaku paten di Indonesia adalah
20 tahun.Setelah paten habis  obat paten  obat generik

Depkes RI (1988) meluncurkan konsep Obat generik (bermerk dan berlogo)

- Obat Generik bermerk (Obat branded) obat dengan kandungan zat
aktif yang sama dgn produk innovator,dengan catatan obat innovator
telah habis masa paten-nya

29 Maret 2005, Pedoman Uji BE dan Peraturan Kepala BPOM-RI, 18 Juli 2005
tentang: Tata Laksana Uji Bioekivalensi, mewajibkan uji BA / BE
terhadap obat copy yang beredar ( obat generik)
 Apa Obat Generic ?
 Tiap produk dari pabrik selain pabrik innovator(research-
based)
 Diharapkan bersifat interchangeable dengan produk
innovator pada individu pasien
 Biasanya dibuat tanpa licence dari pabrik inovator
company
 Dipasarkan setelah masa patent berakhir
 Persyaratan : semua produk industry Farmasi harus
interchangeable  produk harus bersifat BIOEQUIVALENT

FDA / WHO, 2003

Steps involved in the development of potential generic product
Perception that Generics are inferior:
-Made in sub standard facilities
-Low or variable quality
-Stability issues
-Not as safe
-Not as efficacious
-Contain less drug
-Take longer to act in the body
Standard Molecule finding by reseach = innovator
• http://content.onlinejacc.org/cgi/content/full/j.jacc.2011.06.001)
(12-15 yr) (www.cardiosource.org) (www.americanheart.org)
Generic manufactures do not follow prescribed
manufacturing norms :
 Difference in the expiry period.
 Difference in the stability of solution.
 Difference in particle size
 Diiference in Active compound (Salt, Chirality)
 Difference pharmacodynamic activity

Difference in : PK – PD, Drug-Interaction, ADR

EFFICACY AND SAFETY ?

(NTI, Critical Drug Dose, Live Saving Drug)
 Caution: Quality Can vary………
Me too (Copy Drugs, Generic) :
1. Dibuat tanpa ijin dari perusahaan Innovator
2. Bahan baku berbeda (polymorphs, hydrates,
solvates, co-solvates, salts, enantiomers,
prodrugs , ukuran partikel,dll )
3. Proses fabrikasi berbeda
4. Excipien berbeda

Differences in product performance and ADR.

BA (FDA/EMA) dari Apakah cukup sebagai
generik/inovator = kriteria untuk menjamin
80-125%. Dianggap
Therapeutic Equivalent
Bioequivalent.
& Generic Substitution ?
FDA, EMA,2003
 PHARMACEUTICAL ALTERNATIVES
(the same API,diff chem form, (ester or salt), dosage form/strength)

PHARMACEUTICAL EQUIVALENTS
(The same API ,dosage form, route,identical in strength or conc)))

The same Bioavailability

No
WHO, 1998
Clinical Trial ?
BIOEQUIVALENCE
(The same route, Pharm.Equiv, dosage form, labeled, GMP)

GENERIC SUBSTITUTION ???

BA Measurement
Bioavailability
` means the rate and extent to which the
active
` ingredient or active moiety is absorbed from a drug
product and becomes available at the site of action
(FDA Guideline,2003).

Cmax •Absolute bioavailability (F):

AUCextravascular Doseint ravenous
Ka F 
AUCint ravenous Doseextravascular
Concentration

•Relative bioavailability (Frel)

AUCextravascu lar1 Doseextravascu lar 2
MBC Frel  
AUCextravascu lar 2 Doseextravascu lar1
MIC
AUC Study Compound
Reference Compound

Tmax Time
Approved Drug Products With Therapeutic Equivalence Evaluations. 23rd ed. 2003. FDA/CDER
Web site. Available at: http://www.fda.gov/cder/ob/docs/preface/ecpreface.htm#Therapeutic
Equivalence-Related Terms. Accessed September 29, 2003.
BA-BE Measurement
Bioavailability means the rate and
extent to which the active ingredient
or active moiety is absorbed from a
drug product and becomes available
at the site of action
(FDA Guideline,2003).

Criteria for Acceptance 90% confident interval

of AUC, Tmax,Cmax fall between 0.80 – 1.25
( Log Transformed data) of the brtanded drug
 JFC BNF No.59
BMA RPS Great Britain\2010

Health Policy Statement on Therapeutic Interchange and Substitution

Several classes of drugs that require special consideration

when choosing Therapeutic Equivalent , in which
Substitution is not recommended :
 Drugs with problems in bioequivalence
(i.e,crystal polymorphism, insolubility in water, polymorphs,
hydrates, solvates, co-solvates, salts, enantiomers , prodrugs )
 Special release formulation (ER, SR)
 Highly Variable Drug Products (HVDP)
 Critical Dose (CD) (Steep Dose Response Curve)
 Narrow Therapeutic Index (NTI)
 Live Saving Drugs/ Critically ill
(Antibiotics, CVS Drugs, CBV Drugs, Antithrombotic)
 Chiral Drugs / Ratio of Enantiomer
Circulation, 2011: 124: 1290-1310;Meredith,2003;Monoloakis,2007,Pope,2009;FDA-Jan,2008;
FDA-Feb,Mar,2009., Block,G (2013)• http://content.onlinejacc.org/cgi/content/full/j.jacc.2011.06.001)
 Generics: equal or not ?
Controversies and claims arise regarding generic
prescribing and generic substitution

Generic substitution may impaired safety and efficacy of

treatment

Generic substitution may be dangerous for patients with

life-threatening disease (Stroke,Cardiovascular,Epilepsy)

Patients for whom a medication has been substituted

should be carefully monitor

Birkett,Aust Prescrb,2003;
Hofer,JPSW,2009;
Al Jazairi,2008
Why Some Generic Clopidogrel may impair safety and
efficacy of treatment ?

1.Generic substitution may be dangerous for patients with life

threatening disease (MI, Stroke, PCI , Stent placement,
epilepsy)
2.Generic products may contain ratios of ENANTIOMER
(optical isomers) that are different from the innovator
3. Patients for whom a medication has been substituted
should be carefully monitored, in special populations :
Patients with Acute Coronary Syndrome, Stroke, TIA

http://content.onlinejacc.org/cgi/content/full/j.jacc.2011.06.001)
(www.cardiosource.org) (www.americanheart.org)
Birkett,DJ,2003;Wade,J et al,2012; Garbel,PA,2012
 SPECIAL POPULATIONS

• There are very important groups of patients in which

therapeutic interchange/substitution may have markedly
adverse consequences. These consist of the following:

– Elderly Patients (> 65 years of age)

– Pediatric Patients
– Female Patients
– Immunocompromised Patients
– Patients with Acute Coronary Syndromes

http://content.onlinejacc.org/cgi/content/full/j.jacc.2011.06.001)
www.cardiosource.org) and
AHA (www.americanheart.org)
 SPECIAL POPULATIONS:
PATIENTS WITH ACUTE CORONARY SYNDROMES

• Patients with acute coronary syndromes are often

treated with multiple medications raising the issue of
drug-drug interactions but may also warrant the need
for multiple therapeutic interchanges.

• Potential issues may arise with the following

medications:
– Glycoprotein IIb/IIIa (GP IIb/IIIa) Inhibitors
– Low Molecular Weight Heparins (LMWH)
– Antiplatelet Agents
– Fibrinolytic Agents
– Proton Pump Inhibitors
http://content.onlinejacc.org/cgi/content/full/j.jacc.2011.06.001
www.cardiosource.org) and
AHA (www.americanheart.org)
Not All Clopidogrel are the same.
Why ?

Chirality
Crystal Polymorphisme

Pharmacokinetic
Pharmacodynamic
Pharmacogenomic

Efficacy and Toxicity

 PK – PD of Clopidogrel
S R
 Chirality Analysis,2006
RACEMATE Chirality in Drug Design,2008
Chirality in Drug Reseach,2006

(50%S + 50%R)

Single Enantiomer (NSCE)

(98.2% S + 0.8% R)
Perbedaan Efek Farmakologi dan Efek toksik dari enantiomer beberapa obat chiral
 CLOPIDOGREL CHIRAL MOLECULE
GOOD BAD
ENANTIOMER ENANTIOMER

S R
Pharmacon Toxicon
(Aktif) (Tidak Aktif)
Busch,KW and Busch,MA:Chiral Analysis, 2006; Kanavi, Business India, February 13-26, 1995
 Clopidogrel Form 1 ( 50% S + 50 % R)
Racemate
S-Enantiomer R-Enantiomer
(Aktif) (Tidak Aktif)
50 % 40X less well
tolerated
50 %

S R
(+)- (S) - methyl 2-(2-chlorophenyl)-
2-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)acetate (MATTPCA)
(IUPAC : International Union of Pure and Aplied Chemistry)
Artur-Aron Weber et al,Br J Pharmacol. 1999
January; 126(2): 415–420. REIST Marianne,et al:Drug metab & dispos 2000, 28, no12, pp. 1405-1410
Busch,KW and Busch,MA:Chiral Analysis, 2006; Kanavi, Business India, February 13-26, 1995
(IUPAC : International Union of Pure and Aplied Chemistry)
 Clopidogrel Form 2 ( 99% S + 1 % R)
Single Enantiomer

R-Enantiomer
S-Enantiomer (Tidak Aktif)
(Aktif) 40X less well
99.8 % tolerated
0.2 %

S R
(+)- (S) - methyl 2-(2-chlorophenyl)-
2-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)acetate (MATTPCA)
(IUPAC : International Union of Pure and Aplied Chemistry)
Artur-Aron Weber et al,Br J Pharmacol. 1999
January; 126(2): 415–420. REIST Marianne,et al:Drug metab & dispos 2000, 28, no12, pp. 1405-1410
Busch,KW and Busch,MA:Chiral Analysis, 2006; Kanavi, Business India, February 13-26, 1995
(IUPAC : International Union of Pure and Aplied Chemistry)
Top Drugs • About 1/3 of medicinal drugs are chiral
• In 9 out of 10 of the top selling drugs, the active ingredient is chiral
Rouhi, A. M.: Chem. Eng. News. 2004, June 14, p. 47
Rouhi, A. M.: Chem. Eng. News. 2004, Sept. 6, p.41.

NAME GLOBAL ACTIVE FORM OF THERAPEUTIC EFFECT

SALES INGREDIENT ACTIVE
2003 INGREDIENTS
(BILLION $)
LIPITOR 10.3 ATROVASTATIN Single Lipid-Lowering agent
Enantiomer
ZOCOR 6.1 SIMVASTATIN Single Lipid-Lowering agent
Enantiomer
NEXIUM 3.8 ESOMEPRAZO Single Inhibitor of gastric acid
LE Enantiomer secretion
PLAVIX 3.7 CLOPIDOGREL Single Inhibitor of platelet
Enantiomer aggregation
FLUTICASONE Single Anti-inflammatory agent
Enantiomer
ZOLOFT 3.4 SERTALINE Single Inhibitor of serotonin re-
Enantiomer uptake
Mengapa enantiomers menyebabkan perbedaan
farmakokinetik dan farmakodinamik obat ?
Molekul mengadakan interaksi secara stereo spesifik
receptor, enzim, molekul transporter, molekul antiporter, molekul carrier

Clopidogrel Molecule
S-enantiomer R-enantiomer

P2 Y12 Receptor P2 Y12 Receptor

 Clopidogrel Molecule
S-enantiomer R-enantiomer

Cyt P450 Cyt P450

Gardell,SJ: Ticlopidine and Clopidogrel:
Antithrombotic agents That block ADP-mediated
platelet activation,

R-Clopidogrel
Perspect Drug Discov Des 1:521-526,1993

Weber AA et al: Specific inhibition

S-enantiomer
of ADP-induced platelet Aggregation
by Clopidogrel in vitro
British Journal of Pharmacology, 126:415-420,1999
FDA Scientific panel

Synthesis and Thrombolytic Activity of

New Thyenopirimidinone Derivatives
P. DUPIN**, et al Medical College of Jagiellonian
University, Cracow, Poland.,2002

ADP Receptor-Blocker Thienopyridines:

Chemical Structures, Mode of Action and Clinical Use.
A Review
Mehrnoosh Hashemzadeh, et al
J.Invasive Cardiol,2009

Visal Koradia et al,Acta Pharm,54,2004:193-204

US Court of Appeals for the Federal Circuit

(SS – BM research document, 2007)

Specific inhibition of ADP induced Platelet

By ClopidogrelCyt P450
in vitro Side effects, Toxic effects
Aron Weber et al: Brit.J.Pharmacol (1999): (i.e,Neurotoxic  Convulsion)
126,415-420
 High Risk Pharmacokinetics
R.Petkovsska et al,Maced.Chem.Eng,27 (1),53-64,2008
Inactive Metabolites
COOCH3 Carboxylic acid derivative
(85% of ingested clopidogrel)
N T ½ = 8 jam
S
ABCB1 Anti Transporter
P2Y12
Cl
Hepatic
S- Clopidogrel Metabolism
G protein
CYP 1A2 O O CH3
CYP 2B6 C Irreversible binding
CYP2C9
CYP 2C19
O
N P2Y12
S Cl
2-oxo Compound
S - enantiomer O OCH3
CYP 3A4(5)
CYP 2C9
CYP 2C19 HOOC N
CYP 2B6
* HS Cl
Hepatic Active Metabolite
Metabolism S – enantiomer
T ½ = 7 – 11 hari
 Perbedaan kristal Clopidogrel form 1 dan form 2 ?

• SR25990C Form I is a • SR25990C Form II is an

monoclinic space group orthorhombic space group
• Kristal Form I (Racemates = • Kristal Form 2 (single enantiomer)
50% S+50% R) S- enantiomer
 Kristal Form 1 : Racemate (50% : 50%)
Impuritis Kristal Clopidogrel Form I In vitro

50 % 50 %

R.Petkovsska et al,Maced.Chem.Eng,27 (1),53-64,2008

Kristal Form 2 : Racemate (98.2% : 0.8%)
98.2% 0.8%

R.Petkovsska et al,Maced.Chem.Eng,27 (1),53-64,2008

 Kristal S - Clopidogrel (Form 2)
- Bersifat termodinamik stabil
- Kemurnian tinggi (ee > 99%)
- Tidak higroskopik
- Kristal lebih stabil (well defined crystal)
- Tidak mengalami bio conversion menjadi form I (in vitro / in vivo)
- Kristal lebih solid,kompak, dan kurang bersifat elektrostatik
dibandingkan thd Form I
- Lebih mudah diproses secara teknologi farmasetik untuk
formulasi
- Analisa x-ray crystallographic :
kristal 2 mengandung 1 pasangan clopidogrel cation-
bisulfate
kristal 1 mengandung 2 pasangan clopidogrel cation dan 2
pasangan bifulfate anion
- Kristal form II : mempunyai struktur crystalline system space
group Orthorombic

WWW.Freepatents on line.com, EMEA ,2004, www.Frespatents.com ;

http://www.freshpatents.com/-dt20090212ptan20090042930.php
 Clopidogrel Form 1

Decrease solubility and dissolution

Decreased Bioavailability ?

Decreased formation of
Active metabolite ?

Insufficient antithombotic
Efficacy ?

Clinical efficacy ?

Higher Cardiovascular
Event rate ?
 Apa Bukti bahwa Platogrix adalah
CLOPIDOGREL FORM – 2 ?
PT.SAI telah mematenkan Clopidogrel Form 2 di Indonesia
sejak 1998, dimana yang dipatentkan adalah:
- Enantiomer dan senyawa yang mengandung unsur tsb
- Kristal Clopidogrel Form 2
- Proses Pembuatannya berikut formula nya

Hingga saat ini PT. SAI tidak menjual bahan baku

Clopidogrel Form 2 kepihak ketiga.

SAI Indonesia telah mendaftarkan ke POM hanya untuk

memasarkan Clopidogrel form 2 sejak 2001
 Bioavailabilitas Chiral Drugs
(Clopidogrel) ?
Form 2 Form 2
(99,8% S+0.2%R) (50% S+50%R)

Non Stereoselective Assay

Enantioselective Assay

BIAS
 Chiral Drug Bioavailability
Measurement of individual enantiomers in bioequivalency studies is
recommended only when all of the following conditions are met :

1. The enantiomers exhibit difference pharmacodynamics

characteristics
2. The enantiomers exhibit difference Pharmacokinetics characteristics
3. Primary efficacy/safety activity resides with the minor enentiomer
4. Non linear absorption is present (as expressed by a change in the
enantiomeric concentration ratio with change in the input rate of the
drugs) for at least one of the enantiomers.

In such cases, bioequivalency criteria should be applied to the

enantiomers separately.
The above FDA criteria for requiring and enantiospecific assay are very
similar to those for the racemates belonging to category IIIa.

FDA Bioavailability Guideline, 2006

BIOEQUIVALENCE STUDIES FOR GENERIC PRODUCTS CONTAINING
CLOPIDOGREL :

1.Kadar unchanged clopidogrel dalam plasma

= 1/2000 dari kadar metabolit in aktif (carboxylic acid
metabolite)
2. Penentuan BA-BE harus berdasarkan kadar active metabolite
(S-enantiomer form)
3.Berdasarkan perkembangan metode PK yang ada sekarang
(LC-MS-MS),maka minimal hrs berdasarkan kadar unchanged

4. Data PK dari inactive metabolite (Clopidogrel carboxylic acid

hanya bersifat data pendukung bukan merupakan indicator
BA-BE!!!!!
 CHIRALITY DAN BIOAVAILABILITY
Ranade et al: Chiral cardiovascular Drugs, Am.J.Therap 2005,12:439-459
Chiral Analysis,2009.,Chirality in Drug Reseach , 2006

Clopidogrel Form 2 Clopidogrel Form 1 (Clopidogrel

Besylate,Clopidogrel HCl, etc)
(Clopidogrel Bisuphate)
(Clinical Trials ?)

Single Enantiomer Racemates

(S : 99.8 %, R : < 0.2%) (S : 50%, R : 50%)

BIOAVAILABILITY
Plasma concent vs time profile dari kadar R total, S total dan racemix X
Evan A.M et al : Br.J.Clin.Pharmac 26: 771-780, 2008

(Racemate)
50%R+50%S

(Inactive)

(Active)
 Blood level vs time (p.o) of S-Clopidogrel
Plavix tablet (99,8% S + 0.2% R)
Me too drugs (50% S + 50% R)

Me too
Conc.
(ug/ml)
10 Over medication
S –Clopidogrel )

MTC
Therapeutic level Clopidogrel 75 mg

1 MEC
Under medication
Me too
0.1
0 24
12 hr
Times
 61% me –too products mengandung 4 x lebih banyak senyaw
produk hasil hydrolysis (impurities)
67% me-too products mengandung impurities R-enantiomer
dengan konsentrasi 4x lebih banyak
Semua original product (innovator),dalam batas kandungan
/isi yg dapat diterima oleh USP 2007, yaitu 95 – 105% sebagai
kandungan S-clopidogrel
50% me-too product, tidak memenuhi persyaratan yang diwa
oleh USP 2007 (95 – 105%)

Most of the copies product are not Pharmaceutical

Equivalent compared to the innovator product.
BA-BE Flurbiprofen
pengukuran dgn non stereoselectiveAUC tdk berbeda
bermakna
pengukuran dgn stereoselektif  AUC berbeda bermakna
(Jamali, et al;Biopharm Drug Dispos,1991,12:435-445)
BA-BE Ibuprofen
pengukuran dgn non stereoselective Cmax tdk berbeda
bermakna
pengukuran dgn stereoselektif  Cmax dari S-enentiomer
berbeda bermakna
(Walker,SE;J.Clin.Pharmacol 1992,32:33-38)

BA – BE Ketoprofen
Pengukuran non stereoselective  C max, AUC tdk berbeda
Pengukuran stereoselective  S >> R- enantiomer
Valliapan et al,J.Apll.Biomed 4:153-161,2006
 Bioavailability dan Bioequivalence
BUKAN MERUPAKAN INDIKATOR
Therapeutic Equivalence

Bioaequivalent study in Drug Development,Steneijan,2007

Bioequivalent study,Guidance for Industry, US FDA-CDER, 2002
 KESIMPULAN
1.Plactogrix hanya mengandung
Clopidogrel Form 2
2.Di Indonesia, masa paten form 2:
2018
3. Bagi senyawa Chiral (Mis,Clopidogrel)
 Bioavailability dan Bioequivalence
tidak selalu menjamin Therapeutic
Equivalence
Untuk Stroke dan
Penyakit Jantung
Jangan pernah
coba coba
Thank you for your attention !