Bioavailability and Bioequivalence: General concepts and overview

WHAT IS IT???

HOW IS IT???

WHY IS IT???

REGULATION VERSUS PHARMACEUTICAL COMP.

Bioavailability and Bioequivalence

Facts

Generic drugs are safe and effective alternatives to brand name prescriptionsGeneric drugs can help both consumers and the government reduce the cost of prescription drugs

NDA (New Drug Application) vs. ANDA (Abbreviated NDA) Review Process

Original Drug

NDA Requirements

Chemistry

Manufacturing

Controls

Labeling

Testing

Animal Studies

Clinical Studies

(Bioavailability/Bioequivalence)

Generic Drug

ANDA Requirements

Chemistry

Manufacturing

Controls

Labeling

Testing

Bioequivalence Study (In Vivo, In vitro)

Note: Generic drug applications are termed "abbreviated" because they are generally

not required to include preclinical (animal) and clinical (human) data to establish safety and effectiveness.

Instead, generic applicants must scientifically demonstrate that their product is bioequivalent

(i.e., performs in the same manner as the origina; drug).

Generic Drug: Definition

Same active ingredient (s)Same route of administrationSame dosage formSame strengthSame indications

Compares to reference listed drug (RLD)

PENGERTIAN

Ekivalensi farmasetikAlternatif FarmasetikBioavailabilitas Bioavailabilitas AbsolutBioavailabilitas RelatifBioekuivalensiBioinekuivalensi

Ekivalensi Farmasetik

Dua produk obat yg dibandingkan mengandung:

Z.a, Jumlah SamaBentuk SediaanAlternatif Farmasetik

Bila za sama tapi bentuk kimia beda (grm, ester dll) atau beda bentuk sediaan atau kekuatan (dosis) konversi, untuk dosis diambil yang tertinggi

Bioavailabilitas
(Ketersediaan Hayati)

a/: % dan kecepatan z.a dlm suatu produk obat yang mencapai/tersedia dlm sirkulasi sistemik dalam bentuk utuh/aktif setelah pemberian produk obat

diukur kadarnya dalam darah thd waktu atau ekskresinya dalam urin.

Bioavailability

The extent and rate at which its active moiety is delivered from pharmaceutical form and becomes available in the systemic circulation

(quantifies ABSORPTION = ?, Reasons for poor F)

Pharmacokinetics

conc. vs time

Conc.(mg/L)

Time (h)

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25

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The true dose is not the drug swallowed;

BUT is the drug available to exert its effect.

Dissolution Absorption Survive metabolism

May have a drug with very low bioavailability

Dosage form or drug may not dissolve readily Drug may not be readily pass across biological

membranes (i.e. be absorbed)

Drug may be extensively metabolized during

absorption process (first-pass, gut wall, liver)

Important component of overall variability

Variable bioavailability may produce variable

exposure

Why do we care about BIOAVAILABILITY?

Scheme of Oral Dosage Form

Human Intestinal Absorption (HIA)

Oral Bioavailability (%F)

1,2 Stability + Solubility

3 Passive + Active Tr.

4 Pgp efflux + CYP 3A4

Extent of absorption is reflected by AUC

Rate of absorption, ka, is reflected by Tmax

Both Rate and Extent of absorption affect Cmax

Leads to 4 possible relative scenarios:

(R) Rapid, (E) Complete Absorption

yields a short Tmax, high Cmax, high AUC

(R) Rapid, (E) incomplete absorption

yields a short Tmax, low Cmax, low AUC

(R) Slow, (E) complete absorption

yields a long Tmax, high Cmax, high AUC

(R) Slow, (E) incomplete absorption

yields a long Tmax, low Cmax, low AUC

Rate versus Extent of Absorption

Bioavailabilitas Absolut

Bila dibandingkan dg sediaan yang bioavailabilitasnya 100%

Bioavailabilitas relatif

Bila dibandingkan dg sediaan bukan intravena

Bioequivalence (BE): Definition

the absence of a significant difference in the rate

and extent to which the active ingredient or active

moiety in pharmaceutical equivalents or

pharmaceutical alternatives becomes available at

the site of drug action when administered at the

same molar dose under similar conditions in

an appropriately designed study.

CDER U.S. Food & Drug Administration

Bioekivalensi

2 produk obat dibandingkan ekivalensi farmasetik atau alternatif farmasetik pemberian dlm dosis sama BA sebanding efek efikasi & keamanan SAMABioinekivalensi

Hasil BA berbeda bermakna tidak memenuhi kriteria bioekivalen

Bioequivalence

Chart1000.250.250.50.50.750.75112233446688101012121414161620202424Test/GenericReference/BrandTime (hours)Concentration (ng/mL)0022.544.5109252460657077656050523033202479230.510.10.60.010.02Sheet10000.2522.50.544.50.7510912524260653707746560650528303310202412791423160.51200.10.6240.010.02Sheet1Test/GenericReference/BrandTime (hours)Concentration (ng/mL)Sheet2Sheet3

Ekivalensi terapeutik

Dua produk obat mempunyai ekivalensi terapeutik jika keduanya mempunyai ekivalensi farmaseutik atau merupakan alternatif farmaseutik dan pada pemberian dengan dosis molar yang sama akan menghasilkan efikasi klinik dan keamanan yang sebanding

Goals of BE

Ultimate: Bioequivalence studies impact of changes to

the dosage form process after pivotal studies commence

to ensure product on the market is comparable to

that upon which the efficacy is based

Establish that a new formulation has therapeutic equivalence in the rate and extent of absorption to the reference drug product.Important for linking the commercial drug product to clinical trial material at time of NDAImportant for post-approval changes in the marketed drug formulation

FDA Draft-Guidance for Industry (1997)

Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products

New Dosage Form of a Previously Studied Drug

In some cases, modified release dosage forms may be approved on the basis of pharmacokinetic data linking the new dosage form from a previously studied immediate-release dosage form.

Because the pharmacokinetic patterns of controlled-release and immediate release dosage forms are not identical, it is generally important to have some understanding of the relationship of blood concentration to response to extrapolate to the new dosage form.

Badan POM menilai produk sblm & setelah dipasarkan menjamin obat memenuhi standar:EfikasiKeamananMutu

Why do we need Bioequivalence studies?

No clinical studies have been performed in patients with the Generic Product to support its Efficacy and Safety.With data to support similar in vivo performance (= Bioequivalence)
Efficacy and Safety
data can be extrapolated from the Innovator Product to the Generic Product.

Tujuan BA/BE

Umum:

Menjamin efikasi, keamanan, dan mutu obat yang beredar

Khusus:

1. Menjamin produk obat copy yang akan mendapat izin bioekivalen dg produk inovatornya

2. Menentukan BA absolut dan relatif suatu NCE, serta BE zat tersebut dlm formulasi u/ uji klinik dan dalam produk yang akan dipasarkan.

Approaches to Determining BE (21 CFR 320.24)

In vivo measurement of active moiety in biologic fluidIn vivo pharmacodynamic comparison (Topical Corticosteroid)In vivo clinical comparison (Nasal suspensions)In vitro comparison (Nasal Solution, Topical solution, Oral solution)

Study Design: Basic design consideration

Minimize variability not attributable to formulationsMinimize bias

To compare performance of two products!!!

How to insured?

Screening of

Volunteers

Clinical

Chemistry

Clinical

Research

Implementation of

QUALITY SYSTEMS

Bioanalytical

Project

Management

Technology

Services

Pharmacokinetics

& Biostatistics

Quality

Assurance

WHAT IS IT???

HOW to Ensured???

WHY IS IT???

Please explained.

by your word.!!!!

Bioavailability and Bioequivalence

Pelaksananaan UJI BA/BE

Studi/Uji BE

Ada produk copy yg akan diproduksi untuk diedarkanAda produk pembanding/produk inovatorAda pabrik sbg sponsorAda Lab independen sbg pelaksanaAda BPOM dan komisi Etik sbg Penilai

Produk Obat

Produk Patent

Mengandung zat kimia baru (new chemical entity) penilaian lengkap u/ efikasi, keamanan, dan mutu

NCE

Paten o/ pabrik penemu obat inovator bioavailabilitasExpired atau off patent perush lain dpt mengajukan ke badan regulatori u/ membuat copy product/me too product/generiknya

Copy Product

Memiliki ekivalensi farmasetik atau alternatif farmasetik dengan produk inovator dapat dipasarkan dengan nama generik atau nama dagangTidak uji pd hewan dan tdk uji klinik lg u/ keamanan dan efikasinya shg hemat 40-60% dr inovatorBila masuk kriteria BE Harus BE dg inovator sbg produk pembanding (reference product)

Produk Obat

Produk Inovator

Sebagai produk pembanding (Reference Product) dalam studi/uji BE

Diajukan oleh Lab BE atau Sponsornya ke BPOM

Kriteria:

Telah diberi izin edar di IndonesiaPenilaian lengkap thd efikasi, keamanan, dan mutuBila tidak ada di Ina gunakan produk Primary Market (efikasi, keamanan, dan mutu terdokumentasi baik) atau gunakan Market Leader (izin edar telah ada dan tlh lolos penilaian efikasi, keamanan, dan mutunya)

Pengajuan BA/BE

Pelaksana:

Lab BE CUKB atau GCP terakreditasi SNI 19-17025-2000 (adopsi dari ISO 17025) oleh KAN

Sponsor Pelaksana

Pabrik yang akan memproduksi produk me too / copy product

Penilai:

Subdirektorat Standardisasi & Penilaian Bioavailabilitas/Bioekivalensi Obat

Dibawah Direktorat Standardisasi Produk Terapeutik dan PKRT

Kriteria Uji Ekivalensi

Produk obat uji ekivalensi in vivo

Produk Obat uji ekivalensi in vitro (uji disolusi terbanding)

Produk obat uji ekivalensi in vivo

Obat Oral lepas cepat bekerja sistemik dg 1 atau lbh kriteria sbb:

a. indeks terapi sempit

mis: digoksin,teofilin, siklosporin, hipoglikemik, dll

b. indikasi kondisi serius respon pasti

mis: antiTBC, antibakteri, antiaritmia, obat gagal jantung, antiangina, antiepilepsi, antiasma, kontrasepsi oral,dll

c. terbukti ada masalah BA /BE

mis: tetrasiklin (absorbsi bervariasi atau tdk lengkap), difenilhidantoin (farmakokinetik nonlinear), verapamil (eliminasi presistemik tinggi >70%), glukokortikoid & hormon sex steroid (kelarutan rendah), captopril & nipedifin (tidak stabil)

d. eksipien dan proses pembuatan diketahui mempengaruhi BE

2. Produk Obat non Oral dan Non Parenteral sistemik

Sediaan transdermal (nitrat organik, hormon)

Supositoria (teofilin), permenkaret nikotin, gel testoteron, dan kontrasepsi bawah kulit

Produk obat uji ekivalensi in vivo

3. Produk Lepas Lambat atau termodifikasi bekerja sistemik

Diklofenak SR, Nifedipin Oros, Felodipin ER

4. Produk sistemik kombinasi tetap dimana paling sedikit salah satunya perlu studi in vivo

Rifampisin+INH diukur rifampisisn

Levodopa+karbidopa levodopa saja

Etinilestradiol+levonorgestrel, etinilestradiol+noretisteron

5. Produk bukan larutan nonsistemik (oral, nasal, okular, dermal, rektal, vaginal) lokal

uji bioekivalensi studi klinik atau farmakodinamik, dermatofarmakokinetik komparatif dan atau studi in vitro

Kadar dalam darah kdg perlu mel;ihat absorbsi yg tidak diinginkan

Produk obat uji ekivalensi in vivo

Produk Obat uji ekivalensi in vitro (uji Disolusi Terbanding)

Obat yang memerlukan studi in vivo

Produk obat copy yg hy berbeda kekuatan uji disolusi terbanding dapat diterima untuk kekuatan lebih rendah berdasarkan perbandingan profil disolusi

Produk Obat yg tidak perlu uji Ekivalensi

Copy product (CP) intravena (lar dlm air) dg kekuatan sama dg pembanding

CP parenteral (intramuskular, subkutan) sbg lart dlm air, z.a, kekuatan, eksipient sama, eksipien ttn blh beda (bufer, pengawet, antioksidan) asal tdk mempengaruhi keamamanan dan efikasi obat

Produk Obat yg tidak perlu uji Ekivalensi

3. CP lart utk oral (sirup, eliksir, tingtur atau btk larutan lain bkn suspensi), za & kek dg pmbnding sama Hy mengandung eksipien yg tdk berefek thd transit atau permeabilitas dlm sal cerna abs or stabilitas za dlm sal cerna

Produk Obat yg tidak perlu uji Ekivalensi

4. CP berupa bubuk untuk dilarutkan larutan memenuhi kriteria 1,2, dan 3

5. CP bentuk gas

6. Sediaan obat mata atau telinga sbg lar dlm air

7. Sediaan obat topikal sbg lart dlm air

8. CP berupa lart untk aerosol atau inhalasi atau semprot hidung yg digunakan dg atau tanpa alat yg praktis sama

TUGAS INDIVIDU

DOWNLOAD PEDOMAN UJI BE di Website BPOM RIwww.fda.bioequivalence studyBuat makalah tentang Biopharmaceutics Classification System (BCS) Hub. Dg studi BA/BE??

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Time (hours)

Concentration (ng/mL)

Test/Generic

Reference/Brand