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 drugsNDA (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 indicationsCompares to reference listed drug (RLD)
PENGERTIAN
Ekivalensi farmasetikAlternatif FarmasetikBioavailabilitas Bioavailabilitas AbsolutBioavailabilitas RelatifBioekuivalensiBioinekuivalensiDua produk obat yg dibandingkan mengandung:
Z.a, Jumlah SamaBentuk SediaanAlternatif FarmasetikBila 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)
0
25
0.0
The true dose is not the drug swallowed;
BUT is the drug available to exert its effect.
Dissolution Absorption Survive metabolismMay have a drug with very low bioavailability
Dosage form or drug may not dissolve readily Drug may not be readily pass across biologicalmembranes (i.e. be absorbed)
Drug may be extensively metabolized duringabsorption process (first-pass, gut wall, liver)
Important component of overall variability
Variable bioavailability may produce variableexposure
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 Absorptionyields a short Tmax, high Cmax, high AUC
(R) Rapid, (E) incomplete absorptionyields a short Tmax, low Cmax, low AUC
(R) Slow, (E) complete absorptionyields a long Tmax, high Cmax, high AUC
(R) Slow, (E) incomplete absorptionyields a long Tmax, low Cmax, low AUC
Rate versus Extent of Absorption
Bila dibandingkan dg sediaan yang bioavailabilitasnya 100%
Bioavailabilitas relatifBila 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 SAMABioinekivalensiHasil 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)Sheet2Sheet3Ekivalensi 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 formulationFDA 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.
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)Tujuan BA/BE
Umum:
Menjamin efikasi, keamanan, dan mutu obat yang beredarKhusus:
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 biasTo 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 PenilaiProduk Obat
Produk Patent
Mengandung zat kimia baru (new chemical entity) penilaian lengkap u/ efikasi, keamanan, dan mutuNCE
Paten o/ pabrik penemu obat inovator bioavailabilitasExpired atau off patent perush lain dpt mengajukan ke badan regulatori u/ membuat copy product/me too product/generiknyaCopy 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 KANSponsor Pelaksana
Pabrik yang akan memproduksi produk me too / copy productPenilai:
Subdirektorat Standardisasi & Penilaian Bioavailabilitas/Bioekivalensi ObatDibawah 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??0
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Time (hours)
Concentration (ng/mL)
Test/Generic
Reference/Brand
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