merupakan materi pengantar pada mata kuliah Aplikasi Biofarmasetik dan Farmakokinetik pada program profesi apoteker Fakultas Farmasi Unpad

1. BIOFARMASETIKA -
FARMAKOKINETIKA TERAPAN/KLINIK
Taofik Rusdiana, M.Si., PhD., Apt. / Dr. Iyan Sopyan, M.Si., Apt.
Eva Kusumawati, S.Si., Apt.
Rovina Ruslami, dr., Sp.PD., Ph.D

2. PENGANTAR 1
Peranan Biofarmasetika dan PK dalam
Proses Pengembangan Produk Obat
Taofik Rusdiana

3. PHARMACEUTICAL
PRODUCT DEVELOPMENT
Research
and
Development
(RnD)

4. Figure 1. Stages of drug research
Identifikasi dan
Karakterisasi target
makromolekul
Sintesis Senyawa Lead baru
Disain obat berbantu Komputer
(CAAAD)
Kimia Kombinatorial
HTS of leads untuk
penentuan potensi
kelarutan lipofilisitas
Absorpsi
umum
Karakterisasi fisika-kimia dan
biofarmasetik
Preclinical drug development
Pharmacokinetics
Toxicokinetics
pharmacodynamics
Clinical drug development
Phase I, II, III, and IV
DRUG
DISCOVERY
DRUG
DEVELOPMENT
(R. Panchagnula, 2000)

5. • Target identification
• Lead candidate identification
Drug Discovery
• Toxicology
Select or reject lead candidate
Select dose
• Pharmacology in animals (2-3 species
including one rodent and one non-rodent)
Absorption,distribution,metabolism,
excretion
• Analysis of physiochemical parameters
Pre-Clinical Studies/
Preformulation
• Results of Pre-clinical testing
• Chemical Structure
• Side affects in animals
• Preliminary Manufacturing plan
• Detailed clinical studies plan approved by the
Institutional Review Board (IRB)
Annual reports to FDA and IRB
Investigational New
Drug (IND)
Application with
FDA/BPOM
• Dosage form development chart
• Basic Preformulation Studies
 Solubility, pKa
 Partition coefficient
 Chemical stability
 Size, shape, surface area
Crystal properties

6. Clinical Studies
• 20-100 healthy volunteers
• 6 months to 1 year
• Determine safe does range
• Pharmacokinetics
• Duration of affect
Fase 1
• 100-500 volunteers with disease of interest
• 6 months to 1 year
• Placebo-controlled
• Establish efficacy of treatment
• Determine optimal dose strength and schedule
• Note side effects
Fase 2
• 1000-5000 volunteers
• 1 to 4 years
• Randomized, double-blinded treatment
• Close monitoring for efficacy and side effectsFase 3

7. Formulation
• Solid dosage form
• Liquid dosage form
• Semisolid dosage form
• Special drug delivery technologies
Dosage Forms
• Emulsification . Coacervation
• Extrusion . Polymerization
Synthesis
Methods
• Transdermal
• Needle-free injections
• Cellular Implants
• Inhalants
Delivery
Methods
• Physical and chemical stability
Stability
evaluation

8. Scale-up and Manufacturing Plans
o Freeze-thaw
o Lyophilization
o Filling
o Labeling and Packaging
o Accessories
o Costs

9. New Drug Application (NDA)
• Analyzes of all data
• File with FDA if candidate is safe and effective
• 100,000 plus pages detailing every step of the
processes

10. Validation and Regulation
• Drug information
• ICD and DRG
• Stability tests of drug substances and products (FDA)
• Stability tests of new drugs and products (ICH)
• Analytical procedures
• Bioanalytical methods of human studies
• Specifications for new drug substances and products

11. NDA Application and Classification to
Market a New Drug
Post-approval Surveillance
o Phase IV/Post-Market Studies
o Continued evaluation of long-term effects

12. .........INTRODUCTION
T. Rusdiana, 2018
Disiplin ilmu persilangan antara product oriented dan
clinic/patient oriented
• Studi formulasi
dan teknologi
Bentuk
sediaan
Farmasetika
• BIOFARMASETIKA
PREDISPOSISI -
BABE
• Studi in vivo
(ADME)
PK-PD-PGx

13. OBAT DAN RESPON KLINIK
+
-

14. OBAT DAN RESPON KLINIK
OBAT
(produk
Obat)
TUBUH
Interaksi Obat-
Tubuh

15. Leslie Z Bennet, 1973, Biopharmaceutics as a Basis for the Design of Drug
Products in Drug Design, Vol. IV, p. 1-32, Academic Press.

17. Benet was a Founder and first President of the AAPS

20. Pelepasan
(Liberation)
Media GIT
Terdispersi secara
molekular dalam
media
Terlarut
(dissolve)
Disolusi
Membran
intestinal
GIT
GIT
EFEK
Blood circulationDistribusi
Metabolis
meEkskresi
Obat dalam
Bentuk sediaan
padat oral
Copyright @ Taofik Rusdiana, October 25, 2008
(revised on Sept 5, 2014)
Absorpsi
LDA PROCESSES

21. New Drug Discovery and Development
Laboratorium Market/pasein
US$ 400–650 million
Bagaimana Upaya yang dilakukan agar :
t <<< dan Biaya <<<
Lead Structure
Drug candidate
API
Solid dosage form
On an average every new drug molecule
requires 12–15 years to reach the patient
and costs a staggering amount of US$
400–650 million (Collins et al., 1999).

22. Penyebab kegagalan dalam pengembangan obat
Reasons %
Poor biopharmaceutical properties 40
Lack of efficacy 30
Toxicity 21
Commercial reason 8
(R. Panchagnula, 2000)

23. Skrining senyawa Obat
(Drug Compound Screening )
Pengujian Farmakologi dan
Toksikologi (Toxicological
Evaluation)
Pengembangan Formulasi
Produk (Pharmaceutical Product
development)
Obat terapeutik yang
kompleks secara kimia
Contoh : Protein/peptida
rekombinan; Obat berbasis
gen, dll.

24. Tantangan :
• Pendeknya Waktu paruh biologis
• Buruknya Permeabilitas membran
• Masalah Toksisitas terkait dosis
pemberian
• Polimorfisme genetik

25. The most important properties of API :
•its solubility,
•dissolution rate and
•permeability,
which are closely related to the oral
bioavailability of the drug
(Bohumil Kratochvı´l, 2010 )
Konsep BCS
(Amidon, 1995)

26. SIFAT FISIKA-KIMIA YANG PENTING DALAM API
SELECTION
• Solubility
• Hidrofilisitas dan lipofilisitas
• Salt Forms and Polymorphs
• Stability
• Particle and Powder Properties
• Ionization and pKa

27. Formulation Principles
• Tujuan formulator : mengelola sifat-sifat (fisika-kimia)
dan segala hal terkait API utk mengoptimalkan
penghantarannya menuju jaringan target melalui
rute pemberian tertentu
• Hal demikian juga harus “compatible” dengan
pengembangan skala produksi

28. • Excipients dapat ditambahkan, misalnya utk :
– solubilize,
– stabilize,
– modify dissolution rate,
– improve ease of administration (e.g., swallowing or taste-masking
– enable manufacturing (e.g., ensure sufficient compactibility to make tablets,
improve powder flow in a manufacturing line),
– control release rate (immediate vs. prolonged vs. enteric),
– inhibit precipitation (Gennaro, 1995).

29. • Formulasi merupakan kunci bagi profil biofarmasetis suatu
senyawa, karena komposisi, jenis bentuk sediaan, proses
manufaktur dan rute pemberian terkait erat terhadap karakter
farmakokinetiknya.
• Penilaian karakter PK tidak sempurna tanpa memasukkan
parameter formulasi yang relevan untuk menetapkan konteks
yang cocok

30. Pemilihan API yang optimal?
API/Class of API Jumlah polimorf Aktivitas
Atorvastatin
Calcium
> 60 bentuk Terapi kolestrol
Piroxicam > 50 bentuk NSAID
Sulfatiazol > 100 bentuk Antibakteri lokal
Barbiturats 63
Sulfonamid 40

31. Jenis kimia-fisika padatan dari API

32. Comparison of mean blood serum levels after the administration at
chloramphenicol palmilate suspensions using varying ratios of the stable
(α) and the metastable (β) polymorphs. M, 100% α polymorph; N. 25:75 β :
α; 0, 50:50 β : α; P, 75:25 β : α; L, 100% β polymorph. (Reproduced from
Aguiar et at 1976, with permission.)

33. The dissolution behaviour for erythromycin as anhydrate,
monohydrate and dihydrate, showing a progressively faster
dissolution rate as the level ol hydrate is increased.

34. The dissolulion of theophylline monohydrate rising to an equilibrium
solubility, compared with that for theophylline anhidrous which forms
a supersaturated solution with a peak twice that of the dissolving
hydrate, before crystallizing to the true equilibrium solubility.

35. Sifat-sifat
Kimia-Fisik
KARAKTERISTIK
FARMAKOKINETIK
kelarutan, hidrofilisitas/lipofilisitas,
ionisasi dan pka, bentuk garam dan
polimorfisme, solvat/hydrate, stabilitas,
sifat partikel dan serbuk
Disposisi

36. Pengembangan Formulasi :
1. variasi eksipien
2. Metoda proses
3. Mengindentifikasi metoda disolusi
yang spesifik
4. Scale-up produk akhir
PROFIL PELEPASAN
OBAT & PERFORMA
IN VIVO

37. UPAYA KOLABORASI
antara :
AHLI FARMASI FISIKA
AHLI FARMASETIKA
AHLI FARMAKOLOGI
Sistematik
Science-base approach
Terus menerus
Important tool:
Biopharmaceutic
scientist

38. Team Teaching :
Taofik Rusdiana,
Iyan Sopyan,
Eva Kusumawati (Sanclin)
Rovina Ruslami (FK-RSHS)

40. Buku Acuan
BAW :
• Krishna, R., and Yu., L., 2008, Biopharmaceutics Applications in Drug Development,
Springer.
• Chilikuri, D. M.; Sunkara, G. and Young D., 2007, Pharmaceutical Product Development-In
Vitro In Vivo Correlation, Informa Healthcare, New York, London.
• Shargel, L and Yu, A., Applied Biopharmaceutics and Pharmacokinetics, 4th ed., Appleton &
Lange, 1999.
• LARRY A. BAUER, 2008, Applied Clinical Pharmacokinetics, 2nd. Ed., Mc Grow Hill Medical,
BAT :
• Waterbeemd, et. al., 2003, Drug Bioavailability-Estimation of Solubility, Permeability,
Absorption and Bioavailability, Wiley-VCH.
• Niazi, S.K., 2007, Handbook of Bioequivalence Testing, Informa Healthcare, USA.
• Abdou, A.M, 1989, Dissolution, Bioavailability &. Bioequivalence, Mack Publishing
Company, Easton, Pennsylvania.
• Ritschel, W.A. 1980, Handbook of Basic Pharmacokinetics, Ed. 2. Drug Intelligence
Publications, Inc.: Hamilton.