23/08/2022

Arief Rahman Hakim

Pendahuluan
 A multisource drug product
 a drug product that contains the same active drug substance
in the same dosage form and is marketed by more than one
pharmaceutical manufacturer
 Single-source drug products
 drug products for which the patent has not yet expired or has
certain exclusivities so that only one manufacturer can make
it
 usually brand-name (innovator) drug products
 After the patent and other exclusivities for the brand-name
drug expires, a pharmaceutical firm may manufacture a
generic drug product that can be substituted for the
branded drug product

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Pendahuluan
 Since the formulation and method of manufacture of
the drug product can affect the bioavailability and
stability of the drug, the generic drug manufacturer
must demonstrate that the generic drug product is
bioequivalent and therapeutically equivalent to the
brand-name drug product.

Pendahuluan
 Drug product performance, in vivo, may be defined as the
release of the drug substance from the drug product leading to
bioavailability of the drug substance
 The assessment of drug product performance is important since
bioavailability is related both to the pharmacodynamic
response and to adverse events
 Thus, performance tests relate the quality of a drug product to
clinical safety and efficacy
 Bioavailability studies are drug product performance studies
used to define the effect of changes in the physicochemical
properties of the drug substance, the formulation of the drug,
and the manufacture process of the drug product (dosage form)

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Pendahuluan
 Drug product performance studies are used in the development
of new and generic drug products
 Bioequivalence studies are drug product performance tests
that compare the bioavailability of the same active
pharmaceutical ingredient from one drug product (test) to a
second drug product (reference)
 Bioavailability and bioequivalence can be considered as
measures of the drug product performance in vivo

Definisi
 Bioavailabilitas
 ukuran kecepatan dan jumlah obat aktif terapetik
yang dapat mencapai sirkulasi sistemik dan tersedia di
tempat aksi.
 Produk obat bioekivalen
 produk yang ekivalen secara farmasetik dan
bioavailabilitasnya sama, bila diberikan dengan dosis
dan kondisi eksperimen yang sama.

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Definisi
 Ekivalen farmasetik
 Produk obat yang mengandung senyawa aktif yang sama
(bentuk kimia, garam atau ester yang sama) dan dosis,
bentuk sediaan serta rute pemberian yang sama
 Ekivalen terapetik
 produk yang mengandung senyawa aktif sama dan
memberikan efek terapi yang sama serta memiliki potensi
ESO yang sama pula.
 Produk ekivalen terapetik :
 Aman dan efektif
 Ekivalen farmasetik
 Bioekivalen
 Pelabelan yang cukup
 Pabrik pembuat ber CPOB

Studi Bioavailabilitas
 Studi bioavailabilitas in vivo
 Semua formulasi obat aktif baru yang akan registrasi
sebelum dipasarkan
 Uji klinik fase I
 menentukan efek perubahan sifat fisika-kimia obat,
bentuk sediaan, dan proses manufaktur produk obat
pada farmakokinetika obatnya

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Studi Bioavailabilitas
 Bioavailabilitas relatif (BR) :
AUC A / dosis A Du A / dosis A
BR  x100 % BR  x100%
AUC B / dosis B Du B / dosis B

keterangan :
Produk A = produk uji & Produk B = produk standar
referensi

Studi Bioavailabilitas
 Bioavailabilitas Absolut (BA) :

BA 
AUC po / dosis po
x100%
Du po / dosis po
AUCiv / dosis iv BA  x100%
Duiv / dosis iv
keterangan :
 BA = F
 Untuk IV  F = 1 (100%)
 Untuk EV  F  1 (100%)

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Kasus 1
 Bioavailabilitas produk obat baru di teliti
menggunakan 12 orang sukarelawan sehat. Tiap
sukarelawan mendapatkan tablet oral dosis tunggal
200 mg, 5 ml larutan murni oral yang mengandung
200 mg obat tersebut dan sediaan IV 50 mg. Sampel
plasma dicuplik pada periode waktu tertentu sampai
48 jam dan konsentrasi obatnya ditentukan. Harga
AUC0-48 dihitung (lihat tabel)
 Hitunglah biovailabilitas relatif tablet oral terhadap
larutan oral dan hitunglah bioavailabilitas absolut tablet
dan larutan oral

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Produk obat Dosis (mg) AUC0-48 (mean  SD)

Tablet oral 200 89,5  19,7
Larutan oral 200 86,1  18,1
IV bolus 50 37,8  5,7

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Kasus 2
 The data in table represent the average findings in antibiotic plasma samples taken
from 10 humans (average weight 70 kg), tabulated in a 4-way crossover design
Pertanyaan :
 Which of the four drug products in table would be preferred as a reference standard
for the determination of relative bioavailability? Why?
 From which oral drug product is the drug absorbed more rapidly?
 What is the absolute bioavailability of the drug from the oral solution, tablet and
capsule?
 What is the relative bioavailability of the drug from the oral tablet and capsule
compared to the reference standard?
 From the data in table, determine:
 Apparent VD
 Elimination t1/2
 First-order elimination rate constant k
 Total body clearance (ClT)

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Time (h) Plasma Concentration (µg/mL)

IV Solution Oral Solution Oral Tablet Oral Capsule
(2 mg/kg) (10 mg/kg) (10 mg/kg) (10 mg/kg)
0,5 5,94 23,4 13,2 18,7
1,0 5,30 26,6 18,0 21,3
1,5 4,72 25,2 19,0 20,1
2,0 4,21 22,8 18,3 18,2
3,0 3,34 18,2 15,4 14,6
4,0 2,66 14,5 12,5 11,6
6,0 1,68 9,14 7,92 7,31
8,0 1,06 5,77 5,00 4,61
10,0 0,67 3,64 3,16 2,91
12,0 0,42 2,30 1,99 1,83

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Studi Bioekivalensi
 Studi bioekivalensi digunakan untuk membandingkan
bioavailabilitas obat yang sama (garam yang sama
atauester) dari berbagai produk obat

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 Bioavailability and bioequivalence can be considered

as performance measures of the drug product in vivo
 If the drug products are pharmaceutically equivalent,
bioequivalent, and therapeutically equivalent (as
defined by the regulatory agency such as the FDA),
then the clinical efficacy and the safety profile of
these drug products are assumed to be similar and
may be substituted for each other

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METHODS FOR ASSESSING BIOAVAILABILITY AND BIOEQUIVALENCE

 Direct and indirect methods may be used to assess drug bioavailability

 The FDA’s regulations (US-FDA, CDER, 2014a) list the following approaches to
determining bioequivalence :
 In vivo measurement of active moiety or moieties in biological fluid (ie, a
pharmacokinetic study)
 In vivo pharmacodynamic (PD) comparison
 In vivo limited clinical comparison
 In vitro comparison
 For all systemically active drugs, with a few exceptions, bioequivalence should be
demonstrated by an in vivo study based on pharmacokinetic (PK) endpoints, as this
is the most sensitive, accurate, and reproducible approach
 The other approaches—PD, clinical, or in vitro—may be more appropriate for
locally acting drugs that are not systemically absorbed, such as those administered
topically or those that act locally within the gastrointestinal (GI) tract

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IN VIVO MEASUREMENT OF ACTIVE MOIETY OR MOIETIES IN BIOLOGICAL

FLUIDS

 Plasma Drug Concentration

 Measurement of drug concentrations in blood, plasma, or serum after drug
administration is the most direct and objective way to determine systemic drug
bioavailability
 tmax: (the time of peak plasma concentration)
 corresponds to the time required to reach maximum drug concentration after drug
administration
 At tmax, peak drug absorption occurs and the rate of drug absorption exactly equals the rate
of drug elimination
 Drug absorption still continues after tmax is reached, but at a slower rate
 When comparing drug products, tmax can be used as an approximate indication of drug
absorption rate
 The value for tmax will become smaller (indicating less time required to reach peak plasma
concentration) as the absorption rate for the drug becomes more rapid
 Units for tmax are units of time (eg, hours, minutes).

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IN VIVO MEASUREMENT OF ACTIVE MOIETY OR MOIETIES IN BIOLOGICAL

FLUIDS

 Plasma Drug Concentration

 Cmax: the peak plasma drug concentration
 Represents the maximum plasma drug concentration obtained after oral administration of
drug
 For many drugs, a relationship is found between the pharmacodynamic drug effect and the
plasma drug concentration
 Cmax provides indications that the drug is sufficiently systemically absorbed to provide a
therapeutic response
 In addition, Cmax provides warning of possibly toxic levels of drug
 The units of Cmax are concentration units (eg, µg/mL, ng/mL)
 Although not a unit for rate, Cmax is often used in bioequivalence studies as a surrogate
measure for the rate of drug bioavailability
 So, the expectation is that as the rate of drug absorption goes up, the peak or Cmax will also
be larger

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IN VIVO MEASUREMENT OF ACTIVE MOIETY OR MOIETIES IN BIOLOGICAL

FLUIDS

 Plasma Drug Concentration

 AUC: the area under the plasma level–time curve
 A measurement of the extent of drug bioavailability
 Reflects the total amount of active drug that reaches the systemic circulation
 Is independent of the route of administration and processes of drug elimination as long as
the elimination processes do not change
 Can be determined by a numerical integration procedure, such as the trapezoidal rule
method
 The units for AUC are concentration × time (eg, µg·h/mL)

 For many drugs, the AUC is directly proportional to dose (AUC0-inf = = )

 In some cases, the AUC is not directly proportional to the administered dose for all dosage
levels. For example, as the dosage of drug is increased, one of the pathways for drug
elimination may become saturated (salisilat, fenitoin)
 When the AUC is not directly proportional to the dose, bioavailability of the drug is
difficult to evaluate because drug kinetics may be dose dependent

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IN VIVO MEASUREMENT OF ACTIVE MOIETY OR MOIETIES IN BIOLOGICAL

FLUIDS

 Urinary Drug Excretion Data

 Urinary drug excretion data is an indirect method for estimating bioavailability
 The drug must be excreted in significant quantities as unchanged drug in the urine
 In addition, timely urine samples must be collected and the total amount of urinary
drug excretion must be obtained
 𝑫𝒖 : the cumulative amount of drug excreted in the urine
 Related directly to the total amount of drug absorbed
 Experimentally, urine samples are collected periodically after administration of a drug
product
 Each urine specimen is analyzed for free drug using a specific assay

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When the drug is almost completely

eliminated (point C), the plasma
concentration approaches zero and the
maximum amount of drug excreted in the
urine, 𝑫𝒖 , is obtained

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IN VIVO MEASUREMENT OF ACTIVE MOIETY OR MOIETIES IN BIOLOGICAL

FLUIDS

 Urinary Drug Excretion Data

 dDu/dt: the rate of drug excretion
 Because most drugs are eliminated by a first-order rate process, the rate of drug
excretion is dependent on the first-order elimination rate constant, k, and the
concentration of drug in the plasma, Cp
 t∞: the total time for the drug to be excreted
 In Figs. 16-9 and 16-10, the slope of the curve segment A–B is related to the rate
of drug absorption, whereas point C is related to the total time required after
drug administration for the drug to be absorbed and completely excreted, t = ∞

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The maximum rate of drug excretion,

(dDu/dt)max, is at point B,
whereas the minimum rate of drug
excretion is at points A and C

A graph comparing the rate of drug

excretion with respect to time should
be similar in shape to the plasma
level–time curve for that drug

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BIOEQUIVALENCE STUDIES BASED ON PHARMACODYNAMIC ENDPOINTS—

IN VIVO PHARMACODYNAMIC (PD) COMPARISON

 In some cases, the quantitative measurement of a drug in plasma is not available or

in vitro approaches are not applicable
 The following criteria for a PD endpoint study are important:
 A dose–response relationship is demonstrated
 The PD effect of the selected dose should be at the rising phase of the dose–response
curve
 Sufficient measurements should be taken to assure an appropriate PD response profile
 All PD measurement assays should be validated for specificity, accuracy, sensitivity, and
precision
 The use of an acute pharmacodynamic effect to determine bioavailability generally
requires demonstration of a dose–response curve
 Bioavailability is determined by characterization of the dose–response curve
 For bioequivalence determination, pharmacodynamic parameters including the total
area under the acute pharmacodynamic effect–time curve, peak pharmacodynamic
effect, and time for peak pharmacodynamic effect are obtained from the
pharmacodynamic effect–time curve

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BIOEQUIVALENCE STUDIES BASED ON CLINICAL ENDPOINTS—CLINICAL

ENDPOINT STUDY

 The clinical endpoint study is the least accurate, least sensitive to bioavailability
differences, and most variable
 Highly variable clinical responses require the use of a large number of patient study
subjects, which increases study costs and requires a longer time to complete
compared to the other approaches for determination of bioequivalence
 A placebo arm is usually included to demonstrate that the study is sufficiently
sensitive to identify the clinical effect in the patient population enrolled in the study
 The FDA considers this approach only when analytical methods and
pharmacodynamic methods are not available to permit use
 The clinical study is usually a limited, comparative, parallel clinical study using
predetermined clinical endpoint(s)
 Clinical endpoint BE studies are recommended for those products that have
negligible systemic uptake, for which there is no identified PD measure, and for
which the site of action is local

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IN VITRO STUDIES

 Comparative drug release/dissolution studies under certain conditions may give an

indication of drug bioavailability and bioequivalence
 Ideally, the in vitro drug dissolution rate should correlate with in vivo drug
bioavailability
 The test and reference products for which in vitro release rates form the basis of the
bioequivalence usually demonstrate Q1/Q2 sameness (qualitatively same inactive
ingredients in the quantitative same amounts)
 Comparative dissolution profiles may be considered similar if the similarity factor
(f2) is greater than 50
 For drugs whose dissolution rate is related to the rate of systemic absorption, the test
formulation that demonstrates the most rapid rate of drug dissolution in vitro will
generally have the most rapid rate of drug bioavailability in vivo

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• For illustrative purposes, consider a drug

that has been prepared at the same
dosage level in three formulations, A, B,
and C
• The rate of drug absorption from
formulation A is more rapid than that
from formulation B, because the tmax for
formulation A is shorter
• Because the AUC for formulation A is
identical to the AUC for formulation B,
the extent of bioavailability from both of
these formulations is the same
• Note, however, the Cmax for A is higher
than that for B, because the rate of drug
absorption is more rapid

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• The Cmax is generally higher when the

extent of drug bioavailability is greater
• The rate of drug absorption from
formulation C is the same as that from
formulation A, but the extent of drug
available is less
• The Cmax for formulation C is less than
that for formulation A
• The decrease in Cmax for formulation C
is proportional to the decrease in AUC in
comparison to the drug plasma level data
for formulation A.

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