No.1 Amil baba in Pakistan amil baba in Lahore amil baba in Karachi
bioequivalence
1. Why bioequivalence and unconditional
interchangeability of generic drugs are not the same
Gilberto Castañeda-Hernández
Sección de Farmacología
Centro de Investigación y de Estudios Avanzados
del Instituto Politécnico Nacional
México, D.F.
2. Common criteria for declaring bioequivalence are:
1.AUC and Cmax obtained from plasma concentration against time
curves do not differ in more than 20%.
2.Products A and B yield an equivalent effect in a comparative clinical
assays.
3.The active ingredient in two products is the same.
4.Two products are manufactured using the same procedure.
Question 1
Correct answer: Number 1
3. If the Hill coefficient in the concentration-effect relationship is
greater than 1:
• Bioequivalence can be declared.
• The stability of the product is less than 1 year.
• A small change in concentration results in a large change in the
effect.
• It corresponds to a generic product.
Correct answer: Number 3
Question 2
4. Bioequivalence is not enough to ensure the quality of a true
generic product.
1.The package must be of the same color to avoid confusion.
2.The impurities level must be within the permissible limits.
3.Capsule size must be the same.
4.The manufacturer must be the same.
Question 3
Correct answer: Number 2
5. A non-innovator product is considered as a substandard copy, not
a generic, when:
1.Impurities are above the permissible level.
2.Some patients exhibit insufficient therapeutic response with regard to
the innovator.
3.Patients exhibit higher incidence and/or intensity of adverse reactions
with regard to the innovator.
4.Plasma concentrations differ in more than 20% with regard to the
innovator.
5.Any of the above.
Correct answer: Number 4
Question 4
7. AUC Data
Log AUCA/AUCB is obtained for each volunteer.
The mean value and the 90% confidence interval of the log-transformed data are
calculated
NOM-177-SSA1-2013
Sujeto AUCA AUCB AUCA/AUCB
1 100 80 1.25
2 110 84 1.31
3 92 91 1.01
4 101 106 0.95
*** *** *** ***
22 89 120 0.74
23 126 96 1.31
24 99 110 0.90
8. Cmax Data
Log Cmax
A/Cmax
B is obtained for each volunteer.
The mean value and the 90% confidence interval of the log-transformed data are calculated
NOM-177-SSA1-2013
Tabla para la concentración máxima (Cmax)
Sujeto Cmax
A Cmax
B Cmax
A/CmaxB
1 10.8 9.6 1.13
2 12.0 8.0 1.5
3 9.6 12.0 0.8
4 10.9 8.3 1.31
*** *** *** ***
22 7.6 12.0 0.63
23 8.7 10.0 0.87
24 11.8 10.3 1.15
9. To be or not to be (bioequivalent)
Higher bioequivalence
Limit (1.25)
Lower equivalence
Limit (0.80)
Bioinequivalent
Bioequivalent
90% confidence
interval
A/B
(AUC,
Cmax)
1
Adapted from NOM-177-SSA1-2013
10. Clinical Therapeutics/voume 31, Number 8, 2009
Parameter Test
Formulation*
Reference
Formulation†
Cmax μg/mL 9.33 (2.43) 9.32 (2.58)
Tmax, h 1.31 (0.50) 1.21 (0.67)
T1/2, h 6.01 (1.78) 7.48 (4.10)
AUC0-24, μg, h/,mL 62.75 (23.29) 61.33 (20.60)
AUC0-∞, h/mL 73.66 (29.89) 75.45 (28.22)
MeanPlasmaLevofloxacin
Concentration(μg/mL)
10
9
8
7
6
5
4
3
2
1
0
0 2 4 6 8 10 12 14 16 18 20 22 24
Time (h)
Bioavailability of Two Oral Formulations of a Single
Dose of Levofloxacin 500 mg: An Open-Label, Randomized,
Two-Period Crossover Comparison in Healthy Mexican Volunteers
Juan Francisco Galan-Herrera,MD1; Oscar Rosales-Sanchez, BS1; Elvira Fuentes-Fuentes, MD1; Lizbeth Cariño, MS2;
Victoria Burke-Fraga, BS2; Salvador Namur, MS2; and Mario González-de la Parra Phd2
Test formulation
Reference formulation
*Trademark: Evocs II® (Laboratorios Liomont, S.A. de C.V., Mexico City, Mexico)
†Trademark: Tavanic® (Aventis Pharma, S.A. de C.V., Now Sanofi-aventis de México
S.A. de CV Mexico City, Mexico)
Table 1. Pharmacokinetic parameters of 2 oral formlationsof a single dose of
levofloxacin 500 mg in healthy Mexican volunteers (n=25). Values are expressed
as mean (SD=
11. Journal of Bioequivalence & Bioavailability – Open Access
Bioavailability of Two Oral Tablet Formulations of Citalopram 20 mg:
Single-Dose, Open-Label, Randomized, Two-Period
Crossover Comparison in Healthy Mexican Adult Subjects
Jose Antonio Palma-Aguirre1* Lopez-Gamboa Mireya1, Castro-Sandoval Teresita de Jesus1,Pereda-Girón Mariel, Zamora-Bello Elisa1. Melchor-
Baltazar María de los Angeles1, Mendez Carmona Ma Esther, Canales-Gomez Juan Salvador2
www.omicsonline.org JBB/VOL.2 Issue 1
PlasmaConcentrations(ng/mL)
Reference
Test
Time (h)
Centro de estudios Científicos y Clínicos Pharma, S.A. De C.V.,
Mexico City, Mexico 2Productos Medix, S.A. De C.V Mexico City,
Mexico
N=24
Figure 1. Mean plasma citalopram concentration-time curve for the test (Trademark: Prepram®, Crug B) and reference (Trademark: Seropram®, Drug A), Oral tablet formulations of citalopram.
Parameter Ratio
%
(Ref)
CI 90%
Clasiacal
Criteria for
accepting
Bioequivale
nce
Two
one-sided
test of
Schuirmann
P-value Power Conclusion
LnCmax
(ng/ML)
105.36 95.98-
115.65
80%
-
125%
P(q<80%)
=0.0000
P(q>125%) =
0.0023
P<0.05 0.9872 Bioequivalent
LnAUC0-T
(h.ng/mL)
101.12 86.27-
118.53
80%
-
125%
P(q<80%)
=0.0094
P(q>125%) =
0.0159
P<0.05 0.8 Bioequivalent
16. Maximum tolerated concentration
Minimum effective concentration
Therapeutic window
Adverse events: therapeutic failure
Insufficient effect: therapeutic failure
TOXICITY
The Therapeutic Window
BloodConcentration
Time
A
B
C
17. Wide and Narrow Therapeutic Windows
Narrow
Wide
BloodConcentration
Time
A
B
C
20. Log Concentration
Effect(%)
h = 1
Most drugs
h = 3
Ciclosporin
Tacrolimus
Millán et al., 2003
Concentration-Effect Relationship
Emax*Ch
EC50h*Ch
E =100
50
10
0
21. Millán et al., 2003
Log Concentration
Effect(%)
100
50
10
0
Concentration-Effect Relationship
h = 1
Most drugs
h = 3
Ciclosporin
Tacrolimus
Emax*Ch
EC50h*Ch
E =
22. Eur J Clin Pharmacol (1986) 31
Comparison of a Controlled-Release Tablet of Salbutamol
Given Twice Daily with a Standard Tablet Given Four Times Daily
In the Management of Chronic Obstructive Lung Disease
F.P.V. Maesen and J.J. Smeets
Deparment of Respiratory Disease, De Wever Hospital, Heerlen, The Neherlands
24. J Clin Pharmacol. 1990 Feb;30(2 Suppl):S46-54.
The Relationship Between Meteprolol Plasma Concentration
and Beta1-Blockade in Healthy Subjects: A Study on
Coventional Metoprolol and Metoprolol CR/ZOK Formulations
Bertil Abrahamsson, MSc, Peter Lücker, MD, PhD, Bertil Olofsson, MSc, Carl-Gunnar Regardh, PhD, Anders Sandberg,
Ingrid Wieselgren, MSc, and Robert Bergstrand, MD, PhD
26. Metoprolol: Concentration and Effect
Figure 1. The Emax model fitted to plasma concentration versus reduction in exercise-induced heart rate for a representative
subject.
27. Drug Monitoring and Toxicology / Clinical Chemistry 49:11 1891-1899 (2003)
Pharmacodynamic Approach to Immunosuppressive Therapies
Using Calcineurin Inhibitors and Mycophenolate Mofetil
Olga Millán,1; Mercè Brunet,2 Josep M. Campistol,3 Ana Faura,3
Isabel Rojo,1 Elena Vida,2 Olga Jiménez,2 Jordi Vives,1 Federic Oppenheimer,3 and Jaume Martorell1
CAN(CPM/105cells)
800
600
400
200
0
0 100 200 400 0 12.5 25 50
μg/L
Figure 1. Measurement of CAN in PBMCs (6x106) from healthy volunteer, cultured in vitro for 24 h with CsA (0-400 μg/L) or
TRL (0-50 μg/L). After 24 h cells were disfrupted wih hypotonic buffer and the CNA was evaluated. The results are expressed
as cpm/105 cells
28. Concentrationn (μg/L)
Effect
Drug Monitoring and Toxicology / Clinical Chemistry 49:11 1891-1899 (2003)
Pharmacodynamic Approach to Immunosuppressive Therapies
Using Calcineurin Inhibitors and Mycophenolate Mofetil
Olga Millán,1; Mercè Brunet,2 Josep M. Campistol,3 Ana Faura,3
Isabel Rojo,1 Elena Vida,2 Olga Jiménez,2 Jordi Vives,1 Federic Oppenheimer,3 and Jaume Martorell1
96.3 C3
8.4523 + C3
E =Inhibición de Calcineurina
por Tacrolimus
29. González-Ramírez R. PhD Thesis, Cinvestav, Mexico, 2014
96.3 C3
8.4523 + C3
E =
InhibitionCNA(%)
Tacrolimus(μg/L)
Time (h)
Pharmacokinetics and Pharmacodynamics
of Tacrolimus (n=3)
Pk
Inhibition
30. 0.00
0.50
1.00
1.50
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
Log AUC p /AUC r
0.00
0.20
0.40
0.60
0.80
1.00
1.20
1.40
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
Ef AUC p /AUC r
Subject
Patients at risk
Bioequivalence concluded from PK
But not bioequivalent in PD (Effect)
31. Therapeutic substitution of such drugs should no be made unless
the prescribing physician has granted approval.
American Journal of Kidney Diseases Volume 33, Issue 2, Pages 389-397, February 1999
Drug substitution in transplatation:
A National Kidney Foundation white paper
Sandra Sabatini, MD, PhD, Ronald M. Ferguson, MD, PhD, J. Harold Helderman, MD, Alan R. Hull, MD, Beverly S. Kirkpatrick,
MSW, LSW
32. Abticonvulsants: Narrow Therapeutic Indices
J. Lel.orier, MD, PhD M.S. Duh, MPH, ScD P.E. Paradis, MA, Dess, P. Lefebvre, MA, J. Winer, MPA R. Manjuanath,
MSPH, O Sheehy, MSc
Neurology 2008; 70;2179-2186 DOI: 10.1212/01.WNL 0000313154.55518.25
Clinical consequences of generic substitution of
lamotrigine for patients with epilepsty
Contemporary
Issues in
Neurologic Practice
Conclusion: A higher propensity to switch back to branded medications was observed among antiepileptic drug users
compared to user of antihypertensives and antihyperlipidemos, similar to findings from Andermann et al. Switch to generic
lamotrigine was significantly associated with increased physician visits and hospitalizations
33. Abstract
Generic formulations of medications are marketed as therapeutically equivalent and less expensive than
branded ones. Multiple studies and case reports have described relapses and worsening clinical outcome in
patients after a switch from a brand name to a generic medication. Recent studies have shown that generics
do not always lead to the expected costs savings, reducing the impetus to proceed with compulsory generic
switching. We report on three patients who experienced clinical deterioration after commencing the generic
formulation of their previous brand name psychotropic medication. We discuss key clinical differences between
original and generic formulations of the same medication. The use of bioequivalence as an indicator of
therapeutic and clinical equivalence, the lack of appropriate studies comparing generic and brand name
medications and differences in excipients are some of the factors that could explain variation in clinical
response between generic and brand name medications. Generic switching should be decided on a case-by-
case basis with disclosure of potential consequences to the patient.
Int Clin Psychopharmacol. 2010 May;25(3):180-2.
Loss of response after switching from brand name to generic
formulations: three cases and a discussion of key clinical
considerations when switching.
Margolese HC, Wolf JE, BeauclaY, Desmarais ir L.SourceDepartment of Psychiatry, McGill University, Montreal, Quebec, Canada.
34. The Health Protection and Food Branch (HPFB) of Canada issued a specific Guidance for Industry on the
bioequivalence requirements for critical dose drugs (57). According to this guidance “critical dose drugs” are
defined as those drugs for which comparatively small differences in dose or concentration lead to dose- and
concentration- dependent, serious therapeutic failures and/or serious adverse drug reactions. For these
“critical dose drugs” the 90% CI of the relative mean AUC of the test to reference formulation should lie
within 90-112%, according to Canada’s HPFB guidance.
The Revised 2010 EMA Guideline for the Investigation of
Bioequivalence for Immediate Release Oral Formulation with
Systemic Action
Roger K. Verbeeck1,2 and Flora T. Musuamba1
1Louvain Drug Research Institute, Pharmacokinetics/Drug Metabolism, Catholic University of Louvain, Brussels, Belgium 2Faculty of Pharmacy,
Rhodes University, Grahamstown, South Africa
J Pharm Pharmaceut Sci (www.cspsCanada.org) 15(3) 376-388, 2012
35. Pediatr Transplant. 2010 Sep 1;14(6):746-52
Efficacy and Safety of conversion of mycophenolate mofetil to
enteric-coated mycophenolate sodium in Mexican renal
transplant children
Reyes H, Hernández AM, Valverde S, ataneo A, Mendoza A, Barrera I, Ortíz L, García-Roca P, López-Martínez B, Castañeda-
Hernández G, Medeiros M.
36. No Significant Difference in Bioavailability
Table 4. Pharmacokinetic parameters of MPAG in 11
children converted from MMF to EC-MPA
Values are media (25th, 75th percentile).
*p value by Wilcoxon signed rank test.
37. Similar PD Marker Values
Fig 3. Levels of IMPDH2 mRNA in peripheral blood cells in 12 patients when receiving mycophenolate mofetil (MMF)
and two weeks after equimolar conversion to enteric coated mycophenolate sodium (EC-MPS). Box plots show the 10th,
25th, 50th, 75th and 90th percentile values of log transformed ratios of IMPDH2 mRNA copies to 18 srRNA copies.
38. Different Safety
Fig. 1. Patient reported gastrointestinal symptoms evaluated with the gastrointestinal symptoms rating scale (GSRS) and its five symptoms clusters (abdominal pain,
reflux, constipation, indigestion and diarrhea) in 12 patients receiving mycophenolate mofetil (MMF) and two weeks after equimolar conversion to enteric-coated
mycophenolate sodium (EC_MPS). Data are shown as mean.
39. Transplant Proc. 2010 Jan-Feb;42(1):353-6
Low-Quality Formulations
Comparison of Dissolution Properties of 2 Enteric-Coated Formulations
containing Mycophenolate Sodium: Myfortic vs Femulan
A. Esquivel, R. González-Ramírez, J. Alberú, C. Gracida, M. Medeiros, and G. Castañeda-Hernandez
Estándar puro
Myfortic
Femulan
*Data are expressed as percentage of the label claimed dose.
†Indicates a statistically significant difference ( P<.05) with regard to Myfortic at PH6.8.
Table 1. Amount of Mycophenolate Sodium Released From 2 Pharmaceutical
Formulations With a Label Claimed Dose of 360 mg at 2 Different pH Values*
43. Drug Design, Development and Therapy 2014:8 859-867
Assesing the potential impact of non-proprietary
drug copies on quality of medicine and treatment in patients
with relapsing multiple sclerosis: the experience with fingolimod
Jorge Correale1, Erwin Chiquete2, Snezana Milojevic3 Nadina Frider3, Imfre Bajusz3
Drug X10 (≥1μm) X50 (≥12μm) X90 (≥25μm) Out of specification (Yes/No)
Propietary fingolimod 3 6 9 No
Variant 1 15 52 77 Yes
Variant 2 10 37 71 Yes
Variant 3 8 31 66 Yes
Variant 4 15 53 77 Yes
Variant 5 No data No data No data ---
Variant 6 9 31 69 Yes
Variant 7 10 36 72 Yes
Variant 8 10 33 70 Yes
Variant 9 9 34 70 Yes
Variant 10 13 52 78 Yes
Variant 11 8 27 63 Yes
44. Heavy Metals
Ni, Cr, Pd, Fe, Cu, Zn
Unspecific
Impurities
Inorganic
Impurities
Impurities in Finglimod Non-Innovator
Formulations
Correale et al., 2014
45. 31 formulations from Argentina, Brazil, China, Colombia, Ecuador, Egypt,
Philippines, India, Lebanon, Morocco, Pakistan, Uruguay, Venezuela and,
Vietnam.
46. Docetaxel: 74% of non-innovators sampled had an
unacceptably high total impurity content
• Acceptable impurity level (3%) was defined as twice the amount in the reference innovator
20 mg sample
0
2
4
6
8
10
12
14
16
AiSu
Biomedisdocetaxel
Daxotel
Detaxl
Docelibbs
Docetax20
Docetaxel20FU
Docetaxel80Sandoz
DocetaxelEurofarma
DocetaxelGlenmark
DocetaxelServycal
Docetere
Dosatexel
Doxel20
Doxetal20
Lexus
Neotaxel20
Neotaxel80
OkaDocetaxel20
OkaDocetaxel80
Oncodocel
Oncotaxel20
SiQuDi
Texot
Trixotene
Zenotere
Docefrez80
Donataxel
DocetaxelCooper
Doxel
DuPaFei
Taxotere(Standard)
Taxotere80
Sumofimpurities(%)
Taxotere®
Unacceptable level
Acceptable level
Vial J, et al. Curr Med Res Opin 2008;24:2019–33
47. Clinical Evidence of Efficacy and Safety
149 pacientes con glaucoma reclutados en 10 centros de México.
Tamaño de muestra adecuado para demostrar NO INFERIORIDAD en eficacia y seguridad.
GAAP ofteno®: Sophia
versus Xalatan®: Pfizer
Comparison of the Stability, Effcicacy and Adverse Effect Profile of the Innovator 0.005%
Latanoprost Ophthalmic Solution and a Novel Cyclodextrin-containing Formulation
Jaime R. Gonzalez, Leopoldo Baiza-Duran, Juan Quintana-Hau, Ruben Tornero-Montaño, Gilberto Castaneda-Hernandez, Mario Ortiz, Felipe
Alarcon-Oceguera, Marco Beltran-Loustaunau, Marco Cortez-Gastelum, Paczka-Zapata, Marina Torres-Segura and Gustavo Velasco-Gallegos
J. Clin. Pharmacol. 2007;47; 121
48. Effectiveness: Reduction of intraocular pressure
Comparable Efficacy and Safety
Conclusion: A 0.005% latanoprost ophthalmic solution containing cycodextrins exhibits a comparable
efficacy and adverse effect profile with regard to the innovator formulation.
Security: conjunctival hyperemia
49. 1. Some therapeutic agents are considered critical-dose drugs. Small
changes in concentration result in large changes in effect. These are
drugs which exhibit a narrow therapeutics index and/or a high-slope
concentration-response curve.
2. For critical-dose drugs, current bioequivalence criteria (20% tolerance in
AUC and Cmax) are not sufficient to ensure the quality of non-innovators.
3. Products which can be declared as bioequivalent in conventional PK
assays, may not produce equivalent effects.
Conclusions (1)
50. 4. Some regulatory agencies demand a reduced tolerance (10%) for
critical-dose drugs. Not in LATAM.
5. The formulations, and not only PK data, may be critical for drug safety.
6. The presence of impurities is extremely risky. Systematic research of
impurities must be implemented.
7. Several generic products available in LATAM provide therapeutic
equivalence data. This must be encouraged.
Conclusions (2)
