Dúvidas
[email protected]
Arquivo
Estudos de Eficácia com Animais
Sadios
(biodisponibilidade e bioequivalência)
Site
www.gdenucci.com
Administração endovenosa de 200mg em bôlus concentração plasmática vs tempo após administração
Tempo (h)
mg/L
1.0
2.0
4.0
6.0
8.0
10.0
12.0
18.0
24.0
36.0
48.0
15.800
12.600
8.000
5.000
3.200
2.000
1.260
0.320
0.080
0.000
0.000
Administração endovenosa
Concentração (mg/L)
20
10
0
0
10
20
30
Tempo (h)
40
50
60
Cálculo da meia-vida
Concentração (mg/L)
100
10
5
t½
1
0
10
Tempo (h)
20
Meia-Vida
• Primeira meia-vida – 50% do medicamento é eliminado
• Segunda meia-vida – 75% do medicamento é eliminado
• Terceira meia-vida – 87.5% do medicamento é eliminado
• Após cinco meias-vidas, praticamente 100% do
medicamento é eliminado
Concentration Mean Diazepam
Valium
Test formulation
Concentration
(ng/mL)
300
200
100
0
0
4
8
12
16
20
24 48
Time (h)
96 144 192 240
Concentration Mean Nordiazepam
Valium
Test formulation
Concentration
(ng/mL)
40
30
20
10
0
0
4
8
12
16
20
24 48
Time (h)
96 144 192 240
Concentração Plasmática
(µg/L)
Administração de uma cápsula de 150 mg de
Venlafaxina a um voluntário sadio – curva de
concentração em função do tempo
125
100
75
50
25
0
0
2
4
6
8
10
12
14
16
Tempo (h)
18 24
30
36
42
48
Concentração Plasmática
(mg/L)
Administração de um comprimido de 500 mg de
Amoxicilina a um voluntário sadio – curva de
concentração em função do tempo
7
6
5
4
3
2
1
0
0
1
2
3
4
5
6
7
Tempo (h)
8
9
10
11
12
Administração de um comprimido de 5 mg de
Amlodipina a um voluntário sadio – curva de
concentração em função do tempo
Concentração Plasmática
(µg/L)
7.5
5.0
2.5
0.0
0
2
4
6
8
10
12
14
24
Tempo (h)
48
72
96
120
144
110
7000
Venlafaxina
100
6000
90
80
5000
70
4000
60
50
3000
40
2000
30
20
1000
10
0
0
0
24
Tempo (h)
48
Concentração Plasmática
(ug/mL)
Concentração Plasmática
(ug/L)
Amoxicilina
110
7
100
Venlafaxina
6
90
80
5
70
4
60
50
3
40
2
30
20
1
10
0
0
0
24
48
72
Tempo (h)
96
120
144
Concentração Plasmática
(µg/L)
Concentração Plasmática
(ug/L)
Anlodipina
Concentração Plasmática
(µg/L)
Administração de uma cápsula de 150 mg de
Venlafaxina a um voluntário sadio – curva de
concentração em função do tempo
Cmax
125
100
75
50
25
0
0
2
4
6
8
10
12
14
16
Tempo (h)
18 24
30
36
42
48
Concentração Plasmática
(mg/L)
Administração de um comprimido de 500 mg de
Amoxicilina a um voluntário sadio – curva de
concentração em função do tempo
Cmax
7
6
5
4
3
2
1
0
0
1
2
3
4
5
6
7
Tempo (h)
8
9
10 11 12
Administração de um comprimido de 5 mg de
Amlodipina a um voluntário sadio – curva de
concentração em função do tempo
Concentração Plasmática
(µg/L)
Cmax
7.5
5.0
2.5
0.0
0
2
4
6
8
10 12 14 24
Tempo (h)
48
72
96
120
144
Concentração Plasmática
(µg/L)
Administração de uma cápsula de 150 mg de
Venlafaxina a um voluntário sadio – curva de
concentração em função do tempo
125
Cmax
100
75
Tmax
50
25
0
0
2
4
6
8
10
12
14
16
Tempo (h)
18 24
30
36
42
48
Concentração Plasmática
(mg/L)
Administração de um comprimido de 500 mg de
Amoxicilina a um voluntário sadio – curva de
concentração em função do tempo
7
Cmax
6
5
4
3
2
Tmax
1
0
0
1
2
3
4
5
6
7
Tempo (h)
8
9
10 11 12
Concentração Plasmática
(µg/L)
Administração de um comprimido de 5 mg de
Amlodipina a um voluntário sadio – curva de
concentração em função do tempo
Cmax
7.5
5.0
Tmax
2.5
0.0
0
2
4
6
8
10 12 14 24
Tempo (h)
48
72
96
120
144
Concentração Plasmática
(µg/L)
Administração de uma cápsula de 150 mg de
Venlafaxina a um voluntário sadio – curva de
concentração em função do tempo
125
Cmax
100
75
Tmax
50
25
0
0
2
4
6
8
10
12
14
16
18 24
Tempo (h)
Cmax
Tmax
(µg / L)
(h)
96.4
7.5
30
36
42
48
Concentração Plasmática
(mg/L)
Administração de um comprimido de 500 mg de
Amoxicilina a um voluntário sadio – curva de
concentração em função do tempo
7
Cmax
6
5
4
3
2
Tmax
1
0
0
1
2
3
4
5
6
7
8
Tempo (h)
Cmax
Tmax
(mg / L)
(h)
6.42
0.50
9
10 11 12
Concentração Plasmática
(µg/L)
Administração de um comprimido de 5 mg de
Amlodipina a um voluntário sadio – curva de
concentração em função do tempo
Cmax
7.5
Tmax
5.0
2.5
0.0
0
2
4
6
8
10 12 14 24
48
72
96
Tempo (h)
Cmax
Tmax
(µg/L)
(h)
6.7
4.0
120 144
Concentração Plasmática
(mg/L)
Administração de um comprimido de 500 mg de
Amoxicilina a um voluntário sadio – curva de
concentração em função do tempo
7
Cmax
6
5
Absorção > Eliminação
4
3
Tmax
2
1
0
0
1
2
3
4
5
6
7
Tempo (h)
8
9
10 11 12
Concentração Plasmática
(mg/L)
Administração de um comprimido de 500 mg de
Amoxicilina a um voluntário sadio – curva de
concentração em função do tempo
7
Cmax
6
5
Absorção < Eliminação
4
3
Tmax
2
1
0
0
1
2
3
4
5
6
7
Tempo (h)
8
9
10 11 12
Concentração Plasmática
(µg/L)
Administração de uma cápsula de 150 mg de
Venlafaxina a um voluntário sadio – área sob a curva
125
100
75
50
ASC
25
0
0
2
4
6
8
10
12
14
16
Tempo (h)
18 24
30
36
42
48
Concentração Plasmática
(mg/L)
Administração de um comprimido de 500 mg de Amoxicilina
a um voluntário sadio – área sob a curva
7
6
5
4
3
2
ASC
1
0
0
1
2
3
4
5
6
7
Tempo (h)
8
9
10 11 12
Administração de um comprimido de 5 mg de
Amlodipina a um voluntário sadio – área sob a curva
Concentração Plasmática
(µg/L)
7.5
5.0
ASC
2.5
0.0
0
2
4
6
8
10
12
14
24
Tempo (h)
48
72
96
120
144
Biodisponibilidade
A fração da droga não modificada que atinge a
circulação sistêmica independente da via de
administração
Biodisponibilidade absoluta – via oral comparada à
via endovenosa
Biodisponibilidade relativa – comparação de duas
outras vias
Biodisponibilidade (F)
F=
ASC VO
ASC EV
Biodisponibilidade relativa
Frel =
ASC VO teste
ASC VO referência
Administração Oral
Luz
Intestinal
Parede
Intestinal
Veia
Porta
Fígado
Local de
Medida
Metabolismo
Fezes
Metabolismo
Medicamento Genérico
Apresenta a mesma eficácia que o
medicamento de referência, visto ter sido
avaliado através de equivalência
farmacêutica e/ou bioequivalência.
Equivalência Farmacêutica
São testes in vitro que avaliam:
• Teor de princípio ativo
• Características físicas da formulação
• Perfil de dissolução em meios aquosos
Medicamento Genérico
Apresenta a mesma eficácia que o
medicamento de referência, visto ter
sido avaliado através de equivalência
farmacêutica e/ou bioequivalência.
Bioequivalência
São testes realizados em
humanos para avaliar a
biodisponibilidade de 2 ou
mais formulações
Premissa Básica da Bioequivalência
Se
dois
medicamentos
são
bioequivalentes, eles apresentam a
mesma eficácia terapêutica, e
portanto são intercambiáveis.
Bioequivalência
Em uma ocasião o voluntário ou o
paciente toma uma formulação
(medicamento referência por exemplo)
e em outra ocasião ele toma a outra
formulação (formulação teste)
Determinação da Bioequivalência
• Concentração da droga ativa ou metabólito(s)
em fluidos biológicos em função do tempo.
• Excreção urinária da droga
metabólito(s) em função do tempo.
• Qualquer
efeito
apropriado.
farmacológico
ativa
ou
agudo
Determinação da Bioequivalência
• Em 99.9% dos casos, a avaliação da
bioequivalência é feita através da determinação
da concentração da droga ativa ou metabólito(s)
em fluidos biológicos (plasma) em função do
tempo.
• Este estudo é feito em voluntários sadios de
ambos os sexos, tratando-se de estudo clínico
aberto, cruzado de duas fases e aleatorizado.
Parâmetros para estabelecimento de
bioequivalência
• ASC - extensão da absorção
• Cmax - pico da absorção
Parâmetros farmacocinéticos (após
administração oral de um medicamento)
Concentração
plasmática da
droga
8
6
4
ASC 0-12h
2
0
0
3
6
9
12 Horas
Concentração
plasmática da droga
Parâmetros farmacocinéticos (após
administração oral de um medicamento)
8
Cmax
6
4
2
tmax
0
0
3
6
9
12 Horas
Análise estatística para
bioequivalência
• Razões da AUC e Cmax log-transformadas
• Análise Paramétrica ou não-paramétrica
Análise estatística para bioequivalência
• Calcular intervalos de confiança (90%).
• Os intervalos de confiança devem variar
entre 0.8-1.25 (corresponde a + 20%)
Concentração plasmática de sertralina
em função do tempo (média de 24 vols)
ng/mL
30
Zoloft (medicamento referência)
Tolrest (medicamento similar)
20
10
0
0 2 4 6 8 10 12 14 16 18 24 48 72 96
Horas
Análise estatística de bioequivalência
Análise Estatística
TOL/ZOL
Média Geométrica
90% IC
AUC(0-inf)
94.6
89.3 – 100.3
Cmax
99.9
91.73 – 108.8
Objetivo da bioequivalência
• Assegurar o mesmo efeito terapêutico ou
assegurar a similaridade das formulações
farmacêuticas?
Concentration Mean
3000
Hydroxyclarithromycin
Biaxin
Clamicin
ng/ml
2000
Clarithromycin
Biaxin
Clamicin
1000
0
0
2
4
6
8
10
12
Time (h)
14
16
18 24
48
Statistical Analysis for BE
90% CI
Parameters
Clarithromycin
OH-Clarithromycin
AUC(0-last)% ratio
91.1 - 103.7
94.2 - 108.1
AUC(0-inf) % ratio
91.0 - 103.4
Cmax % ratio
87.5 - 108.7
93.9 - 107.2
92.3 - 116.8
Statistical Analysis for BE
90% CI
Parameters
Diazepam
Nordiazepam
AUC(0-last)% ratio
89.00 - 106.65
88.70 - 108.91
Cmax % ratio
50.27 - 72.42
88.28 - 107.52
Statistical Analysis for BE
90% CI
Parameters
Risperidone
OH-Risperidone
AUC(0-last)% ratio
78.60%-98.28%
94.26%-105.94%
AUC(0-inf) % ratio
79.30%-98.95%
92.54%-105.08%
Cmax % ratio
71.55%-92.91%
86.37%-99.09%
J Vet Pharmacol Ther. 2005 Oct;28(5):419-23.
Pharmacokinetics of two once-daily parenteral cephalexin
formulations in dogs.
Rebuelto M, Montoya L, Kreil V, Ambros L, Waxman S, Albarellos G, Hallu R.
Farmacologia, Departamento de Fisiopatologia y Etiopatogenia, Facultad de Ciencias Veterinarias, Universidad
de Buenos Aires, Buenos Aires, Argentina. [email protected]
The aims of this study were to describe and compare the pharmacokinetic profiles and T(>MIC90)
of two commercially available once-daily recommended cephalexin formulations in healthy adult dogs
administered by the intramuscular (i.m.) route. Six beagle dogs received a 10 mg/kg dose of an 18%
parenteral suspension of cephalexin of laboratory A (formulation A) and laboratory B (formulation B) 3
weeks apart. Blood samples were collected in predetermined times after drug administration. The main
pharmacokinetic parameters were (mean +/- SD): AUC((0-infinity)), 72.44 +/- 15.9 and 60.83 +/- 13.2
microg.h/mL; C(max), 10.11 +/- 1.5 and 8.50 +/- 1.9 microg/mL; terminal half-life, 3.56 +/- 1.5 and 2.57
+/- 0.72 h and MRT((0-infinity)), 5.86 +/- 1.5 and 5.36 +/- 1.2 h for formulations A and B, respectively.
T(>MIC90) was 63.1 +/- 14.7 and 62.1 +/- 14.7% of the dosing interval for formulations A and B,
respectively. Median (range) for t(max) was 2.0 (2.0-3.0) h and 3.0 (2.0-4.0) for formulations A and B,
respectively. Geometric mean ratios of natural log-transformed AUC((0-infinity)) and C(max) and their
90% confidence intervals (CI) were 0.84 (0.72-0.98) and 0.83 (0.64-1.07), respectively. The plasma
profiles of cephalexin following the administration of both formulations were similar. No statistical
differences between pharmacokinetic parameters or T(>MIC90) were observed, however, bioequivalence
between both formulations could not be demonstrated, as lower 90% CI failed to fell within the selected
range of 80-125% for bioequivalence.
Biowaivers for oral immediate-release products:
implications of linear pharmacokinetics.
Faassen F, Vromans H.
Department of Pharmaceutics, NV Organon, Oss, The Netherlands. [email protected]
Bioequivalence of drug formulations plays an important role in drug development. Recently, the
Biopharmaceutical Classification System (BCS) has been implemented for the purpose of waiving
bioequivalence studies on the basis of the solubility and gastrointestinal permeability of drug substance. Using
the rationale of the BCS, it can be argued that biowaivers can, however, also be granted on the basis of
standard pharmacokinetic data. If a drug exhibits dose-linear pharmacokinetics and a sufficiently fast
dissolution profile, it can be concluded that this drug appears to pose no problem with respect to absorption. It
should be noted that a change of an immediate-release tablet formulation can only lead to a deviating rate
and/or extent of absorption when release of the drug from the formulation is altered. Logically, the dissolution
profiles of the different formulations should be equal to guarantee bioequivalency. Thus, both BCS and the
alternative linear pharmacokinetics approach require an evaluation of dissolution profiles. The justification of
BCS is found in the permeability classification of the compound, while those of the linear pharmacokinetics
lie in the apparent lack of a permeability problem. For example, in this context P-glycoprotein-transported
drugs form an interesting class of compounds, which may be treated likewise when complying to the
aforementioned requirements. Furthermore, poorly soluble compounds may be less troublesome than
expected. It is shown that linear kinetics can be explained by the solubilising activity of, for example, bile
salts. In this instance, linear pharmacokinetics shows that elevated doses do not appear to exhibit a limiting
role on the dissolution. Hence, a change in formulation without any effect on the dissolution profile is not
expected to cause a change in availability. It is clear that the formulations to be compared should not contain
excipients that display an effect on (presystemic) drug metabolism.
J Pharm Biomed Anal. 2005 Feb 7;37(1):187-93.
High-performance liquid chromatography electrospray ionization
mass spectrometry determination of tulobuterol in rabbit's plasma.
Xu F, Zhang Z, Tian Y, Jiao H, Liang J, Gong G.
Center for Instrumental Analysis, China Pharmaceutical University, Nanjing 210009, PR China.
A sensitive and specific liquid chromatography electrospray ionization mass spectrometry (LC-ESIMS) method has been developed and validated for the identification and quantification of tulobuterol
in rabbits' plasma. After the addition of clenbuterol-HCl, the internal standard (IS) and 1.0 M sodium
hydroxide solution, plasma samples were extracted using a solvent mixture comprised of 5%
isopropanol in n-hexane. The compounds were separated on a prepacked Lichrospher CN (5 microm,
150 mm x 2.0 mm) column using a mixture of methanol-water (10 mM CH3COONH4, pH 4.0) as
mobile phase. A Shimadzu LCMS-2010A mass spectrometer connected to a Shimadzu high
performance liquid chromatograph (HPLC) was used to develop and validate the method. The
method has shown to be sensitive and specific by testing six different blank plasma batches.
Linearity was established for the range of concentrations 0.50-40.0 ng/mL with a coefficient of
determination (r) of 0.9998. The intra-day precision was better than 15%. The lower limit of
quantification (LLOQ) was identifiable and reproducible at 0.50 ng/mL. The proposed method
enables the unambiguous identification and quantification of tulobuterol for pharmacokinetic,
bioavailability or bioequivalence studies.
Evaluation of the bioequivalence of two formulations of deltamethrin
for treatment of sheep with psoroptic mange.
Cadiergues MC, Laguerre C, Roques M, Franc M.
UMR 181 Physiopatholog ie et Toxicologie Experimentales INRA/ENVT, Ecole Nationale
Veterinaire de Toulouse, 23, chemin des Capelles 31076 Toulouse 3, France.
OBJECTIVE: To evaluate efficacy of 2 de ltamethrin emulsifiable concentrates that differed on the basis of
vehicle (methyl glycol acetate [AMG] or 2-propylene glycol 1-methyl ether acetate [AMP]) for the
treatment of sheep with mange. ANIMALS: 30 ewes between 11 months and 7 years old that weighed 16 to
71 kg and were naturally infested with Psoroptes ovis. PROCEDURE: Sheep were randomly allocated into
3 groups (13 sheep in group AMP, 13 sheep in group AMG, and 4 negative-control sheep). Each sheep was
dipped twice (10-day interval between dippings) in the assigned formulation. Assessment of efficacy was
performed on days 3, 7, 14, 21, 28, 35, 42, 49, 56, and 63 after the first dipping. Efficacy was assessed by
determining the number of eggs or live mites on those days, as well as regrowth of wool at the end of the
study. RESULTS: Psoroptic mange infestation was maintained in the 4 control sheep throughout the study.
We did not detect live Psoroptes mites in scrapings after day 7 (AMP group) or after day 14 (AMG group).
No parasites were seen after day 14 in either treatment group. Therefore, efficacy was 100% for both
treatment groups from days 14 to 63. CONCLUSIONS AND CLINICAL RELEVANCE: The 2
formulations of deltamethrin were equally able to eradicate Psoroptes infestation of sheep after 2 dippings
performed in accordance with the label recommendations.
Lack of bioequivalence of two oxytetracycline formulations in the
rabbit.
Chong W, Kim YJ, Kim SD, Han SK, Ryu PD.
Department of Pharmacology, College of Veterinary Medicine and School of Agricultural
Biotechnolog, Seoul National University, Suwon, 441-744, Korea.
Oxytetracycline (OTC) has been used for over 40 years in veterinary medical field. Various forms of
oxytetracycline preparations have been marketed, but little information is available on the bioequivalence
of OTC preparations. This study was conducted to evaluate the bioequivalence of two OTC powder
preparations available in Korea. Fourteen rabbits were randomly allocated into two groups. During the first
period, a dose (200 mg/kg) of reference product was orally administered to the rabbits in Group A and test
product to those in Group B. After 7-day washout period the reference and test products were given in
group B and A, respectively. Blood samples were drawn at 17 points during 48 hours after administration
and plasma OTC concentrations were measured by using HPLC. The solution concentrations of OTC
dissolved from two products were not significantly different in the dissolution test. The mean area under the
curve (AUC0- infinity ) and peak plasma concentration (C(max)) values for test and reference OTCs were
7.22 +/- 3.90 and 11.04 +/- 7.37 microg h/ml, 1.11 +/- 0.65 and 1.85 +/- 1.15 microg/ml, respectively. The
relative bioavailability and C(max) of test product to those of reference product was 65.4% and 60.0%,
respectively. The ranges of AUC and C(max) of test drug compared to those of reference drug under 90%
confidence limits were 27 104% and 28 91.5%, respectively. The results of statistical analysis indicate that
the two pivotal pharmacokinetic parameters, AUC and C(max) of test product are not within the 20% of
The steady-state pharmacokinetics and bioequivalence of carprofen
administered orally and subcutaneously in dogs.
Clark TP, Chieffo C, Huhn JC, Nimz EL, Wang C, Boy MG.
Veterinary Medicine Pharmaceuticals Clinical Development, Pfizer Global Research and Development, Pfizer,
Inc., Groton, CT 06340, USA. [email protected]
Eighteen male Beagle dogs were randomized to oral (p.o.) or subcutaneous (s.c.) carprofen administration in a twosequence, two-period crossover design with a 10-day washout between periods. Twenty-five milligrams of
carprofen was administered p.o. or s.c. every 12 h for 7 days. Plasma concentrations of carprofen collected after
the first and last treatments were determined by high-performance liquid chromatography. Carprofen concentration
data were natural log transformed and geometric means were calculated for maximum plasma concentration
(Cmax) and area under the plasma concentration-time curve (AUC0--12) following the first dose and Cmax and
AUC0--12 following administration of the last dose. Formulations were considered bioequivalent if the 90%
confidence interval (CI) of the mean difference for each variable between formulations were within -20% and 25%
of the oral formulation. The mean Cmax and AUC0--12 were 16.9 microg/mL and 73.1 microg. h/mL, respectively,
following a single oral dose and 8.0 microg/mL and 64.3 microg x h/mL, respectively, following a single s.c.
injection. The 90% CI for Cmax (-56.8 to -48.7%) was outside of the bioequivalence criteria whereas the 90% CI
for AUC0--12 (-16.3 to -7.5%) was within the bioequivalence criteria. At steady-state, the mean Cmax and AUC0-12 were 18.7 microg/mL and 101.9 microg x h/mL, respectively, following p.o. administration and 14.7 microg/mL
and 111.0 microg x h/mL, respectively, following s.c. injection. The 90% CI was outside the bioequivalence
criteria for Cmax (-30.8 to -10.8) but within the bioequivalence criteria for AUC0--12 (2.3-15.9%). The results of
this study indicate that peak plasma concentrations of carprofen differ when administered p.o. and s.c., but that
total drug exposure following a single dose and at steady-state are bioequivalent.