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05/10/2012
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Part 1 v3
What do we know about the effectiveness of drug delivery?
} Measure tissue concentrations
} Measure response } Derive mathematical
relationships
is a science which attempts to explain the factors involved in the absorption, distribution and clearance of drug substances in the body:
it encompasses the physical and chemical properties of the drug which affects dissolution and the permeability and distributive factors characteristics which affect efficacy.
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} A measure of how much drug gets into the systemic circulation and is theoretically available at a site of action
Time (h)
Rel
ease
of dru
g fr
om for
mu
lati
on (m
g)
Pla
sma C
once
ntr
ati
on (u
g/m
l)
Action
Biopharmaceutical Fitness
} For an oral drug candidate (that is for 80% of all drugs in development) to be developed, the compound must
• Dissolve • be absorbed through the gut and • possess sufficient metabolic stability to generate
adequate drug concentrations at the pharmacologically relevant site so that the desired action is obtained in a reproducible manner
Formulation
} Formulation-specific behaviour alters the exposure and time course of absorption
• Matrix tablet versus disintegrating tablet • Multiparticulate versus nanoparticulate • Oil versus versus self-emulsifying dispersion
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} Systemic availability represents the amount of drug that is available to the systemic circulation and is usually described in terms of Cmax and AUC.
} Strictly speaking, it is only the total amount of drug absorbed into the circulation which describes the bioavailable fraction (F).
} This is measured by the AUC.
AUC Units: µg/ml.h
Plas
ma
Conc
entr
atio
n (µ
g.m
l)
} Two products are considered to be bioequivalent when their concentration vs time profiles , from the same molar dose, are so similar that they are unlikely to produce clinically relevant differences in therapeutic and/or adverse events.
• Same drug • Different formulations • At the same strength
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A matter of adequate therapy
} The release rate relates to the Cmax and Tmax
Pla
sma C
once
ntr
ati
on
Time (h)
Pla
sma C
once
ntr
ati
on
Time (h)
Pla
sma C
once
ntr
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on
Time (h)
} Delivery of constructs ◦ To where they are needed ◦ At the appropriate time ◦ For the appropriate period
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} Originally proposed by Amidon and colleagues (Amidon et al., Pharm. Res. 12: 413-420 , 1995)
} Proposed that Permeability and Dissolution are the controlling vehicles
} Adoption by the FDA led to waivers on immediate release products
} Test in vitro mechanistically rather than in vivo empirically
} Little mechanistic information can be obtained through a knowledge of AUC or Cmax
} If two drug products have the same in vitro dissolution profile under all lumenal conditions, they will present the same concentration-time profile at the intestinal surface and this will lead to the same extent of absorption
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Objective: In vivo-in vitro correlation
} ‘Ideal’ vs real life ◦ Lag-phase ◦ Dissolution is faster than
absorption
In v
ivo
abso
rptio
n
In vitro dissolution
100%
100%
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} In vivo in vitro correlation. } An example of the technique:
Time % d
isso
lved
Pla
sma
Con
c
Time Time % d
isso
lved
80%
Pla
sma
Con
c
Time
T80%
Cmax or Tmax
1 2 3
4 5
} Solubility Permeability
Class I High Solubility
High Permeability
Class II Low Solubility
High Permeability
Class III High Solubility
Low Permeability
Class IV
Low Solubility Low Permeability
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} Good SOLUBILTY, Good PERMEABILITY } Paracetamol } Quinidine } Metoprolol } Caffiene } Most drugs at low doses Comment: IVIVC only if gastric emptying is faster than dissolution
} Tablet may be completely dissolved but since drug is not absorbed from the stomach. Gastric emptying has to occur to allow intestinal absorption
} SOLUBILITY is rate-limiting } Digoxin (some crystal forms) } Griseofulvin
} What do you do? ◦ Select a salt form; mill down drug particles
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} Delays gastric emptying
} Provides more time for dissolution
} May bind drugs } May make a better
solvent system - emulsion formation
} Tamoxifen (dose 20mg) : poorly soluble in water
CAN BE MADE MORE ATTRACTIVE BY SOLVENTS
} Alphamethyl DOPA (Aminoacid transporter) } Atenolol (Paracellular transport) } Verapamil (Candidate for p-glycoprotein efflux
pump) } Amoxycillin
} EITHER THERE IS A LIMITED CAPACITY TRANSPORTER ALLOWING THE DRUGS IN
OR:
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} THE BODY RECOGNISES THESE AS POISONS AND TRIES TO THROW THEM OUT OF THE CELL
} Frusemide } Hydrochlorthiazide Comment: Brickdust – but some useful
compounds
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} Fewer clinical trials } Prediction of behaviour by compedial tests } In vitro/ in vivo correlation (IVIVC)
cgw 601
Four Tablet variants manufactured to capture the extreme ends of the variables. Healthy volunteer study
0 8 16 24 32 40 48 Time (h)
0 8 16 24 32 40 48 Time (h)
0 8 16 24 32 40 48 Time (h)
0 8 16 24 32 40 48 Time (h)
Variant 1 Variant 3
Variant 2 Variant 4
Courtesy Tahseen Mirza 2010, Saudi Pharmaceutical Conference
The problems of an over-discriminatory method..
Courtesy Tahseen Mirza 2010, Saudi Pharmaceutical Conference
0 2 4 6 8 10 12 Time (h)
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The 3 Dimensionless Numbers…
MATHS…
ABSORPTION NUMBER
DOSE NUMBER
DISSOLUTION NUMBER
} Defined as the ratio of the permeability and the intestinal radius multiplied by the residence time (the transit time).
} An = =tabs
-1tres = tres/tabs
} Peff/R is the “effective residence time”
} So lets try and use it…
Peff
R tres
} Vila Int J Clin Pharmacol Ther Toxicol. 1992 Aug;30(8):280-6.
} In the small intestine, the absorption rate constants, Ka, at pH 6.2 ranged between 0.38 h-1 for atenolol and 4.28 h-1 for penbutolol. In the colon, the rate of drug absorption at pH 7.5 ranged between 0.12 h-1 for atenolol and 2.15 h-1 for penbutolol.
} An = tres/tabs = 3/0.38 = 7.9 in the small intestine
} = 4/0.12 =33 in the colon } High An Poorly absorbed, Low An well absorbed
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Problems……No problems
} Ratio of the residence time to the dissolution time which itself is ◦ A function of the equilibrium solubility ◦ A function of diffusivity ◦ A function of density ◦ A function of the initial particle radius
} Simplifies to tres / tdiss } Ideally 1 or greater } In the case of solid dosage forms, a combination of
inadequate solubility or diffusivity, or excessive particle size or density can increase the time needed for full dissolution and reduce this ratio
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Time (h) Average Drug released (%)
2 <30
4 30-55
8 55-80
12 65-90
} The dose number is the ratio of the dose to the amount of drug that will dissolve in 250 mL of test solution at the lowest solubility within the pH range 1 to 8.
} Ideally, this ratio should be below 1 if full dissolution is to be possible in principle. Obviously, higher doses will raise the ratio and make good absorption less likely
Mo / Vo Css
Example: Css= 0.4 mg mL 200 mg dose/250 mL = 0.8 mg mL =0.8/0.4 = 2
} Case 1 ◦ Dose that is administered= 50 mg ◦ Volume = 250 ml ◦ Css Solubility of drug = 0.2 mg ml-1
� =0.2/0.2 - DOSE SHOULD DISSOLVE IN ADMINISTERED FLUID
} Case 2 ◦ Dose = 200 mg ◦ Volume = 100 ml ◦ Solubility of drug = 0.01 mg ml-1
◦ =2/0.01 = 200
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} Weak acids ◦ Mefamic acid 500 litres ◦ Troglitazone 100 litres
} Neutral compounds ◦ Danazol 200 litres ◦ Atavaquone 1,785 litres ◦ Felodipine 10 litres
Dressman EDAN 28March 04
} Doesn’t make sense because aqueous solubilities do not reflect what is going on in the gut...
} Felodipine ◦ Dose 10 mg ◦ Solubility in water 1 µg ml-1 ◦ Solubility in simulated intestinal fluid (fasting) 49 µg ml-1 = 204 ml ◦ Solubility in simulated intestinal fluid (fed) 237 µg
ml-1 = 42 ml } Food solves the problem easily
Dressman EDAN 28March 04
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ORANGE ZONE D:S 250 -1000 ml Simple approaches e.g. micronisation may suffice
GREEN ZONE D:S < 250 ml Confirm with Biorelevant Media
RED ZONE D:S > 1000 ml
Confirm with Biorelevant
Media Simple approaches
e.g. micronisation may suffice
Formulation will require expertise and creativity
Dressman EDAN 28March 04
} Slow entry } Efflux and metabolism
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“The Grapefruit Juice Story began 10 years ago, during experiments designed to study interactions between a Ca2+ channel antagonist felodipine and alcohol”. “Grapefruit juice was included in the experiments as it masked the taste of the alcohol better than any other fruit juice tested”. “As a result of this, grapefruit juice became a subject to a study itself, as it was discovered to change the effects of felodipine significantly on its own”.
NARINGIN
Gives juice its characteristic taste and colour
Most prevalent Flavonoid found in grapefruit juice
Has no direct effect on human cytochrome P450 enzymes
Its metabolite is a potent inhibitor of the CyP3A4 enzyme - resulting in The Grapefruit Juice Effect
Is hydrolysed to its metabolite NARINGENIN in the small intestine after oral administration
Here are some examples of drugs whose effects are potentiated by the action of Grapefruit Juice.
Ca2+ channel blockers
eg. Felodipine. Antihistamines
eg. Terfenadine.
Immunosuppresant eg. cyclosporin
other drugs include:
• Benzodiazepines • Oral contraceptives • HIV-protease inhibitors
GRAPEFRUIT JUICE POTENTIATES THE
EFFECTS OF...
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} Multidrug resistance: MDR
} Active in the apical cells of the gut
} Restricts the rate of entry of verapamil and cyclosporine
} Works in concert with CyP3A4
