Why do we care about BIOAVAILABILITY? The “true dose” is not the drug swallowed; BUT is the drug available to exert its effect. • Dissolution • Absorption • Survive metabolism May have a drug with very low bioavailability • Dosage form or drug may not dissolve readily • Drug may not be readily pass across biological membranes (i.e. be absorbed) • Drug may be extensively metabolized during absorption process (first-pass, gut wall, liver) Important component of overall variability • Variable bioavailability may produce variable exposure
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12
n o i t a r t n e c n o C a m s a l P
TOXIC RANGE
10
8
THERAPEUTIC RANGE
6
4
2
SUB-THERAPEUTIC
0 0
1
2
3
4
5
Dose
6
7
8
9
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LOCUS OF ACTION “RECEPTORS ”
Bound
ABSORPTION
Free
TISSUE RESERVOIRS
Free
Bound
Free Drug Bound Drug
SYSTEMIC CIRCULATION
BIOTRANSFORMATION
EXCRETION
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Plasma concentration vs. time profile of a single dose of a drug ingested orally
n 14 o i t a r 12 t n e 10 c n o 8 C a 6 m s a 4 l P
2 0
0
5
10
TIME (hours)
15
20
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FACTORS INFLUENCING BIOAVAILABILITY: Three distinct factors are involved to influencing bioavailability. These are: 1.Pharmaceutical factors: physicochemical properties of the drug. 1. Particle size 2. Crystalline structure 3. Salt form Formulation and manufacturing variables. 1.Disintegration and dissolution time 2.Pharmaceutical ingredients 3.Special coatings 4.Nature and type of dosage form
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2. Patient related factors:
Physiologic factors. 1.Variations in pH of GI fluids 2.Gastric emptying rate 3. Intestinal motility 4. Presystemic and first-pass metabolism 5. Age, sex 6. Disease states Interactions with other substances. 1. Food 2. Fluid volume 3. Other drugs 3. Route of administration: 1.Parentral administration 2.Oral administration 3.Rectal administration 4.Topical administration
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Concept of “Half Life”
½ life = how much time it takes for blood levels of drug to decrease to half of what it was at equilibrium There are really two kinds of ½ life… “distribution” ½ life = when plasma levels fall to half what they were at equilibrium due to distribution to/storage in body’s tissue reservoirs “elimination” ½ life = when plasma levels fall to half what they were at equilibrium due to drug being metabolized and eliminated It is usually the elimination ½ life that is used to determine dosing schedules, to decide when it is safe to put patients on a new drug
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Concept of “Half Life” 5
]
4
3 L/ g [m n
c
.
2 o C
1
0 0
4
8
12
Time [hours]
16
20
24
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Elimination Zero
order:
First
order:
constant rate of elimination irrespective of plasma concentration. rate of elimination proportional to plasma concentration. Constant Fraction of drug eliminated per unit time.
Rate of elimination ∝ Amount Rate of elimination = K x Amount
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Multiple dosing
On continuous steady administration of a drug, plasma concentration will rise fast at first then more slowly and reach a plateau, where:
rate of administration = rate of elimination ie. steady state is reached. Therefore, at steady state: Dose (Rate of Administration) = clearance x plasma conc. Or If you aim at a target plasma level and you know the clearance, you can calculate the dose required.
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C Cpa
t Four half lives to reach steady state
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Single dose – Loading dose
7 n 6 o i t a r 5 t n e 4 c n o 3 C a m2 s a l P 1
Therapeutic level
Repeated doses – Maintenance dose
0 0
5
10
15
Time
20
25
30
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Multiple Dose Administration n o i t a r t n e c n o C
Time (hr)
Minimum and maximum conc should be within therapeutic window – depends on dose, frequency and t1/2 Depending on dosing frequency and t1/2, accumulation occurs Degree of accumulation is important for safety assessment purposes
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Constant Rate of Administration (i.v.)
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Loading Dose
Dose = Cp(Target) x VD
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Maintenance Dose Calculation
Maintenance Dose = CL x CpSSav
CpSSav is the target average steady state drug concentration
The units of CL are in L/hr or L/hr/kg
Maintenance dose will be in mg/hr so for total daily dose will need multiplying by 24
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Bioequivalence A
comparison of the bioavailability of two or more drug products.
Two
products or formulations containing the same active ingredient are bioequivalent if their rates and extents of absorption are the same
Bioequivalence
may be demonstrated through in vivo or in vitro test methods, comparative clinical trials, or pharmacodynamic studies
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Bioequivalence Definition - CFR 320.1 It is the absence of significance difference in the rate and extent to which active ingredient or active moiety in pharmaceutical equivalent or pharmaceutical alternative becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study Note: BE has a specific definition and regulatory requirements. BE is not the same as the BA
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FDA Methods to Determine Bioequivalence
Generic
drug manufacturers must demonstrate that a drug is bioequivalent to a reference drug product In order of FDA preference, methods used to define bioequivalence
Pharmacokinetic studies Pharmacodynamic studies Comparative clinical trials In vitro studies
products are considered pharmaceutical equivalents if they contain the same active ingredient(s), have the same dosage form and route of administration, and are identical in strength or concentration
Equivalent
products contain the same amount of ingredient in the same dosage form but may differ in characteristics, such as shape, release mechanisms, and packaging
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Pharmaceutical Alternatives Drug
products are considered pharmaceutical alternatives if they contain the same therapeutic moiety, are different salts, esters, or complexes of the same moiety, are different dosage forms, or are different strengths
Other
pharmaceutical alternatives
Different dosage forms and strengths within a single product line by a single manufacturer Extended-release formulations when compared with immediateor standard-release formulations
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Therapeutic Equivalents Drug
products are considered therapeutic equivalents if they are all of the following
Pharmaceutical equivalents Bioequivalent Approved as safe and effective Adequately labeled Manufactured in compliance with current Good Manufacturing Practice regulations
Therapeutic
equivalents are expected to have the same clinical effect and safety profile
