Pharmacokinetic Parameters

Pharmacokinetic Parameters
Muhammad Faisal Nadeem
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Bioavailability
Destroyed in gut Not absorbed Destroyed by gut wall Destroyed by liver
Dose
to systemic circulation
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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
Plasma Concentration
10 8 6 4 2 0 0
TOXIC RANGE
THERAPEUTIC RANGE
SUB-THERAPEUTIC
Dose
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LOCUS OF ACTION RECEPTORS
TISSUE RESERVOIRS
Bound
Free
Free
Bound
ABSORPTION
Free Drug Bound Drug

SYSTEMIC CIRCULATION
EXCRETION
BIOTRANSFORMATION
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Plasma concentration vs. time profile of a single dose of a drug ingested orally
14 12 10 8 6 4 2 0 0 5 10 15 20
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TIME (hours)
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

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 life distribution life = when plasma levels fall to half what they were at equilibrium due to distribution to/storage in bodys tissue reservoirs elimination life = when plasma levels fall to half what they were at equilibrium due to drug being metabolized and eliminated It is usually the elimination 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
Conc. [mg/L]
0 0 4 8 12 16 20 24
Time [hours]
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Elimination
Zero order: constant rate of elimination
irrespective of plasma concentration.
First order:
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
Cpav
t
Four half lives to reach steady state
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Single dose Loading dose

Therapeutic level
6 5 4 3 2 1 0 0 5 10 15 20
Repeated doses Maintenance dose
25
30
Time
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Multiple Dose Administration

Concentration
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 Company Logo
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
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FDA Determinations of Bioequivalence

Main Terms
Pharmaceutical equivalents Pharmaceutical alternatives Therapeutic equivalents Bioavailability Bioequivalence
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Pharmaceutical Equivalents
Drug 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
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Therapeutic Index
Therapeutic index = toxic dose/effective dose This is a measure of a drugs safety A large number = a wide margin of safety A small number = a small margin of safety
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Pharmacokinetic Parameters

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Pharmacokinetic Parameters

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Pharmacokinetic Parameters

Muhammad Faisal Nadeem

Why do we care about BIOAVAILABILITY?

LOCUS OF ACTION RECEPTORS

Free Drug Bound Drug

FACTORS INFLUENCING BIOAVAILABILITY:

2. Patient related factors:

Concept of Half Life

Concept of Half Life

Rate of elimination Amount Rate of elimination = K x Amount

rate of administration = rate of elimination ie. steady state is reached.

Single dose Loading dose

Repeated doses Maintenance dose

Multiple Dose Administration

Constant Rate of Administration (i.v.)

Maintenance Dose Calculation

FDA Methods to Determine Bioequivalence

FDA Determinations of Bioequivalence

Pharmaceutical equivalents Pharmaceutical alternatives Therapeutic equivalents Bioavailability Bioequivalence

Other pharmaceutical alternatives

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