kinetics exam 3 Flashcards
During a multiple-dose schedule the more recent a missed dose is, the less the effect the omission has on the current plasma drug concentration.
A
True
B
False
false! according to slide 24, it will have a greater effect!
PLASMA CONCENTRATION-TIME COURSE
AFTER ONE ORAL DRUG ADMINISTRATION
onset of action = when the drug reaches the minimum effective concentration
peak time = the time it takes to reach the peak concentration
duration = the time in which the drug is above the minimum effective concentration
intensity = the window between the peak concentration and the minimum effective concentration
therapeutic window = the window between the minimum toxic concentration and the minimum effective concentration
predicted plasma drug con concentrations for multiple-dose regimen using the superposition principle
taking/giving the patient the same dose at certain time intervals and as a result will result in a total dose after adding the doses taken previous to the one given
towards a steady state
taking a dose at different time intervals will increase the concentration in the body and keep it at a steady state
tou symbol:
At a steady state, concentrations will rise and fall according to a repeating pattern as long as we continue to administer the drug at the same dose level and with the same time period between doses.
This repeated dosing period is often called the dosing interval and is abbreviated using the Greek letter tau (τ).
Predicting Plasma Drug Accumulation
It is assumed:
– that a first-order process eliminates the drug
– that early doses do not affect the pharmacokinetics of later doses
i.e. the pharmacokinetics of later doses are only superimposed (stacked on top of) on those of earlier ones (the principle of superposition)
- Also, the entire 0 Cpdt for a single dose administration is equal to nn+1Cpdt for any dosing interval at a steady state in a multiple-dosing case - so
- the area under the curve of the first dose is equal to the area under the curve of any dose interval at steady state
Predicting Plasma Drug
Accumulation II
Based on the principle of superposition, the concentration-time curve in a multiple-dosing case can be predicted from the concentration-time data of a single-dose administration
- *Ref Table 8.1; if a constant dose is given at constant periods, the plasma concentrations after each dose consist of the same data obtained after the single dose. For each time point, then, the predicted plasma concentration is the sum of the residual concentration resulting from each previous dose
- The prediction holds even if the dosing interval is not fixed
Situations In Which Superposition Would Not Be Valid
The drug does not follow linear kinetics see Table 9.1 for examples
- A Drug’s carrier system gets saturated (for instance, the drug is eliminated by a saturable enzymatic process and so follows Michaelis- Menten kinetics. Recall Vmax and KM)
- There is enzyme induction
- There is enzyme inhibition
- The patient’s disease condition changes significantly between doses
Drug Accumulation
Multiple dosing is intended to keep plasma drug levels within the therapeutic window - which is always the goal!
- The dose and the time between doses () may be adjusted to achieve this.
- Accumulation will not occur if a second dose is given at an interval longer than that required for the elimination of the previous dose
- A steady state should eventually be achieved during accumulation (Cmax and Cmin should remain the same from dose to dose)
- There is no accumulation if at steady state Cmax is the same as for (Cn=1)max for the first dose.
- For drug safety, Cmax should always be less than the minimum toxic dose
Drug Accumulation II
the drug accumulation index:
R = (Cinfinity)max/(Cn=1)max
R = D0/VD[1 - e^-ktou]/(D0/VD)
R = (1/1 - e ^-k(τ))
Thus, accumulation depends not on the dose, but on the dosing interval (which is tau) and the elimination rate constant which is k
- The time required to attain a steady state is dependent on the elimination half-life but is independent of dose or interval between doses
- Average steady-state Plasma Concentration =[AUC]t1^t2/ tau
Drug Accumulation III
The time required to attain one-half of the steady-state plasma levels (the accumulation t1/2):
t1/2acc = t1/2(1 + 3.3log (ka/ka-k))
- For IV infusion administration ka is rapid»_space;>k
t1/2acc = t1/2(1 + 3.3log(ka/ka))
i.e. for an IV-administered drug
t1/2acc = t1/2
Thus t1/2acc is dependent on the elimination t1/2 but not on dose or dose intervals
Drug Accumulation IV
The time needed to reach 90% and 99% steady-state concentrations is 3.3 t1/2 and 6.6 t1/2 respectively.
- The number of doses needed to reach steady-state is dependent on t1/2 and .
(specifically, it is for 99% steady state)
(6.6 x t1/2)/tau
interrelation of elimination half life, dosage interval, maximum plasma concentration, and the time to reach steady-state plasma concentration
table 8.3
Relation Between Loading Dose
and Accumulation Index
Maintenance Dose (DM ) = Loading Dose (DL) – Amount of Drug
Remaining at end of Dosing interval
DL = DM x (1/1-e^ktau)
You would recall the accumulation index
R = 1/(1 - e^ktau)
So the loading dose is the product of the maintenance dose and the accumulation index.
the dose of sulfisoxazole (Gantrisin, Roche) recommended for an adult female patient (age 26 years, 63 kg) with a urinary tract infection was 1.5 g every 4 hours. The drug is 85% bound to serum proteins. The elimination half-life of this drug is 6 hours and the apparent volume of distribution is 1.3 L/kg. Sulfisoxazole is 100% bioavailable.
a.Calculate the steady-state plasma concentration of sulfisoxazole in this patient.
b.Calculate an appropriate loading dose of sulfisoxazole for this patient.
c.Gantrisin (sulfisoxazole) is supplied in tablets containing 0.5 g of the drug. How many tablets would you recommend for the loading dose?
d.If no loading dose was given, how long would it take to achieve 95%–99% of steady state?
Drug Accumulation:
Repeated IV Injections
For a one-compartment open model following first-order
kinetics, after a single dose:
DB = D0e^-ktau
- So given that the interval between a first and second dose is
tau: DB = D0e^-ktau - The fraction of the dose remaining in the body:
f = DB/D0 = e^-ktau
Thus f depends on k and tau e.g. f is large if tau is small.
Drug Accumulation:
Amount of Drug in the Body
- The maximum amount of drug in the body:
Dmax = D0/(1-f)
Since the difference between the maximum and minimum amounts of drug in the body is equal to the administered dose (D0):
Dmin = Dmax - D0
Where F= fraction of dose absorbed (NB: for an IV dose F=1), the average amount of drug in the body at steady-state:
Dav = FD0/ktau
The respective concentrations can be determined by dividing the amounts by the apparent volume of distribution
A new drug is to be given by multiple IV bolus injections to a patient such that drug steady-state concentrations should be maintained between a maximum of 20 and a minimum of 1 mg/L.
Assume a one-compartment linear
the model applies to this drug in this concentration range. The elimination rate constant and apparent volume of distribution for this drug in this patient are 0.223 hr-1 and
40.6 L, respectively.
Calculate the dosing interval that will exactly achieve this concentration requirement.
Also, calculate the maintenance dose.
problem to solve! slide 22 of multiple dosages
table
table
Drug Accumulation: Plasma Level Equations
Cmax = C^0p/(1 - e^-ktau)
Cmin = (C^0pe^-ktau)/(1-e^-ktau)
Cav = (FD0/VDktau)
….
Drug Accumulation: Plasma Level Equations II
After administering n i.v.doses (time between doses), the plasma concentration at time t after the nth dose is given by:
CP = (D0/VD)(1-e^-nktau)
- At steady-state, e-nk approaches zero:
CP^infinity = D0/VD(1/1-e^ktau)e^-ktau
problem to solve
Non-Compliance:
Dose Skipped?
When a dose is missed, the concentration that should have been contributed by the missing dose ((D0/VD)e-ktmiss) is subtracted from the concentration at time t after the nth dose (given that time is time tmiss since that scheduled
dose). For i.v.:
CP = D0/VD[(1 - e^nktau/1 - e^ktau)e^-kt - e^-ktmiss]
Or at steady-state (where n is very large):
CP^infinity = D0/VD(e^-kt/ 1- e^-ktau) - D0/VD e^-ktmiss
NB: The more recent a missed dose is, the greater the effect it will have on the current plasma concentration.
- Missed doses greater than 5 half-lives later should be omitted because of their minimal impact
problem to solve
Non-Compliance: Wrong Time or Wrong Dose?
When a dose is late, the dose not taken on schedule should be regarded as a missed dose and subtracted as before. However, when the dose in question is actually taken (early or late) it is taken into account as follows for
i.v.:
CP = D0/VD(1 - e^-nktau/1 - e^-ktau) -e -ktmiss + e-tactual)
where tactual is the time since the dose is question was actually taken
* If a wrong dose (hopefully non-lethal) is given, Cp may be determined with the right dose and the correction made by subtracting the contribution due to the wrong dose
problem to solve
Repeat IV Infusions
Intermittent short IV infusions prevent transient extreme high plasma levels of a drug and so are better tolerated even though steady-state may not be attained.
where R is the infusion rate. Since R = D/tinf
(D is size of infusion; tinf is the duration of infusion) After any specified time t of IV infusion,
The concentration at any specified time t after IV infusion given Cstop is the concentration when infusion stops
problem to solve
table
table
Repeat Oral (Or Extravascular)
Administrations
- Recall, for a single dose, the plasma concentration at the time
where F is the fraction of drug absorbed and ka is the first-order rate constant for absorption.
After dosing n times ( intervals), the plasma concentration at time t:
At steady-state, n approaches infinity and e-nka approaches zero.
Repeat Oral (Or Extravascular) Administrations II
Repeat Oral (Or Extravascular) Administrations III
tp corresponds to a time after many doses (i.e. n approaches infinity); also tp corresponds to a peak concentration
- tp is the repeat-dosing equivalent of a tmax for a single dose at a steady state.
Example
A drug is given by multiple oral dose of 30 mg every 6 hours. Assume a one compartment linear model applies to this drug in this concentration range. The Clearance and VD for this drug in this patient are 10.7 L/hr and 52.3 L, respectively. For this dosage form and patient
-1
the bioavailability is 0.63 and ka is 1 hr
Assume that e-ka * approaches 0 and ka»_space; k. Calculate the expected Cpaverage, Cpmin value and a ‘very’ approximate Cpmax value at steady state.
Example
A drug is to be given by multiple oral doses every 24 hr. After consideration of the patient’s clinical condition it is decided that the average drug concentrations should be maintained at 9 mg/L. Assume a one compartment linear model applies to this drug in this concentration range. For this dosage form and patient, the bioavailability is 0.65 and the absorption rate constant is 1 hr-1. The half- life and VD for this drug in this patient are 4.3 hr and 35.7 L, respectively. Calculate the dose that will achieve this average concentration of 9 mg/L.
Example
A drug was given by multiple oral doses of 200 mg every 6 hr. Assume a one compartment linear model applies to this drug in this concentration range. For this dosage form and patient the bioavailability is 0.67 and the
-1
absorption rate constant is 3.21 hr
VD for this drug in this patient (63.1 kg) are 0.155 hr-1 and 0.53 L/kg, respectively. Calculate the average drug concentration.
* Solution:………….
Loading Dose Determination
Used to achieve the desired plasma concentration (C ) av
promptly, circumventing the delay that the processes of absorption and elimination introduce.
- Dose Ratio = DL/D0
When the dosage interval is equal to the half-life, the dose ratio has value 2.
Bioavailability
Estimation of ka (in multi-dose regimens ) is difficult because of superposition of doses
- Determination of bioavailability is possible at steady-
state (Cav , AUC0 , tmax and Cmax ). - First sample should be taken just before the administration of the second dose, thereafter, samples should be taken regularly after the administration of each dose
- Multi-dose regimen bioavailability studies can reveal changes that would not be obvious in a single-dose study e.g. the existence of non-linear pharmacokinetics, drug-induced malabsorption syndrome etc…
Bioequivalence
A multiple dose study can be designed to ascertain bioequivalence. Equal doses of a test and reference product may each be administered repeatedly in turn (two-way cross- over) to steady state, separated by a time period required to completely eliminate the drug from the body.
- The AUC and Cmax of the test product should be within 80 -125% of the corresponding values for the reference product using a 90% confidence interval.
relation Between Loading Dose
and Accumulation Index
Maintenance Dose (DM ) = Loading Dose (DL) – Amount of Drug Remaining at end of Dosing interval
So the loading dose is the product of the maintenance dose and the accumulation index.
Circulatory System and Distribution
Drug is borne by blood (via blood vessels) to the site of action
- Volume of blood pumped by the heart per minute (cardiac output) is important
- Cardiac output = stroke volume X heart rate
- At rest, average cardiac output (due to 69 left ventricle contractions per minute) is 5.5 L per minute
- Blood pressure = cardiac output X peripheral resistance
- Left ventricle contraction produces a systolic blood pressure of 120 mmHg, and moves blood at 300 mm/sec through the aorta
Water Volumes in 70 kg Adult
intracellular water volume: 27
interstitial water volume: 12
plasma water volume: 3
blood cell water volume: 2
total blood volume 5L
Factors Affecting Drug Entry Into
Tissues
Physicochemical nature of cell membranes:
Protein + bi-layer of phospholipid
Under certain pathophysiological conditions (e.g. burns and meningitis) permeability could change
Unique features of tissue such as blood-brain barrier
- The physicochemical properties of the drug:
Lipophilic drugs traverse cell membranes more easily than polar ones
Small molecules traverse membranes more easily than larger ones or those forming drug-protein complexes
Diffusion
Most drugs enter cells by way of spontaneous passive diffusion
- Passive diffusion is temperature-dependent and governed by Fick’s Law of Diffusion. The rate of
drug diffusion
Where h=thickness of membrane; A=surface area of membrane; D=diffusion constant; K=lipid-water partition coefficient;Cp=drug concentration in plasma; Ct=drug concentration in tissue
*negative sign because there is a net transfer of drug from the capillary lumen to the extracellular fluid and tissue
Hydrostatic Pressure
The pressure difference between capillaries entering and those leaving tissue
- Hydrostatic (filtration) pressure is caused by capillary blood pressure being higher than that of tissue at the arterial end
- This is responsible for the transfer of water-soluble drugs penetrating spaces between endothelial cells
- Blood pressure of tissues higher than venous capillaries (creating ‘absorptive’ pressure), so filtrate gets transferred to venous capillary
Distribution
Distribution may be flow limited (such as in congestive heart failure) or diffusion limited (such as during inflammation when there is increased capillary permeability)
* The first-order distribution constant for a drug into an organ:
kd = Q/VR
concentration in the organ to that in the venous blood
* R may be estimated from the oil/water partition coefficient (Po/w). A drug with high Po/w will have a high R
* Thus large blood flow (Q) decreases distribution time; a large volume
Q VR
kd
Where Q=blood flow to the organ; V= volume of the organ; R=ratio of drug
(V) increases distribution time.
* The first-order distribution half-life:
td1/2 = 0.693/kd
Accumulation
R indicates the extent to which an organ accumulates a drug. A high R (due to either protein binding or high solubility of the drug in the tissue) means it takes longer
for distribution to be complete
*e.g. flutamide, digoxin
- A high level of accumulation in tissues results in: a long elimination half-life (e.g. etretinate, DDT); plasma levels may not correlate well with pharmacodynamic action if tissue is target tissue*
- Mechanisms of accumulation: dissolution in lipids, reversible binding to biomolecules (e.g. proteins, melanin, calcium), irreversible binding to biomolecules (e.g. in cancer chemotherapy purine/pyrimidine drugs that bind to nucleic acids), enzymatic or active transport systems
image
Drug Protein Binding
Irreversible binding to protein sometimes occurs when an activated form of a drug attaches to a protein via a covalent bond (e.g. acetaminophen hepatotoxicity, chemical carcinogenesis)
- Reversible binding (typical) is usually due to weak bonds such as hydrogen bonds and van der Waals forces
- Protein-bound drugs are usually not active pharmacologically
- Protein-bound drugs are usually not able to cross cells or cell membranes
Drug Protein Binding II
Drug-protein binding may be allosteric: There can be cooperativity in protein binding i.e. binding of first drug molecule can affect the binding of successive molecules to the same protein molecule (e.g. O2 binding to Hb)
- Drug protein binding can result in non-linear pharmacokinetics
- Drug protein binding can result in a “depot” effect (longer duration of action).
Factors Affecting Protein Binding
Drug properties: physicochemical properties and quantity of drug in body
- Protein properties: physicochemical properties and the quantity of protein available for binding
- Drug-protein affinity: Ka.
- Drug-drug interactions: competition for binding site; the binding of one drug alters affinity of protein for another drug e.g. after ASA acetylates lysine in albumin, albumin’s capacity to bind other anti-inflammatory drugs changes
- Disease condition of patient: may reduce blood-protein binding (e.g. in hepatic disease)
Drug Protein Binding:
Blood Proteins- Albumin
albumin: MW 65kDa.
* Largely responsible for maintaining the osmotic pressure of blood.
* Weak acidic drugs (e.g. salicylates, penicillin), free fatty acids, bilirubin, and some hormones (e.g. cortisone, thyroxine) bind to albumin.
* Albumin has several binding sites for which different drugs compete. For instance, sulfonamides, phenytoin, valproic acid and phenylbutazone compete for Binding Site I; medium chain fatty acids, probenecid , benzodiazepines and some penicillins compete for Binding site II
Drug Protein Binding: Blood Proteins- Globulins
1-acid glycoprotein (AAP or orosomucoid): A globulin, 44kDa.
* Many basic drugs (e.g. propranolol, lidocaine) bind to AAP.
* Globulins (, , and ) have low capacity and high affinity for endogenous substances such as corticosteroids.
* Also Immunoglobulins (IgG)
Drug Protein Binding: Blood Proteins- Lipoproteins
Lipoproteins: MW 200 – 3400 kDa.
* Include very-low-density- (VLDL), low- density- (LDL), and high-density- lipoproteins (HDL).
* Bind to and transport plasma lipids to the liver.
Drug Protein Binding: Blood Proteins- RBCs
Some drugs bind strongly to RBCs.
* For such, the hematocrit influences the total amount of drug in the blood.
* Binding to albumin reduces binding to RBCs.
Apparent Volume of Distribution
Any undetected source that reduces the plasma drug concentration increases the apparent volume of distribution. Such sources include binding to proteins within tissues and binding of metabolites to tissues following metabolism of drug
* A VD greater than combined plasma volume and body water indicates that this could be the situation
Drug Protein Binding: VD
Generally speaking, drugs with little plasma protein binding have large fu (unbound drug fraction), diffuse more into tissues and so have large VDs.
* High protein binding in blood reduces penetration to targets of action in tissues. Generally from:
DB= VPCP + VtCt
(Where Vp and Vt are the plasma and tissue volumes, Cp and Ct are the plasma and tissue drug concentrations)
Drug Protein Binding: VD
We get:
Vapp = VP = Vt(fu/fut)
(Where Vapp=apparent distribution volume, fut=unbound drug fraction in
tissue)
* The products of tissue volumes of other organs and (fu/fut) can be added to the RHS of the equation if more tissues are involved
* The volume of distribution, fu and fut should only be measured under equilibrium conditions (drug concentrations between the plasma and tissue equilibrate)
problem to solve
Drug Protein Binding: Drug Elimination
For drugs excreted mainly by filtration in the kidney, as plasma protein binding increases, so does the elimination half-life
* For drugs eliminated by active renal secretion, the elimination half-life can be short even with high protein binding (recall secretion preferentially strips blood protein of drug)
* Drugs eliminated by both renal and biliary secretion, there is poor correlation between plasma protein binding and clearance
Drug Protein Binding: Distribution and Elimination II
Some drugs (e.g. dirithromycin) have high Cl and VD and
low k i.e. large VD assures a long t1/2.
* With others, a low VD assures a long t1/2.
* Some drugs (e.g. propranolol) are eliminated even when they are protein-bound i.e. they are non-restrictively eliminated. In these elimination may not be exclusively hepatic.
* Others (e.g. phenylbutazone and piroxicam) are restrictively eliminated. Generally they have small hepatic extraction ratios (ER < fu) and do not have first pass effects
PROTEIN BINDING KINETICS
Based on the law of mass action (the rate of a chemical reaction is proportional to the product of the concentrations of reactants):
* For: protein + drug protein-drug-complex,
[P] + [D] [PD]
- The association (affinity) constant:
Ka = [PD]/[P][D]
Given the ratio:
Ka
r = moles of bound drug/ total moles of protein
r = [PD]/[PD]+[P]
PROTEIN BINDING KINETICS II
Where there are n identical binding sites per
protein molecule:
Sometimes a protein molecule can have more than one kind of binding site for a drug (e.g. binding of salicylic acid
to albumin). For such:
PROTEIN BINDING KINETICS III
- The dissociation constant
Kd = 1/Ka
Preceding equation may be expressed in terms of
Kd as follows:
r = n[D]/Kd+[D]
problem to solve
Graphical Methods of Determining Ka: Double Reciprocal Plot
Assuming 1 type of binding site and no protein-protein interaction,from earlier equation:
Thus a plot of 1/r against 1/[D] gives a slope of 1/nKa and a y-intercept of 1/n. Since both r and [D] can be determined, Ka may be calculated this way.
Graphical Methods of Determining Ka: Scatchard Plot
Thus a plot of r/[D] versus r (a Scatchard plot) gives a line of slope –Ka.
Graphical Methods of Determining Ka: Scatchard Plot
A non-linear plot would suggest complexities exist e.g. there could be more than one type of binding site
Graphical Methods of Determining Ka: Where Protein Concentration is Unknown
Where [D] is the concentration of bound drug and [PT]is the total protein concentration
Thus a plot of [D]/[D] versus [D] gives a straight line with slope –Ka.
* NB: The ratio of bound drug concentration to free drug concentration ([D]/[D]) depends on the affinity constant (Ka) and on [PT] (which can change during disease).
Factors Affecting Plasma Protein Concentration
Protein synthesis
* Protein catabolism
* Distribution of albumin between vascular and extravascular space
* Age
* Disease
table
table
Protein Concentrations and
Disease
The quality of protein synthesized may be altered during liver or kidney disease or as a result of a genetic defect:This could alter the Ka.
* Albumin levels decrease in liver disease
* During kidney disease, accumulated metabolites (such as uric acid and urea) could compete with drugs for protein binding
* Severe burns could increase movement of albumin into extracelular fluids, resulting in reduced levels in the plasma
At constant protein levels, all available binding sites get bound even at low drug
concentrations i.e. at low drug concentrations, the fraction of bound drug is high. After saturation free drug levels rapidly increase.
THE EFFECT OF PROTEIN SATURATION
Protein Concentrations and
Disease
The fraction of drug bound:
From equations this equation and
Thus, any changes in protein or free drug concentration (such as could occur during a disease) impacts the pharmacokinetics of a drug
Displacement from Binding
Drug displacement from binding to protein or other biomolecules (e.g. melanin or DNA) can result from competition
* Displacement from plasma protein binding increases level of free drug and therefore therapeutic effect (as well as the potential for toxicity)
* Clinical effect of displacement from plasma protein binding may be minimal if distribution or elimination dilute the resulting rapid rise in free drug levels
* Displacement of endogenous ligands such as hormones have little practical significance because of the existence of feedback mechanisms (except in newborn babies e.g. kernicterus)
Displacement from Binding II
Displacement from plasma protein binding is most significant for drugs that are more than 95% protein-bound and have a narrow therapeutic index *example on page 243 (5th Edition Page 292 ) and Table 10.15
* Such displacement causes an increase in the VD and t1/2
* Consider a drug that gets displaced from plasma protein binding which then gets into tissue to which it has high affinity. The volume of distribution would increase but so
would the elimination half-life. Displacement has no effect on clearance (recall Cl = 0.693VD/t1/2) or mean steady-state concentration (if multiple doses are administered)
table
Low Extraction Drug and Protein
Binding
For a low-extraction drug, changes in protein binding have consequence.
* Generally, organ clearance:
where Qorgan is blood flow, fu is fraction of free drug
unchanged Clint is intrinsic clearance
* In the case of a low-extracting drug, Qorgan»_space;> fuClint and so:
* Cl fuClint
* i.e. organ clearance depends on intrinsic clearance (which is flow independent) and fu.
Low Extraction Drug Exposure
where FH is the hepatic bioavailability and QH the hepatic blood flow
where FG and Fabs are the fraction of drug that gets across the gut wall unchanged and the fraction of drug that gets absorbed to the gut wall respectively.
For an unbound drug,
- i.e. unbound drug exposure (AUCoral ) is independent of fu
High Extraction Drug Protein Binding and Exposure
for a high-extracting drug, hepatic Cl (ClH) is flow-dependent, and protein binding is clinically important
* For high-extracted drugs
- The systemic exposure of unbound drug:
i.e. changes in binding may be important clinically
What’s In a Name?
Generic name (established non-proprietary common name of active ingredient): e.g. acetaminophen
* Chemical name (used by organic chemists; indicates structure): e.g. p-acetamidophenol (p-hydroxyacetaniline)
* Brand name (privately owned trade name of a drug): e.g. tylenol
Plasma Observations
“Bioavailability” is a reference to the rate and extent to which a drug is absorbed.
* The F and ka are direct measures of bioavailabilty but are too variable (recall why) to be useful for this purpose.
* FromanoralCpvrstcurve,theCmax,tmaxandAUCare used (as indirect measures) to determine the bioavailability of a drug.
– Cmax,is a measure of rate and extent of absorption tmax is a measure of the rate of absorption
– AUC is a measure of the extent of absorption
plasma level-time curve
linear relationship
Urine Observations
If absorption is greater for one drug product than another, then more of the first product should appear in the urine (for most drugs elimination is first order).
* Enough time should be allowed for the collection of the amount of absorbed drug in the urine (about five t1/2s)
* AU is the total amount of absorbed drug that is ultimately excreted unchanged
* AU is a measure of the extent of drug absorption
plasma level time curves
Relative Bioavailability
This compares the extent of absorption of a test product (generic drug) with a standard or reference product
* The systemic availability of a drug in a given drug product relative to its availability in a standard formulation (such as the Reference Listed Drug)
* For two products given at the same dose:
Relative Bioavailability
Relative Bioavailability II
- If the doses are not the same,
Relative Bioavailability
A high relative bioavailability means two products may be considered bioequivalent. It does not necessarily mean that either product is well absorbed
Absolute Bioavailability
This is a reference to the fraction of the oral dose (of an individual product) that is absorbed.
* For the same drug dose given po and iv:
Absolute Bioavailability
problem to solve
Bioavailability Studies Rationale
these contribute to assure that standards of safety and effectiveness of a drug (identity, strength, purity etc..) are met.
* For new generic products (as well as new formulations of old drugs) FDA requires in vitro and/or in vivo studies of bioavailability along with essential pharmacokinetic parameters (such as t1/2, rates of absorption, excretion and metabolism) are met.
* Data from bioavailability studies help determine appropriate dose regimens
Bioequivalence
Bioequivalent drug products show similar bioavailability when studied under similar conditions
* Bioequivalenceisdemonstratedbyestablishingthat no statistical difference exists among Cmax, tmax and AUC for the test and reference products
* Analysis of Variance (ANOVA) is a commonly used test (level of probability of < 0.05 and a power of 80% certainty). The average parameter value of the test product should be within 20% of that of the reference product
Bioequivalence II
FDA: “The rate and extent of absorption of the test drug do not show a significant difference from the rate and extent of absorption of the reference drug when administered at the same molar dose of therapeutic ingredient under similar experimental conditions in either a single dose or multiple doses”
* Or: where there is no difference in the extent of absorption but a significant difference in the rate of absorption that is intentional, reflected in the label and is medically insignificant
Bioequivalence Studies
Typically single-dose (usually following an overnight fast), two-treatment, randomized cross over design. Plasma sample taken just before dose and at regular intervals thereafter. Food intervention studies and multiple-dose studies are sometimes performed
table
Bioequivalence Studies II
Latin square. Each subject receives each drug product only once, with sufficient time between product administrations to allow for : 1. full description of Cmax, tmax and AUC and 2. elimination of product from the body
– Replicated crossover design: estimates within- subject variance for both products. FDA recommends a four-period, two-sequence, two- formulation design
table
table
Generic Substitution
Generic Substitution: Dispensing an unbranded product or a different brand in place of a prescribed product.
* Same dosage form, same active ingredient, different manufacturer.
* If permitted by prescriber
* The FDA publishes a list of drug products: Approved Drug Products with Therapeutic Equivalence Evaluations, also known as the Orange Book.
* Overall classification: A (deemed therapeutically equivalent) or B (inadequate evidence of bioequivalence)
* Two-letter codes used
table
Pharmaceutical Substitution
- Pharmaceutical Alternatives: same therapeutic entity but presented as different salts, complexes or esters. Also different dosage forms (e.g. elixirs, capsules and tablets) and strengths by a single manufacturer.
- Pharmaceutical Equivalents: same active ingredient, same amount of it, same dosage form for the same route of administration. Must meet same uniformity, disintegration and dissolution rates where applicable. May differ in features such as packaging, shape, color, release mechanism, excipients and some labeling details
- The process of dispensing a pharmaceutical alternative in place of a prescribed product.
- Needs prescriber approval
Therapeutic Substitution
Therapeutic alternatives: different active ingredients share same indications and used for same therapeutic objectives e.g. ibuprofen instead of ASA
* Therapeutic equivalents: are pharmaceutic equivalents that are expected to have the same clinical effect and safety profile
* Therapeutic substitution involves the use of a therapeutic alternative
Drug Review Process
Drug Review Process II
Contrast New Drug Applications (NDAs) and Abbreviated New drug Applications (ANDAs)
* NDAs must have animal and clinical data along with bioavailablity data.
* ANDAs do not need these but must have bioequivalence data
Biopharmaceutics Classification System
Used to predict in vivo absorption based on solubility and permeability characteristics
* Jw = PwCw
* Jw= drug flux (mass/area/time), Pw=permeability of membrane, Cw= drug concentration at intestinal membrane surface
Biopharmaceutics Classification System II
According to the BCS, drug substances are classified as follows:
Class 1: high solubility–high permeability
Class 2: low solubility–high permeability
Class 3: high solubility–low permeability
Class 4: low solubility–low permeability
Criteria Proposed by FDA for Consideration of BCS-Based Biowaivers of Immediate-Release Generic Drug Products
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Recall: Mechanisms of Drug Movement III
Carrier-Mediated Transport
– Intestinal examples
– Facilitated Diffusion: carrier-mediated, moves along concentration gradient, requires no energy expenditure
– Active Transport: carrier-mediated, requires energy * VesicularTransport:exocytosis,endocytosis
* Pore Transport
* Ion-Pair Formation: e.g. propranolol + oleic acid, resulting in neutral (and so more lipophilic entity)
Specialized Mechanisms of
Intestinal Absorption
Recall: anatomy and physiology of digestive system
* Lipid diffusion of unioinized molecule
* Aqueous diffusion of low molecular weight molecules
* Co-absorption with Lipids: some highly lipid soluble drugs are absorbed from the gut along with long chain fatty acid and their monoglycerides, fat-soluble vitamins and cholesterol e.g. griseofulvin
* Active Transport: some drugs are similar to nutrients that are naturally actively transported e.g. levodopa and methyldopa are taken up by an amino acid transport system, some anticancer drugs compete with pyrimidines for active transport system.
* Pinocytosis: some large M wt drugs (e.g. the complex of intrinsic factor and vitamin B12) are taken up by pinocytosis.
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Factors Affecting Gut Absorption:
pH
pH of gastric contents affects the degree of ionization of a drug and therefore its absorption. Drugs that are more than 0.01% ionized are only slowly and erratically absorbed
* The considerations can be complicated. Example of acidic drug ASA: 1/3 to 2/3 absorbed in the stomach despite low pH because of limitations of solubility. The rest of the dose is absorbed in the intestine.
Factors Affecting Gut Absorption: Area of Absorbing Surface
Most absorption takes place in the small intestine (as opposed to the stomach) because the area of absorbing surface (about 200 m2, including the microvilli).
* Although the pKa of a drug may favor gastric absorption per unit area over intestinal, a good proportion may be absorbed in the intestine because of the surface area size
Factors Affecting Gut Absorption: Dissolved Drug Concentration
Recall, for solid oral dosage forms, disintegration and dissolution must precede absorption
* First order absorption process depends on the concentration of dissolved drug
* Highest concentration is achieved on an empty stomach
* Lower concentrations are achieved with meals
Factors Affecting Gut Absorption: GI Secretions
Gastric Acid: hydrolyzes a number of esters. This results in inactivation for certain drugs or the activation of certain other drugs (e.g. chlorazepate diazepam)
* Enzymes: proteolytic enzymes break up polypeptide drugs e.g. insulin, oxytocin
Factors Affecting Gut Absorption: Bacterial Metabolism of Drugs
Commensal bacteria resident in the gut produce enzymes that could act on drugs or drug metabolites
* For instance, they act on glucuronide conjugates, the liberated drug moiety may then proceed along the enterohepatic shunt
Factors Affecting Gut Absorption:
Metabolism During Absorption
Sulfate conjugating enzymes present in the intestinal mucosa can cause the inactivation of certain drugs (e.g. chlorpromazine) during absorption
* Amino acid decarboxylase and monoamine oxidase in the gut mucosa can inactivate part of an orally administered dose of levodopa (used to treat Parkinsonism). The rest of the dose can be decarboxylated in the periphery with only 1% entering the brain intact to be converted to dopamine. This is prevented by concomitant administration of the dopa decarboxylase inhibitor carbidopa. (Carbidopa does not enter the brain).
* Hydrolytic enzymes in the gut mucosa can inactivate glyceryl trinitrate (so given s/l). Hydrolysis of drugs such as ASA and dexamethsone phosphate does not result in loss of pharmacologic activity
Factors Affecting Gut Absorption: Clearance After Absorption
Blood supply via the sub-mucosal capillaries is the limiting factor for the absorption of lipid-soluble drugs
* The faster the removal of a drug from its site of absorption (blood side), the greater the concentration gradient. This facilitates absorption either by lipid or aqueous diffusion.
Factors Affecting Gut Absorption:
GI Motility
Non-propulsive Movements: contribute to solid dosage form disintegration and dissolution
* Propulsive Movements and Transit Time: determine the contact time between dissolved drug and absorbing surface.
– For drugs that are poorly absorbed from the intestine, drugs that increase contact time (e.g. opiates and anticholinergics) increase absorption.
– For drugs that are not absorbed in the stomach, slowing the rate of gastric emptying (e.g. by a fatty meal) slows the rate of absorption; stimulating gastric emptying (e.g. metoclopramide) increases the rate of absorption.
Factors Affecting Gut Absorption: Disorders
In some patients, Crohn’s disease (inflammation of the distal small intestine and colon) causes a decrease in absorption of certain drugs (e.g. trimetoprim) and an increase in the absorption of others (e.g. clindamycin)
* In some patients, Celiac disease (inflammation mainly of the proximal small intestine) causes a decrease in absorption of certain drugs (e.g. digoxin) and an increase in the absorption of others (e.g. clindamycin)
* In achlorhydria patients (low level of acids in stomach), weakly basic drugs cannot form soluble salts and so precipitate out. HIV-AIDS patients show increased gastric transit time, achlorhydria and diarrhea
* In heart failure patients, reduced blood flow to the gut and reduced intestinal motility result in decreased and/or erratic drug absorption.
Factors Affecting Gut Absorption:
Drug Interactions
Most interactions result in decreased absorption. Insoluble chelates can form if tetracyclines (or ciprofloxacin) are administered along with iron preparations or antacids or foods containing polyvalent cations.
* Anticholinergics (or drugs with anticholinergic effects) slow gastric emptying and so delay absorption
* Proton pump inhibitors may render the stomach achlorhydric.
* Non-absorbable ion-exchange resins such as cholestyramine can adsorb other drugs and so reduce their absorption.
* In some cases absorption is enhanced e.g. allopurinol increases iron absorption (by inhibiting a limiting transport system)
Factors Affecting Gut Absorption: Enteric Shunts
- First Pass Effect
- Enterohepatic Shunts
- Other Enteric Shunts
– Saliva (e.g. clonidine)
– Gastric juice (e.g. quinine)
– Bronchial secretions (e.g. bialamicol)
Factors Affecting Gut Absorption:
Food and Nutrients
Food can interact physically or chemically with a drug (especially if the drug is taken shortly after a meal)
* Fatty food can reduce the absorption of certain drugs (e.g. sildenafil) and increase the absorption of others (e.g. griseofulvin)
* Food can stimulate bile flow (and result in double peaks)
* Food can cause a delay in gastric emptying (and result in double peaks)
* Food can change the gut pH
* Food can change the metabolism of a drug in the lumen
* On the other hand, food can reduce a drug’s irritation to the gut mucosa
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Factors Affecting Gut Absorption: Food and Nutrients II
Vitamin B12-Intrinsic factor complex is carried to the ileum, binds to a receptor. There is a separation and Vitamin B12 gets absorbed.
* Grapefruit juice can increase drug bioavailability:
– inhibits the pre-systemic absorption of certain drugs (inhibits the intestinal efflux transporter P- glycoprotein)
– inhibits certain cytochrome P450 enzymes (gut and/or liver) involved in metabolism
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Sublingual and Buccal Administrations
Absorptionintocirculationisdirect, circumventing the possibility of first pass effects
* Lipid soluble molecules are rapidly absorbed by this route. Useful for “emergency” drugs like glyceryl trinitrate and isoprenaline.
* Absorption of ionizable drugs, generally speaking, can be increased by suppressing their ionization e.g. by using a buffer
Rectal and Vaginal Mucosa
Suppositories are solid but soften and melt at body temperature
* Drugs absorbed through the rectal mucosa get into the vena cava and so avoid first pass effects; enemas get into the colon and may reach the ileum and so may be subject to first pass effects
* Vaginal preparations are generally intended for local effects. However, absorption through the vaginal mucosa occurs
Conjuctival and Nasal Mucosa
Drugs designed for conjuctival instillation generally act locally.
* Absorption occurs to some extent.
* Nasal drug delivery could be used for local or systemic effects.
* Nasal mucosa have a rich supply of blood vessels and can deliver a rapid therapeutic effect.
Absorption after Inhalation
The lung has a large absorption surface.
* The airways filter inhaled matter to remove foreign material.
* Droplet size (aerosolization helps) and velocity of application control the extent to which inhaled material can penetrate the airways. Devices, such as spacers, can improve depth of inhalation.
Absorption Through the Skin
Both local and systemic effects are possible; highly lipid soluble drugs penetrate the dermis; hydrophilic/ionizable drugs are impeded (unless driven through by some means e.g. electrophoresis)
Absorption Following Parenteral Injections
Subcutaneous (hypodermic) and intramuscular:
– Subq injections are more painful because of rich sensory innervation of skin
– Larger volumes may be given i.m.
– Drug is disseminated after passage through capillary (M wt < 3000 or intermediate) or lymphatic (M wt > 20 000 or intermediate) endothelium.
* Intravenous: recall bolus administration and infusions. Drugs that may otherwise be irritating to tissues may be administered by this means.
Absorption Following Parenteral Injections II
Others
- intradermal (used e.g. for test sera),
- intraperitoneal (rarely used in man; large absorption area so diffusion into blood is rapid);
- intrathecal (given into subarachnoid space for local action on meninges or spinal nerve roots);
- Intra-arterial (used e.g. in animal experiments to localize administration to a specific organ);
- intracardiac(e.g.duringcardiacsurgerywhenheart is exposed)
