Drug solubility Flashcards
(251 cards)
1
Q
Poor drug solubility is a common cause of non linear PK
A
True-due to limitations in the absorption process
2
Q
What is pharmacokinetics
A
how the body absorbs, distributes, metabolizes and eliminates drugs
3
Q
Name factors that can contribute to a non linear PK between dose and conc
A
limited absorption
saturation of absorption pathways
dissolution rate limited absorption
precipitation in GI tract
4
Q
What is limited absorption
A
Drugs that exhibit poor solubility may have difficulties dissolving in the GI fluids leading to limited absorption. (tends to worsen at higher doses)
5
Q
Reasons for poor drug solubility-intrinsic
A
Chemical structure
hydrophobicity
particle size
crystal form
Pka
6
Q
What molecular characteristics can lead to poor solubility
A
lipophilic
high degree of crystallinity
7
Q
What is pKa
A
ionization constant-state ofa drug at a particular ph can influence its solubility. weakly acidic or basic drugs can become ionized in the GI tract.
8
Q
True or False: The early part of the decline in concentrations vs time curve is predominantly
due to excretion.
A
False, The early part of the decline in a conc vs time curve (alpha/distribution) primarily associated with drug distribution rather than excretion
9
Q
What is the distribution phase
A
The distribution of the drug into various organs and tissues from bloodstream
10
Q
What is the excretion phase?
A
The later part of the decline in curve (beta) is more associated with excretion. Eliminated from body primarily through renal excretion or hepatic metabolism.
11
Q
What physiochemical properties can have an impact on solubility
A
Amorphous vs crystalline form-amorphous generally has a higher solubility than crystalline but tends to be less stable.
Salt formation can improve solubility
12
Q
What extrinsic factors can impact solubility
A
PH of GI tract
Presence of food
Drug-Drug interactions
Excipients in formulations
13
Q
True or False. Highly polar compounds are rapidly absorbed from the gastrointestinal tract
A
False-more difficult to pass membranes
14
Q
Reasons highly polar compounds have poor absorption from GI tract
A
Poor crossing of biological membranes
high affinity for water (membranes lipid)
Absorption mechanisms-usually needs active transport or specialized carriers (as opposed to passive)
More water soluble
15
Q
How can we increase the bioavailability of a polar drug
A
Prodrugs, alter formulation
16
Q
True or False-If first pass metabolism is saturable, bioavailability will decrease with dose
A
false-first pass metabolism typically occurs in liver. refers to biotransformation of a drug that occurs before it reaches the systemic circulation.
If the enzymes are saturable then there is a limited capacity to metabolize the drug. as dose increases the enzyme systems may become saturated leading to a decrease in the proportion of the drug that undergoes metabolism and increase in the amount that reaches systemic circulation.
resultant non linear PK as metabolism not proportional when enzymes saturated.
17
Q
An active metabolite is likely to cause an anticlockwise (counterclockwise) hysteresis in the concentration vs. effect relationship.
A
True-hysteresis in the concentration-effect refers to a time delay or lag between the drug concentration in the body and its pharmacological effect. When the active metabolite has a longer halflife it continues to act despite parent drug conc decreasing
18
Q
True or false biologics often have a high volume of distribution
A
False-small compared to other molecules
19
Q
What is volume of distribution
A
Reflects the relationship between the amount of drug in the body at steady state and plasma drug concentration.
20
Q
Outline the two compartment model of the PK of biologics
A
3 key parameters:
half life
volume of distribution
clearance
21
Q
True or false the lower the pKa value, the stronger the acid
A
True-the definition of Pka is a measure of acidity of a substance. A lower pKa indicates a stronger acid. The pka value is inversely proportional to the strength of an acid (tendency of a substance to donate a proton).
22
Q
What is the disease impact on PK in relation to monoclonal antibodies?
A
Disease-related changes in the body such as inflammation, altered blood flow and change in distribution of proteins can impact.
23
Q
What is the disease impact on clearance of mABs
A
increased inflammation may lead to slower elimination. Tend to have longer half lives.
24
Q
What PK characteristics to mABs typically exert?
A
Biphasic PK profiles-fast distribution and slower elimination. Confined distribution in vasculature due to size and polarity.
25
What is the volume of distribution of mAbs (generally)
mAbs generally exhibit a low volume of distribution of 3–8 L at steady state reflecting the volume of vascular and interstitial spaces
26
True or false? A weak acid will be best absorbed in the proximal duodenum
False (stomach)-proton sharing
27
Give two reasons why weak acids absorb better in the stomach
Tend to be non-ionized in the stomach which is more lipophilic and can pass through lipid rich cell membranes. (passive diffusion)
More alkaline Ph of duodenum will cause them to become ionized
28
True or False-A higher log P value indicates greater lipophilicity
True
29
What is the definition of Log P?
Measure of lipophilicity or hydrophobicity of a compound. It quantifies how well a compound partitions between a hydrophobix and hydrophillic phase.
30
How do we interpret the log-p values
A positive LogP value indicates a compound is more lipophilic (greater affinity for lipid phases)
Negative indicates it is more hydrophillic (greater affinity for aqueous phases)
31
What is the importance of lipophilicity?
Crucial factor as higher lipophilicity more able to permeate lipid rich biological membranes
Drugs with higher lipophilicity tend to have a larger volume of distribution and may accumulate in lipid rich tissues.
32
How many half-lives for steady states (general rule)
5
33
What is steady state
administration and elimination in balance-drug concentration relatively constant (97% of steady state)
34
What percentage should be reached for a metabolite to be considered significant
10%
If a metabolite contributes to more than 10% of the overall pharmacological effect it suggests it plays a substantial role
35
What is the 80-120 rule
Bioequivalence testing. Part of the acceptance criteria used to determine whether the pharacokinetic parameters of a generic drug are equivalent to those of the reference
36
How does the 80-120 rule apply to Cmax
For bioequivalence testing, the generic drugs Cmax and AUC should fall within 80-125% of the reference drug
37
True or False-Acidic drugs are usually bound to plasma albumin
True
Basic usually bind to alpha-1-acid glycoprotein
38
What factors can alter albumin binding
Drug concentration (saturation), Ph changes, Kidney disease (leaks to urine), liver disease (less production), Competing drugs, malnutrition, chronic disease, genetic variability, Age,
39
In the Biopharmaceutical Classification System, a Class III drug has poor
solubility and high permeability-True or False
False
High solubility poor permeability.
Good dissolution properties
bad at crossing membranes
40
What is class one in the BCS
High solubility high permeability
41
What is class 2 in the BCS
low solubility high permeability
42
what is class 3 in the BCS?
High solubility low permeability
43
What is class 4
Low and low
44
45
Is the following statement true or false? Lipophilic drugs are often extensively metabolised before excretion
True-Need to be made more water soluble to be excreted. (and more polar)
46
Lipophilic drugs generally have a large apparent volume of distribution-true or false
True-distribute extensively into lipid rich tissues. (anaesthetics, some antibiotics, sedatives)
47
True or False? The maximum possible volume of distribution of a drug is the total volume of
the body
False
48
True or False-A drug that is highly bound to plasma albumin will generally have a small
volume of distribution
True
49
The concentration of Drug X administered i.v. in a dose of 10 mg at time 0 is
50 ng/mL The Vd = 200L (True or False)
vd=amount of drug/concentration of drug
50
True or False-P-glycoprotein promotes absorption into the portal vein
False-transporter protein, usually does the opposite. An efflux transported located in epithelial cells. Pumps substances out of cells.
51
Half life is the time taken for the plasma concentration to fall by 50% (true or false)
True
52
Half-life is the time taken for the amount of drug in the body to fall by 50%-True or false
false
53
Half-life is a primary PK parameter-True or false
False, Vd and clearance
54
On repeat dosing a drug with t1/2 of 12 hours, no further accumulation will
occur after about 36 hours.-true or false
False (steady state after 5 half lives)
55
Drug Y has a half-life of 12 h. After stopping drug administration, the
proportion of drug remaining in the body after 36 h is 12.5%
True
56
Acidification of urine will promote excretion of a weak acid-true or false
false
57
50% of drugs are metabolised by CYP2C19-True or false
False-3A4
58
Which drugs does CYP2C19 most commonly metabolise
PPI, some antidepressants and clopidogrel
59
Lipophilic drugs tend to be cleared by the kidney-true or false
False need to be water soluble to be excreted by kidneys
60
How are lipophilic drugs excreted?
-most undergo hepatic metabolism
-can be excreted in bile
-some metabolites water soluble and can be excreted in urine (particularly if phase 2 reactions)
61
True or false-Acetylation is an example of Phase II metabolism
True
62
Examples of phase 2 metabolism processes
Acetylation, glucuronidation, sulfation, methylation, amino acid conjugation, glutathione conjugation
63
What is Glucuronidation?
phase 2 metabolism process
uses UGTs
glucoronic acid added to a drug
example would be morphine (makes it more water soluble)
64
What is Sulphation
Phase 2
SULTs
conjugated with a sulfate group
Acetaminophen is an example
65
What is methylation
Phase 2
Methyltransferases
methyl group
Adrenaline (metadrenaline)
66
What is amino acid conjugation
Phase 2
conjugated with an amino acid
example benzoic acid with glycine (more water soluble)
67
What is Acetylation
NATs
Conjugated with an acetyl groqup
Isoniazid
68
What is Glutathione conjugation
GSTs
conjugation with glutathione
electrophiles (detoxified)
69
Stereoisomers of a molecule are generally metabolised by the same
cytochrome enzymes-True or False
False-undergo different metabolic pathways or rates. (racemic mixtures pose an issue)
70
What are Stereoisomers?
molecules that have the same molecular formula and connectivity of attoms but differ in the spatial arrangement
71
What is a Racemic mixture?
Contain equal amounts of two enantiomers (mirror image stereoisomers of each other)
One is often the target drug whilst the other may contribute to side effects
72
What are the types of phase 1 metabolism?
Oxidation, Reduction, hydrolysis, dealkylation, deamination, desulfration, epoxidation
73
True or False-Clearance is measured in units of amount of drug removed per unit of time
e.g. mg/min
False-should be volume measurement
74
Bioavailability is the proportion of administered dose of drug entering the
systemic circulation-True or false
True
75
Clearance of a drug refers to removal of drug-related material from the body-True or False
False (doesn't include metabolites)
76
The accuracy of an assay refers to the variability of concentrations-True or False
True
77
Selectivity of an assay is its ability to produce a response for the target
analyte which is distinguishable from all other responses.-True or false
True
78
Saturation of metabolism may result in non-linear PK
True
79
Michaelis-Menten kinetics refers to non-linear kinetics across the whole of the dose range-T/F
False-Used to describe the initial saturable phase of drug metabolism when enzymes become saturated with substrate
80
After subcutaneous administration of a mAb, the tmax is usually about 5 days.-T/F
True-usually 3-5 days, goes through lymphatic system
81
An increase in dose of a mAb sufficient to saturate the target is likely to increase the duration of effect.-T/F
True-Initially brief effect of drug
As you increase go beyond tmpd
Really only relevant in lower doses, half life can increase to weeks not days
82
Therapeutic proteins are generally metabolised by cytochrome P450 oxidases T/F
False-Cytosis, proteolysis, some recycled (catabolic process)
Delayed by fcrn binding
83
What is Fcrn binding?
Receptor that binds to the Fc portion of IgG antibodies.
Primary function is to protect IgG antibodies from degradation and extend their half life in the bloodstream
OCcurs in acidic environments
OFten used to extend duration of antibody based drugs
84
Drug-Drug interactions are very common with biologicals-T/F
False-very specific drugs
85
Target mediated disposition is a feature of high doses of mAbs.-T/F
False-low doses only
86
To examine the propensity for a drug to inhibit metabolism by CYP2D6, a suitable probe drug is metoprolol. T/F
True
87
What are the four categories of metabolisers?
Poor, intermediate, extensive, ultrarapid
88
What are the 5 key drugs used in drug interaction studies?
Warfarin-P450 (and vitamin K)
Midazolam-3A4
Omeprazole-2C19
Caffeine
Dextromethorphan
89
To establish whether Drug A induces metabolism of Drug B, Drug A should be dosed for about 24 hours before administration of Drug B. T/F
False (as long as it takes for induction
90
In a population PK study sparse blood sampling should generally be performed at steady state. (T/F)
True-estimation of key pharmacokinetic parameters, such as clearance (CL), volume of distribution (Vd), and half-life (t½), with more precision.
Reduces variability intraperson
91
Allometry can often be used to predict clearance in humans. (T/F)
True-Scale even between animals, allows for prediction though not always accurate
92
What is the equation often used in clearance allometry
CLhuman=CLanimal X (body weight human/body weight animal) X 0.75
93
The safety of a metabolite need not be tested if it is present at a concentration less than 20% of total drug related material. (T/F)
False-anything over 10% (usually worked out by mass weight) All over that need testing
94
A person aged 80 should receive the standard daily dose of digoxin (0.25 mg) if their serum creatinine is within the normal range. (t/f)
False-With regard to CR CLEARANCE not just result
95
A creatinine clearance of less than 50mL/min is generally considered severe renal impairment. (t/f)
False
96
Drug A has a half-life of 6 h. Drug B has a half-life of 24 h. A single dose study will be appropriate to investigate whether A inhibits clearance of B. (t/f)
False-Mismatch half lives. A would need to be steady state then introduce B.
97
A drug is administered in a dose of 3 mg every 24 hours The AUCtau, (where tau is the dosing interval) is 1500microgram.h/L. The Clearance is 2 L/h (t/f)
True:
AUCt = Dose/Clearance
98
Therapeutic drug monitoring of gentamycin is best performed immediately before and after dosing-T/f
True
99
Name two disadvantages of using the assumption 'once steady state has been achieved no further accumulation will occur'
1-risk of generating multiple values for accumulation ratio if PK parameters vary widely
2-The achievement of the steady state is assumed without independent confirmation from multiple measures at steady state
(advantage is quick calculation from observed data)
100
What are the three equations that can be used to work out the accumulation ratio from observed data?
AR=AUC multiple dose/AUC single dose
AR= Cmax-multiple dose/Cmax-single dose
AR= Ctrough-multiple dose/Ctrough single dose
101
What is the peak to trough ratio equation
(Css(max)-Css(min) X100/CSS (av)
102
Give a reason why the predicted and measured steady state profile may not work
-May induce its own metabolism (eg carbamezepine)
enzyme saturation
very active metabolite
103
What is non compartmental PK analysis
not reliant on models
depend on accurate drug concs
PK parameters calculated from conc vs time data using combination of descriptive, interpolative and extrapolative techniquws
104
What are the 5 points to PK parameters in NC analysis
Cmax and Tmax directly from data
AUC by trapezoidal rule
KEl is estimated by least squares regression analysis
t 1/2 from kel
Vd, CL and bioavailability require iv data
105
What comprises the central compartment?
Highly perfused tissues/organs such as heart, lungs, kidneys, liver, brain
106
What comprises peripheral compartments
muscle and fat
107
When can NCA not be used?
Sparse sampling (because not enough data)
108
The area of what shape is used for NCA?
Trapezoid
109
By how much must the AUC of index substrate be increased to be considered as strong inhibitor?
>/ 5 fold
110
By how much must the AUC of index substrate be increased to be considered as moderate inhibitor
>/2-<5
111
By how much must the AUC of index substrate be increased to be considered as weak inhibitor
1.25-2
112
By how much must the AUC of index substrate be decreased to be considered as a strong inducer
>/80%
113
By how much must the AUC of index substrate be decreased to be considered as a moderate inducer
50-80%
114
By how much must the AUC of index substrate be decreased to be considered as a weak inducer
20-50%
115
What is bioanalysis?
quantitative measurement of drugs, their metabolites, and other biological molecules in biological samples. The primary aim of bioanalysis is to determine the concentration of specific substances, often drugs or their metabolites, within biological matrices such as blood, plasma, serum, urine, or tissues.
116
What are the common analytical methods used in bioanalysis?
Chromatography, immunoassays, spectroscopy
117
How are calibration standards used?
To quantify the conc of a substance in a sample, a set of callibration standards are used with known concentrations.
118
What are the two main components of a bioanalytical method?
preparation of solution, detection of compound
119
What is the most common method of drug movement across cellular barriers
Passive diffusion
120
When is IM/SC useful as a method of administration?
Sc generally convenient for patients (insulin etc)
Useful for large molecules (such as monoclonal antibodies)
note usually venous
121
What is different about inhaled therapies?
Into capillaries so arterial
122
Why are inhaled therapies quicker to act?
Fewer cell layers to pass through so faster absorption
123
What do drugs taken orally undergo before entering systemic circulation
First pass in liver
124
What factors impact oral absorption?
Physiochemical properties of drug
physiological factors
formulation factors
125
Are Ionized drugs efficiently absorbed?
NO
126
Why do weak acids need an acidic environment?
They will pick up a proton and become un-ionized
127
What is the relationship between PKa and acid strength
Lower the PKa stronger the acid
128
What happens to weak bases in an acidic environment?
They gain a proton and become ionised (NH4+)
129
Why do drugs not absorb well in the stomach?
Thick mucus layer
Relatively small surface area
130
Where do acidic drugs best absorb?
Acidic areas of proximal duodenum
131
Where do alkaline drugs best absorb?
Distal ileum
132
What are the two most common ways of passive diffusion
Transcellular absorption (across lipid membranes)-lipophillic drugs
Paracellular absorption (through aqueous pores at tight junctions)-hydrophillic drugs
133
What are the actions of bile salts on drugs
Improve bioavailability of poorly water soluble drugs (class 2) by increasing rate of dissolution and/or solubility (fed state)
134
What impacts do gastric emptying and intestinal transit time have on drug absorption?
Determine time drug spends in site
135
What is intestinal efflux?
P-glycoprotein efflux pump present in high levels in the small intestine
pumps drugs back into the lumen decreasing their absorption
drugs
Drugs that induce can affect absorption
many drugs that are transported by pgp are also metabolised by 3a4
136
Can drugs be metabolised in the gut?
Yes, CYPs present in the liver are also expressed in the gut wall epithelium especially 3a4
137
What is absolute bioavailability vs relative?
absolute is in comparison to the IV (which is 1)
relative is the comparison between two extravascular routes
138
What effect does food intake have on absorption?
-physiological changes
-slowing of gastric emptying which results in retention of dosage form in stomach
-increase in gastric ph
-increase in bilesalts
-elevated gastric Ph may enhance the dissolution of a weak acid in the stomach but inhibit that of a weak base
139
How can we increase absorption?
Increase surface area of a drug particle
reduce particle size
solubulity of weakly acid and basic drugs can be modified by adding buffer agents
enteric coated formulations
140
How can we assess food effect?
two way crossover study comparing fasted vs fed
(controlled release formulations important)
141
How do we assess effect of elevated gastric PH
Concomitant administration of drug that increase ph of stomach
h2 receptor antagonists reduce gastric acid secretion
PPIs
142
What is first order kinetics?
First-order kinetics – concentration-dependent process; the higher the concentration, the faster the process
143
What is first order absorption?
a constant proportion (%) of drug is eliminated per unit time
144
What is zero order kinetics?
independent of concentration
145
zero order absorption?
constant amount is absorbed per unit time
146
What factors influence distribution?
Blood perfusion
lipophilicity
regional ph
permeability of cell membranes
molecular size
plasma protein binding
147
What do acidic drugs tend to bind to?
Albumin
148
What do basic drugs tend to bind to?
alpha-1-acid glycoprotein or lipoproteins
149
How are the actions of drugs prolonged through accumulation
Accumulate in tissues or body compartments which then release the accumulated drug as plasma drug concentration decreases
150
What drugs do not penetrate well into the brain?
highly protein bound drugs and ionized
151
What is the apparent volume of distribution?
theoretical volume of fluid into which the dose of drug given would have to be diluted to produce the concentration in plasma
152
What vd does highly tissue bound drug have?
very little drug in systemic circulation.
plasma concentration is low and vd is high
153
What vd do acidic drugs have?
highly protein bound and have small apparent volume of distribution
154
what vd do basic drugs have
extensively taken up by tissues and so have an apparent volume of distribution larger than the volume of the entire body
155
What happens in competitive protein drug drug interactions?
these interactions can increase the free plasma concentrations of the displaced drugs. This can be problematic, particularly if there is a narrow therapeutic index.
156
What can affect renal clearance
variation of renal blood flow, variation in unbound plasma drug concentration
157
What is the FDA cut off fraction of dose excreted unchanged in the urine?
>/0.3
158
What are the two processes leading to excretion
phase 1-metabolism
conjugation-phase 2
159
What are examples of large drug molecules
antibodies
antibody drug complexes
proteins and peptides
DNA and RNA fragments
160
What are the main 6 CYP450
1A2, 2C9, C19, 2C6, 3A4, 3A5
161
What are the main 3 things that will impact CYP450 enzymes?
Drug interactions
ageing (liver capacity decreases by 30%)
neonates immature enzyme systems
162
How do we establish accuracy of an assay
replicate analysis of samples containing known amounts of analyte
163
164
What standard does an assay need to meet to be considered accurate?
minimum 3 concentrations in the range of expected
minimum of six determinations per concentration
mean value should be within 15% of actual value
165
What is the LLOQ
Lower limit of quantitation
lowest amount of analyte in a sample that can be quantitively determined with accuracy and precision
(assay allowance is 20%)
166
What is the difference between intra and interday precision
Within/intraday, -assay, -run and –batch commonly used to express repeatability
Interday, -assay, -run and –batch commonly used to express reproducibility
167
What is linearity in analysis?
ICH definition: the linearity of an analytical procedure is its ability (within a given range) to obtain test results which are directly proportional to the concentration (amount) of analyte in the sample
168
What kind of clinical conduct issues can bioanalysis raise?
quantifiable concs pre first dose
BLQ samples post dose
sample swaps
169
What is absorption?
Transfer of the unchanged drug from its site of administration into the systemic circulation
170
What is absolute bioavailability?
Refers to the extent and rate at which the active principle (drug or metabolite) enters the systemic circulation
(fraction of unchanged drug systemically absorbed following oral administration when compared to IV)
171
What reasons are there for losing drugs taken orally
Incomplete dissolution
problems in crossing gut wall membrane
Pre-systemic metabolism by the gut wall and liver
172
What does a high first pass effect lead to in terms of bioavailability
Will lead to a low absolute bioavailability
173
What are the two blood supplies that transport drugs to the liver
common hepatic artery
portal circulation
174
What is relative bioavailability
Compares the absorption from different formulations, different routes of administration and different dosing conditions of the same drug
175
What is bioequivalence
Two medicinal products can be classed as bioequivalent if they are pharmaceutical equivalents and there is no significant difference in the rate and extent of absorption of the active ingredient
176
What are the acceptable limits of bioequivalence
80-125%
177
What is the objective of in vitro dissolution testing?
to evaluate the variables that affect the rate and extent of release of a drug substance from the finished dosage form and in turn the in vivo performance of the drug product
178
What can impact dissolution?
Particle size,
solubility
excipients
binding agents
change in manufacturing process
179
Give an example of a BE study design
Single-dose crossover under fasting conditions
washout interval (7 half lives) to ensure that all the active ingredient from the first treatment has been cleared from the body before administration of the second treatment
180
How to pick number of subjects for BE studies?
Statistical tests must show a power of 80%
A higher power protects against claiming bioequivalence when the formulations are actually different
increasing the number of subjects decreases the standard error
minimum subjects 12
181
When would you have to measure individual enantiomers?
If they have different PK/PD characteristics-including differences in rate of absorption
182
What do we usually measure in BE studies
Plasma conc of unchanged drug
183
What PK parameters are analysed in BE studies
Cmax, Tmax
(nb if cmax particularly important for safety acceptance tightened to 90-111)
184
What are biosimiliars?
Officially approved versions of innovator biological products made by a different company after patent expiry
185
What two food studies must be completed for regulatory requirements?
food effect bioavailability-fed vs fasting
fed BE (fed-fed)
highest dose should be used
186
What study design should be used for food studies
Randomised, balanced, single dose, crossover with washout
187
Why do we repeated dosing?
Ensure a drug is safe and well tolerated
dosing regime with optimal therapeutic window
clinical relevance of fluctuations in plasma levels at steady state
establish if steady state drug concentrations reamin constant over an extended period with same dosing regime
188
What are the two dose phase one study designs
a) single dose-washout-multiple dose-steady state
b) multiple doses-steady state
(10-28 days)
189
What are two examples of phase 1 oncology dose escalaiton trial designs?
a) 3+3
b) continual reassessment
190
Why is it important to wait for full washout between dosing?
Prevent accumulation
191
How many half lives until steady state?
5
192
How do we achieve a steady state more quickly in those drugs with a long half life
loading dose
193
What is non compartmental analysis?
Doesn't rely on modelling, used for calculation of all PK parameters submitted to reg bodies to ensure consistency
194
What is compartmental analysis
fitting conc vs time data onto a pre selected model from which PK parameters are obtained. Uses models and assumptions
195
How are PK parameters calculated in NCA
Conc vs time data
Cmax/Tmax from data
AUC through trapezoidal rule
Kel by least squares regression analysis
t1/2 from kel
Vd, CL, F all require IV data
196
Why study drug interactions?
To minimise the chances of harming patients
Ensure the drugs benefit is not negated
minimise contraindications in the label
make recommendations on dose adjustment
assess the possibility of benefit from a DDI
197
What are the four primary pharmacodynamic DDIs
Additive/synergistic
Physiological antagonism
effect of one drug predisposes toxicity of other
Interactions at receptors
198
What effect do juices such as grapefruit have?
Inhibition of intestinal uptake transporter OATP2B1
199
What drugs delay gastric emptying?
Alcohol
Anticholinergics
Opiates
Tricyclic antidepressants
L-DOPA
Exenatide
200
What effect does delay of gastric emptying have?
Reduce rate of absorption-Tmax longer, Cmax lower
201
What drug promotes gastric emptying?
Metoclopramide
202
What effect does inhibition of P-GP have?
Reduce efflux therefore increasing drug concentrations in plasma and possibly brain
203
Examples of drugs that inhibit Pgp
Clarithromycin
Quinidine
Ketoconazole
Verapamil
204
What effects do DDI's that impact plasma protein binding have?
PPB displacement alone will only usually lead to a temporary and modest increase in free drug conc and effect
only applies to highly protein bound drugs (<99%)
Will only cause clinical effect with drugs having a low therapeutic index
205
Name three nuclear receptors which can be involved in enzyme induction through DDI
Pregnane X receptor
CARb
A-h receptor
206
What impact can potent CYP inhibitors have on prodrugs?
Can prevent conversion of prodrugs to their active metabolite
Mainly 2D6, 2C19, 2C9
207
How can renal excretion be impacted by DDIs?
Tubular secretion provides separate active transport systems for cations and anions
Inhibition of OATS reduces secretion of Anions
Inhibition of OCTs reduces secretion of cations
208
What factors will make us more likely to study interactions in man?
low therapeutic index
high likelihood of being coadministered
belongs to class known to interact
animal data suggests interaction likely at therapeutic concs
pharmacodynamic interaction likely
high plasma protein binding and small vd
209
How long must we allow for enzyme induction in DDI studies?
10-14 days after attaining steady state concs
210
What problems can you have with drugs with short half lives in DDI studies
Can miss an interaction due to inadequate coverage of AUC (may need to repeat dose)
211
Why is multiple dosing sometimes needed in DDI?
May be needed to cover duration of excretion of victim
may be better than single doses to estimate extent of interaction in the clinical situation
required to test effect of inducer (at least 10 days)
Need to achieve steady state concs of victim and possible interactor
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When do we need to test alcohol interactions
CNS activity
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What are the challenges with alcohol DDI studies
Difficult to blind
absorbed and distributed rapidly
metabolic clearance is mainly zero order
rapid tolerance
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What makes the ideal probe?
Safe drug with short half life
total clearance by almost exclusively one metabolic pathway
small within subject variability (reduces sample size)
small between subject variability (minimal sampling)
100% bioavailable
cheap assay
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What are the pros of population PK for DDIs
Cost-effective examination for DDIs under real life conditions if patient group is representative
Can correlate DDIs with altered efficacy or safety
Favoured by FDA especially for elderly
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What are the Cons of population PK for DDIs
Not a safe or practical substitute for early examination of predictable, clinically significant interactions
results often available late phase 3 (lots of money spent by now)
correlation does not mean causation
often poor statistical power
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What are the different PD outcomes?
Continuous
Categorical
Binary
Ordinal
Count data (eg lesions on mri)
time to event (eg disease progression)
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What is an empirical PK/PD model
Models that describe the data well but without biological meaning
Interpretation of parameters can be challenging
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What is a mechanistic PK/PD model
Reflecting underlying physiological process
preferred due to predictive power
Reversible (direct link/response model)
Irreversible (chemo/enzyme inactivation)
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What are examples of biologics?
mAbs
Proteins
peptides
blood products
viruses
therapeutic serum
toxin
anti toxin
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When is the maximum plasma concentrations of mAbs
3-7 days
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What is a usual bioavailability variation for mAbs
50-90%
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What is the typical distribution of mAbs?
3-8L
Central volume usually 2-4L
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How are mAbs broken down through non-specific endocytosis?
FcRn binds to Fc region of IgG and protects the internalized antibody from rapid intracellular catabolism
antibody is released back into the circulation
contributes to relatively long t1/2 of mAbs of 11-30 days
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What is target mediated drug disposition?
PK phenomenon in which the interaction between a drug and its target significantly influences the drug's distribution and elimination from the body.
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How do we use NOAEL to guide FIH dose of mABs
Convert NOAEL to human equivalent dose
mg/kg normalization for proteins >150kDa
Apply a safety factor >/10 fold to give MRSD
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Is MABEL or NOAEL more conservative in dose level?
Usually MABEL, tends to be an order of magnitude lower
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What are Michaelis-menten kinetics
-maximum rate of enzymatic reaction is reached when drug concs achieve 100% enzyme saturation
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What effect does Michaelis mentin elimination kinetics have on clearance
Drug at low concentrations cleared by first order process and by zero order process at higher concentrations (enzyme capacity saturated)
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What is dose proportionality?
Increases in exposure (AUC, cmax) proportional to administered dose (usually include >/3 doses)
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Causes of non linearity in absorption
Solubility/dissolution rate limiting
saturation of carrier medicated transport
saturation of gut wall/hepatic metabolism
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Causes of non linearity in distribution
Saturated plasma protein binding
saturated tissue binding sites
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Causes of non linearity in metabolism
Saturated
enzyme induction
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Causes of non linearity in excretion
Saturable active processes
active tubular secretion
active tubular reabsorption
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What can impact bioavailability?
PKA
Lipophilicity
formulation
concomitant ingestion of food
efflux and influx transporters
liver blood flow and function
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What factors impact Vd?
Plasma protein binding
permeability
active transport into red cells
body composition (can alter with age)
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What factors impact elimination?
Intrinsic clearance
time dependency
disease (renal, hepatic, cardiac)
Demographics
genetics
concomitant medications
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Give three factors that age has on drug ADME
Renal function-decline in GFR can prolong t1/2
Volume-decline in muscle mass. Lipophilic drugs higher vd and t1/2. Polar drugs reduced vd
MEtabolism-enzyme activity decreased, small liver
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What impact can a mutation in Pseudocholinesterase (BuChE) have?
abnormal types (autosomal recessive) can cause suxamethonium sensitivety
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What issues can Hepatic N-acetyltransferase (NAT-2) mutations have?
Rapid acetylators (rapid clearance)
slow acetylators (tendency to toxicity)
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What issues can mutations to Thiopurine methylxtransferase (TPMT) cause
catalyzes metabolism of cytotoxic-6-mercapotopurine and thioguanine
(greater incidence of AEs)
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What issues can a mutation in CYP450 oxidases cause?
Poor, intermediate, extensive, ultrarapid
clear quickly or higher toxicity
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What is a mass balance study?
An in vivo PK study with radiolabelled material to measure the rates and routes of clearance and elimination of drug related material
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What do we normally use as a radiolabel?
Carbon 14
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Why do we do mass balance studies?
To establish fate of drug related material in terms of rates and routes of clearance and excretion of the parent molecule and its metabolites
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Give examples of non clinical studies prior to human mass balance studies
In silico modelling of metabolism
in vitro studies in animal and human cell systems
in vivo pk studies in animals including whole body autoradiography
in vivo pk studies in humans with cold material
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What is the general number for mass balance studies?
6 healthy male volunteers (families must agree to contraception)
248
What percentage must a metabolite hit of the total radioactivity to be investigated
10%
249
Why can metabolites with a long half life be a problem?
likely to accumulate over time
250
How can a mass balance and abs bio study be combined?
full dose c14 drug orally and as microdose iv in combination with cold oral drug
microdose is 1/100th of therapeutic with mx of 1000ug
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