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Solubility > Drug solubility > Flashcards

Drug solubility Flashcards

1
Q

Poor drug solubility is a common cause of non linear PK

A

True-due to limitations in the absorption process

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2
Q

What is pharmacokinetics

A

how the body absorbs, distributes, metabolizes and eliminates drugs

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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

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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)

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5
Q

Reasons for poor drug solubility-intrinsic

A

Chemical structure
hydrophobicity
particle size
crystal form
Pka

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6
Q

What molecular characteristics can lead to poor solubility

A

lipophilic
high degree of crystallinity

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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.

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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

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9
Q

What is the distribution phase

A

The distribution of the drug into various organs and tissues from bloodstream

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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.

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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

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12
Q

What extrinsic factors can impact solubility

A

PH of GI tract
Presence of food
Drug-Drug interactions
Excipients in formulations

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13
Q

True or False. Highly polar compounds are rapidly absorbed from the gastrointestinal tract

A

False-more difficult to pass membranes

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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

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15
Q

How can we increase the bioavailability of a polar drug

A

Prodrugs, alter formulation

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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.

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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

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18
Q

True or false biologics often have a high volume of distribution

A

False-small compared to other molecules

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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.

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20
Q

Outline the two compartment model of the PK of biologics

A

3 key parameters:
half life
volume of distribution
clearance

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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).

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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.

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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.

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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.

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25
Q

What is the volume of distribution of mAbs (generally)

A

mAbs generally exhibit a low volume of distribution of 3–8 L at steady state reflecting the volume of vascular and interstitial spaces

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26
Q

True or false? A weak acid will be best absorbed in the proximal duodenum

A

False (stomach)-proton sharing

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27
Q

Give two reasons why weak acids absorb better in the stomach

A

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

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28
Q

True or False-A higher log P value indicates greater lipophilicity

A

True

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29
Q

What is the definition of Log P?

A

Measure of lipophilicity or hydrophobicity of a compound. It quantifies how well a compound partitions between a hydrophobix and hydrophillic phase.

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30
Q

How do we interpret the log-p values

A

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)

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31
Q

What is the importance of lipophilicity?

A

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.

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32
Q

How many half-lives for steady states (general rule)

A

5

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33
Q

What is steady state

A

administration and elimination in balance-drug concentration relatively constant (97% of steady state)

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34
Q

What percentage should be reached for a metabolite to be considered significant

A

10%
If a metabolite contributes to more than 10% of the overall pharmacological effect it suggests it plays a substantial role

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35
Q

What is the 80-120 rule

A

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

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36
Q

How does the 80-120 rule apply to Cmax

A

For bioequivalence testing, the generic drugs Cmax and AUC should fall within 80-125% of the reference drug

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37
Q

True or False-Acidic drugs are usually bound to plasma albumin

A

True
Basic usually bind to alpha-1-acid glycoprotein

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38
Q

What factors can alter albumin binding

A

Drug concentration (saturation), Ph changes, Kidney disease (leaks to urine), liver disease (less production), Competing drugs, malnutrition, chronic disease, genetic variability, Age,

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39
Q

In the Biopharmaceutical Classification System, a Class III drug has poor
solubility and high permeability-True or False

A

False
High solubility poor permeability.
Good dissolution properties
bad at crossing membranes

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40
Q

What is class one in the BCS

A

High solubility high permeability

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41
Q

What is class 2 in the BCS

A

low solubility high permeability

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42
Q

what is class 3 in the BCS?

A

High solubility low permeability

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43
Q

What is class 4

A

Low and low

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44
Q
A
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45
Q

Is the following statement true or false? Lipophilic drugs are often extensively metabolised before excretion

A

True-Need to be made more water soluble to be excreted. (and more polar)

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46
Q

Lipophilic drugs generally have a large apparent volume of distribution-true or false

A

True-distribute extensively into lipid rich tissues. (anaesthetics, some antibiotics, sedatives)

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47
Q

True or False? The maximum possible volume of distribution of a drug is the total volume of
the body

A

False

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48
Q

True or False-A drug that is highly bound to plasma albumin will generally have a small
volume of distribution

A

True

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49
Q

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)

A

vd=amount of drug/concentration of drug

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50
Q

True or False-P-glycoprotein promotes absorption into the portal vein

A

False-transporter protein, usually does the opposite. An efflux transported located in epithelial cells. Pumps substances out of cells.

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51
Q

Half life is the time taken for the plasma concentration to fall by 50% (true or false)

A

True

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52
Q

Half-life is the time taken for the amount of drug in the body to fall by 50%-True or false

A

false

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53
Q

Half-life is a primary PK parameter-True or false

A

False, Vd and clearance

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54
Q

On repeat dosing a drug with t1/2 of 12 hours, no further accumulation will
occur after about 36 hours.-true or false

A

False (steady state after 5 half lives)

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55
Q

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%

A

True

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56
Q

Acidification of urine will promote excretion of a weak acid-true or false

A

false

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57
Q

50% of drugs are metabolised by CYP2C19-True or false

A

False-3A4

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58
Q

Which drugs does CYP2C19 most commonly metabolise

A

PPI, some antidepressants and clopidogrel

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59
Q

Lipophilic drugs tend to be cleared by the kidney-true or false

A

False need to be water soluble to be excreted by kidneys

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60
Q

How are lipophilic drugs excreted?

A

-most undergo hepatic metabolism
-can be excreted in bile
-some metabolites water soluble and can be excreted in urine (particularly if phase 2 reactions)

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61
Q

True or false-Acetylation is an example of Phase II metabolism

A

True

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62
Q

Examples of phase 2 metabolism processes

A

Acetylation, glucuronidation, sulfation, methylation, amino acid conjugation, glutathione conjugation

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63
Q

What is Glucuronidation?

A

phase 2 metabolism process
uses UGTs
glucoronic acid added to a drug
example would be morphine (makes it more water soluble)

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64
Q

What is Sulphation

A

Phase 2
SULTs
conjugated with a sulfate group
Acetaminophen is an example

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65
Q

What is methylation

A

Phase 2
Methyltransferases
methyl group
Adrenaline (metadrenaline)

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66
Q

What is amino acid conjugation

A

Phase 2
conjugated with an amino acid
example benzoic acid with glycine (more water soluble)

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67
Q

What is Acetylation

A

NATs
Conjugated with an acetyl groqup
Isoniazid

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68
Q

What is Glutathione conjugation

A

GSTs
conjugation with glutathione
electrophiles (detoxified)

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69
Q

Stereoisomers of a molecule are generally metabolised by the same
cytochrome enzymes-True or False

A

False-undergo different metabolic pathways or rates. (racemic mixtures pose an issue)

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70
Q

What are Stereoisomers?

A

molecules that have the same molecular formula and connectivity of attoms but differ in the spatial arrangement

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71
Q

What is a Racemic mixture?

A

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

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72
Q

What are the types of phase 1 metabolism?

A

Oxidation, Reduction, hydrolysis, dealkylation, deamination, desulfration, epoxidation

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73
Q

True or False-Clearance is measured in units of amount of drug removed per unit of time
e.g. mg/min

A

False-should be volume measurement

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74
Q

Bioavailability is the proportion of administered dose of drug entering the
systemic circulation-True or false

A

True

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75
Q

Clearance of a drug refers to removal of drug-related material from the body-True or False

A

False (doesn’t include metabolites)

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76
Q

The accuracy of an assay refers to the variability of concentrations-True or False

A

True

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77
Q

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

A

True

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78
Q

Saturation of metabolism may result in non-linear PK

A

True

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79
Q

Michaelis-Menten kinetics refers to non-linear kinetics across the whole of the dose range-T/F

A

False-Used to describe the initial saturable phase of drug metabolism when enzymes become saturated with substrate

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80
Q

After subcutaneous administration of a mAb, the tmax is usually about 5 days.-T/F

A

True-usually 3-5 days, goes through lymphatic system

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81
Q

An increase in dose of a mAb sufficient to saturate the target is likely to increase the duration of effect.-T/F

A

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

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82
Q

Therapeutic proteins are generally metabolised by cytochrome P450 oxidases T/F

A

False-Cytosis, proteolysis, some recycled (catabolic process)
Delayed by fcrn binding

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83
Q

What is Fcrn binding?

A

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

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84
Q

Drug-Drug interactions are very common with biologicals-T/F

A

False-very specific drugs

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85
Q

Target mediated disposition is a feature of high doses of mAbs.-T/F

A

False-low doses only

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86
Q

To examine the propensity for a drug to inhibit metabolism by CYP2D6, a suitable probe drug is metoprolol. T/F

A

True

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87
Q

What are the four categories of metabolisers?

A

Poor, intermediate, extensive, ultrarapid

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88
Q

What are the 5 key drugs used in drug interaction studies?

A

Warfarin-P450 (and vitamin K)
Midazolam-3A4
Omeprazole-2C19
Caffeine
Dextromethorphan

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89
Q

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

A

False (as long as it takes for induction

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90
Q

In a population PK study sparse blood sampling should generally be performed at steady state. (T/F)

A

True-estimation of key pharmacokinetic parameters, such as clearance (CL), volume of distribution (Vd), and half-life (t½), with more precision.
Reduces variability intraperson

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91
Q

Allometry can often be used to predict clearance in humans. (T/F)

A

True-Scale even between animals, allows for prediction though not always accurate

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92
Q

What is the equation often used in clearance allometry

A

CLhuman=CLanimal X (body weight human/body weight animal) X 0.75

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93
Q

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)

A

False-anything over 10% (usually worked out by mass weight) All over that need testing

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94
Q

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)

A

False-With regard to CR CLEARANCE not just result

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95
Q

A creatinine clearance of less than 50mL/min is generally considered severe renal impairment. (t/f)

A

False

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96
Q

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)

A

False-Mismatch half lives. A would need to be steady state then introduce B.

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97
Q

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)

A

True:
AUCt = Dose/Clearance

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98
Q

Therapeutic drug monitoring of gentamycin is best performed immediately before and after dosing-T/f

A

True

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99
Q

Name two disadvantages of using the assumption ‘once steady state has been achieved no further accumulation will occur’

A

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)

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100
Q

What are the three equations that can be used to work out the accumulation ratio from observed data?

A

AR=AUC multiple dose/AUC single dose
AR= Cmax-multiple dose/Cmax-single dose
AR= Ctrough-multiple dose/Ctrough single dose

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101
Q

What is the peak to trough ratio equation

A

(Css(max)-Css(min) X100/CSS (av)

102
Q

Give a reason why the predicted and measured steady state profile may not work

A

-May induce its own metabolism (eg carbamezepine)
enzyme saturation
very active metabolite

103
Q

What is non compartmental PK analysis

A

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
Q

What are the 5 points to PK parameters in NC analysis

A

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
Q

What comprises the central compartment?

A

Highly perfused tissues/organs such as heart, lungs, kidneys, liver, brain

106
Q

What comprises peripheral compartments

A

muscle and fat

107
Q

When can NCA not be used?

A

Sparse sampling (because not enough data)

108
Q

The area of what shape is used for NCA?

A

Trapezoid

109
Q

By how much must the AUC of index substrate be increased to be considered as strong inhibitor?

A

> / 5 fold

110
Q

By how much must the AUC of index substrate be increased to be considered as moderate inhibitor

A

> /2-<5

111
Q

By how much must the AUC of index substrate be increased to be considered as weak inhibitor

A

1.25-2

112
Q

By how much must the AUC of index substrate be decreased to be considered as a strong inducer

A

> /80%

113
Q

By how much must the AUC of index substrate be decreased to be considered as a moderate inducer

A

50-80%

114
Q

By how much must the AUC of index substrate be decreased to be considered as a weak inducer

A

20-50%

115
Q

What is bioanalysis?

A

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
Q

What are the common analytical methods used in bioanalysis?

A

Chromatography, immunoassays, spectroscopy

117
Q

How are calibration standards used?

A

To quantify the conc of a substance in a sample, a set of callibration standards are used with known concentrations.

118
Q

What are the two main components of a bioanalytical method?

A

preparation of solution, detection of compound

119
Q

What is the most common method of drug movement across cellular barriers

A

Passive diffusion

120
Q

When is IM/SC useful as a method of administration?

A

Sc generally convenient for patients (insulin etc)
Useful for large molecules (such as monoclonal antibodies)
note usually venous

121
Q

What is different about inhaled therapies?

A

Into capillaries so arterial

122
Q

Why are inhaled therapies quicker to act?

A

Fewer cell layers to pass through so faster absorption

123
Q

What do drugs taken orally undergo before entering systemic circulation

A

First pass in liver

124
Q

What factors impact oral absorption?

A

Physiochemical properties of drug
physiological factors
formulation factors

125
Q

Are Ionized drugs efficiently absorbed?

A

NO

126
Q

Why do weak acids need an acidic environment?

A

They will pick up a proton and become un-ionized

127
Q

What is the relationship between PKa and acid strength

A

Lower the PKa stronger the acid

128
Q

What happens to weak bases in an acidic environment?

A

They gain a proton and become ionised (NH4+)

129
Q

Why do drugs not absorb well in the stomach?

A

Thick mucus layer
Relatively small surface area

130
Q

Where do acidic drugs best absorb?

A

Acidic areas of proximal duodenum

131
Q

Where do alkaline drugs best absorb?

A

Distal ileum

132
Q

What are the two most common ways of passive diffusion

A

Transcellular absorption (across lipid membranes)-lipophillic drugs
Paracellular absorption (through aqueous pores at tight junctions)-hydrophillic drugs

133
Q

What are the actions of bile salts on drugs

A

Improve bioavailability of poorly water soluble drugs (class 2) by increasing rate of dissolution and/or solubility (fed state)

134
Q

What impacts do gastric emptying and intestinal transit time have on drug absorption?

A

Determine time drug spends in site

135
Q

What is intestinal efflux?

A

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
Q

Can drugs be metabolised in the gut?

A

Yes, CYPs present in the liver are also expressed in the gut wall epithelium especially 3a4

137
Q

What is absolute bioavailability vs relative?

A

absolute is in comparison to the IV (which is 1)
relative is the comparison between two extravascular routes

138
Q

What effect does food intake have on absorption?

A

-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
Q

How can we increase absorption?

A

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
Q

How can we assess food effect?

A

two way crossover study comparing fasted vs fed
(controlled release formulations important)

141
Q

How do we assess effect of elevated gastric PH

A

Concomitant administration of drug that increase ph of stomach
h2 receptor antagonists reduce gastric acid secretion
PPIs

142
Q

What is first order kinetics?

A

First-order kinetics – concentration-dependent process; the higher the concentration, the faster the process

143
Q

What is first order absorption?

A

a constant proportion (%) of drug is eliminated per unit time

144
Q

What is zero order kinetics?

A

independent of concentration

145
Q

zero order absorption?

A

constant amount is absorbed per unit time

146
Q

What factors influence distribution?

A

Blood perfusion
lipophilicity
regional ph
permeability of cell membranes
molecular size
plasma protein binding

147
Q

What do acidic drugs tend to bind to?

A

Albumin

148
Q

What do basic drugs tend to bind to?

A

alpha-1-acid glycoprotein or lipoproteins

149
Q

How are the actions of drugs prolonged through accumulation

A

Accumulate in tissues or body compartments which then release the accumulated drug as plasma drug concentration decreases

150
Q

What drugs do not penetrate well into the brain?

A

highly protein bound drugs and ionized

151
Q

What is the apparent volume of distribution?

A

theoretical volume of fluid into which the dose of drug given would have to be diluted to produce the concentration in plasma

152
Q

What vd does highly tissue bound drug have?

A

very little drug in systemic circulation.
plasma concentration is low and vd is high

153
Q

What vd do acidic drugs have?

A

highly protein bound and have small apparent volume of distribution

154
Q

what vd do basic drugs have

A

extensively taken up by tissues and so have an apparent volume of distribution larger than the volume of the entire body

155
Q

What happens in competitive protein drug drug interactions?

A

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
Q

What can affect renal clearance

A

variation of renal blood flow, variation in unbound plasma drug concentration

157
Q

What is the FDA cut off fraction of dose excreted unchanged in the urine?

A

> /0.3

158
Q

What are the two processes leading to excretion

A

phase 1-metabolism
conjugation-phase 2

159
Q

What are examples of large drug molecules

A

antibodies
antibody drug complexes
proteins and peptides
DNA and RNA fragments

160
Q

What are the main 6 CYP450

A

1A2, 2C9, C19, 2C6, 3A4, 3A5

161
Q

What are the main 3 things that will impact CYP450 enzymes?

A

Drug interactions
ageing (liver capacity decreases by 30%)
neonates immature enzyme systems

162
Q

How do we establish accuracy of an assay

A

replicate analysis of samples containing known amounts of analyte

163
Q
A
164
Q

What standard does an assay need to meet to be considered accurate?

A

minimum 3 concentrations in the range of expected
minimum of six determinations per concentration
mean value should be within 15% of actual value

165
Q

What is the LLOQ

A

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
Q

What is the difference between intra and interday precision

A

Within/intraday, -assay, -run and –batch commonly used to express repeatability
Interday, -assay, -run and –batch commonly used to express reproducibility

167
Q

What is linearity in analysis?

A

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
Q

What kind of clinical conduct issues can bioanalysis raise?

A

quantifiable concs pre first dose
BLQ samples post dose
sample swaps

169
Q

What is absorption?

A

Transfer of the unchanged drug from its site of administration into the systemic circulation

170
Q

What is absolute bioavailability?

A

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
Q

What reasons are there for losing drugs taken orally

A

Incomplete dissolution
problems in crossing gut wall membrane
Pre-systemic metabolism by the gut wall and liver

172
Q

What does a high first pass effect lead to in terms of bioavailability

A

Will lead to a low absolute bioavailability

173
Q

What are the two blood supplies that transport drugs to the liver

A

common hepatic artery
portal circulation

174
Q

What is relative bioavailability

A

Compares the absorption from different formulations, different routes of administration and different dosing conditions of the same drug

175
Q

What is bioequivalence

A

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
Q

What are the acceptable limits of bioequivalence

A

80-125%

177
Q

What is the objective of in vitro dissolution testing?

A

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
Q

What can impact dissolution?

A

Particle size,
solubility
excipients
binding agents
change in manufacturing process

179
Q

Give an example of a BE study design

A

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
Q

How to pick number of subjects for BE studies?

A

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
Q

When would you have to measure individual enantiomers?

A

If they have different PK/PD characteristics-including differences in rate of absorption

182
Q

What do we usually measure in BE studies

A

Plasma conc of unchanged drug

183
Q

What PK parameters are analysed in BE studies

A

Cmax, Tmax
(nb if cmax particularly important for safety acceptance tightened to 90-111)

184
Q

What are biosimiliars?

A

Officially approved versions of innovator biological products made by a different company after patent expiry

185
Q

What two food studies must be completed for regulatory requirements?

A

food effect bioavailability-fed vs fasting
fed BE (fed-fed)
highest dose should be used

186
Q

What study design should be used for food studies

A

Randomised, balanced, single dose, crossover with washout

187
Q

Why do we repeated dosing?

A

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
Q

What are the two dose phase one study designs

A

a) single dose-washout-multiple dose-steady state
b) multiple doses-steady state
(10-28 days)

189
Q

What are two examples of phase 1 oncology dose escalaiton trial designs?

A

a) 3+3
b) continual reassessment

190
Q

Why is it important to wait for full washout between dosing?

A

Prevent accumulation

191
Q

How many half lives until steady state?

A

5

192
Q

How do we achieve a steady state more quickly in those drugs with a long half life

A

loading dose

193
Q

What is non compartmental analysis?

A

Doesn’t rely on modelling, used for calculation of all PK parameters submitted to reg bodies to ensure consistency

194
Q

What is compartmental analysis

A

fitting conc vs time data onto a pre selected model from which PK parameters are obtained. Uses models and assumptions

195
Q

How are PK parameters calculated in NCA

A

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
Q

Why study drug interactions?

A

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
Q

What are the four primary pharmacodynamic DDIs

A

Additive/synergistic
Physiological antagonism
effect of one drug predisposes toxicity of other
Interactions at receptors

198
Q

What effect do juices such as grapefruit have?

A

Inhibition of intestinal uptake transporter OATP2B1

199
Q

What drugs delay gastric emptying?

A

Alcohol
Anticholinergics
Opiates
Tricyclic antidepressants
L-DOPA
Exenatide

200
Q

What effect does delay of gastric emptying have?

A

Reduce rate of absorption-Tmax longer, Cmax lower

201
Q

What drug promotes gastric emptying?

A

Metoclopramide

202
Q

What effect does inhibition of P-GP have?

A

Reduce efflux therefore increasing drug concentrations in plasma and possibly brain

203
Q

Examples of drugs that inhibit Pgp

A

Clarithromycin
Quinidine
Ketoconazole
Verapamil

204
Q

What effects do DDI’s that impact plasma protein binding have?

A

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
Q

Name three nuclear receptors which can be involved in enzyme induction through DDI

A

Pregnane X receptor
CARb
A-h receptor

206
Q

What impact can potent CYP inhibitors have on prodrugs?

A

Can prevent conversion of prodrugs to their active metabolite
Mainly 2D6, 2C19, 2C9

207
Q

How can renal excretion be impacted by DDIs?

A

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
Q

What factors will make us more likely to study interactions in man?

A

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
Q

How long must we allow for enzyme induction in DDI studies?

A

10-14 days after attaining steady state concs

210
Q

What problems can you have with drugs with short half lives in DDI studies

A

Can miss an interaction due to inadequate coverage of AUC (may need to repeat dose)

211
Q

Why is multiple dosing sometimes needed in DDI?

A

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

212
Q

When do we need to test alcohol interactions

A

CNS activity

213
Q

What are the challenges with alcohol DDI studies

A

Difficult to blind
absorbed and distributed rapidly
metabolic clearance is mainly zero order
rapid tolerance

214
Q

What makes the ideal probe?

A

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

215
Q

What are the pros of population PK for DDIs

A

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

216
Q

What are the Cons of population PK for DDIs

A

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

217
Q

What are the different PD outcomes?

A

Continuous
Categorical
Binary
Ordinal
Count data (eg lesions on mri)
time to event (eg disease progression)

218
Q

What is an empirical PK/PD model

A

Models that describe the data well but without biological meaning
Interpretation of parameters can be challenging

219
Q

What is a mechanistic PK/PD model

A

Reflecting underlying physiological process
preferred due to predictive power
Reversible (direct link/response model)
Irreversible (chemo/enzyme inactivation)

220
Q

What are examples of biologics?

A

mAbs
Proteins
peptides
blood products
viruses
therapeutic serum
toxin
anti toxin

221
Q

When is the maximum plasma concentrations of mAbs

A

3-7 days

222
Q

What is a usual bioavailability variation for mAbs

A

50-90%

223
Q

What is the typical distribution of mAbs?

A

3-8L
Central volume usually 2-4L

224
Q

How are mAbs broken down through non-specific endocytosis?

A

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

225
Q

What is target mediated drug disposition?

A

PK phenomenon in which the interaction between a drug and its target significantly influences the drug’s distribution and elimination from the body.

226
Q

How do we use NOAEL to guide FIH dose of mABs

A

Convert NOAEL to human equivalent dose
mg/kg normalization for proteins >150kDa
Apply a safety factor >/10 fold to give MRSD

227
Q

Is MABEL or NOAEL more conservative in dose level?

A

Usually MABEL, tends to be an order of magnitude lower

228
Q

What are Michaelis-menten kinetics

A

-maximum rate of enzymatic reaction is reached when drug concs achieve 100% enzyme saturation

229
Q

What effect does Michaelis mentin elimination kinetics have on clearance

A

Drug at low concentrations cleared by first order process and by zero order process at higher concentrations (enzyme capacity saturated)

230
Q

What is dose proportionality?

A

Increases in exposure (AUC, cmax) proportional to administered dose (usually include >/3 doses)

231
Q

Causes of non linearity in absorption

A

Solubility/dissolution rate limiting
saturation of carrier medicated transport
saturation of gut wall/hepatic metabolism

232
Q

Causes of non linearity in distribution

A

Saturated plasma protein binding
saturated tissue binding sites

233
Q

Causes of non linearity in metabolism

A

Saturated
enzyme induction

234
Q

Causes of non linearity in excretion

A

Saturable active processes
active tubular secretion
active tubular reabsorption

235
Q

What can impact bioavailability?

A

PKA
Lipophilicity
formulation
concomitant ingestion of food
efflux and influx transporters
liver blood flow and function

236
Q

What factors impact Vd?

A

Plasma protein binding
permeability
active transport into red cells
body composition (can alter with age)

237
Q

What factors impact elimination?

A

Intrinsic clearance
time dependency
disease (renal, hepatic, cardiac)
Demographics
genetics
concomitant medications

238
Q

Give three factors that age has on drug ADME

A

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

239
Q

What impact can a mutation in Pseudocholinesterase (BuChE) have?

A

abnormal types (autosomal recessive) can cause suxamethonium sensitivety

240
Q

What issues can Hepatic N-acetyltransferase (NAT-2) mutations have?

A

Rapid acetylators (rapid clearance)
slow acetylators (tendency to toxicity)

241
Q

What issues can mutations to Thiopurine methylxtransferase (TPMT) cause

A

catalyzes metabolism of cytotoxic-6-mercapotopurine and thioguanine
(greater incidence of AEs)

242
Q

What issues can a mutation in CYP450 oxidases cause?

A

Poor, intermediate, extensive, ultrarapid
clear quickly or higher toxicity

243
Q

What is a mass balance study?

A

An in vivo PK study with radiolabelled material to measure the rates and routes of clearance and elimination of drug related material

244
Q

What do we normally use as a radiolabel?

A

Carbon 14

245
Q

Why do we do mass balance studies?

A

To establish fate of drug related material in terms of rates and routes of clearance and excretion of the parent molecule and its metabolites

246
Q

Give examples of non clinical studies prior to human mass balance studies

A

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

247
Q

What is the general number for mass balance studies?

A

6 healthy male volunteers (families must agree to contraception)

248
Q

What percentage must a metabolite hit of the total radioactivity to be investigated

A

10%

249
Q

Why can metabolites with a long half life be a problem?

A

likely to accumulate over time

250
Q

How can a mass balance and abs bio study be combined?

A

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

251
Q
A

Solubility (1 decks)

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