Pharmaceutics

Question 1

What is the blood supply to the brain?

Answer 1

~100 billion capillaries
Over 400 miles long
Surface area of around 20 m2

Very promising for drug absorption

Question 2

Why can’t all drugs enter the brain?

Answer 2

The brain requires significant amounts of small, hydrophilic molecules such as glucose and amino acids

Ion concentrations need to be tightly controlled

CNS and peripheral pools of neurotransmitters & neuroactive agents need to be kept separate

Brain interstitial fluid has ↓ ↓ protein, ↓ Na+ & K+ and ↑Mg2+ than blood plasma, otherwise similar

The passage of these species is very tightly controlled by specific barriers to ensure the brain has exactly the right biochemical make up, excluding potential neurotoxic compounds

Question 3

What is the BBB?

Answer 3

BBB is barrier from capillaries to brain, protection

Structure between normal and brain blood vessels are different

Brain blood vessekls have extra protection, a physical and biochemical barrier

The barrier function is regulated by complex, yet dynamic communication between the cells of the NVU

Tight junctions are key to the BBB’s ability to physically restrict passage of molecules

Many disease states disrupt the barrier function, e.g., stroke, Alzheimer’s disease, HIV, brain tumours, MS, Parkinson’s disease

Diesease states can interrupt tight junctions to help medicines through

Different chemicals can change this, bradykinin can open tight junctions

Biochemical/molecular barrier due to transporters and metabolic enzymes

Extracellular enzymes include peptidases and nucleosidases
Intracellular enzymes include monoamine oxidases and cytochrome P450 isoforms

In whole brain, glutathione S-transferases and catechol O-methyl transferase expression is higher than in liver

Sulphotransferases present, but at lower levels

Question 4

What are the 4 transport pathways across the BBB?

Answer 4

Water soluble through junctions
Lipid-soluble through oathway
Glucose enters through transport proteins
Insulin through transcytosis

Question 5

What is passive diffusion across the BBB?

Answer 5

The mechanism by which the majority of small drug molecules enter the brain

Non-saturable diffusion down a concentration gradient

Lipophilicity, MW and H-bonding are key parameters

Ideal LogP around 1.5 to 2.5

Ideal MW ~400

Reduced PSA compared to oral

Lower number of H-bonds tolerated

Lipinski’s rule of 5 does not apply! Lipinski’s only applies to oral absorption

Non-saturable diffusipn down a concentration gradient high too low, affecyed by lipophilicity, size and ionisation

Logp changes, MW changes,

Mannitol very hydrophilic, bad getting ginto lipophilic membrane

D-glucose is brain food, active transport

Nicotine – lipophilic so well absorbed

Phenytoin worse due to protein binding

Question 6

What are the methods of non-invasive delivery to the BBB?

Answer 6

• Improving peripheral PK, e.g., peptide and nucleic acid analogues, protein PEGylation (add poly ethylene glycol reduced clearance in kidneys, in blood longer). Enhancing Lipophilicity to make them more fat-soluble to diffuse across the BBB. Can lead to issues with lack of specificity.
• Transporter-Mediated Transport: Exploiting natural transporters (e.g., glucose, amino acid transporters) to carry drugs across the BBB.
• Nanoparticles: Using nanoparticles (liposomes, micelles, dendrimers) to encapsulate drugs and facilitate their crossing of the BBB.
• Receptor-Mediated Transport: Targeting specific receptors (e.g., transferrin receptor) on the endothelial cells of the BBB to facilitate drug uptake.
• Conjugation with Cell-Penetrating Peptides (CPPs): Attaching drugs to peptides like Tat peptides that can cross the BBB.
• Inhibiting efflux systems - P-gp can be inhibited by verapamil, a voltage-gated Ca2+ channel blocker, verapamil has shown promising results in drug-resistant epileptics. However, many endogenous and exogenous ligands are P-gp substrates - potential neurotoxicity
• Viral vectors for gene delivery - gene therapy to treat certain diseases, ideally administer systemically and virus crosses BBB
• Bypassing the BBB - olfactory epithelium, BBB not present. Drugs can enter by paracellukar diffusion.

Question 7

What are the methods of invasive delivery to the BBB?

Answer 7

• Convection-Enhanced Delivery (CED): Continuous positive-pressure infusion of a solution containing a therapeutic agent. It is targeted to diseased region and can be monitored in real-time. Better penetration than diffusion-based delivery
• Disruption of the BBB Hyperosmotic infusion: Hypertonic solution of arabinose or mannitol infused into the carotid artery for 30 s. Non-specific 10-fold increase in BBB permeability lasting ~10 min following hyper-osmotic exposure
  Results in malignant brain tumour treatment are encouraging, but procedure not widely accepted
• Disruption of the BBB Physical disruption - focused ultrasound (FUS): mAbs are generally ~150 kDa and do not normally penetrate. BBB can be perturbed temporarily by FUS
  MRI-guided focused ultrasound (FUS):
  1. Injection of Herceptin
  2. Sonication
  3. Injection of MRI contrast reagent
     Microbubbles are essential for the BBB disruption

Question 8

What are CDDSs?

Answer 8

Preparations designed in such a way that the rate or location of API release is controlled
Often referred to as modified release or extended release preparations

Question 9

Why are CDDSs used?

Answer 9

1. Reduce fluctuations in drug plasma concentrations
   Reduce concentration-related side-effects e.g., rapidly absorbed drugs
   Often used for drug with a narrow therapeutic index
2. Reduce dosing frequency
   Improve patient compliance
   Especially useful for drugs with short half-lives
3. Control delivery site
   Releases drug at site of optimum absorption or site of action (e.g., colon for bowel disease, tumour targeting)
4. Timed release
   Drug release is delayed or pulsed, so it occurs when there is a clinical need e.g., angina, asthma, etc; hormones; vaccines

Question 10

What are the 4 mechanisms for CCD?

Answer 10

Water Penetration-Controlled DDS
Swelling
Osmosis

Diffusion-Controlled DDS
Reservoir devices
Monolithic devices

Chemically-Controlled DDS
Monolithic devices – surface or bulk erosion
Pendant systems

Responsive DDS
Physical
Chemical

Question 11

Water penetration CDDSs

Answer 11

Hydrogels: These are materials that absorb a lot of water and swell up when they come into contact with it. The drug is trapped inside, and as the material swells, the drug slowly escapes. Polyethylene glycol (PEG)-based hydrogels. The rate of swelling is a key factor in controlling the release rate.

Osmotic Systems: These systems use the pressure from water entering the system to push the drug out in a controlled way. Think of it like a small pump inside the body where water moves in, creating pressure that releases the drug.
Example: Some extended-release tablets that release the medicine over time by letting water push the drug out.

Polymeric Matrices: These are materials made of long polymer chains that swell or dissolve when they absorb water. The drug can be spread throughout the polymer, and as the polymer swells, the drug gradually comes out.
Example: A controlled-release pill that slowly lets go of the drug as it breaks down with water.

Question 12

Diffusion-Controlled DDS

Answer 12

Reservoir
solution diffusion
pore diffusion
matrix

Question 13

Chemically-Controlled DDS

Answer 13

Similar to a diffusion-controlled matrix device
Drug dissolved in polymer solution prior to device formation
Drug is released as the polymer matrix dissolves or degrades
Predominantly for long-term implantation
Natural or synthetic polymers

production methods
Compression and melt moulding
Solvent casting
Extrusion
Emulsions e.g. micro- & nanoparticles
Electrospinning
3D printing

Polymeric devices degrade by:
1) Gradual dissolution of the polymer matrix - e.g. enteric coatings
2) Degradation of the polymer matrix via chemical or biological processes:

natural polymers
Collagen
Fibrin
Gelatin
Hyaluronan
Chitin/chitosan
Silk

synthetic polymers
Poly(esters)
Poly(anhydrides)
Poly(ortho esters)
Poly(phosphoesters)

Question 14

Factors affecting polymer degradation rate of Chemically-Controlled DDS

Answer 14

Chemical structure of polymer
Polymer molecular weight
Presence of low MW compounds, e.g., drugs and excipients, residual solvent
Crystalline vs amorphous polymers
Size and shape
Processing method
Porosity
Site of implantation
Degradation mechanism - enzyme vs water

Question 15

enteric coating - delayed release

Answer 15

Tablets coated with a polymer that is insoluble in the highly acidic environment of the stomach, but dissolves in the small intestine (>pH 5.5)
Can protect the drug from the stomach (e.g. erythromycin) or the stomach from the drug (e.g. NSAIDs)
Numerous polymers available, including cellulose derivatives and methacrylic acid co-polymers (Eudragit®)
Release area can be tailored depending on pH/solubility profile

3D printed
Fused deposition modelling (FDM) is the most accessible type of 3D printing
Uses a polymer filament, which is melted and extruded layer by layer to form a 3D print
Huge interest in all types of 3D printing, including FDM, for production of personalized dosage forms - tailoring dose and release profile
Polymer and drug melted together and extruded to generate a filament
Drug matrix printed within enteric coating of different thicknesses

Question 16

chemical-controlled release - bulk erosion

Answer 16

Most commonly poly(esters), especially poly(lactic acid), poly(glycolic acid) and their co-polymer, poly(lactic-co-glycolic acid) - PLA, PGA and PLGA
FDA approved, used in vivo for many years and their degradation produces naturally occurring metabolites
A number of types of matrix are possible e.g., bulk matrices, rods, micro- and nanoparticles, micro- and nanofibers

Question 17

chemical-controlled release - surface erosion

Answer 17

Most commonly poly(ortho esters) and poly(anhydrides)
Hydrophobic polymers with very reactive surface groups
Drug release by surface erosion is more commonly found in implantable devices
More rapidly-eroding matrices can be used in oral formulations
Using the same injection moulding technology found in the plastics industry results in:
Accuracy
Reproducibility
Reduced costs
Rapid device development

Question 18

chemical-controlled release - pendant systems

Answer 18

Modify backbone to control water ingress and drug release
Potential to adjust release rate by changing the linker chemistry

Question 19

Electrospun Matrices for Controlled Drug Delivery

Answer 19

Numerous applications for drug release throughout the body (e.g., dressings, implantables), plus tissue engineering and regenerative medicine
Drug is mixed with polymer and electrospun to give matrix or chemically-controlled DDS
vvPCL undergoes slow bulk erosion
PEVA does not degrade - diffusion-controlled matrix release
Little control from PCL
Would like to extend the release from PEVA
Effectively created a reservoir system, with the PCL layers acting as a rate-controlling membrane
3L matrices effective in killing a variety of bacteria, including clinical MRSA isolates:

Question 20

Responsive DDS

Answer 20

Drug release controlled by:
pH
Chemicals (metabolites)
Enzymes
Ultrasound
Magnetism
Light
Predominantly used in implantable devices or parenterally delivered DDS

Question 21

pH-Sensitive Polymers

Answer 21

Changes in ionization or cleavage of functional groups due to altered pH can affect sol-gel behaviour
e.g. Poly(propylene imine) dendrimers:

Question 22

Acid-Sensitive Linkers

Answer 22

The tumour microenvironment can be 0.5 to 1.0 pH units lower than normal tissues
Acid-sensitive linkers are designed to release drug in the acidic conditions in tumours, endosomes and lysosomes
Binds to circulating albumin following administration
Does not accumulate at non-specific sites (heart, marrow GI tract)
Reduced side effects, improved efficacy and quicker to reach the tumour than doxorubicin alone
A number of clinical trials have shown improvements in patient outcomes compared to doxorubicin alone
Granted orphan drug designation by the FDA for the treatment of patients with soft tissue sarcomas and pancreatic cancer
Current late stage trials for a number of cancers, including Kaposi’s sarcoma, SCLC, late-stage glioblastoma – trial evidence suggests it crosses the BBB

Question 23

Enzyme-Responsive DDS

Answer 23

Ulcerative colitis, Crohn’s, etc
Coating for drug pellets, consisting of ethylcellulose and “glassy” amylose

Question 24

Magnetism and Delivery / Release

Answer 24

Magnetism can be used for both targeting and release of drugs
Drug can be attached by a chemical bond or embedded in the polymer matrix
Release by diffusion, pH change, magnetic field or interaction with cellular component
Can directly kill or remove cancer cells

Question 25

Responsive DDS: Mesoporous Silica Nanoparticles

Answer 25

Inert
Thermally stable
Easy to functionalize
Controlled particle size
Homogeneous, tunable porosity (2-10 nm)
Great potential for controlled delivery of traditional drugs, proteins and nucleic acids
Great interest in responsive systems
Following drug loading, pores can be capped with nanoparticles that can be selectively be removed by pH, light, magnetism, antigen, S-S reduction or saccharide

Question 26

Controlled DDS: Implantable Devices

Answer 26

Pros:
Convenience
Compliance
Control
Commercial

Cons:
Surgery
Failure
Potency
Reactions/compatibility
Commercial

Localized
Ocular
Dental
Contraception
Pain
Vasculature

Long-term
Contraception
Pain management
Diabetes
Incontinence
Systemic infection

Question 27

Rods – Diffusion-Controlled DDS

Answer 27

Jadelle®:
Used from late 1990s
75 mg drug per rod
100 µg/day → 40 µg/day → 30 µg/day

Question 28

Coils - Diffusion-Controlled DDS

Answer 28

52 mg levonorgestrel
PDMS
20 µg/day → 14 µg/day
Local delivery
Easily reversible

Question 29

Vaginal rings– Diffusion-Controlled DDS

Answer 29

Flexible, drug-containing polymer rings (usually silicone-based) which are seated around the cervix
Numerous products on the market, in trials or development for the delivery of:
Contraceptive therapy
HRT
IVF therapy
microbicides (HIV, herpes, etc)
Different types of ring with release of drug from 3 weeks to 3 months
NuvaRing®
2” diameter ethylene-vinyl acetate copolymer ring
Controlled release of contraceptive for 3 weeks
99% effective

Question 30

RETISERT™ Intravitreal Implant (pSivida) – Diffusion-Controlled DDS

Answer 30

Chronic noninfectious uveitis
Approx. 3 mm x 2 mm x 5 mm
0.59 mg tablet of fluocinolone acetonide
Silicone elastomer cup
PVA membrane and suture tab
0.6 µg/day → 0.3 to 0.4 µg/day
30 months total
Age-related Macular Degeneration (AMD)
Diabetic Macular Edema (DME)
Glaucoma
BravoTM polymer matrix
Drug release up to 2 years
15 minute procedure
Sub-conjunctiva

Question 31

Drug-Eluting Stents (DES)

Answer 31

Polylactic acid backbone
Polylactic acid/everolimus coating
Stent bioabsorbed in 2 years - bulk erosion
Vasomotion restored
Restenosis prevented, clinically safe

Question 32

Implantable Osmotic Delivery Devices

Answer 32

~150 µl drug formulation
Zero-order release up to 12 months
Drug protected
Subcutaneous implant

Question 33

Controlled Delivery to the Brain

Answer 33

For treatment of high-grade malignant gliomas
After surgery, residual glioma cells can double in number every 10 days
Normally, treatment starts 14 days after surgery
Typical life-span post-surgery < 1 year
GLIADEL® wafers contain 7.7 mg of the chemotherapeutic carmustine
Systemic delivery can cause low blood count and lung toxicity
14.5 x 1 mm wafers erode over 2 to 3 weeks
Combined with radiotherapy

Question 34

Implantable Pumps

Answer 34

Always “wearing” a device
Change the set every three days
Skin irritation/infection
Some poor skin insert sites
Peripheral insulin delivery
Indicated for:
Chronic intrathecal or epidural infusion of sterile, preservative-free morphine sulphate for chronic, intractable pain of malignant and/or benign origin
Chronic intrathecal infusion of preservative-free ziconotide sterile solution for the management of severe chronic pain
Chronic infusion of baclofen for severe spasticity of spinal or cerebral origin
Chronic intravascular infusion of floxuridine or methotrexate for the treatment of cancer (primary or metastatic)

Question 35

Future Directions CDDs

Answer 35

Micro-Scale Delivery
Long-Term GI Delivery
Long-term oral drug delivery could greatly improve drug efficacy through increased adherence & be utilized for mass drug administration e.g., in combatting malaria
This type of approach is hampered by GI transit
Previous attempts to prolong residence time:
Flotation or swelling in gastric fluids
Sedimentation into gastric folds
Mucoadhesion
Requirements:
1. A shape and size that can be ingested by a subject
2. The ability to adopt a conformation in the stomach the prevents passage to small intestine
3. Ability to carry large drug load
4. Controlled drug release for weeks or months with little or no potential for burst release
5. Maintain long-term drug stability in low-pH
6. Degrade/dissolve or dissociate into forms in a predictable manner that can exit the stomach and pass through the GI lumen with no potential for obstruction or perforation
7. Safety mechanisms enabling dissociation of the device if it accidentally passes into small intestine

Question 36

Dissolution and Release processes as rate-limiting steps

Answer 36

Drugs with poor solubility:
The rate constant for dissolution is smaller than the rate constant for absorption
A very slow dissolution process can limit the rate of the following steps
When this occurs, dissolution becomes the “rate-limiting step”.
Modified-release formulations:
Sustained and extended forms which release the drug slowly over an extended period of time
The rate constant for release is smaller than the rate constant for absorption
The slow release process limits the rate of the following steps and becomes the “rate-limiting step”.
How can we tell?
When an increase/decrease in the dissolution rate leads to faster/slower absorption. E.g., drug in solid dosage form compared to drug in solution
When an increase/decrease in the release rate leads to faster/slower absorption. E.g., immediate versus slow-release formulations.
Either dissolution or release is slow.
Any drug dissolved/released is readily absorbed.
But absorption cannot proceed faster than dissolution/release.
Thus:
The systemic input of the drug (absorption) is rate-controlled by either the dissolution or the release process.
Changes in dissolution rate or in the release rate will modify profoundly the rate of absorption of the drug

Question 37

Absorption rate-limited by permeability

Answer 37

Dissolution and release are fast.
But absorption is limited by poor permeability.
Most of the drug is dissolved before a significant fraction of the drug is absorbed.
Thus:
The systemic input of the drug is absorption (permeability) rate-limited.
Modifying the dissolution and release rates will have little effect on the rate of absorption of the drug.

Question 38

Disposition (elimination) as the rate-limiting process

Answer 38

The most frequent case.
When the absorption rate constant is greater than the elimination rate constant. Or in other words, when the absorption half-life is shorter than the elimination half-life:
kabs&raquo_space; k and t1/2 abs &laquo_space;t1/2
The absorption process is faster than the elimination process
and
The elimination step (and so, the elimination rate constant, k) controls the decline of the drug concentration during the terminal phase.
Most of the drug has been absorbed and little has been eliminated when the peak (tmax,Cmax) is reached.

The decline of the drug in the terminal phase is primarily determined by the elimination (disposition) of the drug.

The rate constant (half-life) obtained from the terminal phase corresponds to the elimination rate constant (elimination half-life).

Question 39

Absorption rate-controlled kinetics (k > kabs)(“flip-flop” kinetics)

Answer 39

Less frequently, the absorption process is slower than the elimination process
The absorption rate constant is smaller than the elimination rate constant. Or in other words, the absorption half-life is longer than the elimination half-life:
kabs &laquo_space;k and t1/2 abs&raquo_space; t1/2
A very slow absorption will rate-limit all subsequent processes including the drug elimination and therefore, the terminal phase of the PK-profile.
At any time, most of the dose of a drug is:
either at the absorption site (i.e., not yet absorbed),
or has been eliminated.
A considerable amount of drug has not yet been absorbed when the peak (tmax,Cmax) is reached.

The decline (elimination) of the drug during the terminal phase is rate-controlled by the absorption process: The drug is eliminated as fast as it is absorbed.

The rate constant (half-life) obtained from the terminal phase corresponds to the absorption rate constant (absorption half-life).

Question 40

How to decide the rate-limiting factor

Answer 40

To do a reasonable guess:
Look at the properties of the drug: good or poor solubility/permeability?
Look at the type of formulation:
immediate or sustained or controlled release?
And decide which step is controlling the kinetics:
dissolution/release
absorption
elimination (most frequent case)
BUT
Absolute certainty requires an IV Bolus/infusion to estimate either the elimination rate constant (k) or elimination half-life (t1/2) in the absence of absorption.

Question 41

Benefits of transdermal drug delivery

Answer 41

Usually patch based (though not always as technology advances…)

Good patient compliance (painless, easy to apply and easy to apply multiple doses)

Can be used for all ages

Avoids first-pass metabolism
Continuous supply of drugs locally and into systemic circulation

Able to maintain drug level within therapeutic window for longer

Relatively easy to stop treatment (peel off patch)

Question 42

Routes of entry into the skin

Answer 42

Intercellular: In between cells (predominant pathway)
Intracellular: Through cells
Follicular: Through hair follicles

Question 43

What makes a drug suitable for TDD

Answer 43

• molecule size
  - hydrophilic + hydrophobic
  - potency important
  - sensitization & irritation
  - patch size

Question 44

What is the bricks and mortar model?

Answer 44

Bricks: Corneocytes (terminally differentiated flat keratinocytes filled with keratin)
Corneodesmosomes link the ‘bricks’
Mortar: Lipid matrix (a mixture of ceramides, cholesterol and free fatty acids)

Hydrophobic drugs can travel
through the ‘mortar’ while
hydrophilic drugs travel mainly
via the ‘bricks’ (though they still
have lipid-rich mortar to navigate
through)

Hair follicles only cover approx.
0.1% of skin surface therefore
not ideal

Question 45

Oral vs topical

Answer 45

Oral
Absorption rapid (faster rate of absorption than rate of elimination)
Quick rise of Cp to maximum with t1/2 corresponding to kinetics of elimination
High Cp but repeated doses needed to maintain

Topical
Absorption slow (slower rate of absorption than rate of elimination- ‘flip-flop’ kinetics)
Slow rise of Cp to maximum with t1/2 (decay) longer than ODD
Cp not as high but sustained (reduced dosing frequency and increased control)

Question 46

Therapeutic window

Answer 46

For potent drugs;
- concentration sustained in therapeutic window
- ‘controllable’ delivery
- reduce the frequency of dosing
- fewer potential side-effects

Question 47

Avoiding fluctuating Cp

Answer 47

Cp can be somewhat controlled (or rather fluctuating Cp levels avoided) by;
- patch size
- skin site
- adjuvant/ skin penetration enhancers
- easily controlling the lag time between patches

Question 48

Nitroglycerin

Answer 48

Glyceryl trinitrate (GTN)

Vasodilatory drug: relief from anginal chest pains
Sublingual tablet (most common) or spray, IV, ointment and transdermal patch

Decreasing angina attacks where sustained drug delivery is useful (and where patient 	has an adverse reaction to sublingual methods)

Can develop tolerance over time
Many side effects: dizziness, palpitations, vertigo, severe headaches, nausea and 	vomiting
Nitroglycerin in acrylic-based polymer adhesive (stead-state Cp ~2 hrs; short t1/2)

log P ~2 (1-5 ideal permeability), MW ~300 and liquid at room temperature

Rate of release linearly dependent on the area (~0.5-1 mg/cm2/day needed)

Avoiding tolerance: drug-free intervals of 10-12 hours needed

Question 49

An ideal TD

Answer 49

Low MW (<500 Da)
Lipophilic log P/ partition coefficient (octanol-water): 1-5 for optimal permeability
Solubility in water (pH 6-7.4)
Half-life in hr (<10)
Dose <10mg/day
Non irritating and nonsensitizing
Patch size <50 cm2………

Question 50

What are the 4 parts of TDD systems

Answer 50

Backing: Impermeable side facing clothes (flexible polymers)
Adhesive: Binds patch parts together and adheres patch to skin (e.g. silicone, rubber…)
Liner: Peelable part to protect patch during storage
Membrane: Added control of drug release profile (polymers/ elastomers)

Question 51

Scopolamine

Answer 51

Transderm-Scop: motion sickness (mostly) and post-operative recovery

Patch behind the ear (postauricular), releases drug over 3 days (approx. 5 µg/hr)

Based on the reservoir system (drug in mixture of mineral oil and polyisobutylene)

Oral tablets or parenteral injections (drug release not sustained)

Question 52

Clonidine

Answer 52

Catapres-TTS: ‘Transdermal Therapeutic System’ vasodilator for hypertension

Usually applied every 7 days (upper, outer arm or upper chest). Issue with adhesion 	(extra ‘adhesion cap’ sometimes supplied)

Drug held in reservoir with mineral oil, polyisobutylene and colloidal silicon dioxide 	(matched with adhesive to create the same environment)- 3.5, 7 & 10.5 cm2

Membrane to control rate of delivery (steady state obtained in ~3 days). 

Sensitization issues! Multiple wear difficult (patch size small)

Question 53

Estradiol

Answer 53

Estradot/ Vivelle/ Evorel…: Post-menopause hormone replacement therapy

Highly potent, delivered via reservoir system (was ethanol which diffused into skin) or 	matrix system (either twice weekly or once weekly)

Log P <3 and MW ~230, high clearance, short t1/2

Oral: high first-pass effect in liver (high dose of 
conjugated equine estrogens with elevated 
estrone/ estradiol ratio- and therefore 
side-effects)

Transdermal patch;
- restores ratio in post-menopausal 
	women (see plot)
- sustains plasma levels (better outcome)

Question 54

Fentanyl

Answer 54

Duragesic® (long-term), Ionsys® (short-term)/ Durogesic DTrans®…..: Opioid drug for managing severe and persistent post-operative/ chronic cancer pain

Requires monitoring (side-effects include breathing difficulties)

12-100 µg/ hr (0.3-2.4 mg/ day)- reservoir initially (Fentadur®) to adhesive matrix 	(Durogesic DTrans®)
	Replacement of patch every 72hrs (12-24 hrs for Cp to stabilise; habit forming (therefore 	controlled decrease needed….+ careful disposal)

Good hydrophilic and hydrophobic properties (+ low MW and high potency)

Adhesive can peel (extra adhesive dressings sometimes needed: Bioclusive® or Askina® 	Derm)	 2019 Alvogen Inc recall: 2 batches of fentanyl transdermal patches (made by 3M Drug 	Delivery Systems)

50 µg/ml instead of 12 µg/ml (mislabelling)! Thankfully no adverse effects reported….

Question 55

Buprenorphine

Answer 55

Butrans/ Transtec…: another opioid analgesic (semisynthetic with both agonistic and antagonistic receptor-binding)

Better safety profile (lower opioid dependency than fentanyl) but some studies report 	better pain management with fentanyl

7-day patch via matrix adhesive

Question 56

Nicotine

Answer 56

Nicorette/ Nicotinell/ Boots NicAssist…: well-known for smoking cessation
(and remains most popular TD patch)

~20 mg/ day (16 hrs/ 24 hrs…). Dose vs time (see plot)

Adhesive/ layered/ reservoir systems (gum, tablets, inhaler, spray also available)

‘Invisibility’ and size important to users (smaller than credit card + clear or ‘skin’ colour)

Question 57

Testosterone

Answer 57

Testoderm/ Androderm/ Androplex …: hypogonadism (not enough testosterone being produced by body)

Review of other drugs used (not with licorice: reduces Cp blocks conversion of 	androstenedione to testosterone)

24 hr (reservoir and matrix adhesive). Testoderm was originally 	applied to scrotum 	(compliance low- moved to upper arm, thigh, abdomen…site rotation/ irritation). 

Neither popular (gel more conventional)

Question 58

Norelgestromin-ethinyl estradiol

Answer 58

Ortho Evra/ Evra…: contraceptive impacting ovulation (combination drug: progestin (norelgestromin) and estrogen (ethinyl estradiol))

28 days (four-week) cycle. New patch applied each week for 3 weeks, and week four is 	patch-free (recommended 7-day adjustment period- steady-state)

Abdomen, upper body, upper outside of arm, buttocks (adhesive matrix) 150 μg/day of norelgestromin and 20 μg/day of ethinyl estradiol

 Cp: 0.6–1.2 ng/mL for norelgestromin and 25–75 pg/mL for EE for up to 10 days

Ortho Evra discontinued in US by Janssen Pharmaceuticals: ‘Due to a business decision’. 	FDA warning excess level of hormones from patch associated with possible increased 	risk of blood clots (still available in Europe and Canada)

Question 59

Oxybutynin

Answer 59

Oxytrol/ Kentera…: Incontinence

Anticholinergic: blocks acetylcholine preventing ‘urgency’ of urination (inc. 	uncontrolled release)

Adhesive matrix system- very thin! (rapid absorption, steady-state ~1 hr). 3.9 mg 	delivered/ day

Extensive 1st-pass effect (metabolised by CYP3A4) 

Twice weekly (abdomen, hip or buttock). Changed every 3–4 days to different site

Question 60

Transdermal methylphenidate

Answer 60

Daytrana…: ADHD in children 6-12 years

Adhesive matrix system (multipolymer: acrylic and silicone). 

Delivery rate affected by time worn (9 hrs on alternating hip) and size of patch

Avoids 1st pass metabolism: better Cp than oral formulation (and higher Cmax) therefore 	lower dose required

Question 61

Selegiline

Answer 61

EMSAM…: Depression in adults and Parkinson’s disease

Matrix adhesive system (potent: 6-12 mg/ day)

Higher Cmax than oral: extensive 1st-pass metabolism avoided, sustained Cp 

Decreased metabolite production

(therefore decreased side-effects)

Question 62

Transdermal rotigotine

Answer 62

Neupro…: Parkinson’s disease and moderate-severe restless leg syndrome

Dopamine receptor agonist

24 hr patch with Cp similar to IV infusion (steady-state within 1-2 days of daily 	application)

Polymer matrix with a permeation enhancer

Question 63

Rivastigmine

Answer 63

Exelon patch…: Parkinson’s disease-associated dementia (active ingredient rivastigmine)

24 hr patch (drug-loaded matrix) to upper torso 

Starting with low dose and increased to 9.5 mg/ day over min 4 weeks to build 	tolerance

Question 64

Granisetron

Answer 64

Sancuso…: prevention of nausea/ vomiting due to chemotherapy (blocks serotonin)

Up to 7-day patch (large patch size on abdomen or upper arm) delivering 3.1 mg/ 24 	hrs

Side-effects complicated by chemotherapy: decreased appetite, dry mouth etc.

Question 65

Donepezil

Answer 65

Adlarity…: Alzheimer’s dementia. Donepezil is reversible inhibitor of the enzyme acetylcholinesterase

7-day patch (drug in matrix with a rate controlling membrane). 5 mg/ day 	(recommended). Increased to 10 mg/ day if required after 4-6 weeks) 

Applied to back (avoid using same site for 2 weeks after removal of patch)

Mild skin irritation reported

Question 66

Metabolite kinetics

Answer 66

Why are we interested in metabolites?
Metabolites can be:
Inactive waste products that could be used to:
measure bioavailability of the parent compound and assess bioequivalence
detect exposure to illicit drugs.
The active compound:
a prodrug is administered that depends on metabolism to be activated.
Pharmacologically active and modify the response to the parent compound
sum to the effect of the parent drug
have a different effect than the parent compound
cause toxic effects.
Modify the disposition of the parent compound.

Question 67

What do we need to know about metabolites

Answer 67

Potential properties of the metabolite:
Activity
Toxicity
Alter binding of the parent compound or other drugs
Alter response to parent drug
AND
Concentration and PK profile of the metabolite:
Will the metabolite concentration be high enough that there is a therapeutic concern/use?
Can we use PK parameters of the metabolite to estimate exposure to parent compound?

Question 68

Drug elimination rate-limits the metabolite kinetics

Answer 68

Case 1 is the most common scenario
Metabolism of a drug results in a metabolite that is eliminated faster than the parent compound.

Typical examples:
Metabolites such as glucuronide, sulphate and glycine conjugates are more polar and water soluble than the parent compound
and
are eliminated faster than the parent compound.

The elimination of the metabolite is rate-limited by its formation (or parent drug elimination). Thus, the slope of the terminal phase (ln Cmet vs time) reflects k
Further demonstrating that Case 1 applies:
Experiments in (a): Inject metabolite IV and inject drug IV in separate occasions
Experiment (b): Inject drug IV
Note the change in the rate constant of the terminal phase for the metabolite reflecting (a) kME and (b) k

Question 69

Metabolite kinetics rate-controlled by metabolite elimination

Answer 69

Metabolism of a drug results in a metabolite that is eliminated more slowly than the parent compound.

Typical examples:
Acetylated or other metabolites which are less polar / less water soluble than the parent compound
and
are eliminated more slowly than the parent compound.

The elimination of the metabolite is rate-controlled by its own elimination (kME)
Metabolite accumulation occurs.
Preferable scenario for pro-drugs
Active metabolite from several 7-chloro-benzodiazepine drugs with long t1/2
Nordazepam Css ~ twice diazepam Css following oral multiple doses (see also the different slopes for drug and metabolite terminal phase)
Nordazepam kinetics independent of parent drug administered as they are controlled by its own elimination (see parallel terminal phase decline)

Question 70

ADME of phenytoin

Answer 70

ABSORPTION
Slowly but completely orally absorbed
Low solubility (14 mg/L) and weak acid (pKa = 8.3).
DISTRIBUTION
Distribution equilibrium in 30-60 min. Vss = 0.6-0.7 L/kg
Rapid distribution to brain; Cbrain  Cp
Crosses placental barrier and distributes into breast milk
fu~0.1 in plasma for usual 0.65 mM albumin. fu constant as far as Cphen<0.1 mM
ELIMINATION
Mostly metabolized, 1-5% renal clearance.
Inactive hydroxylated metabolites, some further metabolized (glucuronides)
60-90% of a dose recovered in urine as p-HPPH and glucuronide p-HPPH
CYP2C9 predominant. PGx variation up to 10-fold in vivo. CYP2C19 also involved

Question 71

Clinical relevance of capacity-limited metabolism

Answer 71

C and AUC are not directly proportional to the dose
Small changes in dosage cause a large, disproportionate difference in Cp
Narrow therapeutic window: 10-20 mg/L and poor correlation between dose and Cp
Difficult dose adjustments
“Do not switch brands” advice
Need for therapeutic drug monitoring (TDM)

Question 72

Loading doses for phenytoin

Answer 72

Phenytoin loading doses are estimated as in linear PK using:
𝐷_𝐿=𝑉(𝐶_𝑑𝑒𝑠𝑖𝑟𝑒𝑑−𝐶_𝑜𝑏𝑠𝑒𝑟𝑣𝑒𝑑 )/(𝑆×𝐹) for an initial dose: Cobserved= 0
S = salt factor: S=1 for acid form and S=0.92 for sodium salt
F = Bioavailability, usually F1

2. Consider route of administration:
   IV: slow to avoid cardiac toxicity and sodium salt used or prodrug
   Oral: DL/3 administered with 2 h difference to avoid GI side effects.
3. V=0.65 L/kg but should be modified for obese patients:
   𝑉_(𝑝ℎ𝑒𝑛𝑦𝑡𝑜𝑖𝑛 𝑖𝑛 𝑜𝑏𝑒𝑠𝑖𝑡𝑦) (𝐿)=𝐼𝐵𝑊(𝑘𝑔)×0.65 𝐿⁄𝑘𝑔+1.33 (𝑇𝐵𝑊(𝑘𝑔)−𝐼𝐵𝑊(𝑘𝑔))
4. Maintenance dose starts on average values: Followed by TDM and individualization