https://youtu.be/C1Rb4BFugzo Attention all NAPLEX students! Are you ready to take your studying to the next level? In this video, we dive deep into the world of Kinetics, DDI, and Pharmacogenomics. With other pharmacy students that seeks to inspire, this lecture provides insight on how to approach your NAPLEX studies with a fresh perspective. But, we want to know, what's been your biggest challenge so far while memorizing this vital information? Leave your thoughts below and let's engage in a discussion that will motivate us all. Remember, don't just study harder, study smarter. Join the conversation and elevate your NAPLEX studying game. https://youtu.be/C1Rb4BFugzo

1. Kinetics, DDIs, and Pharmacogenomics

2. Reminders
• Materials will be provided
• This is intended as a review

3. Agenda
RxPrep 2020 Book:
• Kinetics (pp. 1009)
• Drug-drug interactions (pp. 55)
• Pharmacogenomics (pp. 1020)

4. Kinetics

5. Pharmacokinetics
• Pharmacokinetics (PK): what the human body does to the drug
Kara à Drug
• Pharmacodynamics (PD): what the drug does to the human body
Drug à Kara
• PK involves ADME (absorption, distribution, metabolism, excretion)
• PD involves drug concentration @ site of action, including therapeutic
effects and ADE

6. Absorption
• Intravascular formulations (IV, IA) surpass the A in ADME due to being
injected straight into bloodstream
• Extravascular formulations (PO, SL, buccal, IM, SC, TD, inhaled, topical,
ocular, intraocular, intrathecal, PR) do involve absorption as medication
must be absorbed into bloodstream
• First pass metabolism: extensive metabolism in liver before reaching
bloodstream
• Active vs. passive transport
PO stomach intestine portal vein liver bloodstream
enterohepatic
recycling

7. Absorption (cont.)
• An active ingredient must be released via dissolution before PO
medications can dissolve in GI tract
• Rate of absorption depends on dosage form
• IV à SL à ODT à IR tab à ER tab
• Hydrolysis (lysis with water) can destroy some drug formulations
• Protective coatings can help limit drug degradation in stomach (↑pH)
• E.g. enteric coated Dulcolax
• ↓ particle diameter can ↑ surface area and thus increase dissolution
rate and absorption
• Micronized drugs = very small particle diameter
• Noyes Whitney Equation = rate of dissolution

8. Absorption (cont.)
• Solubility: rate and extent to which a drug can dissolve (only dissolved
drug is absorbed)
• Hydrophilic: freely soluble drugs (usually)
• Hydrophobic: poorly soluble drugs (usually)
• Bioavailability (F): extent to which drug reaches systemic circulation;
percentage of drug absorbed from extravascular relative to
intravascular administration
• High F >70% (e.g. levofloxacin and linezolid à ~100% dose absorbed both PO and IV!)
• Low F <10%
• May be different IV à PO

9. Absorption (cont.)
• Bioavailability: calculated by area under the plasma concentration
time curve (AUC) or total exposure of drug
F (%) = 100 x AUCPO x doseIV
AUCIV dosePO
Dose of new dosage form = amt absorbed from current dosage form
F or new dosage form

10. Distribution
• Process in which drug molecules move from systemic circulation into
organs and tissues
• Higher drug passage and distribution properties:
• High lipophilicity, low MW, unionized, low protein binding
• Protein binding:
• Albumin is most common protein in drug binding
• Only unbound drug can exert effect
• If a drug is highly protein bound but serum albumin is low, more drug
will be in unbound form (and may thus exert more effect)

11. Distribution
• Assessing “free” drug levels
• Some assays cannot tell difference between bound and unbound drug
• Use correct formulas to determine concentration if normal albumin level
• E.g. phenytoin, ionized calcium
Cacorrected = Careported (serum) + [(4.0 - albumin) x 0.8]
Use Ca in mg/dL and albumin in g/dL
Phenytoincorrected = total phenytoin measure
(0.2 x albumin) + 1
Use Phenytoin in mg/dL and albumin in g/dL

12. Distribution
Volume of distribution (Vd) = concentration in body related to
concentration in serum; how large the area of body the drug is
distributed into
Vd = amount/dose of drug in body (mg)
concentration of drug in plasma (mg/L)

13. Metabolism
• Process by which chemical structure is converted into other forms
• Parent drug à metabolites
• Primary sites: gut and liver
• First pass metabolism: hepatic metabolism before a drug reaches
systemic circulation
• Phase I: oxidation, reduction, hydrolysis
• Phase II: conjugation (glucuronidation, acylation, sulfate, or glicine)

14. Excretion
• May occur thru kidneys (urine), liver (bile), lungs (exhaled air), and skin
(sweat)
• To excrete weak base – acidify urine
• To excrete weak acid – alkalinize urine
• Clearance: rate of drug removal in a volume of plasma over time; efficiency
of drug removal from body
• Rate of elimination: usually steady – kidney and liver generally do not speed up or
slow down
Cl (L/hr) = rate of elimination (Re) (mg/hr)
concentration (mg/L)
Cl = F x dose
AUC

15. More PK
• First order kinetics: constant % of drug removed per unit time
• Zero order kinetics: constant amount of drug removed per unit time
• Michaelis-Menten Kinetics: AKA saturable, mixed order, or non-linear
kinetics; increase in dose leads to disproportionate increase in drug
concentration at steady state
• Ex: theophylline, voriconazole, phenytoin
• Lower concentrations à exhibit first order kinetics
• Higher concentrations à exhibit zero order kinetics

16. More PK
• Elimination rate constant (ke): the fraction of drug that is
eliminated/cleared per unit time
ke = Cl
Vd
• Ex: ke = 0.1 hr-1 means that 10% of drug remaining is cleared per hour
• Half-life (t1/2): time it takes for 50% of drug concentration or amount to be
eliminated
t1/2 = 0.693
ke
• A loading dose may sometimes be required to more rapidly achieve
therapeutic concentration
Loading dose = desired concentration x Vd
F
~5 half lives to reach
steady state

17. Drug-Drug Interactions (DDIs)

18. PD DDIs
• Pharmacodynamic drug interaction: when 2 or more drugs are given
together and have either a beneficial or harmful effect
• Antagonism
• Antagonist + Agonist = antagonist blocks agonist
• Ex: opioid + naloxone
• Synergism: effect from 2 drugs together produces greater effect than
individually
• Agonist + Agonist = additive effect at same receptor, or additive effects with
>1 mechanism/receptor being activated
• Ex: benzo + opioid

19. PK DDIs
• Pharmacokinetic drug interaction: when one drug alters the ADME of
another drug, which may be beneficial or harmful
• Chelation: when a drug binds charged ions
• One drug may:
• Increase or decrease absorption of another drug
• Inhibit or induce metabolism of another drug
• Increase or decrease excretion of another drug

20. DDIs
• Drug removal and breakdown
• Kidney:
• Urine is mostly water, and drugs and drug metabolites need to be water-soluble to have
adequate excretion
• Liver:
• When a drug is in the process of being converted to a form (substrate) that can be
removed, it must go through Phase I and Phase II
• CYP enzymes
• Polymorphic
• Enzyme inhibitors and poor metabolizers increase drug metabolism
• Enzyme inducers and ultra-rapid metabolizers decrease drug metabolism
• Exception: pro-drugs have the opposite effect relative to either inhibitor/inducer

21. CYP enzymes
Inhibitors
“G PACMAN”
• Grapefruit
• Protease inhibitors
• Azole antifungals
• Cyclosporine/cimetidine/cobicistat
• Macrolides (clarithromycin & erythromycin only)
• Amiodarone (& dronedarone)
• Non-DHP CCBs
Inducers
“PS PORCS”
• Phenytoin
• Smoking
• Phenobarbital
• Oxcarbazepine (& eslicarbazepine)
• Rifampin (& rifabutin, rifapentine)
• Carbamazepine
• St. John’s wort

22. CYP Genetic Type and Activity Relationship
Genetic Type CYP Activity (CYP2D6 as example) Ethnicity Differences
(approximation)
Poor metabolizers None Caucasians: 6-10%
Mexicans: 3-6%
African Americans: 2-5%
Asians: ~1%
Intermediate metabolizers Low Not established
Extensive metabolizers Normal Most people
Ultra-rapid metabolizers High Finns and Danes: 1%
Caucasians (US): 4%
Greeks: 10%
Saudis: 20%
Ethiopians: 30%

23. Common Drug Interactions
• Amiodarone + Warfarin
• CYP2C9 is inhibited à higher warfarin levels
• Monitor INR, adjust as needed
• Amiodarone + Digoxin
• P-gp is inhibited à lower concentrations of digoxin, higher toxicity
• Monitor serum concentrations, electrolytes, renal function
• Statins + CYP3A4 Inhibitors
• Increased levels of statins
• Rifampin + Most Drugs (CYP/P-gp)
• Concentration of victim drugs will be greatly decreased

24. Common Drug Interactions (cont.)
• Phenytoin/Phenobarbital/Carbazepine/Oxcarbazepine + CYP-
metabolized drugs
• Increased metabolism à decreased drug concentration
• Smoking + Antidepressant/Hypnotics/Caffeine/Theophylline/Insulin
• Cigarettes are inducers
• When stopped à will cause an increase of drug concentration
• When smoking à will cause a decrease of drug concentration
• Lamotrigine + Valproate
• Valproate lowers lamotrigine metabolism à increasing lamotrigine levels
• May cause severe adverse skin reactions: SJS/TEN

25. Pharmacogenomics (PGx)

26. Pharmacogenomics
• The science of examining inherited variations in genes which
determine a patient’s response to a drug
• “Personalized medicine” that increases efficiency in choosing effective
regimens while decreasing adverse reactions
• Psych medications historically “hit-or-miss”
• Important PGx terms:
• Genes vs alleles
• Genotype vs phenotype
• Homozygous vs heterozygous
• Single nucleotide polymorphism (SNP)

27. Actionable PGx
• Testing required/strongly recommended:
• Abacavir (alone or in combo)
• Azathioprine
• Carbamazepine
• Cetuximab and panitumumab
• Trastuzumab, ado-trastuzumab, lapatinib and pertuzumab
• Testing considered (not required):
• Allopurinol
• Capecitabine and fluorouracil
• Clopidogrel
• Codeine
• Phenytoin and fosphenytoin
• Warfarin

28. Actionable PGx (cont.)
Human leukocyte antigen (HLA) testing
Major histocompatibility complex, clas I, B (HLA-B) à important gene in the immune system
Abacavir (Ziagen)
+ abacavir-containing drugs
HLA-B*5701 Fatal/serious hypersensitivity rxns
Test ALL patients
If positive, do NOT use
Allopurinol (Zyloprim, Aloprim) HLA-B*5801 SJS
D/C at first sign of rxn
If positive, do NOT use
Carbamazepine (Tegretol, etc)
Oxcarbazepine (Trileptal)
Phenytoin (Dilantin, etc)
Fosphenytoin (Cerebyx)
HLA-B*1502 SJS/TEN
More common in Asian populations
Test all Asian patients before starting
carbamazepine, suggested for
oxcarbazepine, optional for phenytoin
and fosphenytoin
If positive, do NOT use
(unless benefit outweighs risk)

29. Actionable PGx (cont.)
CYP450 polymorphisms
May affect any population; not yet routinely performed
Clopidogrel (Plavix) CYP2C19 Prodrug
Caution especially in poor metabolizers
(*2 and *3 are PM that have increased
cardiovascular effects)
Consider alternative if *2/*3
Codeine CYP2D6 Prodrug
Caution in ultra-rapid metabolizers
(increased risk of overdose; infant
deaths may also occur in pregnant
mothers who nurse)
If ultra-rapid metabolizer,
do NOT use (toxicity risk)
If poor metabolizer,
do not use (lack of efficacy)
Warfarin (Coumadin, Jantoven) CYP2C9 *2 and *3
VKORC1
Increased bleeding risk
(in decreased function of alleles and
haplotypes: CYP2C9 *2 and *3 or
VKORC1 G > A variant)
Start with lower dose if these
allele variations are present

30. Actionable PGx (cont.)
Trastuzumab (Herceptin) HER2 gene Overexpression of HER2 required for
efficacy (HER2 inhibitors)
Do NOT use if HER2 negative
Cetuximab (Erbitux)
Panitumumab (Vectibix)
KRAS mutation Only use in KRAS negative (wild-type)
Not effective in colorectal cancer if KRAS
positive (~40% of patients)
Do NOT use if KRAS positive
mutation
Azathioprine (Azasan, Imuran) TPMT
(thiopurine methyltransferase)
Increased risk of severe or life-
threatening myelosuppression if
low/absent TPMT activity
Start with low dose or use
alternative agent if
low/absent TPMT activity
Capecitabine (Xeloda)
Fluorouracil (Adrucil)
DPD deficiency Increased risk of severe toxicity
(diarrhea, neutropenia, neurotoxicity) in
DPD deficiency
Do NOT use if DPD deficient

34. Questions?