Pharmacokinetics

Muhammad Zeeshan Khan PharmD, M.S., BCPS, BCIDP

Clinical Staff Pharmacist II,
Abu Dhabi, United Arab Emirates.

 • I have not received any financial or commercial funding or support for today’s session.
• No commercial trade names are used in today’s presentation and I do not promote any specific brand.
• No specific conflict of interest
• I have no financial relationship to disclose.
AND

• I will not discuss off label use and/or investigational use in my presentation.
OR

• I will discuss the following off label use and/or investigational use in my presentation

BCPS Preparatory Class 2

 Agenda
• Basic Pharmacokinetic Relationships
• ADME
• Non-Linear Pharmacokinetics
• Noncompartmental Pharmacokinetics
• Data Collection and Analysis
• Pharmacokinetics in Renal/Hepatic Disease
• Pharmacodynamics
•

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Case # 1

HR is receiving vancomycin for MRSA

HR has renal failure

Dosing:
! 1g on 3/21 at 1200
! Concentration on 3/21 at 1400 = 23.8 mg/L
! Concentration on 3/24 at 1400 = 12.1 mg/L

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Case # 1
If you were to give a 1g dose on 3/24 at 1600 when would you need to give the
next dose?
• One day after the dose on the 24th

• Three days from the dose on the 24th

• Six days from the dose on the 24th

• There is insufficient information to calculate when to redose

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 Basic PK Relationship

" rapid IV (or oral) bolus: Vd = F * dose/Cp0

" Vd = 1000mg / 23.8mg/L = 42L

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Basic PK Relationship

(ln C1 - ln C2)/
"elimination rate constant – k = (t2 - t1)

0.693/
"or t 1/2 = k

" k = (ln 23.8mg/L – ln 12.1mg/L) / 72 hours =

0.0094/hr

Basic PK Relationship

" Δ Conc. = 1000mg / 42L = 23.8mg/L

" 12.1mg/L + 23.8mg/L ~ 36mg/L
" 10mg/L = 36mg/L * e-0.0094*t
t = 136 hours or ~ 6 days
" or in 1 half life the concentration down to
18 mg/L and in another to 9 mg/L – since half life is
3 days, wait 6 days
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Case # 2

Following 100mg of a drug IV and 200mg of the same

drug PO, the AUCs are 50mg/L/hr and 25mg/L/hr.
What is the bioavailability?
A. 25%
B. 37.5%
C. 50%
D. 100%
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 Basic PK Relationship

" F= Doseiv * AUCev / Doseev * AUCiv

" F = (100mg * 25mg/L/hr) / (200mg * 50mg/L/hr)

" F = 25%
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Absorption

" First Pass Effect

! Blood perfusing GI tissues passes through liver
! Buccal and some rectal blood by passes liver
" Enterohepatic Recirculation
! Drugs excreted in bile, metabolized by normal
flora and reabsorbed back into circulation
! Drug expelled by gall bladder on sight, smell or
ingestion of food
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Case # 3
P-glycoprotein:
• is a plasma protein that binds basic drugs.

• transfers drugs through the GI mucosa, increasing absorption.

• diminishes the effect of CYP3A4 in the GI mucosa.

• is an efflux pump that decreases GI mucosa absorption.

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 Absorption
" P-glycoprotein:
• ! CYP3A4 and P-glycoprotein in GI mucosa work
#
together to decrease absorption
• ! efflux pump that pumps drug back into the GI lumen – absorption
#
drug interactions
• ! # most CYP3A4 substrates are also P- glycoprotein substrates
• ! # many CYP3A4inhibitors/inducers also inhibit/induce P-glycoprotein
• ! examples: dabigatran, digoxin, HIV protease inhibitors affected by
#
various inhibitors
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 Distribution

" Volume of Distribution

! Constant that relates the amount of drug in the

body to an observed concentration of drug

! Vd = F * dose/Cp0

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Distribution

" Protein Binding

! Albumin
! Alpha-1-acid glycoprotein
! Lipoprotein

" P-glycoprotein
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Case # 4

Renal transplant with CAP, on cyclosporine. Which is

the least likely to interact?

A. Erythromycin
B. Clarithromycin
C. Azithromycin
D. all macrolides inhibit CYP3A4

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 Clearance

" Cytochrome P450

! a group of heme-containing enzymes responsible

for phase 1 metabolic reactions

! located in endoplasmic reticulum in 1) liver, 2)

small intestine, and 3) brain, lung, kidney

! drugs generally have a high affinity for one CYP450
but may utilize secondary pathways

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Clearance

CYP 3 A 4
Superfamily Family Subfamily Isoform

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Clearance

" Cytochrome P450 characteristics

! inhibition is substrate independent
! some substrates are metabolized by more than one
CYP450
! enantiomers may be metabolized by different CYP450

! differences in inhibition may exist in the same drug class

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 Clearance

" Cytochrome P450 characteristics

! substrates can also be inhibitors
!most inducers and some inhibitors can affect
more than one isozyme
! inhibitors may affect different isozymes at
different doses

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Case # 4

Renal transplant with CAP, on cyclosporine. Which is

the least likely to interact?

A. Erythromycin
B. Clarithromycin
C. Azithromycin
D. all macrolides inhibit CYP3A4

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Case # 5

• WT is a 62 year old man

Chief complaint: CP
Diagnosed with STEMI
Cath lab: DES x2 placed
New meds: aspirin 81mg daily, clopidogrel 75mg daily
Other meds: losartan 25mg daily, carvedilol 25mg
twice daily, amitriptyline 100mg daily, acetaminophen
500mg as needed, simvastatin 20mg daily

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Pharmacogenetics

" Definition – more than one genetic variant (alleles)

which are stable components in the population (>1%
of population)
" phenotype – clinical expression of the trait

" genotype – genetic composition

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 Pharmacogenetics
Pharmacogenetics
Clinical Pharmacogenetics Implementation
Consortium (CPIC)
Designed to facilitate translation of pharmacogenetics
information from research to clinical practice
Clearance
Developing guidelines for utilization of
pharmacogenetic tests results in drug dosing
Focused on specific drug/gene pairs (Table 6)
Drug Gene Drug Gene
Abacavir HLA-B Phenytoin HLA-B
Allopurinol HLA-B Rasburicase G6PD
Capecitabine DPYD Simvastatin SLCO1B1
Carbamazepine HLA-B SSRIs CYP2D6,CYP2C19
Clopidogrel CYP2C19 Tacrolimus CYP3A5
Codeine CYP2D6 Thiopurines (azathioprine, 6-MP) TMPT
Ivacaftor CFTR Tricyclic antidepressants CYP2D6, CYP2C19
Ondansetron CYP2D6 Voriconazole CYP2C19
Peginterferon IL28B Warfarin VKORC1/ CYP2C9

Workbook Page 1-577-578 24

 Pharmacogenetics
Pharmacogenetics
Clinical Pharmacogenetics Implementation
Consortium (CPIC)
Clopidogrel
Requires metabolism by CYP2C19 to active metabolite which
is responsible for antiplatelet activity
CPIC recommendation: Normal dosing for ultrarapid
metabolizer; alternative antiplatelet therapy in intermediate or
poor metabolizers

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Workbook Page 1-577
 Case # 6

" CM is a 55 year old man

" Started on phenytoin, 200mg daily, post

craniotomy.

" Recent steady state concentration = 6 mg/L

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Case # 6
Patient Case #6
If CMs Km is calculated to be 5 mg/L, what will most
likely occur if the dose is doubled (to 400mg po daily)?
A. His concentration will double since phenytoin
clearance is linear above the Km.
B. His concentration will more than double since
phenytoin clearance is non-linear above the Km.
C. His concentration will not change because
phenytoin is an auto inducer and clearance
increases with time.
D. His concentration will increase by only 50% since
phenytoin absorption decreases significantly with
doses greater than 300mg.
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Workbook Page 1-579; Answer Page 1-595
 Non-linear
Non Pharmacokinetics
- Linear Pharmacokinetics
Non-linear elimination
saturation or partial saturation of the elimination
pathway
Michaelis-Menten equation:

Vmax * C
rate of elimination = Km + C

non-linearity occurs when concentration is at or

above Km
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Case # 6
Patient Case #6
If CMs Km is calculated to be 5 mg/L, what will most
likely occur if the dose is doubled (to 400mg po daily)?
A. His concentration will double since phenytoin
clearance is linear above the Km.
B. His concentration will more than double since
phenytoin clearance is non-linear above the Km.
C. His concentration will not change because
phenytoin is an auto inducer and clearance
increases with time.
D. His concentration will increase by only 50% since
phenytoin absorption decreases significantly with
doses greater than 300mg.
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Workbook Page 1-579; Answer Page 1-595
 Data Collection Analysis
" Timing of collection
! ensure completion of absorption / distribution

! ensure completion of redistribution post HD

(especially with high flux/high efficiency)

" Specimen requirements
! whole blood
! plasma
! serum
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Data Collection and Analysis
Data Collection and Analysis
Assay Terminology
Precision (reproducibility)
SD and CV
Accuracy
Correlation coefficient
Predictive performance (measure of accuracy)
and bias
Sensitivity
Specificity

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 Case # 7
Patient Case #7
A drug assay is touted as having high specificity
but low sensitivity. This means:
A.
products, but detects extremely low concs.
B.
products, nor detect extremely low concs.
C. The assay can distinguish drug from like
products, and detects extremely low concs.
D. The assay can distinguish the drug from like

concs.
Workbook Page 1-581; Answer Page 1-595 32
Data
DataCollection andand
Collection Analysis
Analysis
Assay Methodology
Immunoassays
Radioimmunoassay
Advantages: extremely sensitive
Disadvantages: short half-life, nuclear waste, cross
reactivity
Enzyme immunoassay (EMIT)
Advantages: simple, automated, highly sensitive, stable
Disadvantages: measurement more complex,
background interference
Fluorescence immunoassay (FPIA)
Advantages: simple, automated, highly sensitive, stable
Disadvantages: background interference

Workbook Page 1-582 33

 Data
Data Collection
Collection and Analysis
and Analysis
Assays used primarily in pharmacokinetic
research studies:
HPLC

Gas chromatography-mass spectrometry and

liquid chromatography-mass spectrometry

Flame photometry

Bioassay
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 Patient
Case # 8 Case #8

Admitted for pyelonephritis with sepsis

PMH: MI x2, CHF, HTN, osteoporosis,
rheumatoid arthritis, CVA
Serum creatinine: 0.92 mg/dl; albumin 2.9 g/dl
Drugs: TMP/SMZ 280mg IV q12h, lisinopril
10mg po daily, digoxin 0.125mg po daily,
furosemide 40mg po daily, cimetidine 400mg po
BID, APAP 650mg po q6h, CaCO3, and
carvedilol 6.25mg po BID
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 Case # 8
Patient Case #8

A. Her serum creatinine is in the normal range and

no dosage adjustments are necessary.
B. Because of her age, KM has some degree of renal
dysfunction and doses may need to be adjusted.

C. Because of the pyelonephritis, KM has renal

dysfunction and doses may need to be adjusted.
D. Her serum creatinine is in the normal range but
her BUN is elevated so doses may need to be
adjusted.
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Workbook Page 1-583; Answer Page 1-595
 Case # 8
Patient Case #9
Which of KMs drugs may alter serum creatinine
concentrations?
A. Lisinopril and digoxin

B. Trimethoprim/sulfamethoxazole and
cimetidine
C. Furosemide and calcium carbonate

D. Acetaminophen and carvedilol

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PKPK
in Renal Disease
in Renal Disease
Estimation of Kidney Function
Creatinine production and elimination
Calculated CrCl by 24 hour urine
Creatinine clearance estimation
Jelliffe
Cockcroft and Gault
Salazar-Corcoran (obesity)
Schwartz and Counahan-Barratt (pediatric)
GFR estimation
MDRD study equation (standardized creatinine)
Chronic Kidney Disease Epidemiology Collaboration
equation (CKD-Epi)

Workbook Page 1-583-586 38

 PK
PK in Renal
in Renal Disease
Disease
Factors influencing estimates of creatinine
clearance
Disease states / clinical conditions
Diet
Drugs / endogenous substances
Laboratory interaction
Pharmacokinetic interaction

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PKPK in Renal
in Renal Disease Disease

Drug dosing in renal disease

Loading doses
Maintenance doses
Changing the dosing interval
Changing the dose

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KMs estimated CrCl is:
PKPK
in Renal Disease
in Renal(140
Disease Use TBW when BMI < 18.5 kg/m
- Age) * TBW
Use IBW when BMI 18.5-25 kg/m
2
2
CrCl (ml/min) = * 0.85
Use IBW + 0.4(ABW-IBW) when
Scr * 72 BMI > 25 kg/m2
CrCl (ml/min)
KMs estimated= 42CrCl
ml/min
is:
KMs estimated GFR is: (140- Age) * TBW
CrCl (ml/min) = * 0.85
CKD-Epi (ml/min/1.73m2) Scr * 72
= 144 * (SCr/0.7)-1.209 *
CrCl (ml/min)
(0.993)Age = 42 ml/min

KMs estimated
GFR = GFR 2is:
59 ml/min/1.73m (52 ml/min)

CKD-Epi (ml/min/1.73m2) = 144 * (SCr/0.7)-1.209 *

Workbook
(0.993)Age Page 1-583-586

GFR = 59 ml/min/1.73m2 (52 ml/min)

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 Patient
Case # 9 Case #10
SJ is a 55 year old man with fungemia
PMH: hepatic dysfunction ascites, no
encephalopathy
Started on caspofungin decrease dose in
patients with Child-Pugh score of 7 to 9
Labs: AST = 85U/L, ALT = 56U/L, Alk phos =
190U/L, total bilirubin = 1.8mg/dl, albumin =
2.9g/dl, LDH = 270U/L, PT/INR = 14.6/1.7, GGT
= 60U/L

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Case # 9
Patient Case #10
What is his Child-Pugh score?

A. 3

B. 5

C. 8

D. 11

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PK in Hepatic Disease
PK in Hepatic Disease
Rules for dosing in hepatic disease
High ER drugs affected more than low ER drugs
Conjugation maintained in liver disease
Start low and increase dose slowly

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 PK
PK in Hepatic
in Hepatic Disease
Disease

Child-Pugh Classification for Liver Disease

Points
1 2 3
Encephalopathy 0 1 or 2 3 or 4
Ascites 0 + ++
Bilirubin (mg/dL) < 1.5 1.5-2.3 > 2.3
Albumin (g/dL) > 3.5 2.8-3.5 < 2.8
Prothrombin time (seconds over control) 0-4 4-6 >6

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 Patient
Case # 10 Case #12

PL is a 45 y/o man with CRF

Phenytoin 400mg/day for seizures
Labs:
Phenytoin concentration = 13.6 mg/L
Albumin concentration = 4.2 g/dL

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 Case # 10
Patient Case #12
What do you recommend to do with his dose?

A. Make no changes in his current drug

regimen.
B. Keep the total daily dose the same but
change the regimen to 200mg BID.
C. Increase the dose for better seizure
control.
D. Decrease the dose to prevent toxicity.
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 Drug
Drug PK PK Information
Information
DRUG THERA- SAMPLING COMMENTS
PEUTIC ISSUES
RANGE
Phenytoin 10-20 mg/L Generally % free increases with renal failure
Free: 1-2 mg/L obtain trough and hypoalbuminemia;
concentrations induces liver enzymes;
susceptible to metabolic drug
interactions
Carbamazepine 4-12 mg/L Autoinduction;
active metabolite 10,11 epoxide

Phenobarbital 15-40 mg/L Enzyme inducer

Valproic acid 50-100 mg/L Saturable protein binding;

% free increases with renal failure
and hypoalbuminemia

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 Drug
Drug PK PK Information
Information
Equations to correct for increased free
fraction of phenytoin:
For changes in albumin:
Cp'
Cp =
Alb
(0.9 * ) + 0.1
4.4
For changes in albumin and/or renal function:
Cp'
Cp =
Alb
(0.48 * 0.9 * ) + 0.1
4.4
Workbook Page 1-592 49
 Case # 11
Patient Case #13
NR - 63 y/o man, renal insufficiency; A fib,
digoxin - rate control. Which is correct?
A. LD same, MD decreased.

B. LD decreased, MD same.

C. Neither dose should be changed.

D. Both doses should be changed.

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DrugDrug PK Information
PK Information
DRUG THERA- SAMPLING ISSUES COMMENTS
PEUTIC
RANGE
Digoxin 0.8-2.0 Prolonged distribution Vd decreases in renal disease;
mcg/L period necessitates susceptible to drug interactions
sampling > 6-12 hours
post dose
Lidocaine 2-6 mg/L Difficult to interpret due to
binding to AAG and Vd changes
in CHF and AMI
Procainamide 4-12 mg/L Active metabolite NAPA with
poorly defined therapeutic range
Quinidine 2-5 mg/L

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 Case # 12
Patient Case #14
PP - 34 y/o man with CP and UTIs; Tobramycin 400mg
IV daily. This high dose, extended interval regimen:
A.
concentration dependent killing.
B. is more efficacious than standard dosing.

C. does not require concentration monitoring.

D. will not cause nephrotoxicity.

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Drug Drug PK Information
PK Information
DRUG THERAPEUTIC SAMPLING ISSUES COMMENTS
RANGE

Amino- Cpmax = 4-10 mg/L Duration of infusion, High dose extended

glycosides (Amikacin = 20-30 mg/L) timing of first sample
Cpmin < 2 mg/L post-infusion (generally aminoglycoside dosing
(Amikacin = 10 mg/L) should be 0.5-1 hour) is generally
recommended to
decrease toxicity and
improve efficacy.
Vancomycin Cpmin = 10-20 mg/L Controversial whether to Higher trough concs.
obtain peaks or suggested in
concentrations altogether complicated MRSA
infections, but
increased risk of
nephrotoxicity.

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 Drug PK Information
Drug PK Information

DRUG THERAPEUTIC SAMPLING ISSUES COMMENTS

RANGE

Cyclosporine 100-250 mcg/L Whole blood samples Many drug interactions

Lithium 0.3-1.3 mmol/L Prolonged distribution

necessitates sampling
12 hours post dose

Theophylline 10-20 mg/L Treat as continuous

infusion with sustained
release dosage forms

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Case # 13
• A patient took a bolus IV dose of a drug X the serum concentration drawn
after injection was 50 mg. The rate of elimination = 0.3. If physician wants to
give next dose after 6 hour. What will be the serum concentration at this
time?

• A - 14
• B - 47
• C - 58
• D - 20

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Case # 13

• CP = CP’ e-kt
• CP = 50 x e -0.3x6
• Ln cp = ln 50 - (0.3x6)
• Ln cp = 3.9-1.8
• Ln cp=2.1
• Cp = ln 2.1 = 8
• So 8 mg is remaining from previous dose and dose after 6 hours will also
provide 50 mg conc so the new conc will be 58.

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Case # 14
• Current concentra on of drug X is 2 mg/dL. Rate constant of elimina on for
drug X is 0.12 – what is it’s approximate half life?
• A - 6 hours
• B - Can’t be determined from informa on
• C - 12 hours
• D - 3 hours

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ti
ti

ti
Case # 14
• T 1/2 = 0.693/k

• T1/2 = 0.693/0.12

• T1/2 = 5.7 = 6 hours.

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Thank You
zeeshankhan11@hotmail.com
linkedin.com/mwlite/in/zshank

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