Introduction

Clinical Pharmacology

Prof. Dr. dr. M.T. Kamaluddin, M.Sc., SpFK

Department of Pharmacology, Medical Faculty

Sriwijaya University

2021
Learning Objectives in Clinical
Pharmacology :
 Define Pharmacokinetics & Pharmacodynamics
 Identify PK/PD approaches, terminology, and
parameters
 Recognize and develop endpoints for PK/PD
modeling
 Identify barriers to molecularly targeted drugs
 Understand practical considerations in design of PK
studies in clinical protocols
Clinical Pharmacology?
Clinical Pharmacology?
discipline that teaches, does research, frames policy, gives information and
advice about the actions and proper uses of medicines in humans and
implements that knowledge in clinical practice".
Clinical Pharmacology is inherently a translational discipline underpinned
by the basic science of pharmacology, engaged in the experimental and
observational study of the disposition and effects of drugs in humans, and
committed to the translation of science into evidence-based therapeutics.
broad scope, from the discovery of new target molecules to the effects of
drug usage in whole populations.
The main aim of clinical pharmacology is to Generate data for optimum use
of drug's and the practice of 'evidence based Medicine'.
evaluate evidence and produce new data through well-designed studies.
access to enough outpatients for clinical care, teaching and education, and
research as well as be supervised by medical specialists.
responsible to patients in analyzing adverse drug effects, therapeutics, and
toxicology including reproductive toxicology, cardiovascular risks,
perioperative drug management and psychopharmacology.
 KASUS KLINIK

Seorang pasien laki-laki, 62 th menderita

hipertensi dan setelah berobat ke dokter rutin
diberi obat kaptopril 25 mg/hr. Terapi telah
berlangsung selama 2 bulan.
Hasil follow-up terakhir tidak menunjukkan
tekanan darahnya sudah terkendali...
Apa yang perlu di diskusikan???
Pharmacology is the study of drugs (chemicals) that
alter functions of living organisms.

CLINICAL PHARMACOLOGY is the use of drugs in

human :
to prevent, diagnose, or treat signs, symptoms, and
disease processes.

When prevention or cure is not a reasonable goal, relief of

symptoms can greatly improve quality of life and ability
to function in activities
of daily living.
Potential Therapeutic Outcomes

 Efficacy without toxicity

 Palliation
 Efficacy with toxicity
 Treatment, potentially curative
 Toxicity without efficacy
 Poison
 Neither toxicity nor efficacy
 Alternative medicine
Pharmacokinetics

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Plasma Concentrations (g/ml)

6
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0010 20 30 40 50
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PHARMACOKINETICS
Pharmacokinetics involves drug movement through the body
(ie, “what the body does to the drug”) to reach sites of
action,metabolism, and excretion.

Specific processes are absorption, distribution, metabolism

(biotransformation), and excretion.

Overall, these processes largely determine serum drug levels,

onset, peak and duration of drug actions, drug half-life, therapeutic
and adverse drug effects, and other important aspects
of drug therapy.
Pharmacokinetics
Kajian Jurnal
 European Journal of Clinical Pharmacology
 October 2017, Volume 73, Issue 10, pp 1209–1217| Cite as
 Risk of gastrointestinal events with newly approved (after 2011) vascular endothelial growth factor receptor tyrosine kinase inhibitors in
cancer patients: a meta-analysis of randomized controlled trials
• Jing Li ReviewFirst Online: 15 July 2017

 Abstract
 Purpose
 We performed a meta-analysis to systematically review the gastrointestinal (GI) events (diarrhea, nausea, vomiting, anorexia) of
five newly approved (after 2011) VEGFR-TKIs in cancer patients.
 Methods
 The relevant studies of the randomized controlled trials (RCTs) in cancer patients treated with cabozantinib, vandetanib,
lenvatinib, regorafenib, and axitinib were retrieved and the systematic evaluation was conducted.
 Results
 Forty-one randomized controlled trials and 10,860 patients were included. Current analysis suggested that the use of these agents
increased the risk of all-grade and high-grade GI events, and the diarrhea was the most common GI events. The risk of all-grade
and high-grade GI events varies significantly within drug types, tumor types, and VEGFR-TKIs-based regimens.
 Conclusion
 The available data suggested that the use of the five newly approved VEGFR-TKIs may increase risk of GI events in cancer
patients. Physicians and patients should be aware of these risks and frequent monitoring and careful management should be
emphasized when managing these VEGFR-TKIs.
 Keywords
 VEGFR-TKIs Gastrointestinal events  Cancer  Systematic review  Meta-analysis 
Overview of Pharmacokinetics
Drug Absorption
Drug Absorption
Drug Bioavailability
Drug Distribution to Tissues
Drug Metabolism
Drug Excretion
 Category Parameter Formula
Absorption Absorption rate constant Rate of drug absorption ÷ amount of drug
remaining to be absorbed
Bioavailability Amount of drug absorbed ÷ drug dose

Distribution Apparent volume of distribution Amount of drug in body ÷ plasma drug

concentration
Unbound fraction Plasma concentration of unbound drug ÷ total
plasma drug concentration

Elimination (metabolism and Rate of elimination Renal excretion + extrarenal (usually

metabolic) elimination
excretion)
Clearance Rate of drug elimination ÷ plasma drug
concentration, or elimination rate constant ×
apparent volume of distribution

Renal clearance Rate of renal excretion of drug ÷ plasma drug

Metabolic clearance
Fraction excreted unchanged
Elimination rate constant
concentration
Rate of drug metabolism ÷ plasma drug
concentration
Rate of renal excretion of drug ÷ rate of drug
elimination
Rate of drug elimination ÷ amount of drug in
body
Clearance ÷ volume of distribution

Biologic half-life 0.693 ÷ elimination rate constant (for first-

order elimination
 Comparison of pharmacokinetic outcomes for diazepam in a younger man
(A) and an older man (B).

Diazepam is metabolized in the liver to desmethyldiazepam through P-450 enzymes. Desmethyldiazepam is an active
sedative, which is excreted by the kidneys. Elimination half-life is inversely proportional to the terminal slopes of the curves;
flat slopes correspond to long half-lives. 0 = time of dosing. (Adapted from Greenblatt DJ, Allen MD, Harmatz JS, Shader
RI: Diazepamdisposition determinants. Clinical Pharmacology and Therapeutics 27:301–312, 1980.)

diazepam in a younger man (A) and an older man (B)." lang="en" />
diazepam in a younger man (A) and an older man (B).">

Jennifer Le, PharmD, MAS, BCPS-ID, FIDSA, FCCP, FCSHP,

November 2017
 Hypothetical dose-response curve.

Drug X has greater biologic activity per dosing equivalent and is thus more potent than drug
Y or Z. Drugs X and Z have equal efficacy, indicated by their maximal attainable response
(ceiling effect). Drug Y is more potent than drug Z, but its maximal efficacy is lower.

Abimbola Farinde, 2016

Pharmacodynamics
Oral drugs
 Other medications have objectionable tastes
and are sugar-coated to improve tolerability.
If this type of medication is crushed, the
patient would be subject to its unpleasant
taste, which could significantly impair
medication adherence. Additionally, both
sublingual and effervescent medications
should not be crushed because it will
decrease the medication’s effectiveness.
 Practical considerations in designing clinical
drug intervention trials

 Why this drug?

 What dose?
 What schedule?
 What combination?
 What about other interactions?
Administering Drugs: Things to
consider
 Age
 Renal status
 Liver function
 Polymorphisms
 Cytochrome P450 (genetics, drug interactions)
 Acetylator status (genetics)
 “Target” present?
Administering Drugs:
Things to consider
 What should I measure?
 How do I measure it?

Correct sampling schedule
 Validated method available?

and most importantly…

What do I do with the answer?

 Reasons for Attrition During Clinical Development

Percentage of New Drugs Failing 50

40

30

20

10

0
ety cy i on i al g y ds er
f a c lo h
Sa ff ic l at PK er o oo O
t
E m
u
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C
Nature Reviews Drug Discovery 2, 566-580 (2003)
Apparent Volume of Distribution (Vd)

Amt of DrugAmt
(dose)
of Drug (dose)
VConcentration
d = =
Concentration Vd

Small Vd
Low tissue binding Large Vd
Drug tightly bound
Clearance (CL)

Elimination Rate
CL =
Concentration

“It hurts when I pee.”

Area Under the Curve (AUC)

AUC
 Integration of
Conc. vs. Time

Measure of

systemic exposure
Half-life (t½)
 Time required to clear 50%
of drug
 Depends on Volume of
Distribution (Vd) and
Clearance (CL)
 Multi-phasic (if you can
capture the distribution
phase)
 Rule of Thumb: Drug is
cleared in 5 half-lives
t½ = Vd x ln(2) / CL
Other Important Parameters
 Peak plasma concentration [ Cmax, Tmax ]
 Bioavailability [ F ]
 Duration above a threshold concentration
 Free drug vs. total drug
 Cumulative dose
 Bioactivation to active metabolite
 Plasma protein binding
Terminology

10000
Cmax
8000
concentration

6000

4000
AUC
2000
Cmin
0
0 5 10 15 20 25
time (hours)
 PK Analysis
 Linear Pharmacokinetics
 “First order” kinetics

Covers most drugs
 Rate of change depends only
on the current [drug]

Half-life remains constant
no matter how high the
concentration

AUC not affected by dC
schedule dt
= -kC
• Example: doxorubicin
PK Analysis
 Non-Linear Pharmacokinetics (“zero order”)
 Classic examples: ethanol, phenytoin

Saturable metabolism
• Decreased CL at higher doses
• Shortened infusion  increased AUC
– Examples: 5-FU, Taxol


Saturable absorption
• Decreased proportional AUC at higher doses
• Lengthened infusion  increased plasma conc.
– Examples: methotrexate, cisplatin
PK/PD Modeling
 PK Variability in Ovarian Cancer Patients
250 mg/m2, 24 hr infusion, 22-23 hr sample, n = 48

Lowered
efficacy Myelosuppression

Cancer Chemother Pharmacol 33:48-52 (1993)

 PK/PD modeling of Taxol-
induced neutropenia
 Non-linear kinetics

 Myelosuppression related to
duration of threshold plasma
concentration
 [Taxol] ≥ 0.05 M

 Prediction of disposition and

toxicity

Gianni et al J Clin Oncol 13:180-190 (1995)

 PK/PD Modeling (paclitaxel)
First-Order Elimination (Abraxane)

Rate of elimination is proportional to
drug concentration

Constant fraction of drug eliminated
per unit time
Zero-Order Elimination (Taxol)

Rate of elimination constant
regardless of drug concentration

Constant amount of drug eliminated
per unit time
 paclitaxel (Taxol)

6 hr infusion, q 21d
 Cremaphor FORMULATION
275 mg/m
 Premedication
2

250 mg/m2
 Non-linear kinetics
175 mg/m2

J Clin Oncology 9:1261-1267 (1991)

paclitaxel (ABI_007)

NANOPARTICLES

30 MIN INFUSION, Q 21D
 No cremaphor
 No premeds
 Linear kinetics

Clin Cancer Res 8:1038-1044 (2002)

Stratton Clin Pharm AACR/ASCO Vail 2005
 PD Modeling Example: Pharmacogenetics
Myelotoxicity and UGT genetic polymorphisms

 Irinotecan

350 mg/m2
 90 min infusion, q3w

n = 66

 SN-38 metabolism dependent

on UGT variant
Grade 4
 Identification of patients
predisposed to severe
irinotecan toxicity

Innocenti et al. J Clin Oncol 22:1382-1388 (2004)

Molecularly-targeted Drugs

“We found a drug. Now go find something for it to cure.”

 Shift Towards Target-based vs.
Compound-based Development
 Compound-based (backward)

Interesting compound discovered with activity in in
vitro models

 Target-based (forward)

Protein or gene targets identified on carcinogenesis
pathway.

Drugs designed to interfere with these specific
targets
 Compound-based vs. Target-based Drug
Development
Compound-Based Target-Based

Compound isolated Target identified

Compound screened in cell culture Target validated in vitro

Activity in Animal Models Compounds screened for

target selectivity Mechanism

Clinical Trials Toxicology

Toxicology performed Clinical Trials

Phase I Phase I, II, III Clinical Trials
Phase II

in Patients Expressing Target

Phase III
EGFR as a Molecular Target
 Member of erbB family of receptor tyrosine
kinases

EGFR (ErbB1), HER2/Neu (ErbB2), HER3
(ErbB3) and HER4 (ErbB4)

 Overexpressed in various solid tumors


Overexpression has been correlated with poor
prognosis

 EGRF signaling is implicated in

angiogenesis, proliferation, and inhibition of
apoptosis
 EGFR Mechanism
 Extracellular glycosylated
ligand binding domain
 Transmembrane domain with
hydrophobic anchor
 Catalytic tyrosine kinase domain
 C-terminal end contains tyrosine
residues phosphorylated upon
ligand binding
 Dimerizes (homo or hetero)
upon ligand binding

Courtesy of Genentech
EGFR Targeted Therapy
 Neutralizing monoclonal antibodies
 cetuximab (Erbitux), a competitive inhibitor that
prevents dimerization

 Tyrosine kinase inhibitors

 gefitinib (Iressa), erlotinib (Tarceva)
• reversible inhibitors

GW572016 (lapatinib)
• duel EGFR/erbB2 irreversible inhibitor
• Forms covalent bonds with the cysteine residues in the ATP
binding site
Altered response to EGFR inhibitors

Mutations in the EGFR gene

 EGFR mutations have been characterized in
some solid tumors including gliomas, non-small
cell ling cancer, breast and ovarian cancers

 Activating mutations of EGFR correlate with

increased responsiveness to gefitinib in non-
small cell lung cancer
 Resistance to EGFR inhibitors

Activation of redundant pathways

Resistance caused by activation of other tyrosine kinase receptors that

bypass the EGFR pathway

Camp ER et al, Clin Cancer Res 11:397-405 (2005)

 Resistance to EGFR inhibitors

Constitutive activation of pathways downstream of EGFR

Activating mutations in
genes downstream of
EGFR signaling could
bypass the effect of the
EGFR inhibitor

Camp ER et al, Clin Cancer Res 11:397-405 (2005)

Resistance to EGFR inhibitors

Ligand-independent activation of EGFR

 EGFR can be activated by interaction with

integrins

 Urokinase plasminogen activator (uPA) can

activate Erk via the 51 integrin
 Cetuximab could not inhibit this pathway
 Summary: Issues with molecularly targeted
EGFR inhibitors
 Mutation in EGFR
 Activation of redundant pathways
 Constitutive activation of downstream
signaling factors
 Ligand-independent activation of EGFR
Concerns with Targeted Therapy

 “The Butterfly effect”


Predicting toxicities of a single target is difficult when the target of
interest is relatively upstream in a pathway
• Example: bortezomib (Velcade)  myelosuppression, fatigue, etc.

 Dosing regimens are difficult to determine


High potency  difficult detection of drug

Cytostatic mechanism  low toxicity, MED vs. MTD

 Targeted therapies may not be as “specific” as we think

(e.g., imatinib mesylate)

Pleiotropism
Concerns with Targeted Therapy (cont’d)
 Redundancy
 Cells that “find a way” get rewarded and select for
resistance

 Delivery (chemistry)
 The drug may not reach the target in vivo (PK)

 Bogus mechanism
 Almost all in vitro mechanisms are convenient to
believe once the xenograft data is positive
 A good biomarker is hard to find
Practical Advice in PK Study Design
 Practical Advice in PK Study Design
(cont’d)
Regulatory Considerations Patient Considerations

“It’s a baby. Federal regulations prohibit our

mentioning its race, age, or gender.” “I was hoping I could choose my own doctor”
 Practical Advice in PK Study Design
(cont’d)
 Don’t perform “PK” unless you know what to do with
the answer
 Capture adequate data (4-5 half lives95% elimination)

 Know your sample size

 The biometrist is your friend
 visit them early and often

 Be kind to nurses
 Do you really want that 16 hr PK?
 Don’t require a sample at the end of the infusion- too many
things at once is trouble
 Practical Advice in PK Study Design
(cont’d)
 Consider your patients
 Don’t exsanguinate
 Extended PK sampling can be exhausting
 Don’t sample from the infusion port

 Define and monitor sample handling!!

 Shipping whole blood at room temp instead of frozen plasma 
Disaster
 Cheap ink, cheap labels, and freezers don’t mix
 PHARMACODYNAMICS
Pharmacodynamics involves drug actions on target
cells and the resulting alterations in cellular biochemical
reactions and functions (ie, “what the drug does to the
body”).

As previously stated, all drug actions occur at the

cellular level.
Pharmacodynamics
Plasma proteins, mainly albumin (A), act as carriers for
drug molecules (D).
Bound drug (A–D) stays in bloodstream and is pharmacologically inactive.
Free drug (D) can leave the bloodstream and act on body cells.
 Pharmacodynamic Variables
 Maximum Effect (аll pharmacologic responses must have a
maximum effect (Emax). No matter how high the drug
concentration goes, a point will be reached beyond which no
further increment in response is achieved.

 Sensitivity (the sensitivity of the target organ to drug concentration

is reflected by the concentration required to produce 50% of
maximum effect, the EC50. Failure of response due to diminished
sensitivity to the drug can be detected by measuring—in a patient
who is not getting better—drug concentrations that are usually
associated with therapeutic response. This may be a result of
abnormal physiology—eg, hyperkalemia diminishes
responsiveness to digoxin—or drug antagonism—eg, calcium
channel blockers impair the inotropic response to digoxin.
Pharmacodynamic Variables (cont’d)

 Clearance is the single most important

factor determining drug concentrations.
Clearance is readily estimated from the
dosing rate and mean steady-state
concentration. Blood samples should be
appropriately timed to estimate steady-state
concentration.
SERUM HALF-LIFE (T1/2)

Serum half-life, also called elimination half-life, is the time required for the serum
concentration of a drug to decrease by 50%.

It is determined primarily by the drug’s rates of metabolism and excretion. A drug with
a short half-life requires more frequent administration than one with a long half-life.
When a drug is given at a stable dose, four or five halflives are required to achieve steady-state
concentrations and develop equilibrium between tissue and serum concentrations.

Because maximal therapeutic effects do not occur until equilibrium is

established, some drugs are not fully effective for days or weeks.
To maintain steady-state conditions, the amount of drug given must equal the
amount eliminated from the body.
When a drug dose is changed, an additional four to five halflives are required
to re-establish equilibrium; when a drug is discontinued, it is eliminated
gradually over several half-lives.
Вioavailability is defined as the fraction of a
given drug dose that reaches the circulation
in unchanged form and becomes available
for systemic distribution. The larger the
presystemic elimination, the smaller is the
bioavailability of an orally administered
drug.
Сеll membrane contains receptors for physiologic substances
such as hormones (H) and neurotransmitters (NT). These
substances stimulate or inhibit cellular function.
Drug molecules (Da and Db) also interact with receptors to
stimulate or inhibit cellular function
 Drug-Related Variables
 Dosage
 Route of Administration
 Drug–Diet Interactions
 Drug–Drug Interactions:

Increased Drug Effects (Additive effects, Synergism or potentiation,
Interference by one drug with the metabolism or elimination of a
second drug, Displacement of one drug from plasma protein-binding
sites by a second drug increases the effects of the displaced drug)

Decreased Drug Effects - Interactions in which drug effects are
decreased are grouped under the term antagonism (Example:
naloxone (a narcotic antagonist) + morphine (a narcotic or opioid
analgesic) >relief of opioidinduced respiratory depression. Naloxone
molecules displace morphine molecules from their receptor sites on nerve
cells in the brain so that the morphine molecules cannot continue to exert
their depressant effects.
 Client-Related Variables
 Age
 Body Weight
 Genetic and Ethnic Characteristics
 Gender (еxcept during pregnancy and lactation,
gender has been considered a minor influence on
drug action).
 Pathologic Conditions
 Psychological Considerations
 ADVERSE EFFECTS OF DRUGS
Тhe term adverse effects refers to any undesired responses to drug
administration, as opposed to therapeutic effects, which are desired
responses.
Some adverse effects occur with usual therapeutic doses
of drugs (often called side effects); others are more likely to
occur and to be more severe with high doses.
 CNS effects may result from CNS stimulation (eg, agitation,confusion,
delirium, disorientation, hallucinations,psychosis, seizures) or CNS
depression (dizziness, drowsiness, impaired level of
consciousness,sedation, coma, impaired respiration and circulation).
 Gastrointestinal effects (anorexia, nausea, vomiting, constipation,
diarrhea)
 Hematologic effects (blood coagulation disorders, bleeding disorders,
bone marrow depression, anemias, leukopenia, agranulocytosis,
thrombocytopenia)
 ADVERSE EFFECTS OF DRUGS
 Hepatotoxicity (hepatitis, liver dysfunction or failure, biliary tract
inflammation or obstruction)
 Nephrotoxicity (nephritis, renal insufficiency or failure)
 Hypersensitivity or allergy
 Drug fever
 Idiosyncrasy refers to an unexpected reaction to a drug that occurs the
first time it is given.
 Drug dependence
 Carcinogenicity is the ability of a substance to cause cancer.
 Teratogenicity is the ability of a substance to cause abnormal fetal
development when taken by pregnant women.

Drug toxicity (also called poisoning, overdose, or intoxication)

results from excessive amounts of a drug and may
cause reversible or irreversible damage to body tissues.
 Attenuation of adverse effects
 With conventional dosage forms, high peak blood concentrations
may be reached soon after administration with possible adverse
effects related to the transiently high concentration.
 Example : hypertensive patients taking rapid-release nifedipine products.

 The use of an extended-release product avoids the high initial

blood concentrations which cause the sudden reduction in blood
pressure and other significant haemodynamic changes such as
reflex tachycardia.1
 Example :
 is the transient nausea at sub-toxic concentrations which results from the local
irritation caused by high intestinal concentrations of some conventional-release
products such as theophylline.
Bioequivalence
 Relative Bioavailability
 Comparison between a test and
reference drug product
 commercial formulation vs. clinical trial
material

generic drug vs. reference listed drug
 drug product changed after approval vs.
drug product before change
Bioequivalence
 21 CFR 320.1 (e)
 the lack of a difference in the rate and extent
to which the active ingredient or active moiety
in pharmaceutical equivalents or
pharmaceutical alternatives becomes
available at the site of drug action when
administered at the same molar dose under
similar conditions in an appropriately
designed study.
Determining Bioequivalence
 Formulations:

Reference
 Test
 Study design (typical):
 healthy volunteers

single dose, two-way crossover
 administer drug under fasted conditions
 Determining Bioequivalence
 Compare Test vs. Reference

Ratios for AUC and Cmax
 Determine 90% confidence interval for ratios
 Criteria for log-transformed data:
• 90% CI: 0.8 to 1.25 (80% to 125%)
Bioequivalence

1400
test
1200
reference
concentration

1000
800
600
400
200
0
0 2 4 6 8 10 12
time (hours)
Bioequivalence:
Assumptions

 Plasma concentration data- surrogate for

active site
 Rate and extent of absorption are
similar- no significant difference in
exposure to drug
 Can extrapolate safety and efficacy data
from reference product to test product
Bioequivalence
 Flexibility of BE criteria

No flexibility for approval of generic drugs
 Innovator drugs- There is some room for
flexibility. Safety and efficacy data or
exposure-response data may make it
possible to determine that differences are
not meaningful.
Bioequivalence- Flexibility
Example

 Ritonavir SGC vs. Liquid

Parameter Point Estimate 90% Confidence Interval
AUC 1.351 1.036 – 1.762
Cmax 1.350 1.028 – 1.773
 Bioequivalence- Flexibility
Example

 Ritonavir SGC vs. Liquid

 Assessment

Outliers
 Low reference formulation bioavailability
• Review of previous studies
 Supporting safety data from NDA: 700 mg bid
Outline
 Terminology
 Bioequivalence
 Scenarios with antiretroviral drugs
 New formulations
 Alternative dosing regimens
 Drug interactions
 Dosing pediatric patients
 PK/PD Considerations
 Standard of Evidence
 Scenarios with
Antiretroviral Drugs
 New formulations
 Alternative dosing regimens
 Drug interactions
 Dosing pediatric patients

 Apply principles of bioequivalence, to

demonstrate “comparable pharmacokinetic
profiles”.
 New Formulations
 Apply typical BE criteria
 In many cases, we do not expect the
formulations to be bioequivalent.
 Examples:
 Modified release formulations and prodrugs
 Formulations with increased bioavailability
New Formulations
 Modified release formulations or prodrugs

1000
900 reference
800 test
700
plasma conc.

600
500
400
300
200
100
0
0 2 4 6 8 10 12 14
time (hours)
 New Formulations
21 CFR 320.23 (b)
... Some pharmaceutical equivalents or pharmaceutical
alternatives may be equivalent in the extent of their
absorption but not in their rate of absorption and yet may
be considered bioequivalent because such differences in
the rate of absorption are intentional and are reflected in
the labeling, are not essential to the attainment of effective
body concentrations on chronic use, and are considered
medically insignificant for the particular drug product
studied.
 New Formulations
 No approved modified release or prodrug
antiretroviral drug products

 Another situation: new formulation with

increased bioavailability
New Formulations
Formulations with increased bioavailability
 Example: Fortovase vs. Invirase
 Fortovase 1200 mg tid vs. Invirase 600 mg tid:
approximately a 9-fold increase in AUC.
 Concentrations higher at all times with
Fortovase
 Safety question
 Need to demonstrate improved efficacy
Change in Dosing Regimen
 Attempting to simplify dosing regimens
(TID to BID, BID to QD)
 Attempt to demonstrate comparable
plasma drug exposure to the approved
regimen
 Not likely that all exposure measures will
be similar between regimens
Change in Dosing Regimen
Example- Nelfinavir

 Nelfinavir:

Original regimen: 750 mg TID
 New regimen: 1250 mg BID
 Sponsor conducted clinical trial
 PK data submitted with clinical trial data
Change in Dosing Regimen
Example- Nelfinavir

PK change for 1250 mg BID vs. 750 mg TID

AUC  20%
Cmax  35%
Cmin, a.m.  57%
Cmin, p.m.  28%

Concern: safety and efficacy

Change in Dosing Regimen
Example- Nelfinavir

 Clinical Trial Data

 Study 542: 1250 BID vs. 750 TID, with
stavudine and lamivudine
 Results at 48 weeks
 1250 BID (n=323): 61% of patients had <400
copies/mL

750 TID (n=192): 58% of patients had <400
copies/mL

Safety: similar for both regimens
Change in Dosing Regimen
 Example: Protease inhibitor with short
plasma half-life

Change from TID to BID
 Expect:
Similar or higher AUC over 24 hrs.
Higher Cmax (safety question)
Lower Cmin (efficacy question)
Change in Dosing Regimen
Example of efficacy data
 Indinavir 800 mg q8hr vs. 1200 mg q12hr
 24 weeks:
The 1200 mg q12hr regimen was less
efficacious than the 800 mg q8hr regimen.
Change in Dosing Regimen
 Not likely that all exposure measures
will be similar between regimens.
 In some cases, may change formulation
and dosing regimen.
Change in Dosing Regimen
 Formulation change may allow a
change in dosing regimen, with little
change in AUC, Cmax or Cmin.
 In addition to comparing AUC, Cmax
and Cmin, need to consider shape of
the concentration vs. time curve.
Change in Dosing Regimen

250 Test QD
Reference BID
200
concentration

150

100

50

0
0 5 10 15 20 25 30
time (hours)
Guidance for Industry: Providing
Clinical Evidence of Effectiveness for
Human Drug and Biologic Products

To use pharmacokinetic data for

approval, when BE or “comparable
concentrations” have not been
demonstrated:
Need to understand the relationship
between blood concentrations
and response, including the time
course of the response.
Drug Interactions
 Coadministration of two or more drugs
results in a change in exposure and the
potential need for a dose adjustment

 PK enhancer: intentional use of

subtherapeutic dose one drug to
increase concentrations of another drug
Drug Interactions
 Antiretroviral drugs in combination with
other drugs: conventional dose
modification situation
 Example: Indinavir and rifabutin
Drug Interactions- Typical
 IDV 800 mg q8hr + RIF 150 mg qd vs.
IDV 800 mg q8hr

IDV AUC  32%

IDV Cmax  20%

IDV Cmin  40%
 Recommendation:

Increase IDV dose to 1000 mg q8hr when
administered with RIF.
 Drug Interactions
 RIF 150 mg qd + IDV 800 mg q8hr vs. RIF 300
mg qd
 RIF AUC  54%
 RIF Cmax  29%

25-desacetyl-RIF AUC  300%
 25-desacetyl-RIF Cmax  143%
 Recommendation:

Reduce RIF dose to one-half the standard dose when
administered with IDV.
Drug Interactions
 Medical decision: coadminister two
antiretroviral drugs. However, there
may be a PK interaction between these
drugs.
 Should the dose of either drug be
altered?
Drug Interactions
 Indinavir and efavirenz
 Indinavir 800 mg q8hr plus efavirenz:
 No significant change in efavirenz PK

Indinavir AUC  31%
 Indinavir Cmax  16%
Drug Interactions
 Increase indinavir dose to 1000 mg q8hr:

AUC similar to typical 800 mg q8hr
 Cmax higher (50%)
 Cmin similar
 Clinical trial included indinavir 1000 mg
q8hr with efavirenz 600 mg qd (n=429)
Drug Interactions
PK Enhancers
 PI in combination with potent metabolic inhibitor
(e.g., low dose ritonavir)
 Intent: increase concentrations of PI, not
antiviral efficacy of 2nd drug
 Alter dosing regimen for PI
 Exposure measures may be quite different from
approved regimens
Drug Interactions
PK Enhancers

 Example 1:

Increase AUC, Cmax, Cmin
 Indinavir/Ritonavir
Drug Interactions
PK Enhancers
 IDV/RTV 800/100 mg BID vs. IDV 800 mg q8hr:
 IDV AUC  170%

IDV Cmax  58%
 IDV Cmin  10-fold
 IDV/RTV 800/200 mg BID vs. IDV 800 mg q8hr:

IDV AUC  260%
 IDV Cmax  79%

IDV Cmin  25-fold
Drug Interactions
PK Enhancers

 Example 2:

Cmin higher, other exposure measure(s)
lower
 Amprenavir/Ritonavir
Drug Interactions
PK Enhancers
 Simulated amprenavir concentrations
 APV/RTV 450/100 mg BID vs. APV 1200 mg BID:
 APV AUC 

APV Cmax  56%

APV Cmin  340%
 APV/RTV 600/100 mg BID vs. APV 1200 mg BID:
 APV AUC  30%
 APV Cmax  42%

APV Cmin  500%
Drug Interactions
PK Enhancers
 Simulated amprenavir concentrations (continued)
 APV/RTV 900/200 mg QD vs. APV 1200 mg BID:
 APV AUC 

APV Cmax  34%

APV Cmin  200%
 APV/RTV 1200/200 mg QD vs. APV 1200 mg BID:
 APV AUC  22%
 APV Cmax 

APV Cmin  300%
Pediatric Dosing
 There are many factors to consider
when evaluating new formulations,
alternative dosing regimens and drug
interaction results for antiretroviral
drugs.
 Considering these factors in the context
of dosing pediatric patients adds
another layer of complexity.
Pediatric Dosing
 21 CFR 201.57(f)(9)(iv)
 Allows inclusion of pediatric use
information in the label without controlled
clinical trials of the use in children.
 Course of disease should be similar in
pediatric and adult populations.
 Sponsor must provide other information to
support use in children.
 Pediatric Dosing
 Additional information- PK data for drug in
pediatric population, to allow dose selection
 Evidence of comparable concentrations
between children and adults, or exposure-
response data, can link efficacy data.
 Some additional safety data may be
requested.
Pediatric Dosing
Example: Nelfinavir
 Pediatric dose: 20-30 mg/kg TID
 Compare to Adults: 750 mg TID
 Age 2-7 yr (n=6) Age 7-13 yr (n=8)
AUC  AUC 
Cmax  30% Cmax  15%
Cmin   12% Cmin   16%
 Greater PK variability in pediatric patients
 No BID PK data available for pediatric patients. Thus,
cannot extrapolate from adult BID safety and efficacy
data.
 Scenarios
Summary of Potential Issues
 New formulations:
 May not meet BE criteria, particularly for Cmax
 Change in dosing regimen:

Target AUC or Cmin, other exposure measures
will be different

Different shape of concentration vs. time curve
 Drug interactions: typical

Target AUC or Cmin; do not have flexibility to
match all exposure measures
Scenarios
Summary of Potential Issues
 Drug interactions: PK enhancers
 Increase all exposure measures (safety question)

Increase some exposure measures, decrease
others (safety and efficacy questions)
 Pediatric dosing

Try to match AUC or Cmin, other exposure
measures may be different
Scenarios
Summary of Potential Issues
Overall:
 In most situations, it will not be possible
to match AUC, Cmax, and Cmin.

Some lower concentrations: efficacy
question
 Some higher concentrations: safety
question
Outline
 Terminology
 Bioequivalence
 Scenarios with antiretroviral drugs
 New formulations
 Alternative dosing regimens
 Drug interactions
 Dosing pediatric patients
 PK/PD Considerations
 Standard of Evidence
 Using PK/PD
 Goals:

Identify specific exposure measures (AUC,
Cmax, Cmin) that are related to PD endpoints.
 Design exposure-response studies that will
allow the assessment of the clinical
implications of changing formulations or
dosing regimens of antiretroviral drugs.
Using PK/PD
 PD endpoints

Efficacy
 Safety
PK/PD Considerations
Pharmacometrics Consultation

Pharmacometrics Group:
Office of Clinical Pharmacology
and Biopharmaceutics
Pharmacokinetic
Considerations

 Correlation of exposure measures with one

another
 Time of sampling can affect Cmax and AUC
 Diurnal variation
 Shape of concentration vs. time curve
 Identification of Cmin
 Adjustment for protein binding
 Pharmacokinetic
Considerations
 Correlation of exposure measures with one
another

Cmin Cmin

Cmax Cmax
Pharmacokinetic
Considerations
 Time of sampling can affect Cmax and AUC
Example: Typical Cmax observed at 1 hour

Sample at 0, 0.5, 1, 2, 4, 6 hours
• Cmax = 5100
 Sample at 0, 0.5, 1.5, 2.5, 4, 6 hours
• Cmax = 4000

Sample at 0, 2, 4, 6 hours
• Cmax = 3000
Pharmacokinetic
Considerations
 Diurnal variation
 usually estimate AUC0-24 as
• AUC0-8 x 3
• AUC0-12 x 2

Estimation assumes that PK profile is the same in
the morning and evening.

There is some evidence that this estimation is not
appropriate, but do not have data for most drugs.
Pharmacokinetic
Considerations
 Shape of concentration vs. time curve

250 Test QD
Reference BID
200
concentration

150

100

50

0
0 5 10 15 20 25 30
time (hours)
 Pharmacokinetic
Considerations
 Identification of Cmin

high variability

arithmetic mean vs. geometric mean vs. median
example:
• arithmetic mean = 145
• geometric mean = 102
• median = 121

time of sample collection
• different dosing intervals
 Pharmacokinetic
Considerations
 Adjustment for protein binding
 Assume all patients have the same fraction of drug
bound to protein?
Example:
• Drug that is 99% (average) protein bound
• Patients 1 and 2 have Cmin = 1000
• Patient 1: 99.5% bound, 0.5% unbound, corrected Cmin = 5
• Patient 2: 98% bound, 2% unbound, corrected Cmin = 20
Pharmacodynamic
Considerations
 Suppression of virus: Different doses or
regimens may have similar efficacy
early in treatment, but may diverge at
later times.
Additional Considerations

 Mechanism of action
 Other exposure measures
 Multiple drug therapy
 Compliance
 Consumption of other agents or food
 Active metabolites
 Response in naïve vs. previously treated
patients
PK/PD Considerations

 If we do establish a PK/PD relationship,

does it apply to all situations?

3 drug classes
 All drugs within a class
 All populations
Outline
 Terminology
 Bioequivalence
 Scenarios with antiretroviral drugs
 New formulations
 Alternative dosing regimens
 Drug interactions
 Dosing pediatric patients
 PK/PD Considerations
 Standard of Evidence
Standard of Evidence
 Under different scenarios, there may be
different standards of evidence.

New formulation
Change in dosing regimen
PK enhancer
Drug interaction
Standard of Evidence
 The standard of evidence differs for
regulatory decisions vs. managing an
individual patient.
Additional resources

The journal scope includes (but not limited to

following classifications):
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 Medicinal chemistry, drug delivery
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Pharmacokinetics
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Development
 Therapeutic Drug Monitoring, Clinical Trials of Drug
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 Cardiovascular Pharmacology, Advanced Research Techniques in Pharmacology
 Signaling Pathways in Functional Cells, Chemotherapy, Drugs for Respiratory Disorders
 Antifungal, Antiviral, Antiprotozoal and Anthelmintic Drugs
 Pharmacology for Health Sciences, Pharmacology of the Central Nervous System
 Pedagogy in Pharmacology, Practical Problems in Biometry
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 Radio chemicals and Radiopharmaceuticals, Proteomics & Metabolomics
 Thank you
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