Evaluation of anti infective drugs updated

Evaluation of anti-infective drugs
Chemotherapy & immunopharmacology
By - Markos Tadele
Markos Tadele: evaluation of anti infective
drugs

Introduction
• The drug development process starts with the
synthesis of novel chemical compounds
• Substances with complex structures may be
obtained from various sources
– Plants (cardiac glycosides)
– animal tissues (heparin)
– microbial cultures (penicillin G)
– Cultures of human cells (urokinase), or by
means of gene technology (human insulin)
drugs

Parameters need to be addressed for drug evaluation
• To decide for which kind of clinical infection the
antibacterial drug product should be use, the
following information should be developed from
 in vitro studies
 animal models of infection
 (PK/PD) information from animal and
human studies and clinical trials
drugs

I. In vitro anti infective activity evaluation
General considerations for in vitro and in vivo
tests
• The goal should be to learn about a drug
product’s antibacterial activity in vitro and in
animal models of infection
• Tests are recommended to be done in three
replication
• QC parameters for in vitro susceptibility tests
antimicrobials of certified potency in
accordance with standardized procedures
(CLSI)
drugs

Development of QC Parameters for In Vitro
Susceptibility Testing
• should be established before determining the
activity of the antibacterial drug product
• to ensure the generation of precise, accurate,
and reproducible results
• If susceptibility information provided without
proper quality monitoring, the test procedure
and test results may be considered invalid.
drugs

Anti infective activity Information required
A) Antibacterial Spectrum of Activity
• Which type of organisms are affected?
genotypes, serotypes, biotypes, isolates
• known mechanisms of resistance should be
identified
• internationally approved antibacterial drug
products, especially those with the same
mechanism of action as the new drug should
be used
drugs

B. Mechanism of Action
• chemical structure and a description of any
structural or biological similarities to known
antibacterial drug products
• mechanism of action (e.g., inhibition of cell wall
synthesis, lysis of cell membrane, protein
synthesis, and inhibition of DNA or RNA
replication) should be demonstrated
• helps to understand development of resistance/
if occur lately
drugs

C. Intracellular Antimicrobial Concentration
Assessment
• The ability of an antibacterial drug product to
achieve significant intracellular concentrations
may have clinical importance
• when the target organism can reside within the
cell (e.g., Listeria, Chlamydophila, Legionella)
and phagocytosed pathogens
• Ex vivo studies may be suitable for this kinds
of study
drugs

E. Minimum inhibitory concentration/ MIC
• The MIC is the lowest concentration of
antimicrobial agent that completely inhibits
growth of the organism in tubes or micro-
dilution
• reported as the concentration of drug necessary
to inhibit 50% of strains (MIC50) , 90% of strains
(MIC90)
• Since growth and death of Mos are multifactoral
the conditions of the medium and the incubation
requirements must be standardized
drugs

D. Mechanism of Resistance Studies
• Resistance mechanisms may limit the
effectiveness of an antibacterial drug product in
clinical settings
– Mechanisms include alterations of the drug
product by production of enzymes (e.g., β-
lactamases, mutation)
– inability to reach the target
– changes in the affinity of the antibacterial
for the target site
– Drug transporting proteins etc…
drugs

F. Minimum lethal concentration/ MLC
• The bactericidal endpoint (MBC) at which 99.9%
of the final inoculum is killed
• (MBC) or (MFC), also known as the minimum
lethal concentration (MLC)
• MFC is also defined as the lowest concentration
of the drug that yields 98% – 99.9% killing
effect as compared to the initial inoculum
• Can be expressed like MIC, MBC90, MBC98,
MBC99
drugs

G. Immunotoxicology Evaluation of New Drugs
Five adverse event categories should be evaluated
1. Immunosuppression: Effects on the immune
system that result in decreased immune function
2. Immunogenicity: Immune reactions elicited by a
drug and/or its metabolites
3. Hypersensitivity: Immunological sensitization
due to a drug and/or its metabolites
4. Autoimmunity: Immune reactions to self-
antigens
5. Adverse Immunostimulation: Activation of
immune system effector mechanisms
drugs

H. Anti infective drug Interactions and Fixed
Combination Studies
• Drug interaction studies of antibacterial drug
products may provide information (e.g.,
synergy, antagonism, indifference)
• methods can include
– checkerboard titration analyzed by fractional
inhibitory concentration and
– kill curves
• These drug interactions are particularly
important for fixed combination drug products
(e.g., ß-lactam and ßlactamase inhibitor
combination)
drugs

drug Interactions….
• Drug interactions also can reflect the additive
nature of the pharmacodynamic effect of either
drug when taken with the other drug
 Concomitant medications
 dietary supplements
 some foods, such as grapefruit juice, may alter
metabolism and/or
 drug transport abruptly in individuals who
previously had been receiving and tolerating a
particular dose of a drug
drugs

I. Post-Antibiotic Effect (PAE)
• PAE measures the time to reach normal
logarithmic growth – log10
• The standard equation for PAE is:
PAE (hours) = T – C
• T = is the time required for the count of cfu to
increase 1 log10 (10-fold) above the count immediately
seen after drug treatment
• C = is the time required for the count to increase 1
log10 in an untreated control cultureMarkos Tadele: evaluation of anti infective
drugs

Post-Antibiotic Effect (PAE)
1
10
100
1000
10000
0 1 2 3 4 5 6
Time (hours)
Removal of
Antibiotic
ViableCount(cfu/ml)
Control
1.6 hours to increase 1 log10
1 log10 increase
3.1 hours to increase 1 log10
Antibiotic
Induced death
PAE = 3.1 - 1.6 = 1.5 hours
Due to antibiotic effect only
drugs

Post-Antibiotic Effect
• Precise mechanism is still not understood
• Examples of PAE
drugs

J. Other Effects of Antibacterial Drug Product
• post antibiotic leukocyte effect
• sub-MIC effects
• effects on endotoxin
• effects on virulence factors and
• interactions with the host immune
system.
drugs

II. Animal Therapeutic and Pharmacological
Studies
Why animals used in research
• in vitro activity of antibacterial drug products
may not translate into significant activity in
vivo
• Animal models of human disease can be
studied in induced animals
– provide potential efficacy and safety of
antibacterial drug products in humans.
drugs

Why animals used in research
• The basic cell processes are the same in all
animals, and they perform similar vital
functions
• Simple animals can be used to study complex
biological systems
• will mimic the infection of interest and the
pharmacokinetics of the drug product in
humans
• what happens in the body following treatment
with certain drugs (ADME)
drugs

Animals mostly used in research
drugs

Mammals in in researches
drugs

DIFFERENCE BETWEEN RATS AND MICE
• The rat is much larger in size and has greater
body weight as compared to the mouse.
• The mouse has a pointed face when compared
to the rat
• The rat has a thick and heavy tail. On the
other hand, a mouse has a very thin tail
• The rat has a higher pair of chromosomes, ie
22 pairs. On the contrary, the mouse has only a
20 pairs
• The rats have a longer gestation period
compared with the mice.
drugs

Animal experiment
• should at a minimum obtain information on:
– the natural history of the disease or
condition in humans and animals (is it the
same?)
– the etiologic agent and
– the proposed intervention (can work on
both?)
• Results can be reported as (ED50), (PD50),
(CD50)
drugs

III. Human Pharmacological Studies and Clinical
Trials
Steps to indicate the effectiveness and toxicity of
the agent
– investigation in vitro
– study effects in laboratory animals (studies
in cell culture- antivirals)
• The in vitro studies and the in vivo studies in
animals lead to investigational studies in man
• 4 phases
drugs

Clinical Study: Phase 1 (Human Pharmacology)
• Normal subjects; occasionally use patients (eg.
Hypertensive patients, highly toxic drugs)
• See if/how pharmacokinetics data from animal
studies extrapolates to human data
• Usually open label with ascending doses;
establish dose-range
• Build safety profile: monitor adverse effects
drugs

Studies conducted in Phase I typically involve one or
a combination of the following aspects:
a) Estimation of Initial Safety and Tolerability
 dose range expected to be needed for later
 clinical studies and to determine the nature of
adverse reactions
b) Pharmacokinetics
c) Assessment of Pharmacodynamics
 For PK/PD studies may be conducted to estimate
dosage regimen and doses
d) Early Measurement of Drug Activity
 Preliminary studies of activity or potential
therapeutic benefit
drugs

Phase II (Therapeutic Exploratory)
• In Phase II primary objective is to explore
therapeutic efficacy in patients
• patients who are selected by relatively narrow
criteria (relatively homogeneous)
• An important goal for this phase is to
determine the dose(s) and regimen for Phase
III trials.
• Confirm dose range is similar in such people; if
not, re-define range
• Blinding, randomization, controls used
drugs

Phase III (Therapeutic Confirmatory)
• primary objective is to demonstrate, or confirm
therapeutic benefit safety and efficacy profiles
claimed in Phase II
• Conducted on intended users, May have slightly
broader entry criteria - age, severity of disease
• Conducted between efficacy of the medicine is
demonstrated and New Drug Application (NDA)
• intended to provide an adequate basis for
marketing approval.
drugs

Phase III (Therapeutic Confirmatory)
Phase III may also further explore
– the dose-response relationship
– explore the drug's use in wider populations
– Drug performance in different stages of
disease
– combination effect with another drug (For
drugs intended to be administered for long
periods)
– trials involving extended exposure to the
drug are ordinarily conducted in Phase III,
although they may be started in Phase II
drugs

Phase IV (Therapeutic Use/PM surveilance)
• Phase IV begins after drug approval
• Therapeutic use studies go beyond the prior
demonstration, provide additional details about
the medicine's efficacy or safety profile
• New age groups, races, and other types of
patients can be studied
• previously unknown or inadequately quantified
adverse reactions and related risk factors are
an important aspect of many Phase IV studies
drugs

drugs

Subjects used in clinical studies
• Overall investigation Plan
– Phase 1 - Normal subjects: usually < 50
subjects, at one facility, safety parameters
– Phase 2 - Patients: about 50 - 100 subjects;
at two sites; may do some dose-range
assessment; safety and some initial efficacy
– Phase 3 - Patients: few hundred to several
thousand; multiple sites; main support
study
– Phase 4 - Patients (post-marketing): varies
drugs

References
• CLSI, 2009, Development of In Vitro Testing Criteria and
Quality Control Parameters; Approved Standard, CLSI
document M23-A3.
• CLSI, 2007, Methods for Antimicrobial Testing of Anaerobic
Bacteria; Approved Standard, CLSI document M11-A7.
• Background and History of Animal Testing Author: Ian
Murnaghan B.Sc (hons), M.Sc - Updated: 28 April 2015
• www.aboutanimaltesting.co.uk
• Spilker, Bert. Guide to Clinical Trials, Raven Press, 1984.
• Luellman, color atlas of pharmacology, 2005
• FDA, 2009, Microbiological Data for Systemic Antibacterial
Drug Products — Development, Analysis, and Presentation
drugs

Evaluation of anti infective drugs updated

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