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Drug Development Perspectives: |
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Nuggehally R. Srinivas |
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$99.75 |
July 2010 |
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Illustrated: |
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Contents
1. Bioanalytical Considerations in
Present-Day Drug Development:
Case Study of Bioanalysis of
Halofantrine With an Update on Its
Clinical Pharmacology,
Metabolism, Transport, and Distribution
Attributes
ABSTRACT
1.0 INTRODUCTION
2.0 SCOPE
3.0 BIOANALYSIS OF HALOFANTRINE
4.0 CLINICAL PHARMACOLOGY
4.1 Safety
considerations: QTc-related issues
4.2 Establishment of lymphatic
transport in preclinical models
4.3 Halofantrine as a
mechanistic probe for lymphatic drug transport
4.4 Influence of P-gylcoprotein-related efflux mechanisms
4.5 DDI potential with kolanut
4.6 DDI potential with
tetracycline
4.7 DDI potential with
grapefruit juice
5.0 TRANSPORT, DISTRIBUTION,
AND METABOLISM
5.1 Lymphatic absorption and
transport: lack of stereoselectivity
5.2 Stereoselectivity in
metabolism and tissue specificity
5.3 Hyperlipidemia-stereoselective
effects on tissue distribution, lipoprotein binding, and metabolism
5.4 Rat everted intestinal sac
metabolism: interplay among bile, lipids, and cholesterol levels
6.0 CONCLUSIONS: HALOFANTRINE
7.0 GENERAL CONSIDERATIONS AND
DISCUSSION
7.1 Background
7.2 Bioanalytical strategies
during various phases of discovery and development
7.3 Importance and perspectives
of metabolite bioanalysis
7.4 How to tackle the bioanalysis
of DDI samples
7.5 Assaying samples for TDM
7.6 Reducing the number of
calibration standards
7.7 Exploring sensitivity
enhancement by summation of multiple transition pairs
8.0 GENERAL CONCLUSIONS
9.0 REFERENCES
2. Allometry as a Tool in Drug Development: Case Studies,
Perspectives, and General
Consideration
ABSTRACT
1.0 INTRODUCTION
2.0 SCOPE
3.0 NEW CASE STUDIES FOR
ALLOMETRY PREDICTION
3.1 Methods
3.2 Allometry scaling
3.3 Difloxacin
3.4 Verapamil
4.0 DISCUSSION AND GENERAL
CONSIDERATIONS
4.1 Advantages of allometry
4.2 Challenges for allometry
5.0 CRITICAL ANALYSIS OF DATA
GATHERED FROM MULTIPLE SOURCES FOR ALLOMETRY
6.0 ALLOMETRY IN THE CONTEXT OF
CLINICAL ANDIDATE SELECTION AND EARLY DRUG DEVELOPMENT
6.1 Case study of linezolid
6.2 Considerations for a
prospective allometric design
7.0 THE FUTURE OF ALLOMETRY
7.1 Allometry in disease
models
7.2 Allometry for drug
combination strategies
7.3 Allometry for the
elucidation of the role of drug transporters
7.4 Pharrmacokinetic predictions
in humans of drugs that are predominantly absorbed by lymphatic transport
systems
7.5 Allometry for the prediction
of the likely enzymatic inhibition effects in humans
7.6 Allometry for the prediction
of enzymatic induction effects in humans
8.0 KEY LEARNINGS: THOUGHTS ON
PROSPECTIVE USE OF ALLOMETRY
9.0 CONCLUSIONS
10.0 REFERENCES
3. Cytochrome P450 2B6: Stereoselective Metabolism and
Bioassays
for Select Substrates焲ug
Development and Clinical and
Therapeutic Challenges
ABSTRACT
1.0 INTRODUCTION
2.0 SCOPE
3.0 CYP2B6 INVOLVEMENT IN
STEREOSELECTIVE METABOLISM
4.0 ANALYTICAL METHODS:
STEREOSELECTIVE QUANTITATION OF SELECT SUBSTRATES
5.0 SELECTION OF SOLVENTS FOR IN
VITRO MICROSOMAL WORK RELATED TO CYP2B6
6.0 DRUG DEVELOPMENT ISSUES
6.1 POTENTIAL
FOR INDUCTION
6.2 POTENTIAL FOR INHIBITION
7.0 CLINICAL/THERAPEUTIC
CHALLENGES OF INDUCTION AND INHIBITION OF CYP2B6
7.1 Use of rifampicin for
the treatment for chronic conditions
7.2 Rationalizing the use of
antimalarials in spite of CYP2B6 induction potential
7.3 Rationalizing the use of
methadone in HIV patients
7.4 Rationalizing the use of
ifosfamide in cancer patients
7.5 Combination of efavirenz
with dual protease inhibitors
7.6 Phenotyping for CYP2B6 when
known inducers are present
7.7 Challenges of dealing with a
CYP2B6 substrate and inhibitor
7.8 Dodging CYP2B6 inhibition by
variation of dosing schedule: case study of thioTEPA and cyclophosphamide
7.9 Circumventing toxic effects
in CYP2B6 inhibition
7.10 Enhancement of CYP2B6 in the
brain in a preclinical model
8.0 CHALLENGES DUE TO GENETIC
POLYMORPHISM
8.1 S-Methadone
metabolism in poor metabolizers of CYP2B6
8.2 Cyclophosphamide
conversion to active metabolite in CYP2B6 poor metabolizers
8.3 Efavirenz plasma levels in
CYP2B6 genotytpes
8.4 Bupropion and smoking cessation
dilemma: influence of extensive and poor metabolizer genotypes
8.5 Importance of low-affinity
CYP2B6 pathway in CYP2D6 poor metabolizer phenotypes
9.0 SUMMARY AND CONCLUSIONS
10.0 REFERENCES
4. Development, Regulatory, and Practical Considerations in
Clinical Pharmacology: The Use
of Simulations to Study the
Pharmacokinetics of
Orbifloxacin in Rabbits
ABSTRACT
1.0 INTRODUCTION
2.0 SCOPE
3.0 CASE STUDY OF ORBIFLOXACIN
3.1 Background
3.2 Methods
3.3 Results
3.4 Data interpretation and key
learnings
4.0 INTERPLAY OF CLINICAL
PHARMACOLOGY ATTRIBUTES: CASE STUDIES
4.1 Oseltamivir carboxylate
use with a known renal transporter inhibitor
4.2 Docetaxel use with a CYP3A4
inhibitor
4.3 Docetaxel use with a
P-glycoprotein inhibitor
4.4 Methotrexate modulation via
human organic anion transporter inhibitor/breast cancer resistance protein
transporter inhibitor
4.5 Optimization of photodynamic
therapy: role of probenecid to block the hepatobiliary excretion of deuxemether
4.6 Optimization of cytotoxic
therapy: role of probenecid in blocking the hepatobiliary excretion of
belotecan
4.7 Ophthalmology application:
overcoming multidrug resistance protein 1 for drug delivery in conjunctival
epithelial cells
4.8 Induction of uridine
diphosphate glucuronosyltransferase by rifampicin: perceived therapeutic
challenges to mycophenolate mofetil treatment
4.9 Induction of CYP2C19
isozyme: relevance to clopidogrel therapy
4.10 Boosting antiretroviral
therapy with ritonavir, a potent CYP3A4 inhibitor
5.0 PRACTICAL AND PRAGMATIC
CONSIDERATIONS FOR THE USE OF CLINICAL PHARMACOLOGY SCENARIOS
5.1 Drug products with
biopharmaceutical issues or exhibiting presystemic metabolism
5.2 Achievement and simulation
of maximum tolerated dose in humans
5.3 Obtaining high drug exposure
levels relevant to acute toxicology studies in animals
5.4 Short-term dose range榩nding
studies in toxicology when drug substance supply is an issue
5.5 Optimization of
cost-effective therapy
5.6 Exploratory brain
penetration work for targets located in the brain: compound
selection/deselection
5.7 Design elements and
substrate considerations for avoiding transporter-mediated efflux mechanisms
6.0 DEVELOPMENT AND REGULATORY
CHALLENGES
6.1 Selection of the
enzymatic/transporter inhibitor
6.2 Dose optimization considerations
6.3 Treatment duration
consideration
6.4 Potential interaction
liabilities
6.5 Toxicology-related
considerations
6.6 Implications of cholestasis
on transporter-mediated
pharmacokinetic disposition
6.7 Differential effects on
efflux mechanisms of 2 statins (rosuvastatin versus pravastatin) by gemfibrozil
6.8 Prediction of in vivo PK
disposition using in vitro data: 2 contrasting case studies involving
probenecid
6.9 Paradoxical effect of
rifampicin: enzyme induction and transporter inhibition
6.10 Brain penetration:
differential transporter步diated play
6.11 Unexpected induction
phenomenon observed with probenecid
7.0 DISCUSSION
8.0 CONCLUSIONS
9.0 REFERENCES
5. Clinical Pharmacology of Primary Metabolites That Exhibit
Genetic Polymorphic Disposition:
Case Studies of Pactimibe,
Rupatadine, and Rabeprazole
ABSTRACT
1.0 INTRODUCTION
2.0 SCOPE
3.0 BACKGROUND
3.1 CYP2D6-related
genetic polymorphisms
3.2 CYP2C19-related genetic
polymorphisms
3.3 CYP2C9-related genetic
polymorphisms
3.4 Consequences of inhibition
of polymorphic enzyme of primary metabolite
4.0 CASE STUDY OF PACTIMIBE
4.1 Clinical pharmacology
attributes of pactimibe
4.2 Case presentation
4.3 Development and regulatory
challenges
4.4 Key learnings from the case
study
5.0 CASE STUDY OF RUPATADINE
5.1 Clinical pharmacology
attributes of rupatadine
5.2 Case presentation
5.3 Development and therapeutic
challenges
5.4 Key learnings from the case
study
6.0 CASE STUDY OF RABEPRAZOLE
6.1 Description of clinical
pharmacology attributes of rabeprazole
6.2 Differentiation of
rabeprazole from the rest of the class
6.3 Case presentation
6.4 Therapeutic challenges
6.5 Key learnings from the case
study
7.0 GENERAL DISCUSSION
8.0 CONCLUSIONS
9.0 REFERENCES