Drug Development Perspectives:
Considerations, Challenges, and Strategies

Nuggehally R. Srinivas

 $99.75
Discounts on bulk purchases

July 2010
328 pp.

You must select a medium and a shipping option below

Medium

HOME | CONTACT US
Add me to mailing list

Illustrated:
ISBN: 978-0-9664286-9-8

 

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

About the Author | Preface

CATALOG
HOME
| CONTACT US
Add me to mailing list