Most current highly active antiretroviral therapy (HAART) regimens for HIV-positive patients contain two nucleoside reverse transcriptase inhibitors (NRTIs) with either a Protease inhibitor (PIs) or a non-nucleoside reverse transcriptase inhibitors (NNRTI). Notwithstanding the regulatory guidelines recommending therapeutic drug monitoring (TDM) for these drugs, therapeutic failure is a very serious concern implying drug induced toxicity and more importantly viral rebound and viral resistance.
Single dose, steady state and dose ranging studies have all more or less demonstrated that there is a positive correlation between plasma concentrations and therapeutic effects of anti-retrovirals (ARVs). However, one of the main challenges still seems to be the target concentrations for these drugs and their relevant inhibitory quotient. In this talk, we are going to examine these issues along with bioanalytical challenges, drug-effect and drug –toxicity relationships and finally drug-drug interactions within different HAART regimes.
Patient medication adherence, Medication adherence, Causes of medication non-adherence, Problems linked with Medication Non-adherence, Factors affecting medication adherence, Patient related factors, Social and Economic factor, Disease related factor, Health care provider related factors, Therapy related factors, pharmacist role in the medication adherence, role of pharmacist in the medication adherence, monitoring of patient medication adherence, Direct method, Indirect method
Pharmaceutical care concepts - clinical pharmacy ShaistaSumayya
The pharmaceutical care is defined as “the direct, responsible provision of medication-related care for the purpose of achieving definite outcomes that improve a patient’s quality of life.”
Pharmaceutical care involves the process through which a pharmacist cooperates with a patient and other professional in designing , implementation, and monitoring a therapeutic plan that will produce specific therapeutic outcomes for the patient
Patient medication adherence, Medication adherence, Causes of medication non-adherence, Problems linked with Medication Non-adherence, Factors affecting medication adherence, Patient related factors, Social and Economic factor, Disease related factor, Health care provider related factors, Therapy related factors, pharmacist role in the medication adherence, role of pharmacist in the medication adherence, monitoring of patient medication adherence, Direct method, Indirect method
Pharmaceutical care concepts - clinical pharmacy ShaistaSumayya
The pharmaceutical care is defined as “the direct, responsible provision of medication-related care for the purpose of achieving definite outcomes that improve a patient’s quality of life.”
Pharmaceutical care involves the process through which a pharmacist cooperates with a patient and other professional in designing , implementation, and monitoring a therapeutic plan that will produce specific therapeutic outcomes for the patient
Organization and objectives of ICH, expedited reporting, ICSR, PSURs, post approval expedited reporting, pharmacovigilance Planning, good clinical practices
Critical evaluation of biomedical literature - clinical pharmacyShaistaSumayya
Reviewing the ‘Biomedical Literature’ poses a great challenge to the clinical professionals.
Evaluating a scientific article is a complex task.
Knowledge of the standard anatomy of an article and idiosyncrasy of various types of studies will assist the reader to review the ‘Biomedical Literature’ efficiently
Biomedical Literature includes critical appraisal of the following contents:
Title
Abstract
Introduction
Objective
Materials and Methods
Study Designs
Bias
Statistics
Results and Analysis
Discussion and Conclusion
References
Pharmacovigilance in Pediatric Populations: Challenges and ConsiderationsClinosolIndia
Pharmacovigilance, the science and activities related to the detection, assessment, understanding, and prevention of adverse effects or any other drug-related problems, is of critical importance in pediatric populations. However, pharmacovigilance in this population presents unique challenges and requires specific considerations. Here are some key challenges and considerations in pharmacovigilance pertaining to pediatric populations
Pharmacovigilance in Special Populations: Considerations for Pediatric and Ge...ClinosolIndia
Pharmacovigilance is the science and activities related to the detection, assessment, understanding, and prevention of adverse effects or any other drug-related problems. When it comes to special populations, such as pediatric and geriatric patients, there are specific considerations that need to be taken into account in pharmacovigilance efforts. Here are some key points regarding pharmacovigilance in these population
Organization and objectives of ICH, expedited reporting, ICSR, PSURs, post approval expedited reporting, pharmacovigilance Planning, good clinical practices
Critical evaluation of biomedical literature - clinical pharmacyShaistaSumayya
Reviewing the ‘Biomedical Literature’ poses a great challenge to the clinical professionals.
Evaluating a scientific article is a complex task.
Knowledge of the standard anatomy of an article and idiosyncrasy of various types of studies will assist the reader to review the ‘Biomedical Literature’ efficiently
Biomedical Literature includes critical appraisal of the following contents:
Title
Abstract
Introduction
Objective
Materials and Methods
Study Designs
Bias
Statistics
Results and Analysis
Discussion and Conclusion
References
Pharmacovigilance in Pediatric Populations: Challenges and ConsiderationsClinosolIndia
Pharmacovigilance, the science and activities related to the detection, assessment, understanding, and prevention of adverse effects or any other drug-related problems, is of critical importance in pediatric populations. However, pharmacovigilance in this population presents unique challenges and requires specific considerations. Here are some key challenges and considerations in pharmacovigilance pertaining to pediatric populations
Pharmacovigilance in Special Populations: Considerations for Pediatric and Ge...ClinosolIndia
Pharmacovigilance is the science and activities related to the detection, assessment, understanding, and prevention of adverse effects or any other drug-related problems. When it comes to special populations, such as pediatric and geriatric patients, there are specific considerations that need to be taken into account in pharmacovigilance efforts. Here are some key points regarding pharmacovigilance in these population
A slide set covering important pharmacokinetic principles, including drug elimination kinetics, drug clearance, dosing, effective and maximum tolerated concentration and the therapeutic ratio. Provided by Professor John A Peters, University of Dundee.
MANAGEMENT OF HIV FALLS UNDER THREE MAJOR CATEGORIES
1.POST EXPOSURE PROPHYLAXIS(P.E.P)
2.TREATMENT/MANAGEMENT OF HIV-AIDS
3.TREATMENT OF ADJOINING CONDITIONS
eg-
-Fungal Infections
-Bacterial infections
-Viral infections
-NEOPLASIAS
-misc.( recurrent apthos ulcers, xerostomia,salivary G. enlargement)
Switch from Enfuvirtide to Raltegravir Lowers Plasma Concentrations
of Darunavir and Tipranavir: a Pharmacokinetic Substudy of the
EASIER-ANRS 138 Tria
Presentation: What's trending in medicines regulation? A January 2017 reflectionTGA Australia
This presentation provides a local perspective on recent developments in the medical technology and pharmaceutical landscape, and the future of the TGA in a global context.
Jill Blumenthal, M.D., of UC San Diego AntiViral Research Center, presents "International AIDS Conference 2014: A Moderately Rapid Review" at AIDS Clinical Rounds
Antiretroviral Resistance in HIV-1 Patients at a Tertiary Medical Institute in Saudi Arabia: a Retrospective Study and Analysis.
Journal Club,
Virology Rotation , 1/5/2019
Root cause Analysis (RCA) & Corrective and Preventive action (CAPA) in MRCT d...Bhaswat Chakraborty
This presentation describes Identification & differentiation of Protocol deviation & violation; Different methods of RCA & best suitable method for Multiregional Clinical Trial; CAPA management and CAPA application to other trial sites/CRO/SMO/ Country that is involved in same trial (Strategic Management and application of CAPA in MRCT)
This presentation gives effective solutions to outliers issue in bioequivalence trials. It described what would be acceptable to Regulatory agencies as well as some new approaches.
Equivalence approches for complex generics DIA 11 april 2019 Bhaswat Chakraborty
This is a workshop that i gave a few days ago on bioequivalence of complex generics like peptides, polymers, liposomes, colloids, ophthamic and topical produtcts.
Clinical trials that are needed for efficacy & safety evidence of Medical devices include feasibility (pilot) and Pivotal trials. An extended battery of preclinical trials are also needed for high risk devices.
Writing Science papers for for publication requires something more thatn creativity. Target journals, content organization, wrting style, elegance and referencing are equally important.
Multidisc review of NDAs and BLAs nipicon 2018 Dr. ChakrabortyBhaswat Chakraborty
NDAS and BLAs cannot be authoritatively reviewed these days until experts from different disciplines act together like a team. This presentation give some foundational points and an illustrative example in that regard.
Teaching by stories, anecdotes and historical facts sept 25 2018Bhaswat Chakraborty
Many difficult principles in science and humanities can be taught best by a story (of its discovery), by an anecdote or some historical facts about them.
Orientation and Adaptation for Post-Graduate Pharmacy ProgramsBhaswat Chakraborty
PG Pharmacy programs are more focused and professionally oriented than the undergraduate counterpart. Many soft skills are required along with the curricular competence for excellence at the PG level.
Scientific integrity calls for some basic originality. Plagiarism can destroy this original creativity and ideation. This presentation defines plagiarism (stealing from others' works) and some of the creative and systematic remedies.
Best Practices to Risk Based Data Integrity at Data Integrity Conference, Lon...Bhaswat Chakraborty
Data integrity can be implemented using several approaches. One of the most effective ways to implement DI is a risk based approach. The speaker elaborates this.
There are several dimensions in Pharmaceutical ethics -- Practice-, research- and community oriented. This presentation mainly deals with Clinical research oriented Ethics.
Young pharmaceutical scientists are and can get involved in all aspects of new drug discovery and development. They have to be appropriately qualified, trained and experienced though,
This presentation mainly deals with clinical development of biosimilar products. It also gives enough on non-clinical development so that the audience is well oriented.
High variability in PK can be a characteristic of certain drug products which require different from ordinary strategies and study designs for establishing bioequivalence.
High variability in PK can be a characteristic of certain drug products which require different from ordinary strategies and study designs for establishing bioequivalence.
New Directions in Targeted Therapeutic Approaches for Older Adults With Mantl...i3 Health
i3 Health is pleased to make the speaker slides from this activity available for use as a non-accredited self-study or teaching resource.
This slide deck presented by Dr. Kami Maddocks, Professor-Clinical in the Division of Hematology and
Associate Division Director for Ambulatory Operations
The Ohio State University Comprehensive Cancer Center, will provide insight into new directions in targeted therapeutic approaches for older adults with mantle cell lymphoma.
STATEMENT OF NEED
Mantle cell lymphoma (MCL) is a rare, aggressive B-cell non-Hodgkin lymphoma (NHL) accounting for 5% to 7% of all lymphomas. Its prognosis ranges from indolent disease that does not require treatment for years to very aggressive disease, which is associated with poor survival (Silkenstedt et al, 2021). Typically, MCL is diagnosed at advanced stage and in older patients who cannot tolerate intensive therapy (NCCN, 2022). Although recent advances have slightly increased remission rates, recurrence and relapse remain very common, leading to a median overall survival between 3 and 6 years (LLS, 2021). Though there are several effective options, progress is still needed towards establishing an accepted frontline approach for MCL (Castellino et al, 2022). Treatment selection and management of MCL are complicated by the heterogeneity of prognosis, advanced age and comorbidities of patients, and lack of an established standard approach for treatment, making it vital that clinicians be familiar with the latest research and advances in this area. In this activity chaired by Michael Wang, MD, Professor in the Department of Lymphoma & Myeloma at MD Anderson Cancer Center, expert faculty will discuss prognostic factors informing treatment, the promising results of recent trials in new therapeutic approaches, and the implications of treatment resistance in therapeutic selection for MCL.
Target Audience
Hematology/oncology fellows, attending faculty, and other health care professionals involved in the treatment of patients with mantle cell lymphoma (MCL).
Learning Objectives
1.) Identify clinical and biological prognostic factors that can guide treatment decision making for older adults with MCL
2.) Evaluate emerging data on targeted therapeutic approaches for treatment-naive and relapsed/refractory MCL and their applicability to older adults
3.) Assess mechanisms of resistance to targeted therapies for MCL and their implications for treatment selection
micro teaching on communication m.sc nursing.pdfAnurag Sharma
Microteaching is a unique model of practice teaching. It is a viable instrument for the. desired change in the teaching behavior or the behavior potential which, in specified types of real. classroom situations, tends to facilitate the achievement of specified types of objectives.
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We specializes in exporting high quality Research chemical, medical intermediate, Pharmaceutical chemicals and so on. Products are exported to USA, Canada, France, Korea, Japan,Russia, Southeast Asia and other countries.
Recomendações da OMS sobre cuidados maternos e neonatais para uma experiência pós-natal positiva.
Em consonância com os ODS – Objetivos do Desenvolvimento Sustentável e a Estratégia Global para a Saúde das Mulheres, Crianças e Adolescentes, e aplicando uma abordagem baseada nos direitos humanos, os esforços de cuidados pós-natais devem expandir-se para além da cobertura e da simples sobrevivência, de modo a incluir cuidados de qualidade.
Estas diretrizes visam melhorar a qualidade dos cuidados pós-natais essenciais e de rotina prestados às mulheres e aos recém-nascidos, com o objetivo final de melhorar a saúde e o bem-estar materno e neonatal.
Uma “experiência pós-natal positiva” é um resultado importante para todas as mulheres que dão à luz e para os seus recém-nascidos, estabelecendo as bases para a melhoria da saúde e do bem-estar a curto e longo prazo. Uma experiência pós-natal positiva é definida como aquela em que as mulheres, pessoas que gestam, os recém-nascidos, os casais, os pais, os cuidadores e as famílias recebem informação consistente, garantia e apoio de profissionais de saúde motivados; e onde um sistema de saúde flexível e com recursos reconheça as necessidades das mulheres e dos bebês e respeite o seu contexto cultural.
Estas diretrizes consolidadas apresentam algumas recomendações novas e já bem fundamentadas sobre cuidados pós-natais de rotina para mulheres e neonatos que recebem cuidados no pós-parto em unidades de saúde ou na comunidade, independentemente dos recursos disponíveis.
É fornecido um conjunto abrangente de recomendações para cuidados durante o período puerperal, com ênfase nos cuidados essenciais que todas as mulheres e recém-nascidos devem receber, e com a devida atenção à qualidade dos cuidados; isto é, a entrega e a experiência do cuidado recebido. Estas diretrizes atualizam e ampliam as recomendações da OMS de 2014 sobre cuidados pós-natais da mãe e do recém-nascido e complementam as atuais diretrizes da OMS sobre a gestão de complicações pós-natais.
O estabelecimento da amamentação e o manejo das principais intercorrências é contemplada.
Recomendamos muito.
Vamos discutir essas recomendações no nosso curso de pós-graduação em Aleitamento no Instituto Ciclos.
Esta publicação só está disponível em inglês até o momento.
Prof. Marcus Renato de Carvalho
www.agostodourado.com
Lung Cancer: Artificial Intelligence, Synergetics, Complex System Analysis, S...Oleg Kshivets
RESULTS: Overall life span (LS) was 2252.1±1742.5 days and cumulative 5-year survival (5YS) reached 73.2%, 10 years – 64.8%, 20 years – 42.5%. 513 LCP lived more than 5 years (LS=3124.6±1525.6 days), 148 LCP – more than 10 years (LS=5054.4±1504.1 days).199 LCP died because of LC (LS=562.7±374.5 days). 5YS of LCP after bi/lobectomies was significantly superior in comparison with LCP after pneumonectomies (78.1% vs.63.7%, P=0.00001 by log-rank test). AT significantly improved 5YS (66.3% vs. 34.8%) (P=0.00000 by log-rank test) only for LCP with N1-2. Cox modeling displayed that 5YS of LCP significantly depended on: phase transition (PT) early-invasive LC in terms of synergetics, PT N0—N12, cell ratio factors (ratio between cancer cells- CC and blood cells subpopulations), G1-3, histology, glucose, AT, blood cell circuit, prothrombin index, heparin tolerance, recalcification time (P=0.000-0.038). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and PT early-invasive LC (rank=1), PT N0—N12 (rank=2), thrombocytes/CC (3), erythrocytes/CC (4), eosinophils/CC (5), healthy cells/CC (6), lymphocytes/CC (7), segmented neutrophils/CC (8), stick neutrophils/CC (9), monocytes/CC (10); leucocytes/CC (11). Correct prediction of 5YS was 100% by neural networks computing (area under ROC curve=1.0; error=0.0).
CONCLUSIONS: 5YS of LCP after radical procedures significantly depended on: 1) PT early-invasive cancer; 2) PT N0--N12; 3) cell ratio factors; 4) blood cell circuit; 5) biochemical factors; 6) hemostasis system; 7) AT; 8) LC characteristics; 9) LC cell dynamics; 10) surgery type: lobectomy/pneumonectomy; 11) anthropometric data. Optimal diagnosis and treatment strategies for LC are: 1) screening and early detection of LC; 2) availability of experienced thoracic surgeons because of complexity of radical procedures; 3) aggressive en block surgery and adequate lymph node dissection for completeness; 4) precise prediction; 5) adjuvant chemoimmunoradiotherapy for LCP with unfavorable prognosis.
Title: Sense of Taste
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the structure and function of taste buds.
Describe the relationship between the taste threshold and taste index of common substances.
Explain the chemical basis and signal transduction of taste perception for each type of primary taste sensation.
Recognize different abnormalities of taste perception and their causes.
Key Topics:
Significance of Taste Sensation:
Differentiation between pleasant and harmful food
Influence on behavior
Selection of food based on metabolic needs
Receptors of Taste:
Taste buds on the tongue
Influence of sense of smell, texture of food, and pain stimulation (e.g., by pepper)
Primary and Secondary Taste Sensations:
Primary taste sensations: Sweet, Sour, Salty, Bitter, Umami
Chemical basis and signal transduction mechanisms for each taste
Taste Threshold and Index:
Taste threshold values for Sweet (sucrose), Salty (NaCl), Sour (HCl), and Bitter (Quinine)
Taste index relationship: Inversely proportional to taste threshold
Taste Blindness:
Inability to taste certain substances, particularly thiourea compounds
Example: Phenylthiocarbamide
Structure and Function of Taste Buds:
Composition: Epithelial cells, Sustentacular/Supporting cells, Taste cells, Basal cells
Features: Taste pores, Taste hairs/microvilli, and Taste nerve fibers
Location of Taste Buds:
Found in papillae of the tongue (Fungiform, Circumvallate, Foliate)
Also present on the palate, tonsillar pillars, epiglottis, and proximal esophagus
Mechanism of Taste Stimulation:
Interaction of taste substances with receptors on microvilli
Signal transduction pathways for Umami, Sweet, Bitter, Sour, and Salty tastes
Taste Sensitivity and Adaptation:
Decrease in sensitivity with age
Rapid adaptation of taste sensation
Role of Saliva in Taste:
Dissolution of tastants to reach receptors
Washing away the stimulus
Taste Preferences and Aversions:
Mechanisms behind taste preference and aversion
Influence of receptors and neural pathways
Impact of Sensory Nerve Damage:
Degeneration of taste buds if the sensory nerve fiber is cut
Abnormalities of Taste Detection:
Conditions: Ageusia, Hypogeusia, Dysgeusia (parageusia)
Causes: Nerve damage, neurological disorders, infections, poor oral hygiene, adverse drug effects, deficiencies, aging, tobacco use, altered neurotransmitter levels
Neurotransmitters and Taste Threshold:
Effects of serotonin (5-HT) and norepinephrine (NE) on taste sensitivity
Supertasters:
25% of the population with heightened sensitivity to taste, especially bitterness
Increased number of fungiform papillae
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Knee anatomy and clinical tests 2024.pdfvimalpl1234
This includes all relevant anatomy and clinical tests compiled from standard textbooks, Campbell,netter etc..It is comprehensive and best suited for orthopaedicians and orthopaedic residents.
ARTIFICIAL INTELLIGENCE IN HEALTHCARE.pdfAnujkumaranit
Artificial intelligence (AI) refers to the simulation of human intelligence processes by machines, especially computer systems. It encompasses tasks such as learning, reasoning, problem-solving, perception, and language understanding. AI technologies are revolutionizing various fields, from healthcare to finance, by enabling machines to perform tasks that typically require human intelligence.
These simplified slides by Dr. Sidra Arshad present an overview of the non-respiratory functions of the respiratory tract.
Learning objectives:
1. Enlist the non-respiratory functions of the respiratory tract
2. Briefly explain how these functions are carried out
3. Discuss the significance of dead space
4. Differentiate between minute ventilation and alveolar ventilation
5. Describe the cough and sneeze reflexes
Study Resources:
1. Chapter 39, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 34, Ganong’s Review of Medical Physiology, 26th edition
3. Chapter 17, Human Physiology by Lauralee Sherwood, 9th edition
4. Non-respiratory functions of the lungs https://academic.oup.com/bjaed/article/13/3/98/278874
1. Therapeutic Drug Monitoring of
Anti-Retroviral Drugs
Track 3-1 Lecture at International Conference and Exhibition on
Analytical and Bioanalytical Techniques, Hyderabad, India
November 1-3, 2010
Dr. Bhaswat S. Chakraborty
Senior VP, Cadila Pharmaceuticals Ltd.
02.11.2010
2. Contents
• Current highly active antiretroviral therapy (HAART)
• Guidelines for administering HAART
• Correlation between plasma concentrations and therapeutic effects
• Drug –toxicity relationships
• Drug-drug interactions within different HAART regimes
• Therapeutic drug monitoring (TDM)
▫ Purpose
▫ Challenges
▫ Approaches
• Bioanalytical challenges
• Conclusions
3. ARV Drugs Darunavir
Enfuvirtide Maraviroc
• NRTI, Nucleoside reverse transcriptase inhibitor; Atazanavir Raltegravir
• NNRTI, Non-nucleoside reverse transcriptase inhibitor; Emtricitabine Tipranavir Etravirine
• PI, protease inhibitor Fosamprenavir
• Integrase Inhibitor
Tenofovir
• CCR5 Antagonist/Entry Inhibitor Nelfinavir
Delavirdine
Lopinavir/r
Ritonavir
Indinavir Amprenavir
Nevirapine Efavirenz
Abacavir
3TC
Saquinavir
ddC d4T
ddl
AZT
Source : Dr. David Back, Univ. of Liverpool
4. Main classes of ARV drugs
• Nucleoside and nucleotide reverse transcriptase inhibitors
(NRTI) inhibit reverse transcription by being incorporated into
the newly synthesized viral DNA and preventing its further
elongation.
• Non-nucleoside reverse transcriptase inhibitors (NNRTI) inhibit
reverse transcriptase directly by binding to the enzyme and
interfering with its function.
• Protease inhibitors (PIs) target viral assembly by inhibiting the
activity of protease, an enzyme used by HIV to cleave
nascent proteins for final assembly of new virons.
• Integrase inhibitors (II) inhibit the enzyme integrase, which is
responsible for integration of viral DNA into the DNA of the
infected cell.
5. Highly active antiretroviral therapy (HAART)
regimens for HIV-positive patients
• Most current HAART regimens consist of three (3) drugs: 2 NRTIs + a PI
or NNRTI or II
▫ Initial regimens use "first-line" drugs with a high efficacy and low
side-effect profile.
• Current preferred initial regimens
• Emtricitabine, tenofovir (both NRTI) and efavirenz (a NNRTI).
• Efavirenz should not be given to pregnant women.
• Emtricitabine, tenofovir and raltegravir (an II)
• Emtricitabine, tenofovir, ritonavir and darunavir (both latter are PI)
• Emtricitabine, tenofovir, ritonavir and atazanavir (both latter are PI)
6. Meaningful inhibitory concentration
• A parameter to estimate in vivo potency of antiretroviral drugs
• Cmin/IC50 is suitable for across-study, across-patient and across-drug
comparison
• ICmin is generated from in vivo pharmacokinetic data
• IC50 or IC95 are generated in vitro, increasing drug concentration
until 50% or 95% of the virus is inhibited
• How close the IC50 and IC95 values are to each other depends on how
steep the curve is (see lower graph)
• How reliable the values are depends on the system used to measure
them
• IQ (inhibitory quotient):
• IQ = trough concentration in plasma/concentration required for
inhibition in vitro
• Gives an index of how far the concentration of a drug in vivo is in
excess of the viral IC50
7. Guideline websites
Country Website
France www.sante.gouv.fr
Germany
and Austria www.rki.de/infekt/aids_std/az_eng/az_e.htm
Italy www.ministerodellasalute/aids/aids.jsp
UK www.bhiva.org
USA www.cdc.org
Netherlands www.NVAB.org
9. Therapeutic Drug Monitoring
(DHHS Guidelines 2009)
1. When food-drug and drug-drug interactions lead to decreased efficacy
2. Pathophysiological conditions that impair GI, hepatic function, and
renal function, thereby affecting ADME
3. Treatment-experienced pts with virus with reduced susceptibility to
ARVs (higher concentrations may be required).
4. Treatment-naive pts with suboptimal virologic response
5. In pregnant women due to metabolic and physiological changes that
can affect PK
6. For prevention of ARV-induced concentration-dependent toxicity
7. When using unconventional ARV regimens or dosing not studied in
clinical trials
8. Consider in pediatric pts when there are limited dosing data
11. Simulated probabilities of target trough
concentrations of Efavirenz in children
Antivir Ther. 2008;13:77987.
12. Plasma
concentrations and
viral clearance
in 4 drug therapy
Hoetelmans et al. (1998), AIDS. 12:F111-F115
13. Plasma concentrations and viral clearance
in mono & multi therapy
Lotsh et al. (2007), Antimicrob Agents Chemotherap, 51:3264–3272
14. Steady-state saquinavir plasma concentration-
versus-time profiles; n = 56
Very similar
Lotsh et al. (2007), Antimicrob Agents Chemotherap, 51:3264–3272
15. Inter-individual variation in saquinavir
plasma concentrations; n = 56
Lotsh et al. (2007), Antimicrob Agents Chemotherap, 51:3264–3272
16. ADRs vs. Saquinavir plasma concentrations;
n = 56
Log Cmax,saquinavir was predictive (P 0.001 [chi-square after logistic
regression]) of constitutional side effects such as asthenia and
sleepiness (n 7), lymphadenopathy (n 2), orthostatic dizziness (n
2), fever without infection (n 1), weight gain (n 1), peripheral
edema (n 1), and spontaneous pneumothorax (n 1) and GI side
effects.0
Lotsh et al. (2007), Antimicrob Agents Chemotherap, 51:3264–3272
19. TDM of antiretroviral drugs – rationale and
purpose
1. Compliance
2. ARV plasma or cell drug concentrations correlate
with antiviral effects
3. Drug concentrations also correlate with excessive
toxicity
4. High variations are present in plasma or cell drug
concentrations
5. Hepatic dysfunction changes clearance of the drug
20. TDM of antiretroviral drugs – approaches
1. Exactly knowing the target concentrations especially multi-
therapy targets
2. Four drug therapy failures do not tell you exactly what
concentrations of which drug should be changed
3. Resistant isolates may require higher drug concentrations
4. Inter- and intra-individual variability
5. Drug-drug and drug food interaction
6. Bioavalilability enhancement
1. e.g., of indinavir by ritonavir
7. Which PK parameter (AUC, Cmin Cmin/IC50)?
21. Bioanalytical Development of antiretroviral
drugs – approaches
1. Many PIs show low nanograms of levels (also do hair and blood
spots)
2. Sensitive and accurate HPLC or LC-MS-MS methods are most
suitable
3. Plasma, dried blood spots, hair, saliva or lysates of peripheral
blood mononeuclear cells (PBMCs) are the drug containing
matrices
4. Simultaneous analysis many drugs and internal standards
1. Selecting MRMs for all is challenging
5. PBMC or dried blood spot concentration for PIs or NNRTIs
would be more relevant as these drugs act intracellularly
6. Sample pre treatments (e.g., PBMC) may be required for CCs and
QCs
28. PBMC matrix effect
• The number of PBMC cells vary significantly from sample to
sample due to
▫ Natural variation in systemic circulation
▫ Variation in cell recovery
• Therfore, investigation of PBMC ME is required
Heine et al, (2009) J Chromatogr B Analyt Technol Biomed Life Sci. 877: 57580