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Disclaimer: CME certification for these activities has expired. All information is pertinent to the timeframe in which it was released.


Navigating The Concentration Curves: Pharmacologic Considerations In The Treatment Of HIV


GOAL
To provide infectious disease specialists with up-to-date information on the treatment of patients with HIV.

TARGET AUDIENCE
This activity is designed for infectious disease specialists. No prerequisites required.

LEARNING OBJECTIVES
The Johns Hopkins University School of Medicine takes responsibility for the content, quality, and scientific integrity of this CME activity. At the conclusion of this activity, the participant should be able to:

  • Identify the principles of pharmacokinetics and pharmacodynamics most relevant to combination antiretroviral therapy.
  • Discuss the rationale for pharmacoenhancement ("boosting") of protease inhibitors and the potential benefits and shortcomings of boosted double-protease inhibitor regimens.
  • Identify the mechanism and clinical implications of key drug-drug interactions associated with antiretroviral agents.
  • Anticipate, evaluate, and manage potential key drug-drug interactions in patients with HIV-1 infection.

ACCREDITATION STATEMENT
The Johns Hopkins University School of Medicine is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education
for physicians.

CREDIT DESIGNATION STATEMENT
The Johns Hopkins University School of Medicine designates this educational activity for a maximum of 2 AMA PRA Category 1 Credit(s)TM. Physicians should only claim credit commensurate with the extent of their participation in the activity.

The estimated time to complete this educational activity: 2 hours.
Release date: October 15, 2006. Expiration date: October 15, 2008.

DISCLAIMER STATEMENT
The opinions and recommendations expressed by faculty and other experts whose input is included in this program are their own. This enduring material is produced for educational purposes only. Use of The Johns Hopkins University School of Medicine name implies review of educational format, design, and approach. Please review the complete prescribing information of specific drugs or combinations of drugs, including indications, contraindications, warnings, and adverse effects, before administering pharmacologic therapy to patients.

This program is supported by an educational grant from GlaxoSmithKline.

Full Disclosure Policy Affecting CME Activities:
As a provider accredited by the Accreditation Council for Continuing Medical Education (ACCME), it is the policy of the Johns Hopkins University School of Medicine to require the disclosure of the existence of any significant financial interest or any other relationship a faculty member or a sponsor has with the manufacturer(s) of any commercial product(s) discussed in an educational presentation. The Program Director, Lead Author, and Participating Faculty reported the following:

PROGRAM DIRECTOR

John G. Bartlett, MD
Professor, Department of Medicine
Chief, Division of Infectious Diseases
Johns Hopkins University School of Medicine
Baltimore, Maryland
Dr Bartlett reports serving as a consultant on the HIV Advisory Board for Abbott Laboratories, Bristol-Myers Squibb Company, and GlaxoSmithKline.

LEAD AUTHOR

Courtney V. Fletcher, PharmD
Professor and Chair
Department of Clinical Pharmacy
University of Colorado Health Sciences Center
Denver, Colorado
Dr Fletcher reports serving on the speaker's bureau by participating on the ad-hoc advisory boards for Bristol-Myers Squibb Company, GlaxoSmithKline, and Tibotec Pharmaceuticals Limited.

PARTICIPATING FACULTY

Edward P. Acosta, PharmD
Associate Professor of Clinical Pharmacology
University of Alabama at Birmingham School of Medicine
Birmingham, Alabama
Dr Acosta reports having no financial or advisory relationships with corporate organizations related to this activity.

Thomas Gegeny, MS, ELS
Executive Director and Senior Editor
The Center for AIDS Information and  Advocacy
Houston, Texas
Mr Gegeny reports having no financial or advisory relationships with corporate organizations related to this activity.

John G. Gerber, MD
Professor of Medicine and Pharmacology
University of Colorado Health Sciences Center
Attending Physician
University Hospital Infectious Diseases Group Practice
University of Colorado Hospital
Denver, Colorado
Dr Gerber reports serving as a consultant for Bristol-Myers Squibb Company, Roche, and Tibotec Pharmaceuticals Limited; serving on the speaker's bureau for Gilead Sciences, Inc; and financial interests/stock ownerships for Pfizer Inc.

Steven C. Johnson, MD
Professor of Medicine
Division of Infectious Diseases
University of Colorado Health Sciences Center
Director, University of Colorado HIV/AIDS Clinical Program
University of Colorado Hospital
Denver, Colorado
Dr Johnson reports serving as a consultant for Abbott Laboratories, Gilead Sciences, Inc, and GlaxoSmithKline; and serving on the speaker's bureau for Abbott Laboratories, Gilead Sciences, Inc, and GlaxoSmithKline.

Angela M. Kashuba, PharmD, DABCP
Associate Professor of Pharmacy
School of Pharmacy
University of North Carolina-Chapel Hill
Director, University of North Carolina Center for AIDS Research
Clinical Pharmacology/Analytical Chemistry  Core
Chapel Hill, North Carolina
Dr Kashuba reports receiving grants/research support from Abbott Laboratories and Gilead Sciences, Inc; and serving on the speaker's bureau for Boehringer Ingelheim Pharmaceuticals, Inc and Roche.

Jennifer Justice Kiser, PharmD
Antiretroviral Clinical Pharmacology Fellow
University of Colorado School of Pharmacy
Denver, Colorado
Dr Kiser reports serving on the speaker's bureau for GlaxoSmithKline and Vertex Pharmaceuticals Inc.

Stan Louie, PharmD, PhD
Associate Professor of Pharmacy
University of Southern California
Los Angeles, California
Dr Louie reports receiving grants/research support from Bristol-Myers Squibb Company and GlaxoSmithKline.

Andrew D. Luber, PharmD
Consultant
Division of Infectious Diseases
University of Pennsylvania
Philadelphia, Pennsylvania
Dr Luber reports receiving grants/research support from Abbott Laboratories, Boehringer Ingelheim Pharmaceuticals, Inc, GlaxoSmithKline, Pfizer Inc, Roche, and Vertex Pharmaceuticals Inc; serving as a consultant for Abbott Laboratories, Boehringer Ingelheim Pharmaceuticals, Inc, GlaxoSmithKline, Pfizer Inc, Roche, and Vertex Pharmaceuticals Inc; and serving on the speaker's bureau for Abbott Laboratories, Boehringer Ingelheim Pharmaceuticals, Inc, GlaxoSmithKline, Pfizer Inc, Roche, and Vertex Pharmaceuticals Inc.

Notice: The audience is advised that articles in this CME activity contain reference(s) to unlabeled or unapproved uses of drugs or devices.

Dr Fletcher—dual-boosted protease inhibitors and ritonavir-boosted protease inhibitors; some drug interaction data have not yet appeared on the official product labeling, and some drug interaction data for investigational compounds are discussed.

All other faculty have indicated that they have not referenced unlabeled/unapproved uses of drugs or devices.

Johns Hopkins Advanced Studies in Medicine provides disclosure information from contributing authors, lead presenters, and participating faculty. Johns Hopkins Advanced Studies in Medicine does not provide disclosure information from authors of abstracts and poster presentations. The reader shall be advised that these contributors may or may not maintain financial relationships with pharmaceutical companies.

Navigating The Concentration Curves: Pharmacologic Considerations In The Treatment Of HIV
John G. Bartlett, MD

The plethora of antiretroviral agents now available has vastly improved and complicated the management of HIV infection. Clinicians who manage patients with HIV are confronted with an ever-increasing body of clinical information and treatment challenges. Because combination therapy is now considered the standard for HIV treatment, the potential for drug interactions is more prominent and relevant than ever. Not only are drug interactions possible between antiretroviral agents but between these agents and other prescription drugs, over-the-counter drugs, herbal or natural therapies, and recreational or street drugs. Although some drug interactions that occur with antiretroviral agents have little consequence, others can lead to severe toxicities, compromised HIV suppression, and/or the emergence of drug-resistant virus.

As new classes of antiretroviral agents are made available (eg, CCR5 receptor antagonists), in addition to newer formulations and fixed-dose coformulated products, the probability of drug interactions will increase. However, evaluation of potential drug-drug interactions is not likely to keep pace with the evolution of new therapies. Clinicians will continue to require up-to-date knowledge of the significant drug interactions associated with antiretroviral therapy (ART), in addition to a thorough understanding of the mechanisms of these interactions, to choose the most effective and safe therapeutic regimens.

This issue of Johns Hopkins Advanced Studies in Medicine first examines the principles of pharmacokinetic and pharmacodynamic considerations for antiretroviral agents. A drug-drug interaction may be categorized as pharmacokinetic when one drug affects the processes of absorption, distribution, or elimination of another, thereby increasing or decreasing plasma concentration levels. A pharmacodynamic interaction changes the pharmacologic effect or efficacy of an agent, and has the potential to be additive, synergistic, or antagonistic.

Many antiretroviral pharmacokinetic interactions alter the cytochrome P450 (CYP450) enzyme system, which plays an integral role in the liver metabolism of the non-nucleoside reverse transcriptase inhibitors (NNRTIs) or protease inhibitor (PIs). Drugs metabolized by CYP450 enzymes may be classified as substrates, inhibitors, inducers, or a combination of these. Inhibitors can increase plasma concentrations of antiretroviral agents to the extent that toxicity develops, whereas inducers can decrease plasma concentrations to the extent that resistance occurs.

This monograph reviews recent data regarding drug-drug interactions for each antiretroviral class, including specific drug-drug interactions within and between classes. Understanding how antiretroviral agents are metabolized and how they interact with the CYP450 isoenzymes, in addition to recognizing factors that affect their bioavailability, is fundamental to predicting drug-drug interactions. The approach of PI pharmacoenhancement, or PI boosting, accomplished by using a low dose of the PI ritonavir in addition to a therapeutic dose of a second PI, is discussed. The rationale for PI boosting is to improve the pharmacokinetic profile of the PI and/or overcome a decrease in plasma drug exposure resulting from another drug interaction. The advantages of PI boosting are several-fold and include increased potency, lower pill burden, decreased dosing frequency, and less potential for drug-drug interactions. A comprehensive update on drug interactions of the NNRTI and nucleoside reverse transcriptase inhibitor/nucleotide reverse transcriptase inhibitor classes with other antiretroviral drugs is also be presented.

The final segment in this issue of Johns Hopkins Advanced Studies in Medicine is devoted to a discussion of interactions between antiretroviral agents and concomitant medications. Because of the high prevalence of comorbid illnesses in patients with HIV, polypharmacy is common and prone to increase the potential for interactions with ART substantially. Clinicians are frequently unaware of other drugs that their patients may be taking in combination with antiretroviral therapy. Thus, obtaining a thorough history of past and present medications is vital for optimizing medication management and avoiding potentially serious drug interactions.

Because PIs, NNRTIs, and several other medications given concomitantly with antiretroviral agents are metabolized by the CYP3A4 isoenzyme, the potential for drug-drug interactions is significant. Of particular note is the inhibition of CYP3A4 by ritonavir that occurs with boosted PI regimens, which may precipitate high concentrations of concurrently administered drugs, including antiarrhythmic agents, ergot derivatives, and certain HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase inhibitors. Unboosted PIs also have the potential to cause serious or life-threatening interactions when coadministered with certain medications. Potentially serious drug-drug interactions that may occur with antiretroviral agents given in combination with gastric pH-altering medications, antimycobacterials, azole antifungals, and therapies for viral hepatitis are discussed.

Although the potential for infinite drug-drug interactions exists in the context of combination therapy with ART, not all of which may be clinically significant, physician awareness and anticipation of significant and harmful interactions should be guided utilizing pharmacokinetic and pharmacodynamic principles.

The content in this monograph was developed with the assistance of a medical writer. Each author had final approval of his/her article and all its contents.

*Professor, Department of Medicine, Chief, Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Address correspondence to: John G. Bartlett, MD, Professor, Department of Medicine, Chief, Division of Infectious Diseases, Johns Hopkins University School of Medicine, 1830 East Monument Street, Room 437, Baltimore, MD 21287. E-mail:
jb@jhmi.edu.





Johns Hopkins Advanced Studies in Medicine (ISSN-1558-0334), is published by Galen Publishing, LLC, d/b/a ASiM, PO Box 340, Somerville, NJ 08876. (908) 253-9001. Copyright ©2012 by Galen Publishing. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, without first obtaining permission from the publisher. ASiM is a registered trademark of The Healthcare Media Group, LLC.