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Exposure-Response Relationship and Therapeutic Drug Monitoring (TDM) for Antiretroviral Agents

(Last updated:8/4/2015; last reviewed:14/9/2015)

Panel’s Recommendations

  • Therapeutic drug monitoring (TDM) for antiretroviral (ARV) agents is not recommended for routine use in the management of the HIV-infected adult (BII).
  • TDM may be considered in selected clinical scenarios, as discussed in the text below.
Rating of Recommendations:  A = Strong; B = Moderate; C = Optional
Rating of Evidence:  I = data from randomized controlled trials; II = data from well-designed nonrandomized trials or observational cohort studies with long-term clinical outcomes; III = expert opinion

Knowledge about the relationship between a drug’s systemic exposure (or concentration) and responses (beneficial and/or adverse) is key in selecting the dose of a drug, in understanding why patients may respond differently to the same drug and dose, and in designing strategies to optimize drug response and tolerability.

Therapeutic drug monitoring (TDM) is a strategy used to guide dosing of certain antiarrhythmics, anticonvulsants, antineoplastics, and antimicrobial agents by using measured drug concentrations to improve the likelihood of the desired therapeutic and safety outcomes. Drugs suitable for TDM are characterized by a known exposure-response relationship and a therapeutic range of concentrations. The therapeutic range is a range of concentrations established through clinical investigations that are associated with a greater likelihood of achieving the desired therapeutic response and/or reducing the frequency of drug-associated adverse reactions.

#1529 - Therapeutic Drug Monitoring Services Australia
July 2014 - Feedback

Two laboratories in Australia provide this service:

Division of Clinical Pharmacology & Toxicology
SydPath
Xavier Building L6
St. Vincent’s Hospital
Victoria St
Darlinghurst NSW 2010

Contact:

Dr Ross Norris
Principal Hospital Scientist
Phone: +61 2 8382 9190,
Lab Phone: +61 2 8382 9184
Fax: +61 2 8382 3016
ross.norris@svha.org.au

Drug Tests available are:
Darunavir
Atazanavir
Ritonavir
Lopinavir
Raltegravir
Nevirapine
Efavirenz

HPLC / LC-MS/MS Department of Chemical Pathology
Level 3, Block 7
Royal Brisbane Hospital
Herston Road
Brisbane QLD 4102

Contact:
Brett McWhinney
Supervising Scientist
Phone: +61 7 3646 0028
Fax: +61 7 3646 3417 Brett.mcwhinney@health.qld.gov.au

Drug Tests available are:
Saquinavir
Indinavir
Ritonavir
Lopinavir
Amprenavir
Nevirapine
Efavirenz

Several antiretroviral (ARV) agents meet most of the characteristics of agents suitable for a TDM strategy.1 Specifically, some ARVs have considerable interpatient variability in drug concentrations; other ARVs have known drug concentrations associated with efficacy and/or toxicity; and in the case of other drugs, data from small prospective studies have demonstrated that TDM improved virologic response and/or decreased the incidence of concentration-related drug toxicities.2,3

TDM for ARV agents, however, is not recommended for routine use in the management of the HIV-infected adult (BII). This recommendation is based on multiple factors that limit the routine use of TDM in HIV-infected patients. These limiting factors include lack of prospective studies that demonstrate routine use of TDM improves clinical outcomes, uncertain therapeutic thresholds for most ARV agents, great intra- and inter-patient variability in drug concentrations achieved, and a lack of commercial laboratories to perform real time quantitation of ARV concentrations.2-5

Scenarios for Consideration of TDM

Multiple scenarios exist in which both ARV concentration data and expert opinion may be useful in patient management. Consultation with a clinical pharmacologist or a clinical pharmacist with HIV expertise may be advisable in these cases. These scenarios include the following:

  • Suspect clinically significant drug-drug or drug-food interactions that may result in reduced efficacy or increased dose-related toxicities;
  • Changes in pathophysiologic states that may impair gastrointestinal, hepatic, or renal function, thereby potentially altering drug absorption, distribution, metabolism, or elimination;
  • Among pregnant women who have risk factors for virologic failure (e.g., those not achieving viral suppression during earlier stage of pregnancy)—during the later stages of pregnancy, physiologic changes may result in reduced drug exposure and thus further increase the risk of virologic failure;
  • Heavily pretreated patients experiencing virologic failure and who may have viral isolates with reduced susceptibility to ARVs;
  • Use of alternative dosing regimens and ARV combinations for which safety and efficacy have not been established in clinical trials;
  • Concentration-dependent, drug-associated toxicities; and
  • Lack of expected virologic response in medication-adherent persons.

Resources for Therapeutic Drug Monitoring Target Concentrations

Most TDM-proposed target concentrations for ARVs focus on a minimum concentration (Cmin) (i.e., the plasma concentration at the end of a dosing interval before the next ARV dose). A summary of population average ARV Cmin can be found in a review on the role of ARV-related TDM.2 Population average Cmin for newer ARVs can be found in the Food and Drug Administration-approved product labels.

Guidelines for the collection of blood samples and other practical suggestions related to TDM can be found in a position paper by the Adult AIDS Clinical Trials Group Pharmacology Committee.4

Challenges and Considerations in Using Drug Concentrations to Guide Therapy.

There are several challenges and considerations for implementation of TDM in the clinical setting. Use of TDM to monitor ARV concentrations in a patient requires multiple steps:

  • quantification of the concentration of the drug, usually in plasma or serum;
  • determination of the patient’s pharmacokinetic characteristics;
  • integration of information on patient adherence;
  • interpretation of the concentrations; and
  • adjustment of the drug dose to achieve concentrations within the therapeutic range, if necessary.

Guidelines for the collection of blood samples and other practical suggestions can be found in a position paper by the Adult AIDS Clinical Trials Group Pharmacology Committee4.

A final caveat to the use of measured drug concentrations in patient management is a general one—drug concentration information cannot be used alone; it must be integrated with other clinical information, including the patient’s ARV history and adherence before the TDM result. In addition, as knowledge of associations between ARV concentrations and virologic response evolves, clinicians who use a TDM strategy for patient management should evaluate the most up-to-date information regarding the exposure-response relationship of the tested ARV agent.

Table 10a.  Trough Concentrations of Antiretroviral Drugs for Patients Who Have Drug-Susceptible Virus
Click here to view this table as an image

 Drug

 Concentration (ng/mL)

 Suggested minimum target trough concentrations in patients with HIV-1 susceptible to the ARV drugs [2-9]
 Fosamprenavir (FPV)

 400
(measured as amprenavir concentration)

 Atazanavir (ATV)

 150

 Indinavir (IDV)

 100

 Lopinavir (LPV)

 1000

 Nelfinavira (NFV)

 800

 Saquinavir (SQV)

 100-250

 Efavirenz (EFV)

 1000

 Nevirapine (NVP)

 3000

a Measurable active (M8) metabolite

 

Table 10b.  Trough Concentrations of Antiretroviral Drugs for Treatment-Experienced Patients with Virologic Failure
Click here to view this table as an image

 Drug

 Concentration (ng/mL)

 Suggested minimum target trough concentrations for ART-experienced patients who have resistant HIV-1 strains
 Maraviroc (MVC)

 >50

 Tipranavir (TPV)

20500

 Median (Range) Trough Concentrations from Clinical Trials [12-14]
 Darunavir (DRV) (600 mg twice daily)

 3300 (1255–7368)

 Etravirine (ETR)

 275 (81–2980)

 Raltegravir (RAL)

 72 (29–118)


References

  1. Spector R, Park GD, Johnson GF, et al. Therapeutic drug monitoring. Clin Pharmacol Ther. 1988;43(4):345-353.
  2. Pretorius E, Klinker H, Rosenkranz B. The role of therapeutic drug monitoring in the management of patients with human immunodeficiency virus infection. Ther Drug Monit. 2011;33(3):265-274. Available at http://www.ncbi.nlm.nih.gov/pubmed/21566505. 
  3. 3. Kredo T, Van der Walt JS, Siegfried N, Cohen K. Therapeutic drug monitoring of antiretrovirals for people with HIV. Cochrane Database Syst Rev. 2009(3):CD007268. Available at http://www.ncbi.nlm.nih.gov/pubmed/19588422. 
  4. Acosta EP, Gerber JG. Position paper on therapeutic drug monitoring of antiretroviral agents. AIDS Res Hum Retroviruses. 2002;18(12):825-834.
  5. van Luin M, Kuks PF, Burger DM. Use of therapeutic drug monitoring in HIV disease. Curr Opin HIV AIDS. 2008;3(3):266-271. 

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