(Last updated: March 1, 2016; last reviewed: March 1, 2016)
|Rating of Recommendations: A = Strong; B = Moderate; C = Optional
Rating of Evidence: I = One or more randomized trials in children† with clinical outcomes and/or validated endpoints; I* = One or more randomized trials in adults with clinical outcomes and/or validated laboratory endpoints with accompanying data in children† from one or more well-designed, nonrandomized trials or observational cohort studies with long-term clinical outcomes; II = One or more well-designed, nonrandomized trials or observational cohort studies in children† with long-term outcomes; II* = One or more well-designed, nonrandomized trials or observational studies in adults with long-term clinical outcomes with accompanying data in children† from one or more similar nonrandomized trials or cohort studies with clinical outcome data; III = Expert opinion
† Studies that include children or children/adolescents, but not studies limited to post-pubertal adolescents
The goal of therapeutic drug monitoring (TDM) of antiretroviral (ARV) drugs is to optimize treatment responses and tolerability, and to minimize drug-associated toxicity. TDM may be useful in clinical management with drugs that have a known exposure-response relationship and a relatively narrow therapeutic window of desirable concentrations. The therapeutic window is a range of concentrations that are associated with the greatest likelihood of achieving the desired therapeutic response and/or reducing the frequency of drug-associated adverse reactions in clinical investigations. While many ARV drugs (e.g., most protease inhibitors, first-generation non-nucleoside reverse transcriptase inhibitors, the CCR5 receptor antagonist maraviroc) have target plasma trough concentrations associated with viral efficacy, only a few ARV drugs have drug levels associated with toxicity (e.g., nevirapine and efavirenz). Most TDM targets have been established in adult studies, but several drugs (e.g., lopinavir, nelfinavir, efavirenz, nevirapine) have had target concentrations validated in pediatric studies. The suggested efficacy plasma trough concentrations are generally applicable when resistance testing demonstrates susceptibility of the patient’s virus to the particular ARV drug. Table 17 includes data on the efficacy plasma trough concentrations derived from adult clinical trials of the ARV drugs. Currently, most TDM target concentrations for ARV drugs focus on reaching a trough or minimum concentration (Cmin).1 Population average Cmin for all ARV drugs can be found in the Food and Drug Administration-approved product labels.
|Established Efficacy Plasma Trough Concentrations|
|a Adapted from: Department of Health and Human Services. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. 2014.|
|b Measurable amprenavir concentration|
|c Measurable active (M8) metabolite|
|d Suggested median plasma trough concentration in treatment-experienced patients with resistant HIV-1 strain only|
Several adult and pediatric studies have suggested that TDM can have some utility to guide dosing of ARV drugs.1-10 Despite this evidence, the routine use of TDM in adult and pediatric patients is not recommended for the following reasons: lack of prospective studies that demonstrate improved clinical outcomes, uncertain target ranges for most ARV drugs, high intrapatient variability in drug concentrations, and a lack of commercial laboratories willing to provide real-time quantitation of ARV plasma concentrations.
There are special considerations with dosing of ARV drugs in HIV-infected children compared to adults, including dependence on chronologic age and/or body parameters (e.g., height, weight). Ongoing growth requires continuous reassessment of dosing of ARV drugs in order to avoid low drug exposure and development of viral resistance and virologic failure. Developmental differences in drug absorption, distribution, metabolism, and elimination contribute to high variability and a greater frequency of suboptimal exposure to multiple therapeutic agents including ARV drugs in children (particularly very young children) and adolescents compared to adults.11-13 Suboptimal exposure to selected ARV agents with recommended dosing has been demonstrated in pediatric patients, especially in young children.7,14,15
Pediatric ARV drug recommendations are often based on extrapolation of efficacy results from large clinical trials in adults, and dosing recommendations for ARV drugs at the time of pediatric drug approval are frequently derived from a limited number of patients and pharmacokinetic (PK) modeling, and may be revised as newer PK data become available.7 While the Panel on Antiretroviral Therapy and Medical Management of HIV-Infected Children does not recommend routine TDM for pediatric ARV therapy management, TDM can be considered for certain ARV agents when the approved pediatric formulation and/or dosing are based on limited PK and efficacy data in small populations (see specific drug information sections) or for certain clinical scenarios outlined in the text box above to ensure adequate drug concentrations and/or to decrease toxicity.
The accurate interpretation of TDM requires evaluation and documentation of the following:
Additional practical suggestions on TDM of ARV drugs can be found in a position paper by the Adult AIDS Clinical Trials Group Pharmacology Committee16 and pediatric TDM manuscripts.6,17 Most importantly, consultation with an expert in pediatric HIV pharmacology is strongly recommended to obtain guidance on when to obtain samples for TDM, how to interpret the PK data, and how to evaluate the need for dose adjustment and repeat PK evaluation and follow up.