AEGiS-JIAPAC: Therapeutic drug monitoring

Therapeutic drug monitoring

Journal of the International Association of Physicians in AIDS Care - Vol. 1, No. 3, July/September 2002
David Back, PhD, Saye Khoo, MD, and Sara Gibbons, MPhil;
Department of Pharmacology & Therapeutics, University of Liverpool, Liverpool, UK
**Community Research Initiative of Toronto, Toronto, Canada

Highly active antiretroviral therapy (HAART) can suppress viral replication and substantially prolong patient life. It can also fail for a number of reasons, including poor adherence, insufficient drug potency, emergence of resistance, cellular factors, and pharmacokinetic factors. Although many antiretroviral drugs are now available, a limited number of combinations has been proven effective for individual patients. With sequential treatment failures, the durability of virologic response tends to decrease with subsequent treatment regimens until the patient is left with few or no therapeutic options. There is evidence that many treatment-naïve patients will switch from their initial regimen within one year. It is imperative that we adopt strategies that will optimize the use of available therapies, so as to achieve long-term viral suppression.

Monitoring the course of HIV infection has been an essential component of patient management. CD4 counts help track the immunological status of a patient, and viral load assays are used to monitor the antiviral activity and durability of a regimen, and to guide treatment changes. Resistance assays are becoming a standard element of care despite issues around interpretation of results. With emerging evidence linking drug exposure to both antiviral efficacy and toxicity, attention is being focused on the role of monitoring plasma drug levels in patients receiving HAART. If inadequate drug levels—arising from poor adherence, inherent pharmacokinetic factors, or drug interactions— are a major cause of treatment failure, then monitoring these levels and having an intervention strategy seems a logical approach to improve the success rate of therapy. Likewise, high drug levels may relate to toxicity, either in the patient at that time or somewhere down the line.

Managing the therapeutic regimen of a patient on the basis of measured drug concentrations is referred to as therapeutic drug monitoring (TDM). In virtually all cases, TDM is applied to drugs exhibiting a narrow therapeutic window in order to optimize efficacy and/or avoid toxicity. This diagnostic approach has been used for many years with anticonvulsants, immunosuppressants, aminoglycoside antibiotics, and some cytotoxics. In the setting of HIV management, the potential role of TDM is receiving increasing attention. There are clearly several features of current antiretroviral therapy that suggest TDM may have benefit. As pointed out by Flexner and Piscitelli in a recent editorial, 1 generally the most important aspect of HIV therapy that draws us to consider the role of TDM is the lifelong treatment. We still have relatively few options despite the 16 licensed antiretrovirals, so getting it right (ensuring there is enough drug for efficacy, but not too much for toxicity) is surely a major goal. Care providers need to know that drug concentrations achieved in a patient have a high probability of chronically suppressing HIV replication without generating drug resistance or problematic toxicities. They also need to remember that drug levels may more accurately correlate acute, rather than chronic or cumulative toxicities.

A major confounder when considering TDM in a clinical setting is adherence. Patients who do not take their antiretroviral therapy on schedule, or who do not comply with food requirements would be expected to have low plasma drug concentrations and consequently a poor outcome. However, those patients may have apparently "normal" plasma levels if they take the dose just before a hospital visit. A patient failing therapy for poor adherence would appear to have a normal drug level in any outcome analysis. Hence, a thorough assessment of adherence is essential within any TDM program to facilitate interpretation of concentrations, and to ensure good outcome. It is also critical to know the accurate timing of a blood sample in relation to when the dose was taken.

Another important consideration in TDM is setting the target drug concentrations. There is some degree of confidence that we know minimum effective concentrations (MECs), values that are generated and extrapolated from patient studies or in vitro studies, at least in treatment-naïve patients. There is much less confidence surrounding maximum concentrations with the exception of indinavir and possibly efavirenz. The presence of drug-resistant virus for an antiretroviral drug means that it is not rational to use the same set of target concentrations for patients harboring drug-sensitive and drug-resistant virus. This is where relating drug concentrations to the patient viral isolate becomes a much more attractive option than TDM on its own. The use of inhibitory quotients (IQ), virtual IQ (vIQ), or normalized IQ (nIQ) is currently being clinically evaluated for a number of different drugs. Data presented at the 9th Conference on Retroviruses and Opportunistic Infections (CROI)2^,3 gives grounds for optimism that this approach may prove of considerable benefit, and probably better than TDM on its own. There is literally a price to pay for the advance in technology, and the issue of reimbursement is likely to prove a considerable stumbling block to the widespread access to the test. Clearly what we need is good economic evaluation of the cost-benefit factors surrounding the use of TDM with or without resistance testing. In absolute costs TDM is "inexpensive" (US$50 to US$60 per sample), compared with resistance testing (genotype US$300, virtual phenotype US$450).

Defining the clinical situations in which TDM will have the greatest use is a priority. The recent interim analysis of the ATHENA trial4 has suggested that dose adjustment of indinavir reduced toxicity, and maintained patients on the indinavir-containing regimen. On the other hand, TDM of nelfinavir identified patients with low plasma concentrations. By either ensuring the drug was taken with food or dose modification, the TDM arm showed better virological outcome at 12 months.

Despite the lack of randomized controlled trial data, there are probably a number of other specific situations in addition to indinavir and nelfinavir that warrant TDM. The use of lopinavir plus ritonavir (Kaletra) with amprenavir gives rise to a complex interaction of three drugs, and monitoring the levels of both lopinavir and amprenavir may be important. The use of once daily regimens can also lead to trough plasma concentrations that are close to the MEC, which is true of saquinavir plus ritonavir. Thus, TDM will identify any individuals with low and potentially problematic levels.

Certain patient groups are clearly at increased risk for unpredictable and potentially damaging pharmacokinetic profiles, and could benefit from TDM. This includes patients with liver or renal damage, pediatric and pregnant patients, and patients with complex drug interactions. Much remains to be learned, and there are a number of challenges facing the introduction of TDM into clinical practice. If we can benefit some patients by ensuring efficacy or limiting toxicity simply by taking a couple of extra blood samples, we should vigorously standardize and validate this approach.

References

1. Flexner CW, Piscitelli SC. Concentration-targeted therapy and the future of HIV management. AIDS 2002 Mar;16 Suppl 1:S1-3.

2. Fletcher CV, Cheng H, Fiscus S, et al. The inhibitory quotient (IQ) for saquinavir (SQV) predicts virologic response to salvage therapy. Conf Retroviruses Opportunistic Infect. 2002 Feb 24-28;9th:Abstract No. 129).

3. Phillips E, Tseng A, Walker S, et al. The use of virtual inhibitory quotient (vIQ) in antiretroviral (ART)-experienced patients taking amprenavir/lopinavir combinations. Conf Retroviruses Opportunistic Infect. 2002 Feb 24-28;9th:Abstract No. 130).

4. Burger D. Therapeutic drug monitoring: A must for clinical practice? Conf on HIV Pathogenesis and Treatment. 2001 Jul 8-11;1:(Abstract No. 54).

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