Therapeutic Drug Monitoring

Chinese Version

Robert W. Shafer, M.D

Assistant Professor of Medicine

Division of Infectious Diseases and Geographic Medicine

Stanford University

Stanford, California

E-mail: rshafer@stanford.edu

Janell Kobayashi, Pharm. D.

Clinical Pharmacist

VA Palo Alto HCS, Department of Pharmacy, 119

3801 Miranda Avenue, Palo Alto, CA 94304

(650)493-5000#65836

E-mail: janellkobayashi@yahoo.com

               The pharmacokinetics of antiretroviral drugs depend on their absorption, metabolism, protein binding, and interactions with other drugs. Inter-patient pharmacokinetic variability – not just variability in adherence – influences both the success of HAART and the risk of drug toxicity (3, 4, 7). There are large differences among patients in the pharmacokinetics of the protease inhibitors and to a lesser extent the non-nucleoside RT inhibitors (NNRTIs). Therefore, there is a strong rationale for measuring the serum levels of protease inhibitors and possibly NNRTIs so that drug dosages can be modified to maximize the virologic response to therapy while minimizing drug toxicity (5, 8). However, the practical application of therapeutic drug monitoring in routine clinical settings faces many hurdles (3).

Inter-Patient Differences In Pharmacokinetics

               Protease inhibitors and NNRTIs are metabolized by the cytochrome P450 enzyme system, primarily by the 3A4 isoform (CYP3A4). Several membrane transporter proteins, particularly P-glycoprotein (PGP), also play a role in the pharmacokinetics of antiretroviral drugs. Increased PGP activity is expected to lower the antiretroviral activity of compounds affected by this transporter. PGP may also play a role in admittance of antiretroviral drugs to restricted compartments (6).

               The genes coding for CYP450 enzymes and PGP are polymorphic, partially explaining inter-patient differences in activities. The activity of these enzymes is also be affected by other drugs (see Antiretroviral Drug Characteristics), commonly used herbs (e.g. St John's wort induces CYP3A4), liver disease, and pregnancy. The effect of serum binding proteins on antiretroviral activity also varies among patients because many of the proteins are acute phase reactants.

Antiretroviral pharmacokinetics

               C_min, C_max, and AUC refer to the plasma trough level, plasma peak level, and area under the time-concentration curve, respectively. Intensive pharmacokinetic studies are used to measure AUC. Population-based studies are used to measure a drug's steady state C_min. Although these parameters have been defined for most antiretroviral drugs, the therapeutic ranges — the range of concentrations within which the probability of an efficacious response is sufficiently greater than the probability of unwarranted toxicity (2) — for most antiretroviral drugs have not been established. Moreover, the therapeutic range for protease inhibitors may depend on the extent of drug resistance. In this situation the ratio of the C_min to IC₅₀, sometimes referred to as the inhibitory quotient (IQ), may be required to predict antiviral outcome (9).

Recommendations

               A recent consensus panel has listed those clinical situations where therapeutic drug monitoring is more likely to be of clinical benefit (3): (i) In pregnant women, in children, and in individuals with hepatic disease or with particularly low or high body weight, (ii) In cases of suspected drug interactions (e.g. ≥2 drugs with an influence on P450 activity), (iii) Suspected malabsorption or other condition that may cause abnormal drug levels, (iv) For evaluation of unsatisfactory virologic responses, (v) For patients with dose-related adverse drug reactions, (vi) For once daily regimens using ritonavir-boosted protease inhibitors, (vii) In deep salvage, to expose patients to maximal tolerable levels while limiting the risk of toxicity.

               The accuracy and reproducibility of drug measurements within reputable laboratories is probably high enough for following individual patients; inter-laboratory reproducibility is likely to improve over time (1). For most protease inhibitors, the C_min is obtained by measuring drug levels at the end of a dosing interval. Therapeutic drug monitoring for nelfinavir is complicated by delays in absorption and the presence of an active metabolite, M8. For efavirenz and nevirapine — the most commonly used NNRTIs — the half-life of drug elimination is so long that a steady-state level is often achieved, which can be measured at any time during the dosage schedule. Serum levels of NRTIs appear have less inter-patient variability. The extent to which they correlate with the more difficult to measure intracellular drug-triphosphate levels is not known (3).

               As a general rule, trough levels should be obtained as close as possible to the end of the dosing interval after at least 3 weeks of therapy, when steady-state is expected to be attained (2). For treatment-naïve patients without resistant virus, trough levels can be compared to reported trough ranges (see Table 1). Dose adjustments should be considered for sub-therapeutic levels after a thorough patient history has been taken to assess compliance, dietary changes affecting absorption, and recent additions of medications, including over-the-counter medications and herbal supplements. For treatment-experienced patients or patients with drug-resistant virus, phenotypic tests may provide a better estimate of target trough concentrations. With the currently available phenotypic tests, it is important to adjust for protein binding since only unbound drug is active.

Tables and Figures

Table 1. Estimated Minimum Trough Concentration Ranges for Wild-Type Virus (2)

* Measurable active (M8) metabolite

REFERENCES

1. Aarnoutse RE, Verweij-Van Wissen CP, van Ewijk-Beneken Kolmer EW, Wuis EW, Koopmans PP,  Hekster YA, Burger DM. International interlaboratory quality control program for measurement of antiretroviral drugs in plasma. Antimicrob Agents Chemother 2002; 46:884-6. [PubMed]

2. Acosta EP, Gerber JG. Position paper on therapeutic drug monitoring of antiretroviral agents. AIDS Res Hum Retroviruses 2002;18:825-34. [PubMed]

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6. Fellay J, Marzolini C, Meaden ER, Back DJ, Buclin T, Chave JP, Decosterd LA, Furrer H, Opravil M, Pantaleo G,  Retelska D, Ruiz L, Schinkel AH, Vernazza P, Eap CB, and Telenti A. Response to antiretroviral treatment in HIV-1-infected individuals with allelic variants of the multidrug resistance transporter 1: a pharmacogenetics study. Lancet 2002;359:30-6. [PubMed]

7. Khoo SH, Gibbons SE, and Back DJ. Therapeutic drug monitoring as a tool in treating HIV infection. Aids 2001;15:S171-81. [PubMed]

8. Piscitelli SC, and Gallicano KD. Interactions among drugs for HIV and opportunistic infections. N Engl J Med 2001;344:984-96. [PubMed]

9. Shulman N, Zolopa A, Havlir D, Hsu A, Renz C, Boller S, Jiang P, Rode R, Gallant J, Race E, Kempf DJ, and Sun E. Virtual inhibitory quotient predicts response to ritonavir boosting of indinavir-based therapy in human immunodeficiency virus-infected patients with ongoing viremia. Antimicrob Agents Chemother 2002;46:3907-16. [PubMed]