Therapeutic Drug Monitoring In Treatment Research Articles

Implications of rituximab pharmacokinetic and pharmacodynamic alterations in various immune-mediated glomerulopathies and potential anti-CD20 therapy alternatives.

The specific B-cell depleting anti-CD20 monoclonal antibody rituximab (RTX) is effective in terms of the treatment of various immune-mediated glomerulopathies. The administration of RTX has been shown to be reliable and highly effective particularly in patients with ANCA-associated vasculitis, which is manifested predominantly with non-nephrotic proteinuria. Stable long-term B-cell depletion is usually readily attained in such patients using standard dosing regimens. However, in patients with nephrotic syndrome and non-selective proteinuria, the RTX pharmacokinetics is altered profoundly and RTX does not maintain high enough levels for a sufficiently long period, which may render RTX treatment ineffective. Since complement-derived cytotoxicity is one of the important modes of action of RTX, hypocomplementemia, frequently associated with systemic lupus erythematodes, may act to hamper the efficacy of RTX in the treatment of patients with lupus nephritis. This review provides a description of RTX pharmacokinetics and pharmacodynamics in several selected glomerulopathies, as well as the impact of proteinuria, anti-drug antibodies and other clinical variables on the clearance and volume of distribution of RTX. The impact of plasmapheresis and peritoneal dialysis on the clearance of RTX is also discussed in the paper. A review is provided of the potential association between pharmacokinetic and pharmacodynamic alterations in various kidney-affecting glomerular diseases, the sustainability of B-cell depletion and the clinical efficacy of RTX, with proposals for potential dosing implications. The role of therapeutic drug monitoring in treatment tailoring is also discussed, and various previously tested RTX dosing schedules are compared in terms of their clinical and laboratory treatment responses. Since alternative anti-CD20 molecules may prove effective in RTX unresponsive patients, their pharmacokinetics, pharmacodynamics and current role in the treatment of glomerulopathies are also mentioned.

Editorial: proactive therapeutic drug monitoring in treatment of inflammatory bowel disease: it makes sense

Editorial: proactive therapeutic drug monitoring in treatment of inflammatory bowel disease: it makes sense

The role of therapeutic drug monitoring in treatment of HIV infection.

The role of therapeutic drug monitoring in treatment of HIV infection.

The role of therapeutic drug monitoring in treatment of HIV infection

The role of therapeutic drug monitoring in treatment of HIV infection

The role of therapeutic drug monitoring in treatment of HIV infection

The role of therapeutic drug monitoring in treatment of HIV infection

The role of therapeutic drug monitoring in treatment of HIV infection.

Looking back over the development of antiretroviral therapies (ART) for the treatment of HIV infection, probably the turning point in generating a belief that there were real grounds for optimism of ‘therapeutic success’ came with the introduction of protease inhibitors (PIs) in 1995. As a component of antiretroviral therapy, PIs produced a dramatic decrease in mortality and morbidity in HIV infection [1] most clearly demonstrated by the reduction of opportunistic infections and hospital admissions. Today, a triple drug combination regimen containing nucleoside reverse transcriptase inhibitors (NRTIs) plus PIs or non-nucleoside reverse transcriptase inhibitors (NNRTIs) constitutes the standard of care for patients commencing therapy (see Table 1). Table 1 Currently licensed antiretrovirals. Despite its success, combination ART still lacks sufficient potency and durability. Large prospective studies [2] suggest that up to 50% of HIV-positive patients will fail to achieve adequate suppression of plasma HIV RNA (i.e. < 50 copies/ml) with any of the current ART regimens. Even if this is achieved, viral rebound develops in a significant proportion of patients within 1 year of follow-up [3–5]. For example, in the Swiss cohort study [3], rebound HIV viraemia (from < 400 copies/ml to detectable) was approximately 10% per year in ART-naive patients commencing therapy and 20% in ART-experienced patients switching therapy. Although 80% of ART-naive patients achieved viral load below 400 copies/ml at 6 months, this was only sustained in 66% at 30 months and treatment changes were necessary in approximately half of patients by 24 months. In the Frankfurt cohort [4], over half of patients developed viral rebound within 12 months of achieving undetectable RNA. There are also a growing number of patients who fail treatment despite exposure to most antiretroviral agents and consequently receive salvage therapy, which may include ‘mega-ART’ regimens. Such regimens are associated with increased potential for toxicity and serious drug interactions. In this context, some of the most pressing clinical pharmacology questions are: Why do some patients fail treatment regardless of the regimen selected? How can existing therapies be improved or optimized? Will the new drugs in development show significant advantage? Treatment failure is clearly multifactorial, and may include the development of antiviral resistance, poor adherence to therapy and pharmacokinetic reasons. This review will focus on pharmacokinetic variability as an important consideration in treatment failure and current approaches to address the problem. Pharmacokinetic variability is particularly important in relation to PIs – a group of peptidomimetic drugs with considerable inter and intra-individual variability in plasma levels and marked potential for drug interactions leading to reduced or elevated PI plasma concentrations [6, 7]. Reduced concentrations will potentially compromise efficacy while elevated concentrations will predispose to adverse events. When considering the role of therapeutic drug monitoring (TDM) in antiretroviral therapy, the primary focus is therefore on PIs. However before proceeding to develop the arguments for TDM of PIs it is important to highlight the main issues around plasma concentrations of the other two main classes of antiretrovirals. For NRTIs, establishing a relationship between plasma concentration and antiviral effect has been difficult simply because it is the intracellular triphosphate anabolite that is the active moiety (Figure 1). Plasma concentrations of parent nucleosides and intracellular concentrations of triphosphates show only a weak correlation. Figure 2 displays data from studies with zidovudine (ZDV) and lamivudine (3TC) [8, 9]. Therefore meaningful data would require cell separation (i.e. to generate peripheral blood mononuclear cells, PBMCs), a technique which is time consuming, followed by analysis of the active triphosphate, a procedure that is currently available only in a handful of laboratories. This effectively precludes the routine use of TDM for NRTIs in clinical practice until such time as a more rapid throughput analytical system is developed. Figure 1 Activation pathways of nucleoside analogues. Figure 2 The relationship between intracellular nucleoside triphosphate and plasma concentration of parent drug for (a) zidovudine (ZDV) and (b) lamivudine (3TC) (○ 150 mg. • 300 mg). Note the weak correlation between area under the curve in cells ... Data from pharmacokinetic studies of NNRTIs indicate that two of the drugs, efavirenz and nevirapine, have a prolonged half-life, normally achieve adequate steady-state plasma concentrations during a dosing interval and have pharmacokinetics which are less variable than those of PIs. Although we would not entirely rule out a role for TDM of NNRTIs in some circumstances (e.g. in relation to CNS side-effects of efavirenz), presently attention is focused on PIs.

Potential applications of therapeutic drug monitoring in treatment of neoplastic disease by antineoplastic agents

Therapeutic drug monitoring of antineoplastic agents must be considered in terms of cytotoxicity to stem cells and toxicity of normal tissues. The dose-limiting toxicity which is myelosuppression is believed to be a necessary effect for maximal antitumour effect. The areas in which therapeutic drug monitoring can play a role include: predicting patients at risk of toxicity, e.g. high dose methotrexate therapy; low bioavailability, e.g. oral 6-mercaptopurine; identifying patients at risk of treatment failure, e.g. methotrexate clearance in acute lymphoblastic leukemia. Although therapeutic drug monitoring is not clinically useful at present, the potential role it can play is illustrated for cytosine arabinoside, adriamycin and cyclophosphamide. Two problems encountered with drug monitoring of antineoplastic disease are tumour heterogeneity manifested by clonal, nutritional and physical characteristics and the common practice of combination chemotherapy. These problems must be addressed in order to make therapeutic drug monitoring a practical tool in cancer chemotherapy. Future applications of therapeutic drug monitoring will require more studies to define therapeutic ranges for single agents, patient-to-patient variation, course-to-course variation and the effects of drug combinations on pharmacokinetic profiles of the drugs used.