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PubMed2004

Therapeutic drug monitoring of immunosuppressant drugs by high-performance liquid chromatography-mass spectrometry.

The currently expanding range of immunosuppressant agents has placed new challenges on therapeutic drug-monitoring (TDM) services. Many of these drugs require the measurement of concentrations with subsequent dosage adjustment to maximize efficacy while minimizing toxicity. HPLC-mass spectrometry (HPLC-MS) is a relatively new technique for drug quantification and thus TDM of immunosuppressant drugs. Although mass spectrometry relies on producing, differentiating, and detecting ions in the gas phase, the development of the atmospheric pressure ionization interface (electrospray and chemical ionization) has enabled the direct coupling of solution introduction of compounds, via HPLC, to the mass analyzer. The impetus for using HPLC-MS for immunosuppressant measurement has come from the highly potent low-dose immunosuppressant drugs tacrolimus and sirolimus, which have low nanogram per milliliter circulating concentrations. A number of strategies have been reported for sample preparation and ways to automate these processes with solid-phase extraction and 2-dimensional chromatography. The disadvantages of HPLC-MS are initial cost of equipment and availability of suitably skilled scientific staff. The advantages of HPLC-mass spectrometry are high sensitivity, specificity, small sample requirements, minimal sample preparation, rapid throughput, and simultaneous measurement. Further, scientists have the ability to develop methods to measure new immunosuppressant drugs by HPLC-MS before commercial assays become available. With potential applications increasing in immunosuppressive drug monitoring, it can be envisaged that HPLC-MS may become standard equipment in TDM laboratories of the future.

Chromatography, High Pressure Liquid↗

PubMed2003

Therapeutic drug monitoring of antiarrhythmic drugs.

Most antiarrhythmic drugs fulfil the formal requirements for rational use of therapeutic drug monitoring, as they show highly variable plasma concentration profiles at a given dose and a direct concentration-effect relationship. Therapeutic ranges for antiarrhythmic drugs are, however, often very poorly defined. Effective drug concentrations are based on small studies or studies not designed to establish a therapeutic range, with varying dosage regimens and unstandardised sampling procedures. There are large numbers of nonresponders and considerable overlap between therapeutic and toxic concentrations. Furthermore, no study has ever shown that therapeutic drug monitoring makes a significant difference in clinical outcome. Therapeutic concentration ranges for antiarrhythmic drugs as they exist today can give an overall impression about the drug concentrations required in the majority of patients. They may also be helpful for dosage adjustment in patients with renal or hepatic failure or in patients with possible toxicological or compliance problems. Their use in optimising individual antiarrhythmic therapy, however, is very limited.

Anti-Arrhythmia Agents↗

PubMed2002

Therapeutic drug monitoring of immunosuppressant drugs in clinical practice.

BACKGROUND: Therapeutic drug monitoring (TDM) is essential to maintain the efficacy of many immunosuppressant drugs while minimizing their toxicity. TDM has become more refined with the development of new monitoring techniques and more specific assays. OBJECTIVE: This article summarizes current data on TDM of the following immunosuppressant drugs used in organ transplantation: cyclosporine, tacrolimus, sirolimus, everolimus, and mycophenolate mofetil. METHODS: Published data were identified by a MEDLINE search of the English-language literature through March 2001 using the terms therapeutic drug monitoring, cyclosporine, tacrolimus, sirolimus, everolimus, and mycophenolate mofetil. Relevant conference abstracts were also included. RESULTS: TDM of cyclosporine has been well studied, and recent findings indicate that monitoring of drug levels 2 hours after dosing is a more sensitive predictor of outcome than trough (C0) monitoring. C0 levels are being used more widely in TDM of tacrolimus; however, the relationship between C0 and area under the curve has varied widely in clinical trials, with correlations ranging from 0.11 to 0.92. The use of TDM of sirolimus, everolimus, and mycophenolate mofetil is evolving rapidly. CONCLUSIONS: TDM of immunosuppressant drugs that have a narrow therapeutic index is an increasingly useful tool for minimizing drug toxicity while maximizing prevention of graft loss and organ rejection.

Drug Monitoring↗

PubMed2003

Evaluation of therapeutic drug monitoring of antiepileptic drugs.

Results of the therapeutic drug monitoring (TDM) of the concentration of antiepileptic drugs (AEDs), performed at Aseer Central Hospital over a 1-year period were evaluated. Most of the requests were for phenytoin (PHT) determination followed by carbamazepine (CBZ), valproic acid (VPA) and phenobarbital (PB). Serum concentrations of PB, CBZ, VPA and PHT within the presumed therapeutic range constituted 87%, 73%, 45% and 33%, respectively. Valproic acid exhibited age differences in the proportion of concentrations below the presumed therapeutic range, such that subtherapeutic concentrations increased while therapeutic concentrations decreased with age. When the requests were related to particular patients, 71% of patients were on monotherapy with PHT as the most commonly used single drug and PB the least. Patients using 2 AEDs were found to constitute 23.5% of all patients with "PHT + CBZ" and "CBZ + VPA" being the most commonly prescribed 2 drugs combination. The frequency of concentrations within the therapeutic ranges decreased when 1 or 2 more drugs were used with either PHT or VPA. In addition, combination with PHT was associated with a reduction in mean CBZ concentration, while combination with CBZ was associated with a reduction in mean VPA concentration.

Adolescent↗

PubMed2002

Application of pharmacokinetic modelling to the routine therapeutic drug monitoring of anticancer drugs.

Over the last 10 years, proofs of the clinical interest of therapeutic drug monitoring (TDM) of certain anticancer drugs have been established. Numerous studies have shown that TDM is an efficient tool for controlling the toxicity of therapeutic drugs, and a few trials have even demonstrated that it can improve their efficacy. This article critically reviews TDM tools based on pharmacokinetic modelling of anticancer drugs. The administered dose of anticancer drugs is sometimes adjusted individually using either a priori or a posteriori methods. The most frequent clinical application of a priori formulae concerns carboplatin and allows the computation of the first dose based on biometrical and biological data such as weight, age, gender, creatinine clearance and glomerular filtration rate. A posteriori methods use drug plasma concentrations to adjust the subsequent dose(s). Thus, nomograms allowing dose adjustment on the basis of blood concentration are routinely used for 5-fluorouracil given as long continuous infusions. Multilinear regression models have been developed, for example for etoposide, doxorubicin. carboplatin, cyclophosphamide and irinotecan, to predict a single exposure variable [such as area under concentration-time curve (AUC)] from a small number of plasma concentrations obtained at predetermined times after a standard dose. These models can only be applied by using the same dose and schedule as the original study. Bayesian estimation offers more flexibility in blood sampling times and, owing to its precision and to the amount of information provided, is the method of choice for ensuring that a given patient benefits from the desired systemic exposure. Unlike the other a posteriori methods, Bayesian estimation is based on population pharmacokinetic studies and can take into account the effects of different individual factors on the pharmacokinetics of the drug. Bayesian estimators have been used to determine maximum tolerated systemic exposure thresholds (e.g. for topotecan or teniposide) as well as for the routine monitoring of drugs characterized by a very high interindividual pharmacokinetic variability such as methotrexate or carboplatin. The development of these methods has contributed to improving cancer chemotherapy in terms of patient outcome and survival and should be pursued.

Antineoplastic Agents↗

PubMed2002

International Federation of Clinical Chemistry/International Association of Therapeutic Drug Monitoring and Clinical Toxicology working group on immunosuppressive drug monitoring.

Issues surrounding the measurement and interpretation of immunosuppressive drug concentrations have been summarized in a number of consensus documents. The Scientific Division of the International Federation of Clinical Chemistry has formed a working group in collaboration with the International Association of Therapeutic Drug Monitoring and Clinical Toxicology. This paper sets out the goals of the working group in light of the developments that have occurred in the field of immunosuppressive drug monitoring since the publication of the last consensus documents.

Animals↗

PubMed2002

Critical issues in therapeutic drug monitoring of antiretroviral drugs.

The interest in therapeutic drug monitoring (TDM) of antiretroviral drugs is growing rapidly. For the protease inhibitors, and to a lesser extent for the non-nucleoside reverse transcriptase inhibitors, relationships between plasma drug concentrations and their efficacy and toxicity have been identified. Furthermore, the pharmacokinetics of especially the protease inhibitors vary widely between patients, suggesting a role for TDM to individualize antiretroviral therapy. Recently, randomized, prospective clinical trials evaluating the role of TDM in the management of HIV-1-infected patients showed promising results. However, there are still many questions to be answered before large-scale introduction of TDM can be justified (e.g., which pharmacokinetic parameter should be optimized, and what is the minimal effective concentration). This review summarizes the basis for TDM of antiretroviral drugs and discusses the problems and prospects of this potential tool in the care for HIV-1-infected individuals.

Drug Monitoring↗

PubMed1997

The treatment of depression with paroxetine in psychiatric practice in Germany: the possibilities and current limitations of drug monitoring.

A drug monitoring of the antidepressant paroxetine was carried out in Germany from August 1992 to November 1993. The principal aim of this study was to collect demographic, diagnostic, efficacy, and medical-safety data regarding patients who were treated for up to 12 weeks with this SSRI. A secondary goal was the investigation of differences between patients who left treatment after 6 weeks or earlier and those who continued treatment. Evaluable data were obtained from 507 psychiatrists for 2817 patients, 1301 of whom extended treatment beyond 6 weeks. 64% of the patients had been pretreated for the current episode of depression. 50% were considered by their doctors to have either chronic or recurrent illness and 92% to possess moderate to severe symptomatology. Concomitant psychotropic medication was reported in 43% of cases, the most frequent medications being benzodiazepines, neuroleptics, and/or tricyclic antidepressants. Clear or complete improvement was noted for 63% of assessable patients by the end of week 6 and for 79% of the patients who extended treatment to 12 weeks. There were significantly more patients with DSM major depression and severe symptoms in the treatment-extender than in the 6-week treatment group. Paroxetine was tolerated well by most patients: of the 1009 adverse events reported, only 17 were considered "serious". There were no suicides or cases of overdose attributable to paroxetine. The discussion of these results is the basis for a critical appraisal of postmarketing-surveillance methodology. It is concluded that, despite its present structural weaknesses as compared to controlled investigations, drug monitoring of a new medication in the immediate postmarketing period can give insights into the treatment of large numbers of patients under private-practice conditions. However, drug monitoring as it is conducted in Germany can have different and perhaps conflicting functions which may limit its effectiveness. The authors recommend that all interested parties (physicians, the pharmaceutical industry, regulatory bodies) engage in a continuous dialog aimed at clearly formulating the goals and improving the methodology of drug monitoring.

Adult↗

PubMed2005

Therapeutic drug monitoring and drug-drug interactions involving antiretroviral drugs.

The consensus of current international guidelines for the treatment of HIV infection is that data on therapeutic drug monitoring (TDM) of non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (Pls) provide a framework for the implementation of TDM in certain defined scenarios in clinical practice. However, the utility of TDM is considered to be on an individual basis until more data are obtained from large clinical trials showing the benefit of TDM. In April 2004, a panel of experts met for the second time in Rome, Italy. This was following the inaugural meeting in Perugia, Italy, in October 2000, which resulted in the manuscript published in AIDS 2002, 16(Suppl 1):S5-S37. The objectives of this second meeting were to review and update the numerous questions surrounding TDM of antiretroviral drugs and discuss the clinical utility, current concerns and future prospects of drug concentration monitoring in the care of HIV-1-infected individuals. A major focus of the meeting was to discuss and critically analyse recent and precedent clinical drug-drug interaction data to provide a clear framework of the pharmacological basis of how one drug may impact the disposition of another. This report, which has been updated to include material published or presented at international conferences up to the end of December 2004, reviews recent pivotal pharmacokinetic interaction data and provides advice to clinical care providers on how some drug-drug interactions may be prevented, avoided or managed, and, when data are available, on what dose adjustments and interventions should be performed.

Anti-HIV Agents↗

PubMedDate not supplied

Therapeutic drug monitoring and drug-drug interactions: a pharmacoepidemiological perspective.

The present study investigates the potential of therapeutic drug monitoring databases to document co-medication as a possible risk factor for subtherapeutic or excessively high concentrations of psychotropic drugs. Exposure was defined with respect to co-medication including one of five agents known for their capacity to induce (phenytoin, phenobarbital and carbamazepine) or to inhibit (thioridazine and levomepromazine) the metabolism of psychotropic drugs. 87 patients exposed to such co-medication were matched by sex, age and monitored psychotropic medication with 87 patients randomly selected from a pool of subjects whose co-medication did not include any substance known to interact. Outcome was defined with respect to dose-normalized concentrations being below or above therapeutic range. When taking all psychotropic drugs together, the estimated relative risk to reach concentrations above the therapeutic range was 7.8 for patients exposed to phenothiazine co-medication. The relative risk to remain at subtherapeutic level was 2.7 for patients with inducers. When considering the different psychotropic drugs separately, a coherent picture was observed, with increased risk ratios for all substances.

Drug Interactions↗

PubMed2006

The complexity of active metabolites in therapeutic drug monitoring of psychotropic drugs.

In therapeutic drug monitoring (TDM) practice of psychotropic agents, it is common to summarize plasma concentrations of parent drugs and metabolites when these are considered equipotent. However, there is no clear definition of the term equipotent and one should be aware that metabolites referred to as equipotent in the literature could display several-fold differences in affinities toward target proteins. The fact that the parent drug and metabolite may have different abilities to penetrate the blood-brain-barrier further complicates the picture. Potential differences in brain distribution imply that various metabolite/drug ratios representing the same total concentration in plasma reflect different active concentrations in the brain. Plasma metabolite/drug ratios could differ extensively according to metabolic phenotype and administration route. An example is risperidone where the plasma metabolite/drug ratio is 30-fold lower in cytochrome P450 2D6 poor metabolizers compared to ultrarapid metabolizers, and four-fold lower after intramuscular compared to oral administration. As risperidone is more lipophilic and less effluxed by P-glycoprotein in the blood-brain-barrier than the active metabolite 9-hydroxyrisperidone, one might speculate that patients with high plasma metabolite/drug ratios obtain lower active concentrations in the brain. However, the relative drug-metabolite brain distribution needs to be quantified in humans to clarify to what degree drug and metabolite plasma levels reflect active brain concentrations. The present review illustrates the complexity of active metabolites in TDM with focus on amitriptyline, clomipramine, doxepin, imipramine, fluoxetine, venlafaxine and risperidone, all psychotropic drugs where target plasma concentration ranges are based on the sum of parent drug and metabolite. In addition, perspectives on the possibility of using distribution- and activity-weighted plasma concentrations are provided.

Brain↗

PubMed1996

Overview of therapeutic drug monitoring and biotechnologic drugs.

Therapeutic drug monitoring (TDM) is the science that combines measurement of serum drug concentrations with clinical pharmacokinetics. Biotechnological drugs may be obtained by recombinant DNA technology, monoclonal antibody technology, polymerase chain reaction, gene therapy, nucleotide blockade, peptide technology, and carbohydrate technology. Examples of biotechnological drugs include antisense drugs, clotting factors, hematopoietic factors, hormones, interferons, interleukins, monoclonal antibodies, tissue growth factors, and vaccines. For drugs that are physiological peptides used for substitution therapy, TDM is not indicated. For other biotechnological drugs, the criteria developed for monitoring of "classical" therapeutic agents should be used on an individual basis to determine whether there is a role for TDM.

Biotechnology↗

PubMed2004

Therapeutic drug monitoring of thiopurine drugs in patients with inflammatory bowel disease or autoimmune hepatitis.

OBJECTIVE: Thiopurine drugs are commonly used immunosuppressants in the treatment of inflammatory bowel disease (IBD) as well as in autoimmune hepatitis (AIH), rheumatic diseases and in transplantation medicine. The relatively narrow therapeutic range requires useful therapy control. Therefore, the purpose of this study was to further investigate the rationale and usefulness of therapeutic drug monitoring in the surveillance of thiopurine drug therapy in Crohn's disease, ulcerative colitis and autoimmune hepatitis. METHODS: 6-Thioguanine nucleotide (TGN) and 6-methylmercaptopurine nucleotide (MMPN) levels were measured in 182 IBD patients and 18 AIH patients using HPLC-UV. RESULTS: In our cohort of IBD patients, 18% had TGN levels < 235 pmol/8 x 10 red blood cells (RBC) (recommended range, 235-450 pmol/8 x 10 RBC), 41% of these patients were sent for drug failure. Twenty-four per cent of the IBD patients had TGN levels > 450 pmol/8 x 10 RBC, but only 27% of these experienced adverse effects. Fifty-nine per cent of the patients having drug failure had TGN levels in the recommended range and could therefore be classified as non-responders. In the AIH cohort 33% of the patients had TGN levels below the recommended range but showed clinical response to therapy. MMPN levels increased with the duration of treatment and could be useful for controlling compliance. There was 8.8% of IBD patients who were heterozygous for non-functional TPMT alleles. CONCLUSIONS: TGN monitoring did not identify significant differences between patient groups but allowed the identification of non-responders from non-compliant patients and allowed the differentiation of mild side effects, such as malaise, from genuine toxicity caused by highly increased TGN levels.

Adolescent↗

PubMed2006

Therapeutic drug monitoring of psychoactive drugs during pregnancy in the genomic era: challenges and opportunities.

Various symptoms of mental illness occur commonly during pregnancy. It is estimated that serious mental disorders, including major depression, bipolar disorder, schizophrenia, panic and other anxiety disorders, occur with a frequency of 10 to 25% in community samples of US women in their child-bearing years. As a result, approximately a third of all women take at least one psychoactive drug during pregnancy. Fetal drug exposure has been documented for all psychoactive drugs studied to date. However, the rate and extent of placental transfer within and between psychoactive drug classes remains ill defined. The contribution of various genetic factors such as the role of polymorphic drug metabolizing enzymes and drug transporters in controlling the variability of fetal drug exposure is also unclear. Therapeutic drug monitoring (TDM) has traditionally played an important role in psychiatric pharmacotherapy during pregnancy to ensure an adequate drug dose to achieve desired benefits while avoiding excessive fetal accumulation for drugs. In the genomic era, individualized treatment with specific drugs tailored to the mother's and fetus's genotype should eventually become the standard of care. Several methodological problems need to be overcome for this prediction to become reality. One approach to this goal taken by the Specialized Center of Research on Sex and Gender Factors Affecting Women's Health at the Emory University Women's Mental Health Program is described. This research is grounded on TDM of pregnant women receiving antidepressants, antipsychotics, anti-epileptic drugs and mood stabilizers. The use of pharmacokinetic and pharmacogenetic models to predict maternal plasma drug concentrations, fetal drug exposure, and maternal and neonatal outcomes, is expected to improve our understanding of dose-response relationships of psychoactive drugs in pregnancy.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2001

Therapeutic drug monitoring of cytotoxic drugs.

Therapeutic drug monitoring is not routinely used for cytotoxic agents. There are several reasons, but one major drawback is the lack of established therapeutic concentration ranges. Combination chemotherapy makes the establishment of therapeutic ranges for individual drugs difficult, the concentration-effect relationship for a single drug may not be the same as when that drug is used in a drug combination. Pharmacokinetic optimization protocols for many classes of cytotoxic compounds exist in specialized centres, and some of these protocols are now part of large multicentre trials. Nonetheless, methotrexate is the only agent which is routinely monitored in most treatment centres. An additional factor, especially in antimetabolite therapy, is the existence of pharmacogenetic enzymes which play a major role in drug metabolism. Monitoring of therapy could include assay of phenotypic enzyme activities or genotype in addition to, or instead, the more traditional measurement of parent drug or drug metabolites. The cytotoxic activities of mercaptopurine and fluorouracil are regulated by thiopurine methyltransferase (TPMT) and dihydropyrimidine dehydrogenase (DPD), respectively. Lack of TPMT functional activity produces life-threatening mercaptopurine myelotoxicity. Very low DPD activity reduces fluorouracil breakdown producing severe cytotoxicity. These pharmacogenetic enzymes can influence the bioavailability, pharmacokinetics, toxicity and efficacy of their substrate drugs.

Antimetabolites, Antineoplastic↗

PubMed2005

[Current status of therapeutic drug monitoring for immunosuppressive drugs].

Therapeutic drug monitoring(TDM) is advocate to provide information about the adequacy of a dosing regimen or likelihood of toxicity associated with drug. Such situations include large intra- and inter-individual variabilities in pharmacokinetics; correlation between drug concentrations and toxicity or between concentrations and efficacy; narrow therapeutic interval, meaning toxic symptoms close to concentration with full therapeutic effect; and absence of appropriate parameter to recognize pharmacological effect. Current clinical immunosuppressive regimens consist of combinations of drugs, to allow a reduction in the individual drug doses as a means widening the therapeutic interval and reduction the likelihood of individual drug toxicity. With the recent introduction of new immunosuppressive drugs, there is an unprecedented interest in TDM for immunosuppressive drugs. In this review I discuss the current status of pharmacokinetic monitoring for cyclosporine, tacrolimus and mycophenolate mofetil.

Cyclosporine↗

PubMed1988

Italian collaborative study on the utilization of therapeutic drug monitoring in hospital departments. Italian Collaborative Group on Therapeutic Drug Monitoring.

A population base of 6,367 in-patients from 28 general hospital wards was included in a nation-wide project aimed at documenting the extension and criteria of therapeutic drug monitoring (TDM). On randomly selected index days over a 3-month period details of age, clinical status, renal and liver function, diseases, drug therapies, and drug monitoring of all in-patients of eight different clinical specialties were recorded and analyzed. A total of 648 requests for 387 patients (16.3% of the population given drugs for which TDM was available in the hospital) was traced. Digoxin was the most frequently monitored drug (481 requests for 289 patients), accounting for 74% of the overall requests. This finding is consistent with the yearly activity of the laboratories of the same hospitals, which documented that 63% of the whole in-hospital analytical work (29,396 out of 46,692 requests) concerned digoxin. From a more qualitative point of view, data are provided that document a largely inappropriate use of TDM, which was employed only for 20% of patients who might have benefited from it.

Digoxin↗

PubMed1998

Collaboration between pharmacy and laboratory: defining total allowable error limits for therapeutically monitored drugs.

OBJECTIVE: To define the total allowable variability that is clinically tolerated for certain drug assays performed by the therapeutic drug monitoring (TDM) laboratory at our institution. METHODS: The monthly coefficient of variation (CV) for 13 of the most commonly performed drug assays was recorded for two concentrations: the upper and lower limits of the therapeutic range for each drug. A dosing simulation was performed for each drug by using population parameters to estimate the doses that would yield the two target concentrations in an adult patient. The smallest practical dosage adjustment that could be implemented in clinical practice was determined and the serum concentration resulting from this dosage change was estimated. Each change was equated to two standard deviations from the original drug concentration, and the corresponding CV or total allowable error (TEa) was calculated and compared with the laboratory's CV value. RESULTS: The laboratory CV was greater than the clinically defined TEa for amikacin at both trough and peak ranges, and for gentamicin and tobramycin at the trough range. Simulations for a patient with compromised renal function produced TEa values less than the reported CV for amikacin at both trough and peak ranges. Simulations for an obese patient produced TEa values less than the reported CV for amikacin, gentamicin, and tobramycin at both trough and peak ranges. The assay variability for these aminoglycosides is greater than the expected change in serum drug concentrations produced by the dosage changes used in the simulations. The TEa for all other drugs exceeded the laboratory CV, demonstrating assay variability within the clinically tolerated range. CONCLUSIONS: Knowledge of how the variability of a drug assay compares with its TEa allows clinicians to assess the usefulness of a serum drug concentration as a clinical tool.

Adult↗