Critical Dose Drugs Research Articles

Delivery Strategies for Colchicine as a Critical Dose Drug: Reducing Toxicity and Enhancing Efficacy.

Colchicine (COL), a widely used natural drug, has potent anti-inflammatory effects; however, as a narrow therapeutic index drug, its clinical application is limited by its serious gastrointestinal adverse effects, and only oral formulations are currently marketed worldwide. Recent studies have shown that transdermal, injection, and oral drug delivery are the three main delivery strategies for COL. This article elaborates on the research progress of different delivery strategies in terms of toxicity reduction and efficacy enhancement, depicting that the transdermal drug delivery route can avoid the first-pass effect and the traumatic pain associated with the oral and injection routes, respectively. Therefore, such a dosage form holds a significant promise that requires the development of further research to investigate effective COL delivery formulations. In addition, the permeation-promoting technologies utilized for transdermal drug delivery systems are briefly discussed. This article is expected to provide scientific ideas and theoretical guidance for future research and the exploration of COL delivery strategies.

Rapid and simultaneous determination of two immunosuppressants in whole blood by high performance liquid chromatography

Cyclosporine A and sirolimus are immunosuppressants that are widely used in many organ transplantation procedures. They exhibit some complementary mechanisms of action and interact synergistically when used together. However， they are critical-dose drugs and have a narrow therapeutic index. They provide the desired therapeutic effect with acceptable tolerability only within a specific range of blood concentrations. Therefore， the rapid and simultaneous detection of the concentrations of cyclosporine A and sirolimus in whole blood could provide valuable information on planning medicine administration after organ transplantations. In this study， firstly， the chromatographic behaviors of cyclosporine A and sirolimus on a biological liquid chromatography （BioLC） column and traditional liquid chromatography （TraLC） columns were investigated systematically under the same chromatographic conditions. The results suggested that the peak height and peak width of cyclosporine A and sirolimus on the BioLC column， ZORBAX 300SB C8 （250 mm×4.6 mm， 5.0 μm）， were the highest and narrowest， respectively. The number of theoretical plates of cyclosporine A and sirolimus on the ZORBAX 300SB C8 column increased significantly when the volume ratio of acetonitrile in the mobile phases was greater than 70%. Their retention time on the BioLC and TraLC columns was negligibly affected by the use of formic acid and trifluoroacetic acid as the mobile phases. In the range of the experimental column temperature， the number of theoretical plates of cyclosporine A and sirolimus on the ZORBAX 300SB C8 column was significantly higher than that on the two TraLC columns. Furthermore， the relationship between the retention factor and column temperature of cyclosporine A on the ZORBAX 300SB C8 column was different from that on the two TraLC columns. Subsequently， a high performance liquid chromatography method based on the ZORBAX 300SB C8 column was established for the rapid separation and determination of cyclosporin A and sirolimus in whole blood. A sample of whole blood with a volume of 50 μL was prepared by protein precipitation with 1 mol/L sodium hydroxide and then extracted into 500 μL of ether-methanol （95∶5， v/v）. After centrifugation at 14000 r/min for 10 min， the organic layer was removed and evaporated under a stream of nitrogen at 50 ℃. The residue was then reconstituted in 200 μL of methanol for use. Cyclosporin A and sirolimus were separated through isocratic elution on the ZORBAX 300SB C8 column. The column temperature was set at 60 ℃. The mobile phase was acetonitrile-water （70∶30， v/v） and the flow rate was 1.0 mL/min. The detection wavelengths were 205 nm for cyclosporine A and 278 nm for sirolimus. The injection volume was 20 μL. The external standard method was used to quantify cyclosporine A and sirolimus. Under the optimized conditions， cyclosporine A and sirolimus were well-separated within 6 min with a resolution of 3.7 at 205 nm. In addition， the endogenous substances in whole blood negligibly interfered in the detection of sirolimus， while two endogenous substances slightly affected the detection of cyclosporine A. Cyclosporine A and sirolimus both showed good linear relationships in their respective concentration （r>0.997）. The limits of detection （LODs） of cyclosporine A and sirolimus were respectively calculated to be 10 ng/mL and 1 ng/mL based on a signal-to-noise ratio of 3， and the limits of quantification （LOQs） were 30 ng/mL and 2 ng/mL based on a signal-to-noise ratio of 10. In the whole blood samples， the recoveries of cyclosporine A and sirolimus at three spiked levels were in the ranges of 83.5%-89.7% and 95.8%-97.8% with relative standard deviations （RSDs） of 3.2%-9.0% and 3.4%-6.7% （n=5）， respectively. The established method is simple in operation， can be performed with a simple mobile phase， has a short analysis time， and provides a wide linear range and high sensitivity； hence， it can be applied to the determination of cyclosporine A and sirolimus in whole blood.

Therapeutic Drug Monitoring of Tacrolimus-Personalized Therapy in Heart Transplantation: New Strategies and Preliminary Results in Endomyocardial Biopsies

Tacrolimus (TAC) is an immunosuppressant drug approved both in the US and in the EU, widely used for the prophylaxis of organ rejection after transplantation. This is a critical dose drug: low levels in whole blood can lead to low exposure and a high risk of acute rejection, whereas overexposure puts patients at risk for toxicity and infection. Both situations can occur at whole-blood concentrations considered to be within the narrow TAC therapeutic range. We assumed a poor correlation between TAC trough concentrations in whole blood and the incidence of acute rejection; therefore, we propose to study TAC concentrations in endomyocardial biopsies (EMBs). We analyzed 70 EMBs from 18 transplant recipients at five scheduled follow-up visits during the first year post-transplant when closer TAC monitoring is mandatory. We observed five episodes of acute rejection (grade 2R) in three patients (2 episodes at 0.5 months, 2 at 3 months, and 1 at 12 months), when TAC concentrations in EMBs were low (63; 62; 59; 31; 44 pg/mg, respectively), whereas concentrations in whole blood were correct. Our results are preliminary and further studies are needed to confirm the importance of this new strategy to prevent acute rejection episodes.

Monitoring the tacrolimus concentration in peripheral blood mononuclear cells of kidney transplant recipients.

AimsTacrolimus is a critical dose drug and to avoid under‐ and overexposure, therapeutic drug monitoring is standard practice. However, rejection and drug‐related toxicity occur despite whole‐blood tacrolimus pre‐dose concentrations ([Tac]blood) being on target. Monitoring tacrolimus concentrations at the target site (within peripheral blood mononuclear cells; [Tac]cells) may better correlate with drug‐efficacy. The aim of this study was to (1) investigate the relationship between [Tac]blood and [Tac]cells, (2) identify factors affecting the tacrolimus distribution in cells and whole‐blood, and (3) study the relationship between [Tac]cells and clinical outcomes after kidney transplantation.MethodsA total of 175 renal transplant recipients were prospectively followed. [Tac]blood and [Tac]cells were determined at Months 3, 6 and 12 post‐transplantation. Patients were genotyped for ABCB1 1199G>A and 3435C>T, CYP3A4 15389C>T, and CYP3A5 6986G>A. Data on rejection and tacrolimus‐related nephrotoxicity and post‐transplant diabetes mellitus were collected.ResultsCorrelations between [Tac]blood and [Tac]cells were moderate to poor (Spearman's r = 0.31; r = 0.41; r = 0.61 at Months 3, 6 and 12, respectively). The [Tac]cells/[Tac]blood ratio was stable over time in most patients (median intra‐patient variability 39.0%; range 3.5%–173.2%). Age, albumin and haematocrit correlated with the [Tac]cells/[Tac]blood ratio. CYP3A5 and CYP3A4 genotype combined affected both dose‐corrected [Tac]blood and [Tac]cells. ABCB1 was not significantly related to tacrolimus distribution. Neither [Tac]blood nor [Tac]cells correlated with clinical outcomes.ConclusionsThe correlation between [Tac]blood and [Tac]cells is poor. Age, albumin and haematocrit correlate with the [Tac]cells/[Tac]blood ratio, whereas genetic variation in ABCB1, CYP3A4 and CYP3A5 do not. Neither [Tac]blood nor [Tac]cells correlated with clinical outcomes.

Novel thyroxine formulations: a further step toward precision medicine

Levothyroxine (T4) is a critical-dose drug, because little variations in the blood concentration may cause treatment failure as well as iatrogenic thyrotoxicosis. Despite the dose response of this drug being more carefully titrated nowadays, several papers still report that a significant fraction of patients treated with levothyroxine demonstrate a TSH which is not on target. Moreover, some widespread gastrointestinal disorders as well as interfering drugs and foods may cause the "refractoriness" of a significant number of patients to an expected dose of thyroxine. The increasing awareness of the mechanisms interfering with the oral thyroid hormone bioavailability and the body of evidence regarding the complexity of treatment in certain classes of patients prompted pharmaceutical research to identify new hormonal formulations to optimize the performance of this drug. In this brief review, the progression of the scientific knowledge of novel T4 formulations use has been analyzed.

Development and Validation of an LC-MS/MS Method and Comparison with a GC-MS Method to Measure Phenytoin in Human Brain Dialysate, Blood, and Saliva.

Phenytoin (PHT) is one of the most often used critical dose drugs, where insufficient or excessive dosing can have severe consequences such as seizures or toxicity. Thus, the monitoring and precise measuring of PHT concentrations in patients is crucial. This study develops and validates an LC-MS/MS method for the measurement of phenytoin concentrations in different body compartments (i.e., human brain dialysate, blood, and saliva) and compares it with a formerly developed GC-MS method that measures PHT in the same biological matrices. The two methods are evaluated and compared based on their analytical performance, appropriateness to analyze human biological samples, including corresponding extraction and cleanup procedures, and their validation according to ISO 17025/FDA Guidance for Industry. The LC-MS/MS method showed a higher performance compared with the GC-MS method. The LC-MS/MS was more sensitive, needed a smaller sample volume (25 µL) and less chemicals, was less time consuming (cleaning up, sample preparation, and analysis), and resulted in a better LOD (<1 ng/mL)/LOQ (10 ng/mL). The calibration curve of the LC-MS/MS method (10–2000 ng/mL) showed linearity over a larger range with correlation coefficients r2 > 0.995 for all tested matrices (blood, saliva, and dialysate). For larger sample numbers as in pharmacokinetic/pharmacodynamic studies and for bedside as well as routine analyses, the LC-MS/MS method offers significant advantages over the GC-MS method.

Generic immunosuppressants.

Immunosuppressive drugs for solid organ transplantation are critical dose drugs with a narrow therapeutic index. Many of the most commonly used innovator drugs are off patent and have been replicated by generic counterparts, often at substantial cost-savings to the patient. However, serious adverse events caused by the transition from innovator to generic medications, specifically in pediatric solid organ transplant recipients, have questioned these autosubstitutions. The purpose of this review is to summarize the criteria set forth by the regulatory bodies, and to examine how major immunosuppressive drugs conform to these recommendations. Regulatory bodies have established inconsistent criteria to demonstrate bioequivalence between innovator and generic medications, causing approved generic variations to have varying levels of equivalence with the innovator drugs. In order to minimize the risk for under-immunosuppression, the following recommendations have been concluded. Brand prescribing of cyclosporine and tacrolimus are recommended due to evidence of adverse events after conversion to generic formulations and differences in dissolution parameters. Mycophenolate mofetil (MMF) shows better bioequivalence between innovator and generic formulations, however caution should be advised when switching between formulations. The institution of 'innovator only' policies may be appropriate at this time in order to minimize the risk of under-immunosuppressing patients until the evidence of more stringent bioequivalence has been established.

A high intrapatient variability in tacrolimus exposure is associated with poor long-term outcome of kidney transplantation.

Tacrolimus is a critical dose drug with a considerable intrapatient variability (IPV) in its pharmacokinetics. We investigated whether a high IPV in tacrolimus exposure is associated with adverse long-term renal transplantation outcomes. Tacrolimus IPV was calculated from predose concentrations measured between 6 and 12 months post-transplantation of 808 renal transplant recipients (RTRs) transplanted between 2000 and 2010. One hundred and eighty-eight (23.3%) patients reached the composite end point consisting of graft loss, late biopsy-proven rejection, transplant glomerulopathy, or doubling of serum creatinine concentration between month 12 and the last follow-up. The cumulative incidence of the composite end point was significantly higher in patients with high IPV than in patients with low IPV (hazard ratio: 1.41, 95% CI: 1.06-1.89; P = 0.019). After the adjustment for several factors, the higher incidence of the composite end point for RTRs with a high IPV remained statistically significant (hazard ratio: 1.42, 95% CI: 1.06-1.90; P = 0.019). Younger recipient age at transplantation, previous transplantation, worse graft function (at month 6 post-transplantation), and low mean tacrolimus concentration at 1 year post-transplantation were additional predictors for worse long-term transplant outcome. A high tacrolimus IPV is an independent risk factor for adverse kidney transplant outcomes that can be used as an easy monitoring tool to help identify high-risk RTRs.

Are We Getting the Best Return on Investment From Clinical Drug-Drug Interaction Studies?

Are We Getting the Best Return on Investment From Clinical Drug-Drug Interaction Studies?

Monitoring of calcineurin inhibitors by NFAT-regulated gene expression in de novo renal allograft recipients on cyclosporine A.

Calcineurin inhibitors are critical-dose drugs with a narrow therapeutic range and optimal monitoring strategies are discussed in terms of safety and efficacy. A new pharmacodynamic monitoring tool - assessing the expression of nuclear factor of activated T-cells (NFAT)-regulated genes - has been established to directly measure the functional effect of cyclosporine A (CsA) in an individual patient. Until now, only sparse data on NFAT-regulated gene expression within the early post-transplant period have been available. Altogether 80 de novo renal transplant patients were enrolled in this non-interventional cohort-study. Immunosuppression consisted of interleukin (IL)-2 receptor antagonist induction, CsA, mycophenolic acid and steroids. Expression of NFAT-regulated genes (IL-2, granulocyte-macrophage colony stimulating-factor (GM-CSF), interferon-γ (IFN-γ)) was determined by qRT-PCR (real-time reverse transcription-PCR) at CsA C0 (prior to CsA intake) and C2 (2 hours after CsA intake) at regular follow-up visits within 6 months after transplantation. The median age of all patients was 47.9 ± 13.7 years (54 male). Residual NFAT-regulated gene expression showed a high interindividual variability. Inversely to reduction of CsA doses, NFAT-regulated genes increased from 1.78 ± 1.33% to 8.04 ± 7.36% in month 1 to month 6. Despite comparable CsA C0 levels, NFAT-regulated gene expression was significantly less inhibited in patients with treated biopsy-proven acute rejections (2.9 ± 2.2% vs. 2.0 ± 1.7%, p = 0.047). Patients with very low residual expression of NFAT-regulated genes were at an increased risk for early infectious episodes. Residual expression of IFN-γ and GM-CSF genes correlated significantly with clinical outcomes. NFAT-regulated gene expression is highly inhibited in the early post-transplant period in renal allograft recipients on CsA treatment. High residual NFAT-regulated gene expression was related to acute rejection episodes and low residual expression with infectious complications. Thus, NFAT-monitoring has the potential to support pharmacokinetic monitoring during the early post-transplant period.

Is It Ethical to Prescribe Generic Immunosuppressive Drugs to Our Transplanted Patients?

In various countries, drug patents for immunosuppressive drugs have recently expired or are about to expire. As a result, generic versions of these immunosuppressive drugs have emerged on the market. The use of generic drugs is widely accepted for chronic diseases such as hypertension and dyslipidemia. In organ transplantation, the use of generic drugs is debated. Some transplant societies discourage their use while others recommend extreme caution. This reluctance to use generic drugs in organ transplantation is partly related to the fact that most of these drugs are “critical dose drugs” and either low dosing of the drug or overdosing could have serious adverse consequences for the patient. This situation led us to question whether it was ethical to prescribe generic immunosuppressive drugs to transplanted patients. How much evidence and how many bioequivalence studies are needed to ensure the safety of generic drugs? Do the beneficence and nonmaleficence principles require the use of brand name immunosuppressive drugs? Given that transplant physicians are stewards of a precious resource (organs), should they prescribe brand name immunosuppressants in order to minimize the risk of rejection? Should patients be involved in the debate and how should physicians help them make informed decisions? Are there any conflicts of interest that might influence the debate? From a societal point of view, is the use of brand name immunosuppressive drugs a fair allocation of resources? Our review of the literature and ethical analysis led us to conclude that it would be ethical, under certain circumstances, to prescribe generic immunosuppressive drugs. That said, further health economics studies are needed to look at all of the costs related to the substitution (e.g., frequent and closer monitoring of patients).

Pharmacoepidemiology of Tacrolimus in Pediatric Liver Transplantation.

The aim of this study was to implement an intensive pharmacovigilance program of Tacrolimus (FK) in pediatric liver transplant patients at Hospital de Pediatria JP Garrahan, Buenos Aires, Argentina. Control of adverse events resulting from the post transplant immunosuppressive therapy is essential to promote both patient compliance and their overall survival. Despite pharmaco-therapeutic and surgical advances, complications and adverse events occur, increasing morbid- mortality in these patients. FK is a critical dose drug thus close therapeutic drug monitoring and vigilance of adverse events are recommended. We retrospectively evaluated patients that underwent liver transplant between 2010 and 2011 (n=59), through review of medical records and physician consultations. We followed up the cohort of patients prospectively for 2 years. Adverse drug reactions (ADRs) were reported to the national health authority, classified by causality using the Naranjo algorithm, and according to severity. Fifty seven out of 59 liver transplant patients were analyzed based on the accessibility of clinical records. A total of 68 ADRs were reported, standing hypomagnesemia (59%), post transplant lymphoproliferative disease (6%), hypertension (6%) and nephrotoxicity (16%). The rate of Epstein Barr Virus infection was 70%. A total of 98% of ADRs was moderate or severe and 96% of ADRs have been grouped as probable or definitive. A total of 39% of patients present one o more episodes of Biopsy Proven Acute Rejection in the first year post transplant and 72% of the study group received induction therapy with basiliximab. The present is the first project reported in Latin America that aims to evaluating and reporting safety and efficacy of FK in pediatric liver transplant patients. It is important to continue the study since the results may help to show safety and efficacy profiles that have not been described so far.

Is it ethical to prescribe generic immunosuppressive drugs to renal transplant patients?

Purpose of the reviewThis review was conducted to determine the ethical acceptability of prescribing generic immunosuppressive drugs to renal transplant patients.Sources of informationThe literature search was conducted using Pubmed and Google Scholar.FindingsThe use of generic immunosuppressive drugs (ISDs) in transplantation is a controversial topic. There is a consensus among transplant societies that clinical data is lacking and that caution should be exercised. The reluctance to use generic ISDs in organ transplantation is partly related to the fact that most are “critical dose drugs”, and that either low dosing or overdosing could have serious adverse consequences for both patients and society (i.e., the loss of scarce organs). In this paper, we examine the various ethical issues involved such as distributive justice, physician duties, risks versus benefits, conflict of interest, informed consent, and logistical and economic issues.LimitationsOur analysis was limited by the paucity of clinical data on generic ISDs and the absence of health economics studies to quantify the benefits of prescribing generic ISDs.ImplicationsOur study led us to conclude that it would be ethical to prescribe generic ISDs provided certain conditions were met. These include regulatory safeguards to minimize the risks of substitution; education of patients; and further clinical and health economics studies to better inform clinicians, patients and society of the risks and costs related to drug substitution.

GRP-077 Generic Mycophenolate Mofetil in Heart Transplant Recipients: Implementation of Active Pharmacovigilance

BackgroundImmunossupressant drugs have an important role in the prophylaxis of transplant rejection, so they are considered ‘critical dose drugs’. Use of a generic immunosuppressant represents a significant cost savings to...

A Model-Based Approach to Improve Tacrolimus Therapeutic Drug Monitoring in Paediatric Liver Transplantation

Introduction: Tacrolimus (TAC) is currently the most widely used immunosuppressive agent in transplantation. Its effectiveness as an immunomodulator is well demonstrated. Moreover its use is characterized by the occurrence of some side-effects, such as nephrotoxicity, and by high pharmacokinetics (PK) variability and risk of drug-drug and drug-food interactions. It is therefore considered as a critical dose-drug with a low therapeutic index drug, which can benefit from blood levels therapeutic drug monitoring (TDM). As frequently performed in paediatric patients, this TDM is based on trough concentrations known to poorly correlate with clinical outcome (graft rejection and TAC toxicity). Moreover, therapeutic ranges were defined based on adult clinical data. Area under the concentrations time curve (AUC) is expected to be a better marker of global systemic exposure to TAC, but is difficult to obtain from classical approach for ethical reasons. The aim of this study is therefore to develop a mathematical model to predict the TAC exposure (AUC) in children based on data collected during clinical routine (C0, proteins, patient age, body weight, body surface area, co-medications, hematocrit, time post-transplantation, etc …). Methods: Nonlinear mixed effect approach was used to develop and validate a model to better characterize TAC PK and therefore routinely predict AUC in children. Retrospective data from 51 pediatric liver transplant patients were used. All patients were primary transplants, aged 0 to 18 years old and receiving living-donor liver transplantations. The study only included patients who had not experienced rejection episode since transplantation and who received TAC as monotherapy. Results: A one compartment model with first order absorption and elimination best described the data. The apparent volume of distribution (Vd) and clearance (CL) were 330 L and 8.4 L/h, respectively and the interindividual variability on Vd and CL were 70% and 37%, respectively. Parameters were estimated with good precision (CV< 20% for all parameters). Hematocrit levels, body weight and time post-transplantation were the covariates retained in the final model that influenced TAC distribution and clearance. An example of predicted (−) and observed (x) concentrations over time is illustrated in graph1.Figure: [Patient TAC concentrations example]Conclusion: This model could be considered as a useful tool to better define the target tacrolimus AUC in paediatrics, currently lacking in the literature, and to optimize AUC-based TDM in children.

Generic Immunosuppression in Solid Organ Transplantation

The introduction of generic immunosuppressant medications may present an opportunity for cost savings in solid organ transplantation if equivalent clinical outcomes to the branded counterparts can be achieved. An interprofessional working group of the Canadian Society of Transplantation was established to develop recommendations on the use of generic immunosuppression in solid organ transplant recipients (SOTR) based on a review of the available data. Under current Health Canada licensing requirements, a demonstration of bioequivalence with the branded formulation in healthy volunteers allows for bridging of clinical data. Cyclosporine, tacrolimus, and sirolimus are designated as "critical dose drugs" and are held to stricter criteria. However, whether this provides sufficient guarantee of therapeutic equivalence in SOTR remains controversial, and failure to maintain an appropriate balance of immunosuppression may have serious consequences, including rejection, graft loss, and death. Published evidence supporting therapeutic equivalence of generic formulations in SOTR is lacking. Moreover, in the setting of multiple generic formulations the potential for uncontrolled product switching is a major concern, since generic preparations are not required to demonstrate bioequivalence with each other. Although close monitoring is recommended with any change in formulation, drug product switches are likely to occur without prescriber knowledge and may pose a significant patient safety risk. The advent of generic immunosuppression will require new practices including more frequent therapeutic drug and clinical monitoring, and increased patient education. The additional workload placed on transplant centers without additional funding will create challenges and could ultimately jeopardize patient outcomes. Until more robust clinical data are available and adequate regulatory safeguards are instituted, caution in the use of generic immunosuppressive drugs in solid organ transplantation is warranted.

Objective assessment of nonadherence and unknown co-medication in hospitalized patients

The intake of medications (drugs) without the knowledge of the treating physician (unknown co-medication) and nonadherence strongly influence drug safety. The aim of our study was to objectively assess unknown co-medication and nonadherence in hospitalized patients by screening urine for a large number of drugs using highly sensitive full scan gas chromatograpy/mass spectrometry (GC/MS). Secondary objectives were to determine the relationship of co-medication and nonadherence to the number of drugs prescribed and to compare history-taking by a pharmacist versus a physician. In 152 patients, the drug histories taken by physicians, patients' self-reported adherence, and information compiled during as many as three structured interviews conducted by a trained pharmacist on days 1-2, 3-4, and 7-11 of the hospital stay were compared with the GC/MS results from urine samples collected after each interview. In the interviews performed by the pharmacist, 235 additional drugs were identified that were not documented in the chart. Of all the drugs indicated in any interview, 16.9% were identified only by the physician, 24.1% only by the pharmacist, and 59% by both. Overall, in 78% of the patients at least one additional drug was identified by urine screening. The findings suggest overall nonadherence to at least one drug in 13.0% of patients on admission and in 23.3% of patients at any time during hospitalization. Nonadherence was less frequent for critical dose drugs and correlated with the number of prescribed drugs. The drug history among hospitalized patients is often incomplete, and nonadherence and unknown co-medication are alarmingly frequent. This lack of knowledge might impact the overall success of drug therapies in the hospital setting.

ACCF/AHA 2011 Health Policy Statement on Therapeutic Interchange and Substitution

Preamble . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1291 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1291 1. Purpose of This Document . . . . . . . . . . . . . . .1291 2. Document Development Process . . . . . . . . . .1291 3. Definitions, Terminology, and Regulations . . .1292 1. Terminology . . . . . . . . . . . . . . . . . . . .1292 2. Generics . . . . . . . . . . . . . . . . . . . . . . . .1293 3. Bioequivalence . . . . . . . . . . . . . . . . . .1293 4. Biologics and Biosimilars. . . . . . . . . . .1294 2. Pharmacogenomics . . . . . . . . . . . . . . . . . . . . . . . .1295 3. Federal Regulations and State Laws . . . . . . . . . . .1296 4. Therapeutic Approaches . . . . . . . . . . . . . . . . . . . . .1296 1. Therapeutic Interchange . . . . . . . . . . . . . . . . .1296 2. Therapeutic Substitution . . . . . . . . . . . . . . . . .1297 3. Generic Substitution . . . . . . . . . . . …

Phytopharmaka als Ursache von unerwünschten Arzneimittelwirkungen

Herbal medicines are used by many patients. Their known or potential adverse events should be taken into account during treatment with herbal medicines. In this article adverse effects of commonly used herbs are presented. St. John's wort is known to be a potent inducer of cytochrome P450 (CYP) 3A4 leading to reduced blood concentrations of a number of CYP3A4 substrates. For many other combinations evidence is sparse but due to a number of case reports of adverse interactions they should only cautiously be combined with certain critical dose drugs until their risk is fully assessed. Pertinent examples are the immunostimulant Echinacea which could decrease the effect of immunosuppressants. Ginseng and ginkgo should not be combined with anticoagulants. Excessive sedation may occur with concomitant use of valerian and barbiturates.

Counterpoint: Is Pharmacokinetic or Pharmacodynamic Monitoring of Calcineurin Inhibition Therapy Necessary?

Individual dose adjustment of cyclosporine (CsA)1 and tacrolimus (TAC), which are critical-dose drugs widely used in transplantation, is important not only to prevent acute rejection but also to prolong graft (and patient) survival. New therapeutic regimens such as calcineurin inhibitor (CNI)-sparing strategies have recently strengthened the need for fine individual dose adjustment of these drugs. A good treatment-personalization strategy should employ a marker or a set of markers with (a) strong relationships with therapeutic and/or adverse effects; (b) low intraindividual variability; (c) established, and ideally, validated target values; and (d) easy and fast measurement. So far, dose individualization has mainly been based on pharmacokinetics, which monitors the handling of the drug by the body. Pharmacodynamics (PD), which focuses on the biologic effect of the drug on its target(1), might also be useful as a replacement or an adjunct. Early on in the use of CsA, monitoring of the predose (trough, C) concentration became the standard of care(2). However, no trial has been conducted in transplantation patients to determine whether C monitoring is superior to no therapeutic monitoring with respect to efficacy or toxicity(2), and conducting such a trial now would not be ethically acceptable given the obvious improvements brought to transplantation patients by therapeutic drug monitoring. However, it has long been recognized that the results of C monitoring are suboptimal, and retrospective analysis of transplantation populations monitored on C has shown that the full interdose area under the concentration-time curve (AUC0–12h), abbreviated AUCs (AUC0–6h or AUC0–4h), and Cmax (maximum concentration) have stronger links with the residual inefficacy or toxicity episodes than C. Because of the impracticability of routine AUC0–12h monitoring, limited sampling strategies have been proposed as a more practical approach. In 2002, the CONCERT (Consensus …