Clinical utility of drug measurement and pharmacokinetics – therapeutic drug monitoring in psychiatry

Based on the assumption that a relationship between blood levels and clinical effects (therapeutic effects, adverse events and toxicity) can be defined and considering that after equal doses plasma concentrations vary markedly between individual patients, therapeutic drug monitoring (TDM) can assist to personalize dose adjustment. Taken together, drug levels and a knowledge of the pharmacological profile of the administered drugs can enable the optimal dosage to be tailored according to the need of the individual patient. Therapeutic drug monitoring has been established for a limited number of drugs. In psychiatry, it has a 40-year-long history, which started with nortriptyline. Evidence has accumulated which shows that TDM is a valid tool for the optimization of psychopharmacotherapy. When used adequately, TDM is helpful for many patients and in many situations. Combined with pharmacogenetic tests, the metabolic status of a patient can be well characterized. Several new observations have been made during routine TDM that have stimulated clinical pharmacological research, such as investigations on inherited differences in drug metabolism that are closely linked to TDM in psychiatry. The contributions of individual forms of cytochrome P450 (CYP) to the metabolism of drugs was elicited by clinical observations on pharmacokinetic drug interactions. Therapeutic drug monitoring requires a close collaboration between the prescribing physician, the laboratory specialist, the clinical pharmacologist and the patient. This complexity may result in errors which can be detected by analysing the appropriate use of TDM in clinical practice. More education has to be provided to the prescribing clinicians on the pharmacology of the drugs and the algorithm of TDM. Moreover, clinical trials should include measurements of blood concentrations during drug development to generate valid data on the relationships between drug concentrations and clinical outcomes under well-controlled conditions. This would merely increase the amount of work and costs, as high-throughput methods are now available in many laboratories. Any progress in TDM has direct benefits for the treatment of many individual patients.     

Cushing’s syndrome: drug targets and therapeutic options

Cushing’s syndrome is caused by endocrine and metabolic alterations produced by high levels of glucocorticoids. Glucocorticoid excess is usually a result of exogenous administration of glucocorticoids or alteration of the hypothalamus-pituitary-adrenal (HPA) axis. However, in the majority of patients it is due to an adrenocorticotrophic hormone (ACTH)-secreting pituitary adenoma. Other possible causes are ectopic ACTH-secreting tumours of the lung, glucocorticoid-producing adrenal tumours and other ectopic tumours. The symptoms include central fat deposition, altered energy and protein metabolism, hypertension and depression. The molecular mechanisms that regulate the HPA axis provide a rationale to correct the alterations observed in Cushing’s syndrome. Recent developments have identified possible targets and drugs for therapy at different levels of the HPA axis. This article reviews patents claiming novel targets and drugs for Cushing’s syndrome in the period 1997–2002.     

A guide to therapeutic drug monitoring of β-lactam antibiotics

Therapeutic drug monitoring (TDM) opens the door to personalized medicine, yet it is infrequently applied to β-lactam antibiotics, one of the most commonly prescribed drug classes in the hospital setting. As we continue to understand more about β-lactam pharmacodynamics (PD) and wide inter- and intra-patient variability in pharmacokinetics (PK), the utility of TDM has become increasingly apparent. For β-lactams, the time that free concentrations remain above the minimum inhibitory concentration (MIC) as a function of the dosing interval (%fT>MIC) has been shown to best predict antibacterial effect. Many studies have shown that β-lactam %fT>MIC exposures are often suboptimal across a wide variety of disease states and clinical settings. A limitation to implementing this practice is the general lack of understanding on how to best operationalize this intervention and interpret the results. The instrumentation and expertise needed to quantify β-lactams for TDM is rarely available locally, but certain laboratories advertise these services and perform them regularly. Familiarity with the modalities and nuances of antimicrobial susceptibility testing is crucial to establishing β-lactam concentration targets that meet the relevant exposure thresholds. Evaluation of these concentrations is best accomplished using population PK software and Bayesian modeling, for which a multitude of programs are available. While TDM of β-lactams has shown an ability to increase the rate of target attainment, there is currently limited evidence to suggest that it leads to improved clinical outcomes. Although consensus guidelines for β-lactam TDM do not exist in the United States, guidance would help to promote this important practice and better standardize the approach across institutions. Herein, we discuss the basis for β-lactam TDM, review supporting evidence, and provide guidance for implementation in specific patient populations.     

siRNA and the lung: research tool or therapeutic drug?

Oligonucleotide-based therapeutics have been hailed as 'the next great wave of the biotechnology revolution' starting with antisense oligonucleotides (ASOs) nearly 20 years ago to RNA interference (RNAi) currently. Is RNAi just the latest research tool or does it have real potential as a therapeutic drug modality? As a research tool, it is evident that RNAi has revolutionized the biological sciences by allowing selective silencing of messenger RNA (mRNA) expression. With the advent of the postgenomic era, RNAi offers a therapeutic platform on which to identify potential picomolar active drug candidates to any target, including those that are conventionally undruggable. In this review, we will discuss the progress made in developing RNAi therapeutics for the treatment of respiratory diseases.     

Do evacuated blood collection tubes interfere with therapeutic drug monitoring?

The influence of various brands of evacuated blood collection systems (the old type, red stoppered Vacutainer^®; the new type, blue stoppered Vacutainer^®; Monoject^® and Venoject^®) on therapeutic drug monitoring was investigated. No interferences were found in the assay of ethosuximide, phenobarbital, phenytoin, valproic acid, digitoxin, digoxin, procainamide, gentamicin and theophylline. Using Monoject^® and old type Vacutainer^® tubes, lower levels were found in the disopyramide assay: 91.3±4.6% (p<0.05) and 91.7±7.0% (not significant) respectively, and in the quinidine assay: 82.8±6.7% (p<0.02) and 83.9±4.4% (p<0.001) respectively as compared with glass tubes. In the carbamazepine assay a decrease was found in the Monoject^® tubes only: 93.7±1.7% (p<0.01). The stoppers of Monoject^® tubes and the old type Vacutainer^® tubes contained the plasticizer tris(2-butoxyethyl)phosphate (tbep), which has been shown to be a potent inhibitor of the binding of several drugs to α₁-acid glycoprotein. Using the new type Vacutainer^® and the Venoject^®, no interferences were found.     

Is there a role for therapeutic drug monitoring with codeine?

Codeine is an old and commonly used analgesic agent for mild to moderate pain. It is the prototypical "prodrug" in that its analgesic effect is almost wholly dependent on its biotransformation to morphine, a process that is mediated by the polymorphic cytochrome P450 2D6 enzyme. As such, interindividual variability in codeine metabolism and response is a clinical reality, and there has been much progress in characterizing the genetic causes of this variability in diverse populations. Yet despite the potential for both life-threatening adverse reactions and lack of therapeutic effect, codeine is not commonly indicated for therapeutic drug monitoring. This review will discuss the relative role of pharmacogenetics and therapeutic drug monitoring in predicting and/or maintaining adequate and safe analgesia with codeine. The review will end on a discussion of how the marriage of these 2 fields may provide new insights into the mechanisms of codeine-induced toxicity and analgesia.     

Is there a role for therapeutic drug monitoring of new anticonvulsants?

Despite the fact that all new anticonvulsants have undergone extensive pharmacokinetic scrutiny prior to their introduction to the market, the opportunity to perform good prospective studies on their concentration-effect relationship has been largely missed, in some cases deliberately because therapeutic drug monitoring (TDM) is considered unfavourable for the marketing of a new drug. However, there are reasons to believe that TDM may play a useful role in maximising the therapeutic potential of new anticonvulsants. In fact, these drugs have a narrow therapeutic index, careful individualisation of dosage to optimise response is required, and inter- and intra-individual pharmacokinetic variability may translate into differences in dosage requirements. The wide interindividual variability in the serum concentrations at which therapeutic and toxic effects of these drugs are observed does not necessarily imply that TDM cannot be useful: indeed, a marked pharmacodynamic variability has also been reported for all the currently monitored older anticonvulsants. The new anticonvulsants which, based on their properties, are particularly attractive candidates for TDM include lamotrigine, topiramate, tiagabine, zonisamide and felbamate. However, in the absence on sound information on the target concentration ranges of these drugs, the routine concentration monitoring of these drugs cannot be recommended. Despite this, serial measurements of serum drug concentrations may be useful in selected patients, especially those suspected of poor compliance and those in whom pharmacokinetic changes caused by disease or administration of concomitant medication are anticipated. Even in the presence of marked interindividual pharmacodynamic variability, it is often possible to empirically determine the concentration at which each patient exhibits the best response, and apply that information in subsequent management. Prospective studies, using preferably a randomised concentration-controlled design, are necessary to better characterise concentration-effect relationships for these agents.     

Lithium in bipolar disorder: can drug concentrations predict therapeutic effect?

The evidence is reviewed for effective serum lithium concentrations for the acute and prophylactic treatment of mania and depression in patients with bipolar disorder. The efficacy of lithium in the treatment of acute manic episodes has been recognised for several decades, primarily using concentrations in the range of 0.8 to 2 mmol/L. The number of patients responding increases as the serum lithium concentration increases, although individual patients may respond at lower concentrations (<0.8 mmol/L). Lithium doses and serum concentrations similar to those used to treat acute mania have been studied in bipolar depression, with no evaluation of a relationship between concentration and clinical response. Several prospective controlled trials have evaluated this relationship in the prophylactic treatment of bipolar disorder. Maintaining higher serum lithium concentrations (0.8 to 1 mmol/L) improves the likelihood of good effect in prophylactic treatment, although individual patients may do well on lower concentrations. Despite the paucity of evidence to specifically support the efficacy of lithium at lower serum lithium concentrations in the elderly, lower target ranges (0.5 to 0.8 mmol/L) are commonly recommended due to an increased sensitivity to adverse effects, particularly neurotoxicity. The serum lithium concentrations recommended in adults have been applied to children; however, this has not been studied. Overall, the evidence suggests a relationship between serum lithium concentration and therapeutic effect, although the exact nature of this relationship is not clear. For example, it is not known why some people respond to lower concentrations and others do not. There are many factors that influence studies trying to elucidate this relationship. Many of these factors are related to the interpretation of the serum lithium concentration. In summary, patients have an increased chance of responding to lithium if 12-hour serum lithium concentrations at steady state are above 0.8 mmol/L. Many patients will respond to lower concentrations (0.4 to 0.7 mmol/L), but we are unable to identify these patients a priori. The relationship between serum lithium concentrations and adverse effects is also very important in determining appropriate target lithium concentrations. The current best advice is to individualise the target serum lithium concentrations based on efficacy and tolerability and to optimise the interpretation of these concentrations by ensuring within-patient consistency with respect to dosage schedule, lithium preparation and the timing of blood sampling.     

Can fluconazole concentrations in saliva be used for therapeutic drug monitoring?

The saliva/plasma concentration ratio of fluconazole was investigated in 22 HIV-1-infected individuals with an oropharyngeal Candida infection to determine whether saliva fluconazole concentrations could provide useful information for therapeutic drug monitoring in this population. Steady-state paired plasma and saliva samples were obtained after approximately 1 week of treatment with 50-or 100-mg fluconazole as capsules. A significant correlation between plasma and salivary levels of fluconazole was observed. The median saliva/plasma concentration ratio was 1.3 and was independent of the ingested dose and the plasma fluconazole concentration. The prediction of fluconazole concentrations in plasma from the concentrations in saliva was, although unbiased, not precise. From these findings, the authors conclude that although stimulated salivary fluconazole concentrations are significantly correlated with plasma concentrations, it is not possible to predict plasma fluconazole levels from the salivary concentrations with adequate precision. However, saliva fluconazole concentrations have sufficient value to test for compliance and even semiquantitative prediction of plasma concentrations.     

Peptide deformylase – a promising therapeutic target for tuberculosis and antibacterial drug discovery

Background: Tuberculosis (TB) remains the most important infectious disease causing morbidity and death, due to the human pathogen Mycobacterium tuberculosis. The emergence of multi-drug-resistant and extensively-drug-resistant forms of TB have resulted in an increase in the number of TB cases. Thus, there is an urgent need to identify new drugs with novel targets to ensure future therapeutic success. Studies have indicated that peptide deformylase is an interesting potential candidate for discovering antimicrobial agents. Objective: To explore the role of peptide deformylase, a highly conserved metalloprotease and an essential enzyme in bacterial life cycle, as a target for antibacterial as well as antimycobacterial drug development. Methods: This review is based on recent published literature and online resources related to peptide deformylase inhibitors and their anbacterial potential. Results/conclusion: Peptide deformylase is an emerging therapeutic target for the treatment of tuberculosis and peptide deformylase inhibitors can act as potential future antibacterial agents.     

Colloid drug delivery systems: a response to therapeutic expectations arising from biotechnological advances?

New and fascinating advances in biotechnology have open new perspectives since the use of monoclonal antibodies for therapeutic application, particularly cancer, has been approved. Over the last two decades, numerous research teams have demonstrated that the progression of cancer is often associated with an over-expression of one or several proteins, called tumor antigens. In order to target tumors specifically, researchers have tried to couple monoclonal antibodies with colloid vectors such as liposomes, nanoparticles, and emulsions containing cytotoxic compounds. Use of these conjugated vector-antibody systems for the treatment of cancer is designed to target cancerous cells while sparing healthy cells. We present here a discussion on the synergy between biotechnology and modern molecular pharmotechnology, opening new horizons for therapy.     

Clozapine and therapeutic drug monitoring: is there sufficient evidence for an upper threshold?

Rationale

Clozapine levels are advocated in the monitoring of patients on this drug and have now been used for a number of years. A safety-related threshold has also been proposed, as well as therapeutic lower and upper thresholds. While there has been reasonable consensus regarding a lower therapeutic threshold, this is not the case for the upper thresholds.

Objectives

Our aim was to review available evidence related to upper thresholds.

Methods

We carried out an electronic search of different databases and a manual search of articles between 1960 and 2011, cross-referencing the following terms with clozapine—interactions, monitoring, pharmacokinetics, plasma levels, serum levels, and toxicity.

Results

Sixty-nine articles met our search criteria and these could be divided into reviews (11), studies (24), and case reports (35). Study quality was evaluated, and none met criteria for a prospective, randomized controlled trial specifically addressing higher plasma levels, e.g., >500 ng/ml. Case reports emphasize in particular the impact of interactions, e.g., antidepressants and smoking. There is clear evidence indicating a dose-related increased risk of seizures, at least to 500–600 mg/day, but a lack of data to suggest such a relationship between plasma levels, dose, and side effects linked to safety, e.g., seizures, myocarditis, and agranulocytosis. The very limited evidence addressing an upper threshold related to clinical response suggests a “ceiling effect” in the range of 600–838 ng/ml.

Conclusions

It appears that the current safety-related threshold is not supported by evidence. There may be an upper threshold for clinical response, beyond which chance of response falls off, although further studies are warranted.     

Consistency of psychotropic drug–drug interactions listed in drug monographs

Background

With an increasing prevalence of psychotropic polypharmacy, clinicians depend on drug–drug interaction (DDI) references to ensure safe regimens, but the consistency of such information is frequently questioned.

RNA interference： an exciting new target validation tool of drug action and therapeutic approach on cardiovascular diseases

RNA interference (RNAi) is an evolutionarily conserved mechanism for silencing gene expression by targeted degradation of mRNA. Short double-stranded RNAs, known as small interfering RNAs (siRNA), are incorporated into an RNA-induced silencing complex that directs degradation of RNA containing a homologous sequence.