Therapeutic drug monitoring assay development to improve efficacy and safety

The development of therapeutic drug management (TDM) utilizing diagnostic assays as biomarker tests is described. TDM can be useful in establishing an individual patient's optimal blood concentration range, and benchmarking blood concentrations at which seizures are controlled, as well as those associated with AED-specific adverse effects. TDM requires the application of pharmacokinetic, pharmacodynamic, pharmacogenomic, pathophysiological and clinical principles to the management of patients in order to achieve safe and effective therapy. Optimal therapy requires rational application of all these principles to personalize patient care.     

Individualized immunoglobulin therapy in chronic immune‐mediated peripheral neuropathies*

Despite the well‐recognized importance of immunoglobulin therapy individualization during the treatment of chronic inflammatory demyelinating polyneuropathy (CIDP), the pathway to best achieve optimization is unknown. There are many pharmacokinetic and immunobiologic variables that can potentially influence the appropriateness of any individual therapy. Although identification of specific autoantibodies and their targets has only been accomplished in a minority of patients with CIDP, already the diagnostic and treatment implications of specific autoantibody detection are being realized. Individual variability in IgG pharmacokinetic properties including IgG catabolic rates and distribution, as well as the IgG level necessary for disease control also require consideration during the optimization process. For optimization to be successful there must be a measure of treatment response that has a clinically meaningful interpretation. There are currently available well‐defined and validated clinical assessment tools and outcome measures that are well suited for this purpose. While there remains much to learn on how best to manipulate immunopathology and immunoglobulin pharmacokinetics in the most favorable way, there currently exists an understanding of these principles to a degree sufficient to begin to develop rational and evidence‐based treatment optimization strategies.     

Psychopharmacology in psychiatric emergencies

Pharmacotherapy is crucial to the emergency psychiatric treatment of patients who are out of control in a variety of psychiatric and medical disorders. The time required for the more definitive pharmacological treatment of the major psychiatric syndromes is such that they can best be only started in the emergency setting. The emergency treatment of patients who are severely agitated, violent, or psychotic is based on IM administration of antipsychotic medications, such as haloperidol. In conjunction with psychological support this can provide effective, safe, and humane treatment. Sedative-hypnotics, such as diazepam, can be helpful for less severe anxiety states. This article focused on clinical and pharmacokinetic principles of the use of these medications, the understanding of which can help maximize their effective use in emergencies. Topics which are emphasized include sedative, antipsychotic and disinhibiting effects, side effects, absorption after oral and IM administration, and the concepts of steady-state kinetics and the "loading dose."     

Pharmacokinetics of Old, New, and Yet-to-Be-Discovered Antiepileptic Drugs

Summary: The pharmacokinetics of antiepileptic drugs have been investigated extensively during the last two decades. It has become evident that the therapeutic management of epileptic patients would be significantly improved with the elimination of the drawbacks associated with existing antiepileptic drugs. Based on the information accumulated to date, the following set of principles is proposed: (1) The requirement of central nervous system (CNS) penetration automatically creates vulnerability to CNS toxicity. (2) The narrower the therapeutic range of a given drug, the more limiting its pharmacokinetic properties become. (3) The requirements of chronic administration and compliance place narrow limits on the optimum half-life (24 h). (4) The practice of polytherapy and the potential for pharmacodynamic and pharmacokinetic interactions make it necessary to simplify metabolic schemes (i.e., use of meta-bolically directed design approaches). (5) New antiepileptic drugs have shown that widely different structures are associated with anticonvulsant properties–it becomes important to minimize toxicity and optimize pharmacokinetic characteristics early in the development of future antiepileptic drugs. (6) Yet-to-be-discovered antiepileptic drugs will probably include biotechnology-based pharmaceuticals. Such biologic agents as neuropeptides present a new set of pharmacokinetic requirements because they are generally receptor targeted, they do not cross absorption barriers easily, and they are labile and subject to degradation.     

Basic principles of clinical pharmacology

This article reviews basic principles of clinical pharmacology and their therapeutic application. The effects of drug absorption, distribution, protein binding metabolism, and excretion are discussed. Models for repetitive oral and intravenous dosing are presented, and the difference between pharmacokinetic and pharmacodynamic analysis emphasized. The final section reviews the effects of physiologic and pathologic processes on clinical pharmacology.     

Practical aspects in the treatment of epilepsy

ABSTRACT The different forms of epilepsy require different treatment, and drug choice depends on certain pharmacological and pharmacokinetic principles. Optimal treatment is based on single drug therapy, if possible, and monitoring of plasma antiepileptic drug levels. Such treatment, together with clinical observations and the cooperation of a well-informed patient, will achieve the best seizure control. Nevertheless, seizure recurrence or increased seizure frequency is a possibility. When withdrawal of treatment is indicated, it must be done according to certain principles.
The possibility of pregnancy must be considered when choosing antiepileptic drugs for fertile women. Drug kinetics are different during pregnancy, and frequent monitoring and adjustment of the regimen are essential. Special care is necessary during delivery because of a higher risk of complications and apparently increased perinatal mortality. Plasma half-life of antiepileptic drugs may be increased or decreased in newborns. Slow elimination of diazepam contributes a special risk. Breast feeding is safe in most cases, but phenobarbital and diazepam may cause sedation of the infant.     

Reflections on the use of the concept of plasticity in neurobiology. Translation and adaptation by Bruno Will, John Dalrymple-Alford, Mathieu Wolff and Jean-Christophe Cassel from J. Paillard, J Psychol 1976;1:33-47

After having underlined the ambiguities of the concept of plasticity and the dangers of its purely metaphoric use in neurobiology, it is suggested that we return to a more precise definition of the structure, the operating principles and the function of the "systemic" unit or "integron" relevant to the particular level of analysis in question. Any change can then be described as a modification of function, a change in the operation principles, or an alteration of the material structure of the system. It is suggested that the term plastic should be restricted to describing, among the possible variations in the operating principles or the function of a given system, any lasting alteration of the connectivity network of the system under the influence of an external force or environmental constraint. Therefore, systematic or random variations of performance, functional flexibility or the vicarious(1) processes or strategies that can be found in a rigidly wired system are not justified examples of plasticity.     

Controversies in Blood-level Monitoring: Reexamining Its Role in the Treatment of Epilepsy

Summary: This article reexamines the role of blood-level monitoring (therapeutic drug monitoring, TDM) of antiepileptic drugs (AEDs) in the current treatment of epilepsy and identifies situations in which TDM can be useful. Basic pharmaco-kinetic and pharmacodynamic principles are reviewed, with specific emphasis on kinetics of absorption/distribution/metabolism, elimination half-life, time to steady state, and plasma drug concentrations. The relationship between AED intensity of effect (pharmacodynamics) and plasma concentration (pharmacokinetics) is expressed mathematically, examined in the context of the major old and new AEDs, and integrated with a historical look at the role of TDM. Situations in which TDM can be useful in the modern treatment of epilepsy are presented and discussed. For both older and newer AEDs, TDM is useful in six clinical situations: establishing "baseline" effective concentrations, evaluating potential causes for lack of efficacy, evaluating potential causes for toxicity, evaluating potential causes for loss of efficacy, judging "room to move' or when to change AEDs, and minimizing predictable problems. TDM remains a valuable tool in the modern treatment of epilepsy. It can be selectively and appropriately utilized to help maximize seizure control and minimize side effects if levels are obtained in response to a patient-specific pharmacokinetic or pharmacodynamic issue or problem.     

Social model philosophies and principles: Their applications to therapies for aphasia

Background : The social model of disability has, on occasion, created confusion and contention among those working in the field of aphasia. Some have treated it as an alternative or substitute for traditional therapies. Aims : This paper makes an effort to clarify the issues surrounding discussions of the social model, and attempts to reduce some of the disagreement associated with its use. It is argued that the social model can provide principles for practice that can be used as a guide for any types of therapies. Methods & Procedures : The study examines the literature on the social model. A distinction is drawn between social model philosophies and social model principles. Once the distinction is made, a set of principles is presented as a guide for planning and evaluating support services for people with aphasia. Outcomes & Results : The particular principles drawn from the social model philosophy are: equalising social relations, creating authentic involvement, creating engaging experiences, establishing user control, and becoming accountable to users. Illustrations are given of how each of these social model principles was used by staff and people with aphasia to guide different support services offered by a UK charity called Connect – The Communication Disability Network. The principles were also found useful in evaluating social model activities. Conclusions : A case is made that the social model principles can provide speech therapists with a guide for conducting their therapies, whatever form those practices take.     

Population pharmacokinetics in geriatric psychiatry.

Although geriatric patients are the major recipients of drugs, most research during drug development is conducted in healthy younger adults. Safe and effective drug therapy in the elderly requires an understanding of both drug disposition and response in older individuals. One of the major issues in studying the elderly relates to the ability to study a large number of people in a minimally invasive way. Population pharmacokinetics can be used to model drug concentrations from a large population of sparsely sampled individuals. Population pharmacokinetics characterizes both the interindividual (between-subject) and intraindividual (within-subject) variability, and can identify factors that contribute to pharmacokinetic and pharmacodynamic variability. Population pharmacokinetics can be used to aid in designing large clinical trials by simulating virtual data based on the study design. It can also be used to assess consistency of drug exposure and evaluate its effect on clinical outcome. This article reviews the methods used in pharmacokinetic modeling, as well as providing examples of population pharmacokinetic modeling, highlighting its application to geriatric psychiatry.     

The role of proximity, immediacy, and expectancy in frontline treatment of combat stress reaction among Israelis in the Lebanon War

The authors examined the effectiveness of the prevailing treatment doctrine stressing the principles of proximity, immediacy, and expectancy for combat stress reaction among Israeli soldiers in the Lebanon War. Two treatment outcomes were measured: return to military unit and presence of posttraumatic stress disorder. All three treatment principles were associated with a higher rate of return to the military unit. The beneficial effect of frontline treatment was also evidenced by lower rates of posttraumatic stress disorder. The authors suggest that these principles can also be effective in treating other forms of posttraumatic stress disorder.     

Pharmacokinetics of SSRI antidepressants: half-life and clinical applicability

The selective serotonin reuptake inhibitors (SSRIs) antidepressants are at present time the most useful for the treatment of depression. SSRIs exhibit differences in potency of inhibiting serotonin reuptake, although the differences do not correlate with clinical efficacy. There are substantial pharmacokinetic differences among the five SSRIs, fluvoxamine, fluoxetine, paroxetine, sertraline and citalopram. Optimum use of these drugs requires a working knowledge of these differences. Among these pharmacokinetic parameters, half-life and metabolism pathways are the most relevant. There are substantial differences in term of their half-life between fluoxetine and others SSRIs. The half-life of fluoxetine and its active metabolite norfluoxetine is respectively 2 to 4 days and 7 to 15 days, more extended than other SSRIs (approximately 1 day). The extended half-life of fluoxetine and its active metabolite may be an advantage in the poorly compliant patient and may offer a potential safety advantage over shorter-acting SSRIs, with respect to abrupt discontinuation of therapy. Conversely, this long half-life needs a long period of wash-out (5 weeks) before introducing other drugs (MAOIs, sumatriptan) which can interact with serotonin function and can lead to the serotoninergic syndrome. SSRIs are potent inhibitors of the hepatic isoenzyme P450-2D6 and would be expected to have effects on the clearance of drugs metabolized by this enzyme. Paroxetine is the most potent inhibitor, followed by fluoxetine, sertraline, citalopram and fluvoxamine. The metabolite elimination of citalopram, paroxetine and fluvoxamine is delayed by renal disease and dosages should be lowered in elderly patients. Conversely the pharmacokinetic of fluoxetine and sertraline are not affected by either age or renal impairment and, for fluoxetine, by obesity.     

Considerations in the use of psychotropic drugs in elderly mentally retarded persons

ABSTRACT. Elderly people tend to be large consumers of medication in general and psychotropic drugs in particular. Sedative/hypnotics, anxiolytics, antidepressants, and neuroleptic drugs tend to be the most commonly used psychotropic medications among elderly people who are not developmentally disabled. These drugs are probably commonly employed among elderly mentally retarded people as well; although the rank order of use probably differs. A number of physiological changes which accompany greater age are described and the impact on pharmacokinetic variables outlined. Other factors associated with aging, which influence drug actions, are also outlined. The net effect appears to be that most drugs are more potent, more toxic, or longer lasting among the elderly. Data are also presented on tardive dyskinesia insofar as aging is concerned. This is followed by overall conclusions and some suggested guidelines for the use of these drugs in older mentally retarded persons.     

Drug Interactions in Neurocritical Care

Drug–drug interactions (DDIs) are common and avoidable complications that are associated with poor patient outcomes. Neurocritical care patients may be at particular risk for DDIs due to alterations in pharmacokinetic profiles and exposure to medications with a high DDI risk. This review describes the principles of DDI pharmacology, common and severe DDIs in Neurocritical care, and recommendations to minimize adverse outcomes. A review of published literature was performed using PubMed by searching for ‘Drug Interaction’ and several high DDI risk and common neurocritical care medications. Key medication classes included anticoagulants, antimicrobials, antiepileptics, antihypertensives, sedatives, and selective serotonin reuptake inhibitors. Additional literature was also reviewed to determine the risk in neurocritical care and potential therapeutic alternatives. Clinicians should be aware of interactions in this setting, the long-term complications, and therapeutic alternatives.     

Psychotropic drug prescription in Nigeria

A study of prescribing practice in three psychiatric institutions in Nigeria revealed high frequency of polypharmacy liberal routine use of antiparkinsonian agents and daily multiple administration of drugs. In the treatment of depression and schizophrenia older and better known oral neuroleptics were preferred to newer ones, but there was apparent tendency for depressives to be under-treated and long-acting depot preparations were seldom administered to schizophrenics. Several aspects of drug use were similar to those observed elsewhere, particularly in the Anglo-American practice - an observation presumed explicable in terms of common psychiatry training background. The need for clinicians to comply with acceptable pharmacokinetic principles of drug treatment is stressed.     

Pharmacology of Antiepileptic Drugs

Summary: Several different types of chemical compounds are useful as antiepileptic drugs. Their mechanisms of action, as well as their physical structures, differ. Compounds such as carbamazepine, phenytoin, and probably valproate act by modifying ionic conductances, particularly sodium and calcium, in excitable membranes, thus limiting sustained high-frequency neuronal discharges. In contrast, barbiturates and benzodiazepines tend to affect 7-aminobutyric acid (GABA) mediation of the chloride channel opening. Knowledge of drug mechanisms is important for choosing the proper drug for various seizure types. In addition, an understanding of antiepileptic drug pharamcokinetics, nonther-apeutic effects, and interactions is essential for optimal therapy. The lack of uniform pharmacokinetics among patients and among different formulations of a drug can make it difficult to arrive at uniform criteria for both seizure control and determinations of toxicity. Both pharmacokinetic and pharmacodynamic interactions can occur between antiepileptic medications and other drugs. Three major types of side effects with anticonvulsants can be identified: dose-related alterations of neurologic function, idiosyncratic reactions, and nonidiosyncratic direct actions on other organ systems. These effects often compromise treatment.     

Intermittent vs continuous levodopa administration in patients with advanced Parkinson disease: a clinical and pharmacokinetic study

BACKGROUND: Levodopa-related motor complications can be an important source of disability for patients with advanced Parkinson disease. Current evidence suggests that these motor complications are related to the relatively short half-life of levodopa and its potential to induce pulsatile stimulation of striatal dopamine receptors. Motor complications can be diminished with a continuous infusion of levodopa. OBJECTIVE: To investigate the specific pharmacokinetic changes associated with the benefits of levodopa infusion. DESIGN: We performed an open-label study in 6 patients with Parkinson disease who experienced severe motor complications while receiving standard oral formulations of levodopa/carbidopa. Patients were subsequently treated for 6 months with continuous daytime intraintestinal infusions of levodopa methyl ester. Levodopa pharmacokinetic studies were performed at baseline and 6 months in 3 of these patients. RESULTS: Compared with treatment with intermittent doses of a standard oral formulation of levodopa, continuous infusion provided significant improvement in both "off periods" and dyskinesia. Results of plasma pharmacokinetic studies demonstrated that compared with oral administration, continuous levodopa infusion was associated with a significant increase in the levodopa area under the curve and avoided the low plasma trough levels seen with oral drug administration. CONCLUSIONS: This study confirms that a continuous levodopa infusion is associated with reduced motor complications compared with the standard oral formulation of the drug in patients with advanced PD. Pharmacokinetic studies demonstrate that reduced motor complications are associated with avoiding low plasma levodopa trough levels and are not adversely affected by relatively high plasma levodopa concentrations. We propose that if levodopa/carbidopa could be administered orally in a manner that mirrors the pharmacokinetic pattern of the infusion, it might lead to a similar reduction in motor complications.     

Pharmacological aspects of antiseizure medications: From basic mechanisms to clinical considerations of drug interactions and use of therapeutic drug monitoring

Antiseizure medications (ASMs) are the cornerstone of treatment for patients with epilepsy. Several new ASMs have recently been introduced to the market, making it possible to better tailor the treatment of epilepsy, as well as other indications (psychiatry and pain disorders). For this group of drugs there are numerous pharmacological challenges, and updated knowledge on their pharmacodynamic and pharmacokinetic properties is, therefore, crucial for an optimal treatment outcome. This review focuses on educational approaches to the following learning outcomes as described by the International League Against Epilepsy (ILAE): To demonstrate knowledge of pharmacokinetics and pharmacodynamics, drug interactions with ASMs and with concomitant medications, and appropriate monitoring of ASM serum levels (therapeutic drug monitoring, TDM). Basic principles in pharmacology, pharmacokinetic variability, and clinically relevant approaches to manage drug interactions are discussed. Furthermore, recent improvements in analytical technology and sampling are described. Future directions point to the combined implementation of TDM with genetic panels for proper diagnosis, pharmacogenetic tests where relevant, and the use of biochemical markers that will all contribute to personalized treatment. These approaches are clinically relevant for an optimal treatment outcome with ASMs in various patient groups.     

Clinical pharmacology of antiepileptic drugs. Selected topics

This article illustrates basic principles of clinical pharmacology presented in article 1 with specific examples from the treatment of seizure disorders. The discussion includes protein binding, the role of a major carbamazepine metabolite, alterations in pharmacology of AEDs in the elderly, and AED withdrawal. The last topic, in particular, is a good example of the interaction of pharmacokinetic and pharmacodynamic considerations in explaining the clinical effects of a drug.