Serum Drug Concentration Monitoring Research Articles

Concomitant Treatment of Tuberculosis and Hepatitis C Virus in Coinfected Patients Using Serum Drug Concentration Monitoring.

Concern for drug-drug interactions leading to treatment failure and drug-resistant strains have discouraged clinicians from attempting concomitant treatment of hepatitis C virus (HCV) and tuberculosis (TB). Increased metabolism of direct-acting antivirals (DAAs) by rifamycins has hindered concurrent use. Development of an assay for ledipasvir and sofosbuvir (LDV/SOF) serum concentrations for therapeutic drug monitoring (TDM) can ensure adequate therapy. We present the first cases of concomitant therapy of active TB and HCV with rifamycin-containing regimens and DAAs using TDM. Using TDM, we aim to determine whether concomitant therapy with rifamycin-containing regimens and DAAs is safe and effective for patients coinfected with TB and HCV. Five individuals with TB and HCV who experienced transaminitis before or during TB therapy were concomitantly treated with rifamycin-containing regimens and LDV/SOF. Therapeutic drug monitoring was performed for LDV, SOF, and rifabutin during therapy. Baseline laboratory tests and serial liver enzymes were performed. Hepatitis C virus viral load and mycobacterial sputum cultures were obtained upon completion of therapy to determine efficacy of therapy. All patients were found to have nondetectable HCV viral loads and negative mycobacterial sputum cultures upon completion of therapy. No clinically significant adverse effects were reported. These cases illustrate concomitant use of LDV/SOF and rifabutin in patients with HCV/TB coinfection. Utilizing serum drug concentration monitoring to guide dosing, correction of transaminitis were achieved, which allowed the use rifamycin-containing TB therapy. These findings suggest that concomitant therapy of TB/HCV is possible, safe, and effective.

万古霉素治疗新生儿败血症的血药浓度监测和疗效分析

万古霉素治疗新生儿败血症的血药浓度监测和疗效分析

Practical considerations to drug dosing in children with acute kidney injury.

Medication dosing for children with acute kidney injury (AKI) needs to be individualized based on pharmacokinetic and pharmacodynamic principles of the prescribed drugswhenever possible to optimize therapeutic outcome and to minimize toxicity. The pediatric RIFLE criteria should be prospectively utilized to identify patients at highest risk of developing AKI. Serum creatinine and urine output along with volume status should be utilized to guide drug dosing when urinary biomarkers including kidney injury molecule 1, interleukin-18, or neutrophil gelatinase-associated lipocalin are not readily available. Because of the presence of a positive fluid balance in early stages of AKI, the dosing regimen for many drugs, especially antimicrobial agents, should be initiated at a larger loading dose based on the expected volume of distribution to achieve target serum concentrations.When possible, therapeutic drug monitoring should be utilized for those medications where serum drug concentrations can be obtained in a clinically relevant time frame. For these medications, close monitoring of serum drug concentrations is highly recommended. This review addresses drug-dosing strategies in pediatric patients with AKI including the roles of therapeutic drug monitoring and newer kidney injury biomarkers.

How I treat mucormycosis

AbstractUnlike invasive aspergillosis, the prognosis and outcome of hematologic malignancy patients who develop invasive mucormycosis have not significantly improved over the past decade as a majority of patients who develop the infection still die 12 weeks after diagnosis. However, early recognition and treatment of invasive mucormycosis syndromes, as well as individualized approaches to treatment and secondary prophylaxis, could improve the odds of survival, even in the most persistently immunosuppressed patient receiving chemotherapy and/or of stem cell transplantation. Herein, we describe the subtle clinical and radiographic clues that should alert the hematologist to the possibility of mucormycosis, and aggressive and timely treatment approaches that may limit the spread of infection before it becomes fatal. Hematology patients with this opportunistic infection require integrated care across several disciplines and frequently highly individualized and complex sequence of decision-making. We also offer perspectives for the use of 2 antifungals, amphotericin B products and posaconazole, with activity against Mucorales. The availability of posaconazole in an oral formulation that can be administered safely for prolonged periods makes it an attractive agent for long-term primary and secondary prophylaxis. However, serum drug concentration monitoring may be required to minimize breakthrough infection or relapsing mucormycosis associated with inadequate blood concentrations.

Retrospective analysis of serum drug concentration monitoring in the Tenth People’s Hospital affiliated to Tongji University from 2003 to 2009

Objective:To summarize the results of serum drug concentration monitoring in the Tenth People's Hospital affiliated to Tongji University from 2003 to 2009.Methods:Serum concentrations of sodium valproate(255 cases),phenytoin sodium(33 cases),carbamazepine(48 cases) and digoxin(141 cases) were determined by immune fluorescence polarization method and the results were statistically analyzed.Results:Sodium valproate was the most frequently monitored drug among the three antiepileptic drugs,which accounted for 75.89%,while phenytoin sodium was the least.Serum concentration of carbamazepine of thirty-five cases was within the normal range,accounting for 72.92%(35/48),which was the highest among the three antiepileptic drugs.Serum concentration of digoxin of 114 cases was within the normal range,accounting for 80.85%(114/141).Conclusion:Serum drug concentration monitoring plays an important role in clinic.Its significance should be interpreted in conjunction with clinical manifestation.

Application of the Cockcroft–Gault method to estimate lithium dosage requirement

The aim of the present study was to assess the precision and bias of a priori methods in the estimation of lithium dosage requirement among bipolar patients. The charts of 82 Diagnostic and Statistical Manual of Mental Disorder-fourth edition bipolar patients with previous history of lithium intoxication were reviewed. After excluding patients who had discontinued lithium treatment, 69 patients were entered to the study. Another 60 bipolar patients without history of lithium intoxication were also included in the study. The demographic data regarding factors thought to affect serum lithium concentrations, including gender, weight, and renal function, was retrospectively collected. Predicted daily lithium doses were calculated by using the new equation derived by the present authors and a priori methods proposed by Pepin et al., Zetin et al., Terao et al. and Keck et al. Mean error was calculated to assess the precision and bias of each a priori method. The Zetin method, the Terao method, and the Keck method had a significant tendency to overpredict dosage requirement. The Pepin method significantly underpredicted dosage. Only the 95% confidence interval of mean error of the present authors' equation was across zero. The present authors' equation represents a precise approach to estimate the lithium dose requirement and is easy to calculate. Regardless of the accuracy of each a priori method in predicting a patient's drug dosage, there is no substitute for proper serum drug concentration monitoring and good clinical judgment. Predictions made by any method should always be assessed clinically before applying its use in a patient.

Therapeutic Monitoring of Class I Antiarrhythmic Agents Using High-Resolution Electrocardiography Instead of Blood Samples.

Antiarrhythmic therapy requires monitoring of serum drug concentrations to determine a patient's optimal oral dose of medication. Repeated examination of blood samples, however, is costly and time-consuming, so the present study evaluated whether changes in serum concentrations could be estimated from changes in electrocardiographic (ECG) parameters. Of 36 patients receiving antiarrhythmic drugs for supraventricular or ventricular arrhythmias, 12 were treated with flecainide, 12 with pilsicainide, and 12 with pirmenol. Signal-averaged ECG (SAECG) were recorded before starting drug administration, 1 month later, and twice during ongoing therapy. At the time of the 2nd to the 4th recordings, serum concentrations of the drugs were also measured. As previously reported, all agents, but especially flecainide and pilsicainide, prolonged the filtered QRS (f-QRS) and the duration of low-amplitude signals at the terminal portion of the QRS complex. The SAECG parameters varied between the recordings made during therapy. Differences in the duration of the f-QRS between 2 recordings correlated significantly with differences in serum drug concentrations (r=0.91 for flecainide, r=0.70 for pilsicainide, and r=0.61 for pirmenol). No significant correlation between drug concentration and other SAECG parameters was found. Changes in the serum concentration of flecainide, pilsicainide and pirmenol can be estimated from changes in the duration of the f-QRS on the SAECG and periodic monitoring of such could help reduce the number of repeat measurements of drug concentrations in blood samples.

Clinically significant pharmacokinetic drug interactions between antiepileptic drugs.

Pharmacokinetic interactions between antiepileptics represent a major potential complication of epilepsy treatment because drug combinations are common. This review discusses pharmacokinetic drug interactions of clinical significance involving antiepileptics and cytochrome P450 (CYP). Most commonly used antiepileptics are eliminated through hepatic metabolism, catalysed by the enzymes CYP2C9, CYP2C19 and CYP3A4 and uridine diphosphate glucuronosyltransferase (UDGPT). Antiepileptics are associated with a wide range of drug interactions, including hepatic enzyme induction and inhibition. Phenytoin, phenobarbiral, primidone and carbamazepine induce CYP and UDPGT enzymes while valproic acid inhibits them. Avoidance of unnecessary polypharmacy, selection of alternative agents with lower interaction potential and careful dosage adjustments based on serum drug concentration monitoring and clinical observation are the main methods for reducing the risks associated with these interactions.

Economic aspects of antibacterial adverse effects.

The economic impact of adverse effects is often understated. Increased hospitalisations attributed to adverse drug reactions alone account for billions of dollars each year within the US healthcare system. Although most classes of antibacterials are well tolerated, severe reactions do occur and can add significantly to the cost of care. Among hospitalised patients, antibacterial adverse effects account for nearly 25% of adverse drug reactions. Published pharmacoeconomic data on direct and indirect costs of antibacterial adverse effects are lacking. The importance of determining the most cost-effective treatment regimen is becoming more apparent due to limited resources available within the healthcare system. When considering the cost of new antibacterials, a simple comparison of acquisition costs may not accurately reflect the true costs of treatment. A drug with a lower acquisition cost may be more toxic and/or less effective, resulting in higher complication rates and/or treatment failures, thus leading to a higher overall treatment cost. In addition, nephrotoxic agents such as aminoglycosides and vancomycin often require close monitoring of serum drug concentrations and creatinine levels, which also contributes to the total cost of therapy. Indirect costs as a result of reduced quality of life or loss of productivity are certainly not reflected in the acquisition costs of antimicrobials. Institutions must evaluate a drug's potential for causing and adverse event, among various other factors, when considering drugs for inclusion on their formularies. Drugs with good safety profiles may minimise hospitalisation or facilitate early discharge. Thus, the adverse effect profile of an antimicrobial agent can contribute significantly to its overall direct costs, primarily as a result of higher monitoring costs and additional days of hospitalisation. For example, in the US, the cost associated with adverse effects, such as nephrotoxicity, observed with aminoglycosides and vancomycin, may add approximately $US2500 per patient with nephrotoxicity (1990 values). Indirect costs can also be substantial as a result of reduced productivity. Many adverse effects of antibacterial agents are predictable and may be minimised with appropriate monitoring and care. This article reviews the pharmacoeconomic aspects of adverse effects associated with some of the more important antibacterial classes such as the beta-lactams, aminoglycosides, vancomycin, macrolides and fluoroquinolones.

Clinically significant pharmacokinetic drug interactions with carbamazepine. An update.

Carbamazepine is one of the most commonly prescribed antiepileptic drugs and is also used in the treatment of trigeminal neuralgia and psychiatric disorders, particularly bipolar depression. Because of its widespread and long term use, carbamazepine is frequently prescribed in combination with other drugs, leading to the possibility of drug interactions. The most important interactions affecting carbamazepine pharmacokinetics are those resulting in induction or inhibition of its metabolism. Phenytoin, phenobarbital (phenobarbitone) and primidone accelerate the elimination of carbamazepine, probably by stimulating cytochrome P450 (CYP) 3A4, and reduce plasma carbamazepine concentrations to a clinically important extent. Inhibition of carbamazepine metabolism and elevation of plasma carbamazepine to potentially toxic concentrations can be caused by stiripentol, remacemide, acetazolamide, macrolide antibiotics, isoniazid, metronidazole, certain antidepressants, verapamil, diltiazem, cimetidine, danazol and (dextropropoxyphene) propoxyphene. In other cases, toxic symptoms may result from elevated plasma concentrations of the active metabolite carbamazepine-10,11-epoxide, due to the inhibition of epoxide hydrolase by valproic acid (sodium valproate), valpromide, valnoctamide and progabide. Carbamazepine is a potent inducer of CYP3A4 and other oxidative enzyme system in the liver, and it may also increase glucuronyltransferase activity. This results in the acceleration of the metabolism of concurrently prescribed anticonvulsants, particularly valproic acid, clonazepam, ethosuximide, lamotrigine, topiramate, tiagabine and remacemide. The metabolism of many other drugs such as tricyclic antidepressants, antipsychotics, steroid oral contraceptives, glucocorticoids, oral anticoagulants, cyclosporin, theophylline, chemotherapeutic agents and cardiovascular drugs can also be induced, leading to a number of clinically relevant drug interactions. Interactions with carbamazepine can usually be predicted on the basis of the pharmacological properties of the combined drug, particularly with respect to its therapeutic index, site of metabolism and ability to affect specific drug metabolising isoenzymes. Avoidance of unnecessary polypharmacy, selection of alternative agents with lower interaction potential, and careful dosage adjustments based on serum drug concentration monitoring and clinical observation represent the mainstays for the minimisation of risks associated with these interactions.

Vancomycin Serum Concentration Monitoring

The recent increase in the use of vancomycin has led to renewed interest in its pharmacokinetics, and, in particular, the importance of monitoring serum drug concentrations. A review of the literature and evaluation of pharmacokinetic data from Vancouver Hospital and Health Sciences Centre demonstrated that vancomycin meets the criteria necessary for serum drug concentration monitoring. These include the availability of a sensitive and specific assay, substantial interpatient and intrapatient variability in drug disposition, and evidence suggesting a correlation between vancomycin serum concentration and both efficacy and toxicity. A review of vancomycin disposition data for 371 consecutive treatment courses at this hospital revealed significant interpatient variability in drug clearance and volume of distribution. Accordingly, it would be difficult to accurately predict the change in serum concentration resulting from a given vancomycin dose. There appears to be less intrapatient variability in volume of distribution; however, serum elimination half-life tends to increase during treatment, necessitating an alteration in dose interval. Although convenient, physiological parameters to monitor serum creatinine concentration and bodyweight are not accurate predictors of drug clearance and volume of distribution. Serum concentration monitoring is also necessary to ensure that vancomycin concentrations are in excess of the minimum inhibitory concentration of the organism at all times during treatment. Although a causal relationship between vancomycin and toxicity has been difficult to prove, there is some evidence in the literature to support a relationship between high troughs and nephrotoxicity. In view of the available evidence, we do not believe that serum concentration monitoring should be totally abandoned. We have created empiric dosage guidelines and a decision-making algorithm for serum drug concentration monitoring that have streamlined the process of drug prescribing and monitoring at this institution.

Pharmacological problems in the management of epilepsy in children.

Rational prescribing of anti-epilepsy drugs in children may be complicated by a number of problems, which include: (i) difficulties in arriving rapidly at a syndromic diagnosis, at least in some cases, with consequent uncertainties about therapeutic management; (ii) difficulties in evaluating drug response in young age groups, particularly with respect to subjective side-effects affecting cognitive function; (iii) the vulnerability of infants and children to specific aspects of drug toxicity, such as liver damage induced by valproic acid or behavioural disorders caused by barbiturates; and (iv) the need to adjust dosage to account for age-dependent pharmacokinetic changes. In particular, it is known that the rate of drug metabolism changes markedly during development. Metabolic drug elimination is often reduced at birth, but drug metabolizing enzymes mature rapidly and biotransformation in infants and children usually occurs at a faster rate than in adults. The elimination of drug which are excreted unchanged in urine appears to be less influenced by age in paediatric patients, though impairment in renal drug clearance may be seen in newborns. Monitoring of serum drug concentrations may be helpful for dosage adjustments, but it is not a substitute for careful clinical observation.

Factors associated with preventable adverse drug reactions

Factors associated with preventable adverse drug reactions (ADRs) in a community hospital patient population were studied. The following data were collected by concurrent review of all ADRs reported from July 1992 through January 1993: patient demographics, ADR variables, length of stay, and preventability of ADR. These data were analyzed to determine factors associated with preventable ADRs. Of the 203 ADRs reported, 38 (19%) were identified as preventable. The only significant difference found between preventable and nonpreventable ADRs was in severity (preventable ADRs were more severe). Length of stay (LOS) for patients who experienced ADRs was longer than the national average for patients in the same diagnosis-related group. Most of the preventable ADRs involved (1) a documented allergy to medication ordered or to similar medications, (2) anticoagulants or thrombolytics, (3) that required serum drug concentration monitoring (in the absence of pharmacokinetics service involvement), and (4) renally eliminated drugs for which dosage adjustments were not made in patients with impaired renal function. Strategies for minimizing ADRs were developed based on these factors. An ADR reporting program helped in identifying preventable ADRs, determining factors associated with preventable ADRs, and developing strategies for preventing ADRs in a community hospital patient population.

Effect of Continuous Hemofiltration on Phenytoin Elimination

Phenytoin is frequently used to treat seizure episodes in critically ill patients. Some of these patients have acute renal failure, requiring continuous hemofiltration to help maintain fluid and solute balance. We evaluated the removal of phenytoin in patients who received the drug while undergoing continuous hemofiltration treatment. Arterial and ultrafiltrate sample pairs were collected for phenytoin concentration determination. The ultrafiltrate drug concentrations were almost identical to the free serum phenytoin concentrations. Thus the ultrafiltrate/arterial drug concentration ratios resembled the percentages of serum free drug. Between 0.32 and 0.78 mg of phenytoin/h was removed by hemofiltration. The magnitude of hemofiltration phenytoin removal was related to the free drug concentration, total serum drug concentration, and ultrafiltration flow rate. When the ultrafiltration flow rate was low, the amount of phenytoin removed by hemofiltration was small relative to the usual daily dose. However, in patients with renal failure in whom serum phenytoin protein binding is substantially reduced, continuous hemofiltration at a high ultrafiltration rate may remove a clinically significant amount of the drug. Higher daily doses of phenytoin may be needed to maintain the therapeutic effect. Serum drug concentration monitoring will be necessary to determine the optimal dosage regimen.

Treatment options for the pharmacological therapy of neonatal meningitis.

Neonatal bacterial meningitis has a relatively low incidence in developed countries, but continues to cause morbidity and mortality despite advances in antimicrobial therapy. Bacterial pathogens commonly associated with neonatal meningitis include Group B streptococci, Escherichia coli K1 and other coliforms, Listeria monocytogenes and staphylococci. As it can be difficult to differentiate meningitis from septicaemia in neonates, empirical antibiotic therapy should be effective for both. Selection of an empirical antibiotic regimen should be based on: (a) bacterial prevalence and susceptibility; (b) drug characteristics; (c) postnatal age at the onset of disease; and (d) patient-specific factors. A penicillin in combination with an aminoglycoside or cefotaxime is commonly used in empirical therapies. The increased risk of staphylococcal infection in older neonates requires consideration of an antistaphylococcal antibiotic in the empirical therapy regimen. Once a causative organism has been identified, antimicrobial therapy should be directed towards that pathogen. Duration of therapy remains empirical, but should be at least 7 days for documented bacterial meningitis. Viral meningitis continues to have a high mortality despite the availability of antiviral agents. Adjunctive therapies may further reduce the morbidity and mortality of meningitis. While most of these therapeutic options have not been investigated in neonates, they may prove to be of benefit in the future. Anti-inflammatory agents, such as glucocorticoids, nonsteroidal anti-inflammatory agents and immunoglobulin, may modulate the inflammatory response of a meningeal infection. Other possible therapies in neonatal meningitis include cerebral blood flow modulators and disease prevention with maternal vaccines and perinatal antibiotics. Practical aspects of drug therapy such as route of administration and serum drug concentration monitoring can improve both drug therapy and patient outcome. While antibiotics have greatly improved the treatment outcome of neonatal meningitis, it is clear that additional intervention will be required to increase cure rates and reduce sequelae.

Therapeutic Drug Monitoring in the Neonate and Paediatric Age Group

Therapeutic drug monitoring should encompass not only serum concentration monitoring but also assessments of organ and clinical functions. This is especially important in children, in whom receptor drug concentration or sensitivity may be different from that seen in the adult population. Therapeutic end-points should be identified and serum drug concentrations adjusted to meet these goals. This is further complicated by the added impact of pharmacokinetic idiosyncrasies displayed by children, coupled with the routine pitfalls of therapeutic drug monitoring seen in any patient population. Neonates and infants present the additional challenge of having a set of mechanisms whose degree of maturation sometimes changes on a day-to-day basis with alarming rapidity. It is this phenomenon which makes the definition of pharmacokinetic parameters following a single dose so unreliable and potentially hazardous. Therapy should be based not only on the capacity of the infant to eliminate and respond to a particular agent, but also on the understanding of the dynamic changes that will occur on an ongoing maturational basis. A basic familiarity with the patient population under study is essential in obtaining relevant data for pharmacokinetic analysis. Special consideration in children should focus on potential problems with drug administration, drug absorption, metabolite patterns, changing drug disposition, idiosyncratic reactions, receptor sensitivity and chronopharmacokinetics. As with other patient populations, serum drug concentration monitoring is only a small part of the clinical scenario, the whole of which must be the basis for therapeutic decisions and pharmacodynamic titration.

Use of serum drug concentrations in surgical patients

Surgical patients frequently require drug treatments that can be assessed with serum drug concentrations. Of the agents for which serum drug concentrations are routinely available, the aminoglycosides theophylline, vancomycin, digoxin, and phenytoin are used most frequently in surgical patients. When using serum drug concentrations, the clinician should have an understanding of the relationships (or lack of) between drug concentrations and therapeutic or toxic effects. When blood is collected for serum concentration determinations, the exact timing of the sample in relation to the dose must be considered. For some drugs, (such as the aminoglycosides, it is necessary to determine peak and trough concentrations, whereas for other agents, like theophylline, the average or mid-dose level may be more important to consider. There are many factors that affect serum drug concentrations. Among these are various disease states, obesity, fluid imbalances, the drug dosage form used, and concurrent drug use. Not all patients require serum drug concentration monitoring; however, with each drug there are high-risk patients who may benefit. When used properly, serum drug concentrations may be helpful in maximizing therapeutic benefits, minimizing or diagnosing drug toxicity, and assessing patient compliance with drug regimens.

Therapeutic monitoring of psychotherapeutic drugs: Role of the clinical laboratory

Therapeutic monitoring of drugs is a well established clinical tool.However, the state of the art is somewhat less advanced for drugs used in psychiatry than it is for other classes of drugs, for several reasons. Most psychotherapeutic drugs have large volumes of distribution and achieve relatively low plasma concentrations following therapeutic doses. Many have one or more active metabolites. While psychotherapeutic drugs act through biochemical mechanisms, they are used to treat clinical syndromes which may be heterogeneous in their biochemical pathogenesis. As a consequence, the analytical methodologies are often complex and not always reliable; well-controlled clinical studies are difficult to perform; and therapeutic ranges have been difficult to establish. Despite these limitations, prudent and selective monitoring of serum drug concentrations, particularly of the tricyclic antidepressants, can be helpful in clinical management.

Interpretation of drug levels in acute and chronic disease states.

Serum drug concentration monitoring can be an invaluable aid to patient management, particularly in certain pathological conditions when individualisation of dosage is particularly critical. To be clinically useful, however, drug levels must be interpreted in the context of all factors that could influence the correlation between the concentration of the drug in plasma and the intensity of action. Several such factors may be operating in acute and chronic disease states. For example, a number of pathological conditions are associated with marked changes in the fraction of free, pharmacologically active drug in plasma and this will result in disruption of the normal relationship between total serum drug level and effect, as seen for phenytoin in uraemia. An altered response to a given serum drug level in disease states may also be caused by changes in tissue distribution, by abnormal accumulation of pharmacologically active metabolites in plasma or by changes in end-organ responsiveness. The latter are best illustrated by the altered sensitivity to digoxin in patients with various conditions, including hypokalaemia and thyroid disease. In addition to the factors listed above, consideration should also be given to potential interactions with concomitantly used drugs and to the possibility of analytical errors, especially in view of the evidence that the performance of otherwise reliable drug assays may be grossly impaired in certain diseases (e.g. uraemia), due to abnormal plasma composition and/or accumulation of interfering metabolites. In view of these complexities, a correct interpretation of serum drug levels requires a good knowledge of clinical pharmacology and a close collaboration between physician and laboratory. In any case, serum drug concentrations, like other laboratory tests, are not a substitute for careful patient observation, and any decision about drug treatment should be primarily based upon evaluation of the clinical state and, whenever possible, direct measurement of drug effects.