Therapeutic Drug Monitoring Results Research Articles

Cerebrospinal Fluid Compartmental Pharmacokinetics of Amikacin in Neonates

To describe and investigate the covariate effects of cerebrospinal fluid (CSF) amikacin pharmacokinetics in neonates, CSF samples were prospectively collected from neonates in whom amikacin had been initiated before a diagnostic lumbar puncture was performed. CSF analysis (amikacin concentration, white blood count [WBC], glucose content, and protein concentration) and amikacin therapeutic drug monitoring results (peak and trough concentrations) in serum were recorded. Correlations (Spearman rank) between the CSF amikacin concentration and the CSF WBC and glucose and protein concentration were investigated. There were 44 CSF amikacin concentrations and 83 serum samples available from 43 neonates (mean postmenstrual age, 36 weeks [range, 26 to 41 weeks]; mean weight, 2.43 kg [range, 0.87 to 3.86 kg]). The median time interval between initiation of amikacin administration and CSF sampling was 25 h (range, 2.5 to 93.7 h). The median amikacin concentration in the CSF was 1.08 mg/liter (range, 0.34 to 2.65 mg/liter), and the mean trough and peak amikacin concentrations in serum were 3.8 +/- 2.5 mg/liter and 35.7 +/- 5.9 mg/liter, respectively. A correlation between CSF amikacin and CSF protein contents (P < 0.01, r = 0.41, 95% confidence interval = 0.13 to 0.63) but not between CSF WBC and CSF glucose was documented. A two-compartment (central and CSF) linear disposition model was used to estimate population pharmacokinetics. The half time for equilibration (T(eq)) between serum and CSF compartments was used as a measure of blood-brain barrier permeability. The T(eq) was 7.58 h (coefficient of variation [CV] = 49.1%) with a partition coefficient of 0.103 (CV = 26.4%). There was no relationship between the T(eq) and CSF WBC, CSF glucose content, or CSF protein content.

Orosomucoid (α1-acid glycoprotein) plasma concentration and genetic variants: Effects on human immunodeficiency virus protease inhibitor clearance and cellular accumulation

Protease inhibitors are highly bound to orosomucoid (ORM) (alpha1-acid glycoprotein), an acute-phase plasma protein encoded by 2 polymorphic genes, which may modulate their disposition. Our objective was to determine the influence of ORM concentration and phenotype on indinavir, lopinavir, and nelfinavir apparent clearance (CL(app)) and cellular accumulation. Efavirenz, mainly bound to albumin, was included as a control drug. Plasma and cells samples were collected from 434 human immunodeficiency virus-infected patients. Total plasma and cellular drug concentrations and ORM concentrations and phenotypes were determined. Indinavir CL(app) was strongly influenced by ORM concentration (n = 36) (r2 = 0.47 [P = .00004]), particularly in the presence of ritonavir (r2 = 0.54 [P = .004]). Lopinavir CL(app) was weakly influenced by ORM concentration (n = 81) (r2 = 0.18 [P = .0001]). For both drugs, the ORM1 S variant concentration mainly explained this influence (r2 = 0.55 [P = .00004] and r2 = 0.23 [P = .0002], respectively). Indinavir CL(app) was significantly higher in F1F1 individuals than in F1S and SS patients (41.3, 23.4, and 10.3 L/h [P = .0004] without ritonavir and 21.1, 13.2, and 10.1 L/h [P = .05] with ritonavir, respectively). Lopinavir cellular exposure was not influenced by ORM abundance and phenotype. Finally, ORM concentration or phenotype did not influence nelfinavir (n = 153) or efavirenz (n = 198) pharmacokinetics. ORM concentration and phenotype modulate indinavir pharmacokinetics and, to a lesser extent, lopinavir pharmacokinetics but without influencing their cellular exposure. This confounding influence of ORM should be taken into account for appropriate interpretation of therapeutic drug monitoring results. Further studies are needed to investigate whether the measure of unbound drug plasma concentration gives more meaningful information than total drug concentration for indinavir and lopinavir.

Pharmacologic Optimization of Protease Inhibitors and Nonnucleoside Reverse Transcriptase Inhibitors (POPIN)-A Randomized Controlled Trial of Therapeutic Drug Monitoring and Adherence Support

We evaluated the feasibility and effectiveness of therapeutic drug monitoring (TDM) and adherence support (collectively, AT) vs standard of care (SOC) in patients receiving HIV protease inhibitors (PIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs) within a nurse-led clinic. Primary end points were failure to achieve viral load of <50 copies/mL at 24 weeks, viral rebound, or development of treatment limiting toxicity. One hundred twenty-two patients (AT 63 and SOC 59) were followed-up every 12 weeks, for a median of 72 weeks. No difference was observed between arms in risk of reaching a study end point or between groups of patients with abnormal vs "therapeutic" drug concentrations. Interindividual variabilities (coefficient of variation) were the following: efavirenz, 77.5%; nevirapine, 74.5%; lopinavir, 73.4%; nelfinavir, 83.7%; indinavir, 80.8%; saquinavir, 112.4%. Intraindividual variabilities (median coefficient of variation) were the following: NNRTIs, approximately 25%; PIs, 48.4%. Despite persistently abnormal results in 26 of patients in the AT arm (38%), dosage adjustment was only undertaken in 9 patients (35%).A significant proportion of patients had drug concentrations outside the therapeutic range. The Pharmacologic Optimization of PIs and NNRTIs (POPIN) study confirms that TDM trials are complex to interpret and statistically underpowered, with effectiveness better assessed through the clinical utility of a TDM result, whether normal or abnormal. Although TDM of PIs and NNRTIs may be useful in selected patients, routine and unselected use is not supported by current evidence.

Clinical benefit of interventions driven by therapeutic drug monitoring

Adequate plasma concentrations of antiretroviral drugs are key to achieving and maintaining long-term suppression of HIV replication. Multiple factors may influence drug levels, causing increases or reductions that may, respectively, result in toxicity or virological failure. Therapeutic drug monitoring (TDM) might help to detect and correct such abnormalities. To evaluate the usefulness of TDM in the care of HIV-infected patients in an out-patient clinical setting. S All the requests for TDM of protease inhibitors (PIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs) for patients attending our HIV out-patient clinic from October 2000 to August 2003 were analysed. Blood samples were collected before the morning dose. Drug concentrations were measured by high performance liquid chromatography by ultraviolet waves (HPLC-UV). R:A total of 151 requests from 137 patients were assessed. The reasons for requesting TDM were drug toxicity (59%), virological failure (39%) and possible drug interactions (2%). NNRTI levels were more often requested because of toxicity, while PI levels were more often requested because of virological failure. Elevated drug levels were confirmed in 36% of patients with suspected drug toxicity, while subtherapeutic levels were found in 37% of patients failing virologically. Based on the results of TDM, dose modifications were made in 37% of patients, allowing correction of such abnormalities in 80% of cases. Moreover, adequate plasma concentrations were confirmed in 79% of patients whose levels were assessed again. Therapeutic drug monitoring may be a useful tool to identify toxic levels of NNRTI and subtherapeutic concentrations of PI. Dose adjustments following TDM may ameliorate drug-related toxicities or improve virological response rates.

British HIV Association (BHIVA) guidelines for the treatment of HIV‐infected adults with antiretroviral therapy (2005)

British HIV Association (BHIVA) guidelines for the treatment of HIV‐infected adults with antiretroviral therapy (2005)

Drug Monitoring and Viral Response to Lopinavir/Ritonavir or Saquinavir/Ritonavir Containing Regimens in Individuals Infected with the Human Immunodeficiency Virus Type1

The aim of this study was to correlate results of therapeutic drug monitoring, genotypic resistance and viral response to lopinavir/ritonavir (LPV/r) or saquinavir/ritonavir (SQV/r) containing antiretroviral regimens. The retrospective short-term study included 20 patients with LPV/r and 20 patients with SQV/r containing highly active antiretroviral therapy (HAART). At baseline 7 LPV/r patients and 10 SQV/r patients had CD4+T cell counts above 410 cells/microl. After 6 months CD4+T cells had doubled in 5 LPV/r and 2 SQV/r patients. In LPV/r patients the mean serum concentration of lopinavir (LPV) was 2.6 ppm and 67% of all LPV/r samples had 50 or fewer viral copies/ml. In SQV/r patients the mean serum concentration of saquinavir (SQV) was 2.1 ppm. 79% of all SQV/r samples had 50 or fewer viruses/ml. Pharmacoenhanced regimens efficiently suppress human immunodeficiency virus type 1 (HIV-1) and the risk of developing resistance mutations is therefore reduced. The implementation of drug monitoring is an additional tool to determine optimal treatment conditions.

Practical Guidelines to Interpret Plasma Concentrations of Antiretroviral Drugs

Several relationships have been reported between antiretroviral drug concentrations and the efficacy of treatment, and toxicity. Therefore, therapeutic drug monitoring (TDM) may be a valuable tool in improving the treatment of HIV-1-infected patients in daily practice. In this regard, several measures of exposure have been studied, e.g. trough and maximum concentrations, concentration ratios and the inhibitory quotient. However, it has not been unambiguously established which pharmacokinetic parameter should be monitored to maintain optimal viral suppression. Each pharmacokinetic parameter has its pros and cons. Many factors can affect the pharmacokinetics of antiretroviral agents, resulting in variability in plasma concentrations between and within patients. Therefore, plasma concentrations should be considered on several occasions. In addition, the interpretation of the drug concentration of a patient should be performed on an individual basis, taking into account the clinical condition of the patient. Important factors herewith are viral load, immunology, occurrence of adverse events, resistance pattern and comedication. In spite of the described constraints, the aim of this review is to provide a practical guide for TDM of antiretroviral agents. This article outlines pharmacokinetic target values for the HIV protease inhibitors amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir and saquinavir, and the non-nucleoside reverse transcriptase inhibitors efavirenz and nevirapine. Detailed advice is provided on how to interpret the results of TDM of these drugs.

Use of Therapeutic Drug Monitoring for Multidrug-Resistant Tuberculosis Patients

Therapeutic drug monitoring (TDM) is the process of obtaining the serum concentration of a medication and modifying the dose based on the results. Little is known about the application of TDM in the treatment of patients with multidrug-resistant (MDR) tuberculosis (TB) in clinical practice. This study characterized how TDM was applied in the management of MDR TB patients, and examined the clinical indications for ordering TDM, the process for obtaining drug concentrations, and the clinician response to the drug concentrations. In a retrospective study, we compared the clinical and demographic characteristics of MDR TB patients who received TDM with those who did not. The clinical application of TDM also was described in patients who received TDM. A municipal TB control program. Patients in whom TB was diagnosed that was caused by an isolate resistant to at least isoniazid and rifampin, and who received treatment for TB in one of the health department chest clinics between July 1, 1993, and August 31, 1997, were studied. Forty-nine patients receiving TDM had a longer time to culture conversion and treatment duration, more pulmonary TB in combination with an extrapulmonary site, drug resistance, and visits to the health department clinics (p < 0.05) than the 60 patients without TDM. Of the 49 patients who had initial TDM, 73.5% of them had the reason for being tested specified. A total of 85.7% of initial TDM results were collected at the appropriate time of blood sampling. Clinician response to TDM results varied with the drug that was being tested. The use of TDM depended largely on the patient's clinical presentation. Site-specific guidelines on the use of TDM for managing TB patients may maximize the benefit of TDM.

Risk of undertreatment with the standard abacavir 300 mg dose

Purpose To study the relevance of the current 300 mg B.I.D. abacavir dose for H.I.V.-infected adults. Methods Abacavir plasma concentrations were obtained from therapeutic drug monitoring results. Population pharmacokinetic analysis was performed using a nonlinear mixed effects modeling method. Results Abacavir concentration-time profiles were best described by a one-compartment open-model with linear absorption and elimination. Typical values of absorption rate constant, apparent distribution volume and apparent plasma clearance (CL/F) were 3.3 h−1, 98 L and 48 L/h respectively. CL/F was positively related to BW. A risk of undertreatment as a function of BW was identified as the percentage of patients reaching the area under the curve value providing the optimal antiviral efficacy decreased from 94 to 22 % when BW increased from 36 to 102 kg. Conclusion This study identified BW as a major determinant of abacavir clearance. These results suggest the administration of larger doses to high BW patients. Clinical Pharmacology & Therapeutics (2004) 75, P16–P16; doi: 10.1016/j.clpt.2003.11.058

Practical Guidelines to Interpret Plasma Concentrations of Antiretroviral Drugs

Several relationships have been reported between antiretroviral drug concentrations and the efficacy of treatment, and toxicity. Therefore, therapeutic drug monitoring (TDM) may be a valuable tool in improving the treatment of HIV-1-infected patients in daily practice. In this regard, several measures of exposure have been studied, e.g. trough and maximum concentrations, concentration ratios and the inhibitory quotient. However, it has not been unambiguously established which pharmacokinetic parameter should be monitored to maintain optimal viral suppression. Each pharmacokinetic parameter has its pros and cons. Many factors can affect the pharmacokinetics of antiretroviral agents, resulting in variability in plasma concentrations between and within patients. Therefore, plasma concentrations should be considered on several occasions. In addition, the interpretation of the drug concentration of a patient should be performed on an individual basis, taking into account the clinical condition of the patient. Important factors herewith are viral load, immunology, occurrence of adverse events, resistance pattern and comedication. In spite of the described constraints, the aim of this review is to provide a practical guide for TDM of antiretroviral agents. This article outlines pharmacokinetic target values for the HIV protease inhibitors amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir and saquinavir, and the non-nucleoside reverse transcriptase inhibitors efavirenz and nevirapine. Detailed advice is provided on how to interpret the results of TDM of these drugs.

Optimisation of Vancomycin Regimen in Neutropenic Haematological Patients with Normal Renal Function

Objective: To assess the appropriateness, on a pharmacokinetic basis, of a twice-daily regimen of vancomycin 1g in neutropenic patients with normal renal function, a regimen frequently used in the empirical treatment of this patient group. The study also used a Bayesian pharmacokinetic approach to predict vancomycin concentrations in order to determine the optimal dosage frequency of the drug (two or four daily doses) in this population. Patients and Methods: Data were collected retrospectively as part of routine therapeutic drug monitoring (TDM) of vancomycin in 16 adult neutropenic patients. TDM of vancomycin peak (Cmax) and trough (Cmin) serum concentrations was performed after twice daily administration of vancomycin lg as a 1-hour intravenous infusion for 48 hours. According to TDM results (Cmin≥7 or <7 mg/L), the vancomycin regimen was individualised (total daily dose split into two or four divided doses) by means of a Bayesian-based pharmacokinetic computer programme. TDM was then repeated on day 7. Optimal Cmin were defined as with the range of 7 to 10 mg/L. Results: On day 3 of therapy, nine patients had subtherapeutic Cmin (3.97 ± 0.59 mg/L; range 2.98 to 4.95 mg/L) according to ahigh estimated creatinine clearance (CLcr 1.79 ± 0.49 ml/kg/min; range 1.39 to 2.79 ml/kg/min), and another three patients had Cmin <7 mg/L. On day 7, higher vancomycin Cmin were achieved (8.92 ± 2.87 mg/L) in the 12 patients in whom their total daily dose was split into four (Cmin were optimal in nine and supratherapeutic in three patients), despite no major differences in the total daily dosage of vancomycin (29.77 ± 5.89 vs 30.85 ± 6.68 mg/kg; p = 0.79) and CLcr (1.63 ± 0.43 vs 1.90 ± 0.45 ml/kg/min; p = 0.19) versus day 3. Dose-normalised results suggested large interindividual pharmacokinetic variability. Conclusion: Since the volume of distribution and/or clearance of vancomycin can be increased in patients with haematological malignancies and normal renal function, increasing the number of daily doses from two to four (with the same total daily dose) may increase t > MIC, an important determinant of vancomycin efficacy. However, because of interpatient variability, TDM of vancomycin is strongly recommended to individualise therapy in this subpopulation.

Setting Standards of Practice in Therapeutic Drug Monitoring and Clinical Toxicology: a North American View

Standards for therapeutic drug monitoring (TDM) must address the factors required for a valid TDM result. These are that the test be ordered with an appropriate indication, samples be obtained at the appropriate time, analysis be precise and accurate, and the result be interpreted and used correctly. General indications for ordering drug concentrations are to assess patient compliance, lack of response, adverse effects, initial or new baseline concentration after steady state has been achieved, and drug interactions. In establishing standards for clinical toxicology testing, the following points need to be considered: relatively few drugs will be involved in the majority of overdoses in a given location, the majority of drug overdoses and poisonings are treated symptomatically and supportively, and there are a relatively small number of drugs the testing of which may provide useful information in the emergency setting. An effective toxicology screen can be designed by first developing a list of candidate drugs that have antidotes, require specific treatment, are frequently encountered, or have a delayed onset of toxicity. Once such a list is in hand, it can be further evaluated to determine whether qualitative or quantitative testing is most appropriate and if rapid, convenient methods of analysis are available.

ＴＤＭによる服薬指導 小児てんかん患者の服薬上の問題点とその改善

Noncompliance with drug therapy was suspected based on the results of therapeutic drug monitoring (TDM) in two 3-and 4-year-old children with epilepsy. An analysis of the data for both children showed the serum concentration of the antiepileptic drugs estimated from individual parameters to deviate remarkably from those established based on population parameters, and that the difference between these values varied after each measurement.After a careful evaluation of patient compliance according to the results of TDM, it was revealed the dosage due to the fact that mother had not realized her inaccurate dosage while another mother admitted that she had reduced the dosage due to the fact that her child refused to take the drug. The time needed to correct the noncompliance after its discovery using TDM was 3 months in the case of inaccurate dosage, and 12 months in the case where the child had refused to take the drug, by means of compliance education and training given to the mothers once -a-month at the outpatient clinic.

Comparison of Therapeutic Drug-Monitoring Assays

Clinical chemistry laboratories can choose from several immunoassay methods for therapeutic drug monitoring (TDM). We evaluated 11 new fluorescence polarization TDM assays manufactured by Roche Diagnostic Systems (Montclair, NJ) and Abbott Laboratories (Abbott Park, III). These assays were performed on the Roche Cobas FARA II (Roche Diagnostic Systems) random-access centrifugal analyzer, and their results were correlated with those obtained using an existing Abbott TDx batch analyzer (Abbott Laboratories). Our study indicated that using the Cobas FARA II random-access analyzer in lieu of the Abbott TDx batch analyzer yields comparable TDM results and significantly reduces operator time and reagent costs.

Misuse of Therapeutic Drug Monitoring: An Analysis of Causes and Methods for Improvement

The quantification of serum drug levels provides physicians with an indication of attainment of the desired pharmacologic goals. However, based on the preceding evidence, therapeutic drug monitoring (TDM), which is commonly used in conjunction with the prescribing of anticonvulsants, antiarrythmics, cardiac glycosides, antibiotics, antineoplastics, bronchodilators, lithium, antidepressants, neuroleptics, benzodiazepines, and other psychotropic drugs, is not used effectively for therapeutic intervention in the elderly. In addition to determining if a blood level is within the therapeutic range, TDM can also be helpful in identifying the reasons why a patient is not responding to a prescribed drug or is exhibiting toxic signs or symptoms, as well as in elucidating causes of coma, patient noncompliance, poor absorption, and excessively rapid metabolism. Furthermore, drug blood levels can be an asset in the diagnosis and monitoring of treatment programs for alcohol and drug abuse. Despite the existence of computerized programs for drug level determination in clinical laboratories, and the existence of individualized computer programs for optimizing the choice and dosage of drugs for many categories of patients with a multitude of metabolic and pathophysiologic problems, most physicians still rely on tradition, imitation, and information provided by drug advertising and sales representatives to choose therapeutic regimens for patients. To make proper use of TDM, a physician has to have at least a working knowledge of the basic concepts of pharmacokinetics. This advancing medical science also demands a thorough knowledge of the routes of absorption, distribution, metabolism, and excretion of drugs. Results from TDM determinations indicate how effectively the appropriate amount of drug is delivered to the desired location of action from the site of administration. One of the most common reasons for misuse of TDM results is that physicians order specimens for drug monitoring to be drawn at inappropriate times. Accurate TDM requires that (most) specimens be drawn at trough levels, after steady-state levels have been attained. Trough levels occur immediately prior to the administration of the next dose. Such measurements avoid the absorptive peaking levels that occur shortly (usually) after drug administration. Steady-state levels are attained when the amount of drug absorbed and the amount excreted are essentially equal. This usually occurs after the drug has been administered for approximately five half-lives.(ABSTRACT TRUNCATED AT 400 WORDS)

Case mix and medicaid payment

In order to monitor the free concentration of VPA in plasma, a simple and rapid method needs to be developed.The free fraction of VPA in plasma was obtained by centrifugal ultrafiltration (CF-UF) devices. Cyclohexanecarboxylic acid was used as internal standard. Valproate in plasma was converted to VPA by sulphuric acid acidification, and dichloromethane was used as solvent for extraction. Nitrogen was the carrier gas, the samples were separated by capillary column, and the flame ionization detector was used to detect VPA fragment ions for quantitative analysis.The assay had good specificity and stability. The linear range of the assay was 0.56–28.11 mg/L. The intra-day and inter-day precision (RSDs) of the assay were all within 15%, and the accuracy (RE) was 2.58%. The recoveries of VPA with three different concentrations were 102.03 ± 1.05, 101.45 ± 2.08 and 102.58 ± 3.38. The results of therapeutic drug monitoring (TDM) in pediatric inpatient group and outpatient group showed significant differences between the two groups (P < 0.001).This assay has low cost and good analytical performance, so it can be developed into a routine TDM method of unbound VPA. We recommend the monitoring of unbound VPA concentration in pediatric inpatients during clinical use of VPA.

コンプライアンスに影響を与える要因

Therapeutic drug monitoring (TDM) has been widely practiced in the clinical field. TDM requires the concentration of a drug in a steady state. In order to obtain reliable results of TDM, patients should take medicine according to physician's direction. We have studied the factors which have effect on patient's compliance by interviewing 640 patients. As a result, the average ratio of patient's compliance was about 40%. From this study 3 factors which increase patient's compliance and 4 factors which have little effect have been selected, as follows:A) Factors which increse patient's compliance: 1) Patient's recognition of the importance of medication. 2) Patient's refraining from discretion in taking. medicine. 3) Keeping exactly the frequency of daily medication.B) Factors which have little effect: 1) Frequency of daily medication. 2) Period of medication. 3) Kind of medicine. 4) Concern about the adverse effect of medicine.In addition, the ratio of patient's compliance varied with the kind of disease. For example, the ratio was high among tuberculous patients and low among hypertensive patients.