Results Of Drug Monitoring Research Articles

What, if all alerts were specific – Estimating the potential impact on drug interaction alert burden

PurposeClinical decision support systems (CDSS) may potentially improve prescribing quality, but are subject to poor user acceptance. Reasons for alert overriding have been identified and counterstrategies have been suggested; however, poor alert specificity, a prominent reason of alert overriding, has not been well addressed. This paper aims at structuring modulators that determine alert specificity and estimating their quantitative impact on alert burden. MethodsWe developed and summarized optimizing strategies to guarantee the specificity of alerts and applied them to a set of 100 critical and frequent drug interaction (DDI) alerts. Hence, DDI alerts were classified as dynamic, i.e. potentially sensitive to prescription-, co-medication-, or patient-related factors that would change alert severity or render the alert inappropriate compared to static, i.e. always applicable alerts not modulated by cofactors. ResultsWithin the subset of 100 critical DDI alerts, only 10 alerts were considered as static and for 7 alerts, relevant factors are not generally available in today's patient charts or their consideration would not impact alert severity. The vast majority, i.e. 83 alerts, might require a decrease in alert severity due to factors related to the prescription (N=13), the co-medication (N=11), individual patient data (N=36), or combinations of them (N=23). Patient-related factors consisted mainly of three lab values, i.e. renal function, potassium, and therapeutic drug monitoring results. ConclusionThis paper outlines how promising the refinement of knowledge bases is in order to increase specificity and decrease alert burden and suggests how to structure knowledge bases to refine DDI alerting.

Primary Drug-Resistant Tuberculosis in Hanoi, Viet Nam: Present Status and Risk Factors

IntroductionResistance of Mycobacterium tuberculosis (MTB) to anti-tuberculosis (TB) drugs presents a serious challenge to TB control worldwide. We investigated the status of drug resistance, including multidrug-resistant (MDR) TB, and possible risk factors among newly diagnosed TB patients in Hanoi, the capital of Viet Nam.MethodsClinical and epidemiological information was collected from 506 newly diagnosed patients with sputum smear- and culture-positive TB, and 489 (96.6%) MTB isolates were subjected to conventional drug susceptibility testing, spoligotyping, and 15-locus variable numbers of tandem repeats typing. Adjusted odds ratios (aORs) were calculated to analyze the risk factors for primary drug resistance.ResultsOf 489 isolates, 298 (60.9%) were sensitive to all drugs tested. Resistance to isoniazid, rifampicin, streptomycin, ethambutol, and MDR accounted for 28.2%, 4.9%, 28.2%, 2.9%, and 4.5%, respectively. Of 24 isolates with rifampicin resistance, 22 (91.7%) were MDR and also resistant to streptomycin, except one case. Factors associated with isoniazid resistance included living in old urban areas, presence of the Beijing genotype, and clustered strains [aOR = 2.23, 95% confidence interval (CI) 1.15–4.35; 1.91, 1.18–3.10; and 1.69, 1.06–2.69, respectively). The Beijing genotype was also associated with streptomycin resistance (aOR = 2.10, 95% CI 1.29–3.40). Human immunodeficiency virus (HIV) coinfection was associated with rifampicin resistance and MDR (aOR = 5.42, 95% CI 2.07–14.14; 6.23, 2.34–16.58, respectively).ConclusionIsoniazid and streptomycin resistance was observed in more than a quarter of TB patients without treatment history in Hanoi. Transmission of isoniazid-resistant TB among younger people should be carefully monitored in urban areas, where Beijing strains and HIV coinfection are prevalent. Choosing an optimal treatment regimen on the basis of the results of drug susceptibility tests and monitoring of treatment adherence would minimize further development of drug resistance strains.

Monitoring of tobramycin levels in patients with cystic fibrosis by finger-prick sampling: Figure 1–

To the Editors: Chronic pulmonary infection is the major cause of morbidity and premature mortality in patients with cystic fibrosis (CF). The major pathogen for patients with CF is Pseudomonas aeruginosa . Tobramycin, an aminoglycoside antibiotic, is widely used against Gram-negative bacterial infections and is particularly useful for the treatment of P. aeruginosa in patients with CF [1]. Intravenous tobramycin has a narrow therapeutic range and monitoring of the drug is required to reduce serious side-effects, such as nephrotoxicity and ototoxicity [2]. Dosage alterations based on the results of drug monitoring can improve efficacy and minimise toxicity. Monitoring currently requires venesection and patients may find finger-prick samples less painful and more acceptable. Finger-prick blood sampling is routinely performed by patients with diabetes mellitus, is an easy technique to teach and uses inexpensive equipment which is widely available. We have previously shown that finger-prick sampling is a safe and accurate alternative to venous sampling for measurement of tacrolimus levels in children with kidney transplants [3]. Anecdotal experience in children's hospitals suggest that children generally prefer finger-prick sampling to venous sampling, even where topical anaesthetic agents are used for the latter. Studies in adult patients, including solid organ transplant recipients [4] and those receiving anticoagulant therapy [5], have shown a preference for finger-prick over venous blood sampling. We performed a prospective study to compare the results of tobramycin levels in adult patients with CF measured by finger-prick samples with those from …

Patterns of drug use in the older chronic pain population

People fifty years of age and older are the fastest growing sector of the population and also the largest group of chronic pain patients. Many of these patients are prescribed chronic opioid therapy to manage their pain and it is essential to closely monitor these individuals. In addition, it has been shown that it is difficult to predict which patients are adherent with their prescription regimen and which patients are not. The purpose of this study was to evaluate patterns of drug use in the older chronic pain population by examining urine drug monitoring results. A retrospective review was conducted on the database of urine drug monitoring results from samples submitted to Ameritox for patients ages 50 and above from October 1, 2009 - September 30, 2011. Descriptive patient data was collected along with the results of urine drug monitoring. The results of urine drug monitoring were categorized as follows: illicit drug found, a non-prescribed drug detected, a prescribed drug not detected, and no abnormality found. The total number of samples from this age group was 725,679. Illicit drugs were present in 7.6% samples, 28.1% samples were found to have a non-prescribed drug, 31.8% samples did not have the prescribed drug present, and 45.9% of samples had no abnormality found. This data showing a significant rate of non-adherence, specific to the older population, should aid clinicians in making decisions regarding the utility and need for urine drug monitoring in older adults and improve clinical decision making.

Factors influencing the pharmacokinetics of prophylactic posaconazole oral suspension in patients with acute myeloid leukemia or myelodysplastic syndrome

To estimate the pharmacokinetic (PK) properties of posaconazole in patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) undergoing chemotherapy in a clinical setting. Posaconazole concentrations in patients with AML/MDS receiving prophylactic posaconazole were determined by high-performance liquid chromatography. A population PK model with nonlinear mixed effect modeling was developed. The list of tested covariates included age, weight, height, gender, posaconazole dose, ethnicity, co-administration of antineoplastic chemotherapy, ranitidine or pantoprazole, coincident fever, diarrhea, leukocyte counts, and γ-glutamyltransterase plasma activity. A total of 643 serum concentrations of posaconazole from 84 patients were obtained. A one-compartment model with first order absorption and elimination as the basic structural model appropriately described the data, with an apparent clearance of 56.8 L/h [95% confidence interval (CI) 52.8–60.8 L/h] and an apparent volume of distribution of 2,130 L (95% CI 1,646–2,614 L). Significant effects on apparent clearance (CL/F) were found for presence of diarrhea and for co-medication with proton-pump inhibitors (1.5- and 1.6-fold increase in CL/F, respectively), weight (33.4 L larger apparent volume of distribution per kilogram), and co-administration of chemotherapy (0.6-fold lower apparent volume of distribution). We developed a prediction basis for mean posaconazole concentrations in AML/MDS patients. Patient weight, presence of diarrhea, and concomitant medication (chemotherapy and pantoprazole) showed significant effects on posaconazole exposure. Corresponding adjustments of the starting dose according to the presence of diarrhea and during the co-administration of chemotherapy or proton-pump inhibitors appear justified before therapeutic drug monitoring results are available. Further investigation of the interaction between different chemotherapeutic regimens and posaconazole is warranted.

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.

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