Eleonora L. Swart

Therapeutic Drug Monitoring by Dried Blood Spot: Progress to Date and Future Directions

This article discusses dried blood spot (DBS) sampling in therapeutic drug monitoring (TDM). The most important advantages of DBS sampling in TDM are the minimally invasive procedure of a finger prick (home sampling), the small volume (children), and the stability of the analyte. Many assays in DBS have been reported in the literature over the previous 5 years. These assays and their analytical techniques are reviewed here. Factors that may influence the accuracy and reproducibility of DBS methods are also discussed. Important issues are the correlation with plasma/serum concentrations and the influence of hematocrit on spot size and recovery. The different substrate materials are considered. DBS sampling can be a valid alternative to conventional venous sampling. However, patient correlation studies are indispensable to prove this. Promising developments are dried plasma spots using membrane and hematocrit correction using the potassium concentration.

Potential drug interactions in cancer therapy: a prevalence study using an advanced screening method

BACKGROUND In cancer patients, drug interactions may intensify adverse events or reduce antitumour effects. We assessed the prevalence of potential drug interactions (PDIs) among ambulatory cancer patients on i.v. treatment using an advanced screening method. PATIENTS AND METHODS Data on drugs used for comorbidities, anticancer agents, over-the-counter (OTC) drugs, and comorbidities were collected by means of a structured interview among the patients and review of medical charts. PDIs were identified using electronic (Drug Interaction Facts software, version 4.0) and manual screening methods (peer-reviewed reports). RESULTS In this study, 278 patients were enrolled. We identified 348 PDIs. Of all patients, 161 (58%) had at least one PDI. Of all PDIs, 34% was classified as major and 60% as moderate. Coumarins, quinolones, antiepileptics, and hydrochlorothiazide were frequently part of a PDI. Interactions that potentially cause QT interval prolongation, gastrointestinal toxicity, and central nervous system depression were also common. In multivariate analysis, an increasing number of drugs [odds ratio (OR) = 1.4, confidence interval (CI) 1.23-1.52; P < 0.001] and the use of an OTC drug (OR = 0.56, CI 0.32-0.97; P = 0.045) were risk factors. CONCLUSIONS PDIs are common in patients treated for an (haemato-) oncological disease. Screening for potential interactions should take place routinely before administering chemotherapy.

Adherence and patients experiences with the use of oral anticancer agents

Abstract A rapidly growing number of oral anticancer agents has become available in oncology and hematology. Though these introductions have several benefits, medication adherence is an issue of concern. Little is known about the factors influencing adherence to treatment with oral anticancer agents in daily practice. Material and methods. In this observational, multicenter study including 216 patients, carried out between October 2010 and March 2012, the use of oral anticancer drugs was assessed by means of a telephonic pill count, a questionnaire and a review of the patients medical file and pharmacy medication records. Parameters collected were patients’ demographics, treatment characteristics, beliefs and attitude towards disease and medicines, self-reported adherence, side effects, quality of life and satisfaction about information. Patients off treatment filled out a questionnaire about the reasons for discontinuation. Optimal adherence was defined as ≥ 95%–≤ 105%. Results. The mean adherence rate (AR) (n = 177) was 99.1% with 20.3% of patients having a sub-optimal AR (< 95%, > 105%) consisting both of under- and over-adherence. Multivariate analyses showed that being on a cyclic dosing regimen (rather than a continuous regimen), not living alone and being highly educated increased the chances of optimal adherence (ORs = 4.88, 4.59 and 2.53, respectively). In addition, optimal adherence was found to be less common in patients reporting treatment control (OR = 0.77). One third of 79 patients off treatment reported their experienced side effects as one of the reasons for discontinuation. Discussion. Although most patients are fully adherent to oral anticancer agents, there is a substantial number tending to non-adherence. Patients living alone and those on a continuous dosing regimen are most likely to adhere sub-optimally. Interventions to improve adherence should specifically address these patients and be tailored to the needs of the individual patient.

Potential drug interactions and duplicate prescriptions among ambulatory cancer patients: a prevalence study using an advanced screening method.

BackgroundThe pharmacotherapeutic treatment of patients with cancer is generally associated with multiple side-effects. Drug interactions and duplicate prescriptions between anti-cancer drugs or interactions with medication to treat comorbidity can reinforce or intensify side-effects.The aim of the present study is to gain more insight into the prevalence of drug interactions and duplicate prescriptions among patients being treated in the outpatient day care departments for oncology and hematological illnesses. For the first time the prevalence of drug interactions with OTC-drugs in cancer patients will be studied. Possible risk factors for the occurrence of these drug-related problems will also be studied.Methods/DesignA multicenter cross-sectional observational study of the epidemiology of drug interactions and duplicate prescriptions is performed among all oncology and hemato-oncology patients treated with systemic anti-cancer drugs at the oncology and hematology outpatient day care department of the VU University medical center and the Zaans Medical Center.DiscussionIn this article the prevalence of potential drug interactions in outpatient day-care patients treated with anti-cancer agents is studied using a novel more extensive screening method. If this study shows a high prevalence of drug interactions clinical pharmacists and oncologists must collaborate to develop a pharmaceutical screening programme, including an automated electronic warning system, to support drug prescribing for ambulatory cancer patient. This programme could minimize the occurrence of drug related problems such as drug interactions and duplicate prescriptions, thereby increasing quality of life.Trial registrationThis study is registered, number NTR2238.

Clinical validation of dried blood spot sampling in therapeutic drug monitoring of ciclosporin A in allogeneic stem cell transplant recipients: direct comparison between capillary and venous sampling.

Background:The immunosuppressive drug ciclosporin A has a narrow therapeutic window and a large inter- and intraindividual pharmacokinetic variability. Therapeutic drug monitoring of ciclosporin is usually performed in ethylenediaminetetraacetic acid blood, obtained by venous sampling. Dried blood spot sampling (DBS) could be a useful alternative sampling method, which also easily allows multiple sampling, for example, for obtaining area under the curve. With DBS, capillary blood is obtained from a finger prick with an automatic lancet by the patients themselves, and the drop of blood is applied to sampling paper. This may limit the number and duration of hospital visits for these patients. Methods:We describe a validation study in which venous and finger prick blood samples were collected at the same time. Venous sampling was performed by venipuncture, and the ethylenediaminetetraacetic acid blood samples were collected and stored at 4°C until analysis. Finger prick blood samples were collected using an automatic lancing device. The volume of the blood drops of patients was approximately 30 &mgr;L, and blood spots of about 10-mm diameter were produced. Paper disks with a diameter of 8 mm were punched out with an electromagnetic-driven hole puncher. DBS was compared with the routine assay in venous blood. The study population consisted of adult patients (18 years or older) who were treated with ciclosporin A and routinely monitored for adequate blood concentrations. Results:Thirty-eight duplicate dried blood spots and venous samples were studied. Using weighted Deming regression, the slope was 1.01 with a standard error of 0.03 associated with an intercept of −9.0 (standard error = 5.9). These results indicate that there is no significant difference between the 2 sampling methods. For the medical decision level of 300 mcg/L, the bias was −4.7 mcg/L with a 95% confidence interval of −19.2 to 9.8 mcg/L. The Altman–Bland plot showed no difference between the 2 sampling methods. Conclusions:Our results demonstrate that DBS is a valid alternative for conventional venous sampling in allogeneic stem cell transplant recipients.

Quantitative analysis of sildenafil and desmethylsildenafil in human serum by liquid chromatography-mass spectrometry with minimal sample pretreatment.

A simple, sensitive and specific liquid chromatography tandem mass spectrometry method with minimal sample pretreatment was developed for the simultaneous analysis of sildenafil and its metabolite desmethylsildenafil in human serum. Sample pretreatment consisted of adding a methanolic solution of the internal standard vardenafil to the samples. After vortexing and centrifugation the samples were directly injected onto the C18 column using gradient elution. The aqueous and organic mobile phases were ammonium acetate 2 mM supplemented with 0.1% formic acid in water and methanol, respectively. The detection by a triple quadrupole mass spectrometer in positive ESI ionization mode was completed within 5 min. The lower limits of quantification for sildenafil and desmethylsildenafil are 1.0 ng/ml. The intra- and inter-day precisions measured as relative standard deviation were within 10% for both compounds over the linear range. Intra- and inter-day accuracy of sildenafil and desmethylsildenafil ranged from 92 to 103%. This method has been used in a clinical pharmacokinetic study of sildenafil in intensive care patients.

Reversed-phase ion-pair HPLC method for the direct analysis of 1-OH midazolam glucuronide in human serum

In recent years, it has become clear that the presence of high concentrations of 1-OH midazolam glucuronide is probably the cause of unexplained prolonged midazolam comas in patients with poor renal function. Until recently, only indirect methods for the analysis of this glucuronide were known, which had several disadvantages, such as a long analysis period (>6 hours). This article describes the validation of a method for the direct analysis of this compound in human serum, using reversed-phase ion-pair high-performance liquid chromatography (HPLC) in combination with solid phase extraction. The intraday and interday coefficients of variation have values below 6% for different possible serum concentrations. The limit of quantification (0.1 mg/L) is much lower than concentrations found in patients with a coma caused by the accumulation of 1-OH midazolam glucuronide. Recovery of 1-OH midazolam glucuronide is almost 100% at three different serum concentrations. Linearity is confirmed for normal serum levels (<1 mg/L) and for serum levels that might occur in patients with impaired renal function (<20 mg/L). Detection is performed at 254 nm with a diode array detector, which can also be used to check the peak purity in case of unexpected impurities.

Haematocrit corrected analysis of creatinine in dried blood spots through potassium measurement

We developed a method for the analysis of creatinine in dried blood spot (DBS) samples to facilitate monitoring of renal function in combination with TDM of immunosuppressive drugs for transplant patients outside the hospital. An 8-mm disc of the DBS was punched, extracted and followed by LC–MS/MS analysis. The haematocrit proved to have a significant influence on the analysis of creatinine in DBS samples. As potassium is a suitable marker for haematocrit, we implemented a method for measuring potassium in DBS and correct the creatinine for haematocrit. For both creatinine and K+ in DBS analytical and DBS, validation was performed, both components met the validation criteria and no other influences beside the haematocrit were detected. To assess the haematocrit correction, samples were compared to the ‘golden’ standard and plotted before and after correction. The correction showed a great improvement in agreement between the DBS assay and venous blood assay.

Intravenous fat emulsion therapy for intentional propafenone intoxication

To the Editor:Clinical Toxicology recently published a systematic review on lipid emulsions in the treatment of acute poisoning.1 Intravenous fat emulsion (IFE) therapy in oral intoxications is onl...

Normal saline to dilute parenteral drugs and to keep catheters open is a major and preventable source of hypernatremia acquired in the intensive care unit

PURPOSE We wanted to identify modifiable risk factors for intensive care unit (ICU)-acquired hypernatremia. MATERIALS AND METHODS We retrospectively studied sodium and fluid loads and balances up to 7 days prior to the development of hypernatremia (first serum sodium concentration, [Na+], >150 mmol/L; H) vs control (maximum [Na+] ≤150 mmol/L; N), in consecutive patients admitted into the ICU with a normal serum sodium (<145 mmol/L) and without cerebral disease, within a period of 8 months. RESULTS There were 57 H and 150 N patients. Severity of disease and organ failure was greater, and length of stay and mechanical ventilation in the ICU were longer in H (P<.001), with a mortality rate of 28% vs 16% in N (P=.002). Sodium input was higher in H than in N, particularly from 0.9% saline to dissolve drugs for infusion and to keep catheters open during the week prior to the first day of hypernatremia (P<.001). Fluid balances were positive and did not differ from N on most days in the presence of slightly higher plasma creatinine and more frequent administration of furosemide, at higher doses, in H than in N. CONCLUSIONS High sodium input by 0.9% saline used to dilute drugs and keep catheters open is a modifiable risk factor for ICU-acquired H. Dissolving drugs in dextrose 5% may partially prevent potentially harmful sodium overloading and H.