No abstract

Anti‐epileptic drugs (AEDs) have various pharmacokinetic profiles, inter‐individual variabilities, high possibilities of drug‐drug interactions and narrow therapeutic indices. To provide optimal treatment for patients, therapeutic drug monitoring (TDM) is necessary. However, TDM requires sufficient quantities of blood samples to measure drug concentrations. Therefore, TDM could be a burden, particularly in paediatric cases. A good alternative that overcomes these disadvantages is the dried blood spot (DBS) method, which is simple, convenient to use and less invasive, requiring a lower quantity of blood than traditional blood sampling methods. However, the DBS method is affected by haematocrit (Hct) levels to varying extents depending on the drug properties. In addition, different papers with varying characteristics are available for use when applying the DBS method. Therefore, it has not yet been applied to TDM in clinical practice. To achieve this, several steps are required, including method development, method validation and clinical validation. Currently, the development status of the DBS method is different for each AED and unclear. Therefore, we assessed the development status of the following 19 AEDs in 26 studies: lamotrigine, valproic acid, levetiracetam, phenytoin, topiramate, carbamazepine, carbamazepine epoxide, gabapentin, phenobarbital, pregabalin, clobazam, clonazepam, ethosuximide, felbamate, monohydroxycarbamazepine, nitrazepam, rufinamide, vigabatrin and zonisamide. Among them, carbamazepine, lamotrigine, topiramate and valproic acid have been developed such that they are nearly available for TDM. In addition, Whatman 903 Protein Saver Cards and concentration analysis by liquid chromatography with triple quadrupole mass spectrometer were used most often.

Glioblastoma multiforme (GBM) is a lethal and aggressive malignant tumor of the central nervous system. The World Health Organization classifies it as a grade IV astrocytoma. Controlling seizures is essential during GBM treatment because they are often present and closely associated with the quality of life of GBM patients. Some antiepileptic drugs (AEDs) exhibit antitumor effects and could decrease the mortality of patients with GBM. In this retrospective cohort study, we examined 418 patients treated with surgery, radiotherapy, and chemotherapy with temozolomide (TMZ) at Severance Hospital in South Korea, per the current protocol. Median overall survival (OS) was 21 months [95% confidence interval (CI): 18.1–23.9] in the levetiracetam (LEV) treatment group, whereas it was 16 months [95% CI: 14.1–17.9] in the group without LEV, exhibiting a statistically significant difference between the two groups (P < 0.001). Of nine AED groups, only LEV treatment [P = 0.001; hazard ratio (HR), 0.65; 95% CI: 0.51–0.83] exhibited a statistically significant difference in the OS, in the univariate analysis. In the risk analysis of the baseline characteristics, age, administration of LEV, and O6-methylguanine-DNA methyltransferase (MGMT) promoter status correlated with OS. The use of LEV in the group with a methylated MGMT promoter resulted in a positive impact on the OS [P = 0.006; HR, 0.174; 95% CI: 0.050–0.608], but the effect of LEV on the OS was not statistically significant in the unmethylated MGMT promoter group (P = 0.623). This study suggests that, compared with other AEDs, the administration of LEV may prolong the survival period in GBM patients with methylated MGMT promoters, who are undergoing chemotherapy with TMZ.

BackgroundNephrotoxicity of intravenous (IV) colistin has impeded its clinical use; aerosolized (AS) colistin may be an alternative, but safety data are lacking. Therefore, this study aimed to evaluate the incidence of acute kidney injury (AKI) and risk factors associated with IV and AS colistin administration.MethodsA retrospective study was performed in a tertiary referral hospital. Data were collected before and after colistin administration between October 2012 and April 2016. Exclusion criteria were as follows: age less than 18 years, previous colistin administration, concurrent use of IV and AS colistin, dialysis before colistin use, and colistin use for less than 3 days. We compared AKI incidence following administration of IV versus AS colistin and analyzed risk factors for colistin-associated nephrotoxicity.ResultsA total of 464 patients were enrolled (n = 311, IV group; n = 153, AS group). Incidence of AKI was significantly higher in the IV group (IV vs AS, 20.26% vs 7.84%, p-value < 0.001). Duration of colistin use (OR 1.033, 95% CI 1.009–1.058, p-value 0.008) and presence of chronic kidney disease (OR 2.710, 95% CI 1.348–5.448, p-value 0.005) were associated with nephrotoxicity. There were no significant risk factors associated with AS colistin.ConclusionsAlthough AS colistin was not associated with any significant risk factors for nephrotoxicity, duration of colistin use and baseline kidney function may affect AS colistin-associated nephrotoxicity.

The pharmacokinetics (PK) of drugs are known to be significantly altered in patients receiving extracorporeal membrane oxygenation (ECMO). However, clinical studies of the PK of drugs administered during ECMO are scarce, and the proper dosing adjustment has yet to be established. We developed a population PK model for teicoplanin, investigated covariates influencing teicoplanin exposure, and suggested an optimal dosing regimen for ECMO patients. Samples for PK analysis were collected from 10 adult patients, and a population PK analysis and simulations were performed to identify an optimal teicoplanin dose needed to provide a Ͼ50% probability of target attainment at 72 h using a trough concentration target of Ͼ10 g/ml for mild to moderate infections and a trough concentration target of Ͼ15 g/ml for severe infections. Teicoplanin was well described by a two-compartment PK model with first-order elimination. The presence of ECMO was associated with a lower central volume of distribution, and continuous renal replacement therapy (CRRT) was associated with a higher peripheral volume of distribution. For mild to moderate infections, an optimal dose was a loading dose (LD) of 600 mg and a maintenance dose (MD) of 400 mg for ECMO patients not receiving CRRT and an LD of 800 mg and an MD of 600 mg for those receiving CRRT. For severe infections, an optimal dose was an LD of 1,000 mg and an MD of 800 mg for ECMO patients not receiving CRRT and an LD of 1,200 mg and an MD of 1,000 mg for those receiving CRRT. In conclusion, doses higher than the standard doses are needed to achieve fast and appropriate teicoplanin exposure during ECMO. (This study has been registered at ClinicalTrials.gov under identifier NCT02581280.)

The medication regimen complexity index (MRCI), originally developed in English, is a reliable and valid tool to assess the complexity of pharmacotherapy. This study aimed to validate the Korean version of MRCI (MRCI-K). A cross-cultural methodological study comprising 335 discharged patients of a tertiary hospital in Korea was conducted. The translation process included translation into Korean by two clinical pharmacists, back translation by two native speakers, and a pretest of the tool, culminating in the Korean version of MRCI-K. Reliability analysis was assessed using inter-rater and test–retest reliability with 25 randomly selected patients. Convergent and discriminant validity analyses were conducted by correlating MRCI scores with medication number, age, sex, adverse drug reaction (ADR) reports, and length of stay. The criterion validity was confirmed through evaluation by a nine-member expert panel that subjectively ranked these regimens. The reliability analysis demonstrated excellent internal consistency (Cronbach’s α = 0.977), and the intraclass correlation coefficient exceeded 0.90 for all cases. The correlation coefficient for the number of medications was 0.955 ( P < 0.001). Weak significant correlations were observed with age and length of stay. The MRCI-K group with ADR reports scored higher (mean, 31.8) than the group without ADR reports (mean, 27.3). The expert panel’s ranking had a stronger correlation with the MRCI ranking than the medication number ranking. MRCI-K has similar reliability and validity as MRCI and is useful for analyzing therapeutic regimens with potential applications in both practice and research in Korea.

Extracorporeal membrane oxygenation (ECMO) is associated with pharmacokinetic (PK) changes of drugs. It presents considerable challenges to providing optimal dosing regimens for patients receiving ECMO. We aimed to describe the population PK of remifentanil in critically ill adult patients receiving venoartrial extracorporeal membrane oxygenation (VA-ECMO) and to identify determinants associated with altered remifentanil concentrations. The population PK model of remifentanil was developed using nonlinear mixed effects modelling (NONMEM). Fifteen adult patients who received a continuous infusion of remifentanil during VA-ECMO participated in the study. The PK of remifentanil was best described by a one-compartment model with additive and proportional residual errors. Remifentanil concentrations were affected by sex and ECMO pump speed. The final PK model included the effect of sex and ECMO pump speed on clearance is developed as followed: clearance (L/h) = 366 × 0.502sex × (ECMO pump speed/2350)2.04 and volume (L) = 41. Remifentanil volume and clearance were increased in adult patients on VA-ECMO compared with previously reported patients not on ECMO. We suggest that clinicians should consider an increased remifentanil dosing to achieve the desired level of sedation and provide a dosing regimen according to sex and ECMO pump speed.

Type 2 diabetes mellitus (T2DM) is a chronic disease that requires long-term therapy and regular check-ups to prevent complications. In this study, insurance claim data from the National Health Insurance Service (NHIS) of Korea were used to investigate insulin use in T2DM patients according to the economic status of patients and their access to primary physicians, operationally defined as the frequently used medical care providers at the time of T2DM diagnosis. A total of 91,810 participants were included from the NHIS claims database for the period between 2002 and 2013. The utilization pattern of insulin was set as the dependent variable and classified as one of the following: non-use of antidiabetic drugs, use of oral antidiabetic drugs only, or use of insulin with or without oral antidiabetic drugs. The main independent variables of interest were level of income and access to a frequently-visited physician. Multivariate Cox proportional hazards analysis was performed. Insulin was used by 9,281 patients during the study period, while use was 2.874 times more frequent in the Medical-aid group than in the highest premium group [hazard ratio (HR): 2.874, 95% confidence interval (CI): 2.588–3.192]. Insulin was also used ~50% more often in the patients managed by a frequently-visited physician than in those managed by other healthcare professionals (HR: 1.549, 95% CI: 1.434–1.624). The lag time to starting insulin was shorter when the patients had a low income and no frequently-visited physicians. Patients with a low level of income were more likely to use insulin and to have a shorter lag time from diagnosis to starting insulin. The likelihood of insulin being used was higher when the patients had a frequently-visited physician, particularly if they also had a low level of income. Therefore, the economic statuses of patients should be considered to ensure effective management of T2DM. Utilizing frequently-visited physicians might improve the management of T2DM, particularly for patients with a low income.