Decline In Plasma Concentration Research Articles

Study on Factors Associated with Poor Seizure Control in Epileptic Patients during Pregnancy

The management of epilepsy during pregnancy is always challenging. This study aims to analyze the factors associated with poor seizure control during pregnancy and to describe the most commonly used antiseizure drugs in these patients. We conducted a casecontrol study of pregnant patients with epilepsy between 2017 and 2022. 50 pregnant women with poorly controlled epilepsy were taken as cases and 50 pregnant women with well-controlled epilepsy were taken as controls. Patients were evaluated in the first and second trimesters of pregnancy and after delivery. Patients’ mean age was 32.6 years. 53% had focal epilepsy, 40% had generalized epilepsy and 5 % had undetermined epilepsy. The factors associated with poor control of seizure during pregnancy were duration of epilepsy, poor seizure control in the year prior to pregnancy, treatment with 2 or more antiseizure drugs, untreated epilepsy, missed medication dosages, decline in plasma concentrations of antiepileptic drug, presence of focal activity in EEG and abnormal imaging findings. Anti-seizure medications most widely used in monotherapy were lamotrigine, levetiracetam, carbamazepine, and valproate. EWMCJ Vol. 12, No. 1&2, January-July 2024: 99-103

More than an Amide Bioisostere: Discovery of 1,2,4-Triazole-containing Pyrazolo[1,5-a]pyrimidine Host CSNK2 Inhibitors for Combatting β-Coronavirus Replication.

The pyrazolo[1,5-a]pyrimidine scaffold is a promising scaffold to develop potent and selective CSNK2 inhibitors with antiviral activity against β-coronaviruses. Herein, we describe the discovery of a 1,2,4-triazole group to substitute a key amide group for CSNK2 binding present in many potent pyrazolo[1,5-a]pyrimidine inhibitors. Crystallographic evidence demonstrates that the 1,2,4-triazole replaces the amide in forming key hydrogen bonds with Lys68 and a water molecule buried in the ATP-binding pocket. This isosteric replacement improves potency and metabolic stability at a cost of solubility. Optimization for potency, solubility, and metabolic stability led to the discovery of the potent and selective CSNK2 inhibitor 53. Despite excellent in vitro metabolic stability, rapid decline in plasma concentration of 53 in vivo was observed and may be attributed to lung accumulation, although in vivo pharmacological effect was not observed. Further optimization of this novel chemotype may validate CSNK2 as an antiviral target in vivo.

Phenotypic changes in low-density lipoprotein particles as markers of adverse clinical outcomes in COVID-19.

Low-density lipoprotein (LDL) plasma concentration decline is a biomarker for acute inflammatory diseases, including coronavirus disease-2019 (COVID-19). Phenotypic changes in LDL during COVID-19 may be equally related to adverse clinical outcomes. Individuals hospitalized due to COVID-19 (n=40) were enrolled. Blood samples were collected on days 0, 2, 4, 6, and 30 (D0, D2, D4, D6, and D30). Oxidized LDL (ox-LDL), and lipoprotein-associated phospholipase A2 (Lp-PLA2) activity were measured. In a consecutive series of cases (n=13), LDL was isolated by gradient ultracentrifugation from D0 and D6 and was quantified by lipidomic analysis. Association between clinical outcomes and LDL phenotypic changes was investigated. In the first 30days, 42.5% of participants died due to Covid-19. The serum ox-LDL increased from D0 to D6 (p<0.005) and decreased at D30. Moreover, individuals who had an ox-LDL increase from D0 to D6 to over the 90th percentile died. The plasma Lp-PLA2 activity also increased progressively from D0 to D30 (p<0.005), and the change from D0 to D6 in Lp-PLA2 and ox-LDL were positively correlated (r=0.65, p<0.0001). An exploratory untargeted lipidomic analysis uncovered 308 individual lipids in isolated LDL particles. Paired-test analysis from D0 and D6 revealed higher concentrations of 32 lipid species during disease progression, mainly represented by lysophosphatidyl choline and phosphatidylinositol. In addition, 69 lipid species were exclusively modulated in the LDL particles from non-survivors as compared to survivors. Phenotypic changes in LDL particles are associated with disease progression and adverse clinical outcomes in COVID-19 patients and could serve as a potential prognostic biomarker.

The use of population modeling to optimize dosing of drugs used in anaesthesiology and intensive care

Effective pharmacotherapy requires an adequate drug dose that maximizes the effectiveness of therapy while minimizing adverse effects. Difficulties in dose selection arise from interindividual differences in drug pharmacokinetics and pharmacodynamics. Population modeling describes pharmacokinetic and pharmacodynamic processes in a population, taking into account the relationships in each patient, differences between patients, and the influence of covariates on drug pharmacokinetics and pharmacodynamics. The aim of this study was to develop population models for drugs used in anesthesiology and intensive care in special patient populations. The pharmacokinetics of sufentanil was described in infants and children after epidural and intravenous administration. The estimated absorption rate constant from the epidural space suggests slow systemic absorption of sufentanil and the possibility of flip-flop kinetics, which results in a slower decline in plasma concentrations at the end of drug administration compared with intravenous administration. The dependence of metabolic clearance on body weight and age was also demonstrated. A population model for the pharmacokinetics of tigecycline was developed for patients with sepsis or septic shock. No relationship between pharmacokinetic parameters and patient characteristics was detected, and the estimated interindividual and inter-occasion variability for clearance was small. This suggests that a universal dose is sufficient to achieve homogeneous drug exposure in critically ill patients. The pharmacokinetics of caspofungin was described in critically ill patients. The clearance and volume of central compartment showed systematic increase over time that was not explained by the covariates. The estimated increase in clearance values for three consecutive doses results in a clinically relevant reduction in drug exposure. The developed population models extend the knowledge of the pharmacokinetics of sufentanyl, tigecycline, and caspofungin. Simulations based on these models can aid the dosing decision-making process.

Pharmacokinetics and biodistribution of a collagen-targeted peptide amphiphile for cardiovascular applications.

Atherosclerosis remains a leading cause of death and disability around the world and a major driver of health care spending. Nanomaterials have gained widespread attention due to their promising potential for clinical translation and use. We have developed a collagen‐targeted peptide amphiphile (PA)‐based nanofiber for the prevention of neointimal hyperplasia after arterial injury. Our goal was to characterize the pharmacokinetics and biodistribution of the collagen‐targeted PA to further its advancement into clinical trials. Collagen‐targeted PA was injected into the internal jugular vein of Sprague Dawley rats. PA concentrations in plasma collected at various times after injection (0 to 72 hours) were measured by liquid chromatography‐tandem mass spectrometry. Pharmacokinetics of the collagen‐targeted PA were characterized by a three‐compartment model, with an extremely rapid apparent elimination clearance resulting in a plasma concentration decrease of more than two orders of magnitude within the first hour after injection. This rapid initial decline in plasma concentration was not due to degradation by plasma components, as collagen‐targeted PA was stable in plasma ex vivo for up to 3 hours. Indeed, cellular blood components appear to be partly responsible, as only 15% of collagen‐targeted PA were recovered following incubation with whole blood. Nanofibers in whole blood also adhered to red blood cells (RBCs) and were engulfed by mononuclear cells. This work highlights the unique pharmacokinetics of our collagen‐targeted PA, which differ from pharmacokinetics of small molecules. Because of their targeted nature, these nanomaterials should not require sustained elevated plasma concentrations to achieve a therapeutic effect the way small molecules typically do.

Unusual Distribution Kinetics of Gadoxetate in Healthy Human Subjects Genotyped for OATP1B1: Application of Population Analysis and a Minimal Physiological-Based Pharmacokinetic Model.

Gadoxetate (Gd-EOB-DTPA) isahepatobiliary-specific contrast agent for magnetic resonance imaging. Using a minimal physiological-based pharmacokinetic (PBPK) model, it has been shown for the first time, that the rapid initial decline of plasma concentration after intravenous injection is the result of an uptake into hepatocytes rather than of a distribution into the extravascular extracellular space. About 50% of the steady-state distribution volume is related to hepatic uptake. The hepatic extraction ratio and hepatic clearance estimated based on the liver model as a part of the PBPK model were in accordance with literature data. The same holds for the predicted time course of the amount of gadoxetate in liver parenchyma. In elucidating the impact of OATP1B1 genotype (*1a/*1a and *15/*15) on the pharmacokinetics of gadoxetate, we found that tissue uptake and back-transfer rates were significantly reduced, whereas the hepatic sinusoidal efflux rate was significantly increased in carriers of the *15/*15 haplotype compared with those of the *1a/*1a (wild type). Themodelispotentiallyuseful for determining hepatic kinetic parameters and distribution properties of drugs.

Physiologically Based Pharmacokinetic Modeling and Tissue Distribution Characteristics of SHetA2 in Tumor-Bearing Mice.

The orally available novel small molecule SHetA2 is the lead sulfur-containing heteroarotinoid that selectively inhibits cancer cells over normal cells, and is currently under clinical development for anticancer treatment and cancer prevention. The objective of this study was to assess and characterize the tissue distribution of SHetA2 in tumor-bearing mice by developing a physiologically based pharmacokinetic (PBPK) model. An orthotopic SKOV3 ovarian cancer xenograft mouse model was used to most accurately mimic the ovarian cancer tumor microenvironment in the peritoneal cavity. SHetA2 concentrations in plasma and 14 different tissues were measured at various time points after a single intravenous dose of 10mg/kg and oral dose of 60mg/kg, and these data were used to develop a whole-body PBPK model. SHetA2 exhibited a multi-exponential plasma concentration decline with an elimination half-life of 4.5h. Rapid and extensive tissue distribution, which was best described by a perfusion rate-limited model, was observed with the tissue-to-plasma partition coefficients (kp = 1.4-21.2). The PBPK modeling estimated the systemic clearance (76.4mL/h) from circulation as a main elimination pathway of SHetA2. It also indicated that the amount absorbed into intestine was the major determining factor for the oral bioavailability (22.3%), while the first-pass loss from liver and intestine contributed minimally (< 1%). Our results provide an insight into SHetA2 tissue distribution characteristics. The developed PBPK model can be used to predict the drug exposure at tumors or local sites of action for different dosing regimens and scaled up to humans to correlate with efficacy.

Development of an oral bentonite-based modified-release freeze-dried powder of vactosertib: Pharmacokinetics and anti-colitis activity in rodent models of ulcerative colitis.

Vactosertib is a novel inhibitor of transforming growth factor-β signaling. Clinical applications of vactosertib have been challenging since conventional oral formulations such as immediate-release tablets demonstrate a rapid rise and fast decline in plasma concentrations. In this study, a novel bentonite-based, modified-release, freeze-dried powder of vactosertib was developed and evaluated to determine its potential in the treatment of ulcerative colitis. The formulation released vactosertib slowly and steadily in an in vitro drug release test. The extent of vactosertib released from the formulation was markedly low (18.0%) at pH 1.2 but considerably high (95.6%) at pH 7.4. Compared with vactosertib oral solution, the formulation demonstrated a 52.5% lower mean maximum concentration of vactosertib and three times longer median time to maximum concentration without a significant change in the extent of vactosertib absorption in a rodent colitis model. Furthermore, colitis mice administered with this formulation showed a significant reduction in the total histopathological score by 30% compared with those administered with the positive control, whereas the administration of vactosertib oral solution resulted in only a 10% reduction. Collectively, this novel formulation resolved the pharmacokinetic drawbacks of vactosertib and is expected to enhance its therapeutic effect by delivering vactosertib to the colitis lesions in the lower gastrointestinal tract.

Infrared thermography and behavioral biometrics associated with estrus indicators and ovulation in estrus-synchronized dairy cows housed in tiestalls

Most Canadian dairy herds operate in tiestall housing (61%), where average estrus detection rates may be lower than 54%. The objective of this study was to evaluate infrared thermography and behavioral biometrics as indicators of estrus in dairy cows. Eighteen cyclic multiparous cows (Synch) were subjected to an estrus synchronization protocol, and 18 pregnant cows (control) received a sham protocol on the same schedule and frequency as the cyclic cow treatment. A decline in plasma concentrations of progesterone and the appearance of a dominant follicle using transrectal ultrasonography were used as indirect indicators of estrus, and the disappearance of a dominant follicle was used to confirm ovulation. All cows were monitored via visual cameras to determine the frequency of treading, drinking, neighbor interaction, tail movement, lying, and shifting behaviors. Infrared thermograms were recorded at the eye, muzzle, cheek, neck, front right foot, front left foot, rump, flank, vulva area, tail head, and withers. To evaluate the accuracy of behavioral and thermal parameters, a predefined minimum acceptable value (i.e., threshold) for estrus alerts (>0.30 Youden J index and >0.60 area under the curve) was used. Ovulation was confirmed in 14 (77.7%) out of 18 Synch cows. Eye, cheek, neck, rump, flank, vulva area, and wither thermograms exhibited higher temperatures at 48 h [cycle threshold (Δt) = +0.30 to 1.20°C] and 24 h before ovulation compared with 4 d prior to ovulation (Δt = 0.06 to 0.11°C) and during ovulation day (Δt = 0.03 to 0.32°C) in the Synch group. In addition, control cows exhibited greater treading activity per day compared with Synch cows (20.84 ± 0.39 vs. 16.35 events/5 min ± 0.34), and tail movement frequency was greater in Synch cows compared with control cows (14.84 ± 2.7 vs. 10.11 ± 4.7 events/5 min). However, within Synch cows, tail movement was the only behavior that significantly increased in frequency 2 d before ovulation (11.81 ± 1.71 events/5 min) followed by a decrease in frequency 1 d before ovulation (4.67 ± 1.05 events/5 min) compared with ovulation day (0 d; 6.10 ± 1.25 events/5 min) and during luteolysis (3 d before ovulation; 6.01 ± 1.25 events/5 min). Upon evaluation of all variables (thermograms and behavior frequencies) as estrus indicators at 48 and 24 h before ovulation, treading and tail movements before milking and 9 thermal locations satisfied the predefined minimum acceptable value for estrus alerts. This study demonstrates that fluctuations in radiated temperature measured at specific anatomical locations and the frequency of tail movements and treading behaviors can be used as a noninvasive estrus alerts in multiparous cows housed in a tiestall system.

Decline of Plasma Concentrations of Interleukin-18 in Severely Malnourished Patients with Anorexia Nervosa: Exploratory Analysis.

Multiple studies on the dynamics of inflammatory cytokines in patients with anorexia nervosa (AN) have been published, although results are not consistent among reports. Thus the pathophysiologic roles of these cytokines are not clear. We performed an exploratory analysis that included (1) comparisons of plasma interleukin-18 (IL-18) concentrations between patients with AN (n = 21) and healthy controls (n = 39), and (2) correlations between body mass index (BMI) and IL-18 concentrations in both groups, exploring the relationship between malnourishment and IL-18. Plasma IL-18 levels were significantly decreased in patients with AN compared with controls. Plasma IL-18 levels correlated to BMI in controls, but not in patients with AN. These results suggest that a decline in plasma IL-18 levels in patients with AN is not only due to malnourishment, but other pathophysiologic changes as well. IL-18 has a role in the brain’s reaction to sadness and chronic stress. Therefore, decreased levels of IL-18 may commonly occur in patients with chronic AN.

Effect of CYP2D6 Poor Metabolizer Phenotype on Stereoselective Nebivolol Pharmacokinetics.

Nebivolol is a drug available as a racemate of d-nebivolol (SRRR) and lnebivolol (RSSS). In human liver microsomes, CYP2D6 mainly catalyses the metabolism of lnebivolol, while CYP2C19 catalyses the metabolism of d-nebivolol. Nebivolol stereoselective pharmacokinetics has been described only for extensive metabolizers (EM). To describe the stereoseletive nebivolol pharmacokinetics in CYP2D6 poor metabolizers (PM) and to assess whether the phenotype has an impact on nebivolol pharmacokinetics. Three healthy volunteers PM phenotyped (ratios of 20.1, 220 and 244 for the 8 h urinary excretion of metoprolol/alfa-hydroxymetoprolol) received a single oral dose of racemic nebivolol and sequential blood samples were collected between zero (predose) and 48 h. The obtained data were compared to 22 EM subjects with normal kidney function enrolled in our previous study. For both isomers, Cmax, Tmax and AUC0-48 were significantly greater in the PM group compared to the EMs (p = 0.006 - 0.001). For d-nebivolol, Cmax, Tmax and AUC0-48 were, on average, 5.9, 2.7 and 15.0 larger in PMs. The corresponding values for l-nebivolol were 4.4, 2.7 and 17.5. The decline in plasma concentration of both nebivolol isomers in PM phenotypes, especially those with MR of 220 and 244, which indicate minimal or absent CYP2D6 activity, points to alternative mechanisms for nebivolol elimination. Collectively, our results are the first to show the significant impact of CYP2D6 PM phenotype on the metabolic disposition and in vivo exposure to both nebivolol isomers.

Effect of zinc and vitamin E supplementation on hormones and blood biochemicals in peri-partum Sahiwal cows

Thirty-two advanced pregnant multiparous Sahiwal cows were used to study the effect of additional zinc (Zn) and vitamin E (VE) supplementation on hormonal and biochemical changes. Cows were randomly assigned to four groups and fed a basal diet of compounded concentrate, berseem fodder, and wheat straw in a ratio of 60:20:20. The groups were: (1) the basal diet with no supplement (control treatment); (2) the basal diet supplemented with 60 mg/kg DM/cow daily of Zn (Zn treatment); (3) the basal diet supplemented with 1000 IU/cow daily of vitamin E (VE treatment); and (4) the basal diet supplemented with a combination of 60 mg Zn/kg DM/cow and 1000 IU vitamin E/cow/d (Zn + VE treatment). Blood samples were collected on −60, −45, −30, −15, −7, −3, 0, 3, 7, 15, 30, 45, 60, 90, and 120 d in relation to expected date of calving and were analyzed for endocrine variables and biochemical changes. Plasma concentrations of leptin, insulin, insulin like growth factor-1 (IGF-1), triidothyronine (T3), and tetraiodothyronine (T4) were decreased toward calving and observed lowest (P < 0.05) on 3 d post-partum. However, plasma levels of growth hormone (GH) and cortisol increased toward calving and were found highest (P < 0.05) on 3 d post-partum. Pre-partum concentrations of leptin and IGF-1 were higher (P < 0.05) than its respective concentration observed during post-partum. Post-partum concentrations of GH and cortisol were higher (P < 0.05) than its respective pre-partum concentration. Pre-partum concentrations of urea, triglycerides, Zn, and VE were higher (P < 0.05) and total cholesterol and HDL cholesterol were lower than its values observed in post-partum among all the groups. Treatments had significant (P < 0.05) effect on plasma hormonal levels and levels of Zn and VE but no effect on biochemical attributes. Cows fed on diet supplemented with Zn + VE had highest (P < 0.05) pre as well as post-calving concentrations of leptin (6.38 vs 5.01 ng/ml), insulin (1.39 vs 1.33 ng/ml), GH (9.29 vs 13.72 ng/ml), IGF-1 (14.55 vs 12.59 nmol/l), T3 (1.45 vs 1.40 ng/ml), T4 (32.44 vs 31.79 ng/ml) whereas as lowest concentration of cortisol hormone (3.05 vs 3.44 ng/ml). Cows supplemented with combination of Zn and VE showed minimum decline in plasma concentration of leptin, insulin, GH, IGF-1, T3, and T4, and minimum increase in cortisol concentration. In conclusion, dairy cows around parturition faces various endocrine and biochemical alterations and supplementation of Zn in combination with VE can ameliorate adverse effect of calving stress by maintaining circulatory concentration of hormone and biochemicals towards the basal levels.

Biochemistry of the menopause.

The life of a human female is characterized from teenage years by monthly menstruation which ceases (the menopause) typically between the age of 40 and 60 years. The potential for reproduction declines and ceases as the ovaries become depleted of follicles. A transition period in mid-life, for 2 to 10 years, when menstruation is less regular is called the perimenopause. The menopause is associated with a significant decline in plasma concentrations of sex hormones, an increase in the concentrations of the gonadotrophins and changes in other hormones such as the inhibins. These changes are superimposed with effects of aging, social and metabolic factors, daily activity and well-being. Although the menopause is entirely natural, in some cases ovarian failure can occur earlier than usual; this is pathological and warrants careful biochemical investigations to distinguish it from conditions causing infertility. Elderly females are affected by a range of clinical disorders including endocrine, cardiovascular, skeletal, urogenital tract and immunological systems, body mass, vasomotor tone, mood and sleep pattern. Reference intervals for many diagnostic biochemical tests for the menopause need to be used when interpreting results in clinical investigations for patient management. The standardization and harmonization of assays are being addressed. Many women now choose to develop their career before bearing children, and the health service has had to change services around this. This review does not cover screening for and tests during pregnancy. The review is timely since the population is aging and there will be more demand on healthcare services.

A mathematical model of a recombinant humanized anti-cocaine monoclonal antibody's effects on cocaine pharmacokinetics in mice

AimsA recombinant humanized anti-cocaine monoclonal antibody (mAb), h2E2, is at an advanced stage of pre-clinical development as an immunotherapy for cocaine abuse. It is hypothesized that h2E2 binds to and sequesters cocaine in the blood. Main methodsA three-compartment model of the effects of h2E2 on cocaine's distribution was constructed. The model assumes that h2E2 binds to cocaine and that the h2E2-cocaine complex does not enter the brain but distributes between the central and peripheral compartments. Free cocaine is eliminated from both the central and peripheral compartments, and h2E2 and the h2E2-cocaine complex are eliminated from the central compartment only. This model was tested against a new dataset measuring cocaine concentrations in the brain and plasma over 1h in the presence and absence of h2E2. Key findingsThe mAb significantly increased plasma cocaine concentrations with a concomitant significant decrease in brain concentration. Plasma concentrations declined over the 1-hour sampling period in both groups. With a set of parameters within reasonable physiological ranges, the three-compartment model was able to qualitatively and quantitatively simulate the increased plasma concentration in the presence of the antibody and the decreased peak brain concentration in the presence of antibody. Importantly, the model explained the decline in plasma concentrations over time as distribution of the cocaine-h2E2 complex into a peripheral compartment. SignificanceThis model will facilitate the targeting of ideal mAb PK/PD properties thus accelerating the identification of lead candidate anti-drug mAbs.

Pharmacokinetic Modeling and Simulation Analysis of LCB01-0371, A New Oxazolidinone Antibiotic Under Clinical Development

LCB01-0371, a new oxazolidinone with cyclic amidrazone under clinical development, has been shown to have a superior animal safety profile and better efficacy than those of linezolid. It works by binding to the 23S ribosomal RNA of the 50S subunit, thereby preventing the formation of the 70S initiation complex and inhibiting protein synthesis. The aims of this study were to develop a population pharmacokinetics (PPK) model for oral LCB01-0371 in healthy Korean volunteers and to predict the plasma LCB01-0371 concentration over time on various dosing regimens of LCB01-0371 via Monte-Carlo simulation Pharmacokinetics (PK) data were collected from 110 healthy, Korean, male subjects in three Phase 1 studies for LCB01-0371. LCB01-0371 was administered at single or multiple oral doses of 50 ~ 3,200 mg, and blood and urine samples were collected serially for PK. Plasma and urine concentrations of LCB01-0371 were measured by validated LC/MS-MS. PPK analysis were performed using nonlinear mixed effect modeling software NONMEM (version 7.3) with the first-order conditional estimation with interaction (FOCE-I) method. Plasma LCB01-0371 was absorbed fast after oral administration with followed by rapid decline in plasma concentration. The LCB01-0371 concentration in plasma and amount excreted in urine over time were best described by two-compartment model (central Vd, 82.4 L; peripheral Vd, 8.59 L) with absorption lag (ALAG1, 0.212 hour) and mixed zero (D1, 0.286 hour) and first order absorption (Ka, 80.7 /hour) process. Basic goodness of fit plots, visual predictive check plots exhibited that the final plasma and urine PPK model describe the data reasonably well. The current modeling and simulation analysis adequately characterized the pharmacokinetics of LCB01-0371 in Korean healthy adult male subjects, which will be a valuable tool in the search for the optimal dosing regimens of LCB01-0371.

Importance of TDM During Pregnancy and Breastfeeding

Therapeutic drug monitoring (TDM) is specific method of clinical pharmacology for monitoring of the therapy using measurement of drugs serum concentrations followed by interpretation and good cooperation with clinicians. Almost every pregnant woman is exposed to some type of medication during pregnancy. It was found a significant correlation between teratogenic effects and maternal or umbilical cord concentrations of some drugs, but not dose. For this reason, TDM in mother during pregnancy is more valuable than the given dose for estimating and possibly obviating the teratogenic risk of these drugs on the fetus. However, the data relating to the transplacental passage for most of drugs remain sparse. It was reported that analytical models should also take into account not only type and dose, but also levels of drugs in the mother and the neonate at birth as a closer surrogate marker for fetal exposure. Measuring the umbilical cord/maternal serum drug level ratio at birth is the method recommended to assess transplacental transfer. The decline in plasma concentrations during pregnancy was also observed with a considerable interindividual variability in the effect of pregnancy on kinetics of some drugs. Therefore, frequent TDM during pregnancy and after delivery is necessary to optimize treatment in women taking these drugs in the period of instable kinetics. The data on the transfer of drugs to the milk and the risk of exposure to the breastfed infants remain also sparse and only a limited number of studies have actually measured the infant blood levels. It was reported that the monitoring of breastfed infant’s concentrations appears to be the most relevant method for analysis of drugs exposure in breastfed infants (especially in those with some clinical problems such as sedation, poor suckling, and life-threatening rashes), overriding any other calculation.

Importance of TDM During Pregnancy and Breastfeeding

Therapeutic drug monitoring (TDM) is specific method of clinical pharmacology for monitoring of the therapy using measurement of drugs serum concentrations followed by interpretation and good cooperation with clinicians. Almost every pregnant woman is exposed to some type of medication during pregnancy. It was found a significant correlation between teratogenic effects and maternal or umbilical cord concentrations of some drugs, but not dose. For this reason, TDM in mother during pregnancy is more valuable than the given dose for estimating and possibly obviating the teratogenic risk of these drugs on the fetus. However, the data relating to the transplacental passage for most of drugs remain sparse. It was reported that analytical models should also take into account not only type and dose, but also levels of drugs in the mother and the neonate at birth as a closer surrogate marker for fetal exposure. Measuring the umbilical cord/maternal serum drug level ratio at birth is the method recommended to assess transplacental transfer. The decline in plasma concentrations during pregnancy was also observed with a considerable interindividual variability in the effect of pregnancy on kinetics of some drugs. Therefore, frequent TDM during pregnancy and after delivery is necessary to optimize treatment in women taking these drugs in the period of instable kinetics. The data on the transfer of drugs to the milk and the risk of exposure to the breastfed infants remain also sparse and only a limited number of studies have actually measured the infant blood levels. It was reported that the monitoring of breastfed infant’s concentrations appears to be the most relevant method for analysis of drugs exposure in breastfed infants (especially in those with some clinical problems such as sedation, poor suckling, and life-threatening rashes), overriding any other calculation.

Measurement of piperacillin plasma concentrations in cancer patients with suspected infection.

Piperacillin (PIP) in combination with tazobactam is commonly used for anti-infective treatment in cancer patients. PIP exerts a time-dependent killing. Thus, the maintenance of plasma concentrations above a pre-defined target concentration for a pre-defined time may be relevant for optimal efficacy. It is assumed that PIP-plasma concentrations above the clinical breakpoint of the target pathogen [Pseudomonas aeruginosa, clinical breakpoint at minimal inhibitory concentration (MIC) 16mg/L] should be reached for 100% of the dosing interval or>4xMIC (64mg/L) for 50% of the dosing interval. Whereas studies in the intensive-care setting have shown underdosing in patients with sepsis, little is known about PIP-plasma concentrations in cancer patients. Data of 56 cancer patients who received piperacillin/tazobactam (PIP/TAZ, 4.5g three times daily) as empiric therapy for suspected infection were analysed at baseline and 4h after the infusion. Median trough concentrations in steady state [median 3days (IQR 3-5) after start of PIP/TAZ] were 4.6mg/L (95% CI 0.3-136.3) and median PIP-plasma concentrations 4h after infusion were 46.2mg/L (95% CI 10.1-285.6). A second evaluation 5days (IQR 4-7) after start of PIP/TAZ confirmed these results: trough concentrations were 2.7mg/L (95% CI 0.5-6.3), concentrations after 4h 28.0mg/L (95% CI 1.7-47.3). A good renal function was associated with lower plasma concentrations (r=-0.388, p<0.003). Detailed pharmacokinetic measurements in six patients showed low maximum plasma concentration (median 165mg/L) and a rapid decline of plasma concentrations (median plasma half time 1.38h). In conclusion, piperacillin plasma concentrations in cancer patients are below target levels warranting prospective trials to investigate therapeutic drug monitoring.

Idarucizumab, a Specific Reversal Agent for Dabigatran: Immediate, Complete and Sustained Reversal of Dabigatran-Induced Anticoagulation in Japanese Healthy Male Volunteers

Background: Specific reversal agents for oral anticoagulants may be necessary to manage life-threatening bleeding or prior to emergency surgical procedures. While many reversal agents are in development, idarucizumab is approved and now available commercially in many countries. Idarucizumab is a humanized antibody fragment that specifically binds to dabigatran with high affinity and has shown immediate, complete and sustained reversal of dabigatran-induced anticoagulation in healthy male Caucasian volunteers. The present study investigated the safety, tolerability and pharmacokinetics of idarucizumab (part 1) and explored the effective dose of idarucizumab to reverse the dabigatran-induced anticoagulant effect (part 2) in healthy male Japanese volunteers.Methods: This was a two-part, phase I, randomized, placebo-controlled, double-blind, single-center, rising dose study. In part 1, subjects (n = 32) were randomized to receive either placebo (n = 2/dose group) or single intravenous doses of idarucizumab, 1, 2, or 4 g as a 5-minute infusion or 8 g as a 1-hour infusion (n = 6/group). In part 2, subjects (n = 48) were treated orally for 3 days with dabigatran etexilate (DE, 220 mg bid). On day 4, subjects received a final DE dose, followed a 3-day wash out period. Subjects were again treated orally for 3 days with DE, 220 mg bid. On Day 11, subjects received a final DE dose followed 2 hours later by placebo (n = 3/group) or idarucizumab (1, 2, 4, or 5 g [2.5 g followed by 2.5 g given 15 minutes apart]) as a 5-minute intravenous infusion, n = 9/group). The number of subjects with adverse events (AEs), emergence of anti-idarucizumab antibodies (ADAs), pharmacokinetics and the impact of idarucizumab on coagulation parameters were assessed (diluted thrombin time, ecarin clotting time, activated partial thromboplastin time, and thrombin time). In addition, potential procoagulant effects were monitored as D-dimer and prothrombin fragment F1.2.Results: Idarucizumab attained a maximum concentration in plasma around the end of each infusion followed by a biphasic decline in plasma concentrations with a rapid initial phase and a longer terminal phase.. Dabigatran treatment prolonged the clotting times of all coagulation parameters. Idarucizumab infusion resulted in immediate and complete reversal of dabigatran-induced anticoagulation, reducing coagulation parameters below the upper limit of normal. The duration was dose-dependent; at 4 and 5 g of idarucizumab, complete reversal was sustained up to 72 hours, at lower doses ≤ 2 g a partial return of the anticoagulation activity of dabigatran was observed 1-2 hours after idarucizumab administration. Concentration of unbound dabigatran decreased to below the limit of quantification immediately after administration of a single dose of idarucizumab. Idarucizumab was safe and well tolerated, and no AEs were reported. There was no elevation of either D-dimer or F1.2 levels post idarucizumab as compared to levels prior to infusion in any of the dose groups. Treatment-emergent ADAs occurred in 6 of 60 patients receiving idarucizumab.Conclusion: Idarucizumab infusion achieved immediate, complete and sustained reversal of dabigatran-associated anticoagulation in healthy male Japanese volunteers. Idarucizumab was safe and well tolerated with no procoagulant effects. Disclosuresvan Ryn:Boehringer Ingelheim: Employment. Yasaka:Sanofi: Research Funding; Nippon Boehringer Ingelheim: Other: received lecture fees (over 1 million Yen); Bristol-Myers Squibb: Other: received lecture fees (over 1 million Yen); Bayer Yakuhin: Other: received lecture fees (over 1 million Yen); Daiichi-Sankyo: Other: received lecture fees (over 1 million Yen). Harada:Boehringer Ingelheim: Employment. Taniguchi:Boehringer Ingelheim: Employment. Imazu:Boehringer Ingelheim: Employment. Norris:Boehringer Ingelheim: Employment. Gansser:Boehringer Ingelheim: Employment. Stangier:Boehringer Ingelheim: Employment.

Massive Life-Threatening Hemorrhages Due to Toxic Oral Intake of 3750 Mg Dabigatran Etexilate As a Suicide Attempt and the Clinical Management

The direct thrombin inhibitor dabigatran etexilate is a novel oral anticoagulant agent. The drug is used for the prevention of stroke and systemic embolism in nonvalvular atrial fibrillation. There is no specific antidote for the reversal of the anticoagulant effects of dabigatran etexilate. Therefore, the management of the clinical bleeding due to dabigatran etexilate represents a great challenge for the clinician. We would like to share our experience regarding the massive life-threatening hemorrhages due to toxic oral intake of 3750 mg dabigatran etexilate as a suicide attemp and the clinical management.A 83-year-old man with a medical history of atrial fibrillation, coronary artery disease, hypertension and myelodisplastic syndrome presented to the emergency room with massive hematuria. Because of atrial fibrilation, he was using dabigatran etexilate as a prophylaxis of stroke or systemic embolism. He had received about 50 capsules of dabigatran etexilate (3750 mg) with the purpose of suicide, 30 hours before transfer to hospital. On the admission, physical assessment showed hypotension, massive hematuria and spontaneous pethechial areas and purpuras on the skin. The thrombin clotting time (TT) was 130 s (normal range 20- 30 s), activated partial thromboplastine time (aPTT) was 59 s (normal 22-35 s), prothrombin time - international normalized ratio (INR) was 1,4. Complete blood count showed that hemoglobin was 7,4 g/dL and platelets were 30000 /µL. The patient received 1000 U prothrombin complex concentrates (PCC), for two days. And 2 units of erytrocyte suspensions were administered. The bleeding ceased within the first day and the thrombin time normalized 3 days later.Dabigatran etexilate is a safer drug than the other anticoagulants. When compared to the warfarin and enoxaparin, dabigatran etexilate has been shown to reduce the rates of bleeding. However, the patients receving dabigatran etexilate have still a risk of bleeding. Because of the predictable pharmacokinetic and pharmacodynamic profile of dabigatran etexilate, there is no need for routine therapeutic coagulation monitoring while using the drug. In case of active bleeding, a possible overdose, or the need for an invasive procedure, the monitoring gains importance. TT and aPTT are the most sensitive laboratory assays to determine the dabigatran etexilate levels. Since the prothrombin time is not affected by dabigatran etexilate, it is not sensitive. There is a strong correlation between the TT measurements and dabigatran etexilate plasma levels. So in monitoring effectivity of therapy or determining the dabigatran etexilate levels in plasma, thrombin clotting time is very useful. However, at dabigatran etexilate concentrations above 600 ng/mL, the maximum measurement of the test is exceeded, correlating to a TT of greater than 120 seconds. Our patient on admission had an elevated TT of >120 seconds indicating accumulation of dabigatran etexilate with levels >600 ng/mL and massive hematuria. There were a bleeding associated dabigatran etexilate and overdose of drug. In order to stop bleeding we need to reverse anticoagulant effects of dabigatran etexilate. There is no specific antidote for dabigatran etexilate and there is limited guidance for treatment in these situations. Fortunately, dabigatran etexilate has short half-life which provides a relatively quick decline in plasma concentrations after discontinuance of the drug in a patient with normal renal function In case of overdose, it is suggested that discontinuing dabigatran etexilate therapy, initiating supportive care, the potential use of hemodialysis, and investigating the source of the bleed. In patients who require more urgent reversal of their anticoagulation, the use of prothrombin complex concentrates (PCCs) may be helpful. PCCs contain vitamin K–dependent coagulation factors II, VII, IX, and X. We started the patient PCCs at the dose of 1000 IU/d and supportive care. The bleeding was ceased in the first day and there was no need to hemodialysis.Thus, the advantages of using dabigatran etexilate instead of warfarin will lead to widespread use. But it must be kept in mind that dabigatran etexilate is not completely innocent drug and the patients using dabigatran etexilate still have the significant risk of bleeding. And acute reversal of the effects of dabigatran etexilate in the actively bleeding patient is a significant challenge. DisclosuresNo relevant conflicts of interest to declare.