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This case series suggests that successful eradication therapy of BCC in cystic fibrosis can be done with a combination of inhaled and oral medication, which in many cases may eliminate the need for intensive treatment with intravenous antibiotics https://bit.ly/40oOMIn.

Introduction Dosing of antibiotics in people with cystic fibrosis (CF) is challenging, due to altered pharmacokinetics, difficulty of lung tissue penetration, and increasing presence of antimicrobial resistance. Areas covered The purpose of this work is to critically review original data as well as previous reviews and guidelines on pharmacokinetics of systemic and inhaled antibiotics in CF, with the aim to propose strategies for optimization of antibacterial therapy in both children and adults with CF. Expert opinion For systemic antibiotics, absorption is comparable in CF patients and non-CF controls. The volume of distribution (Vd) of most antibiotics is similar between people with CF with normal body composition and healthy individuals. However, there are a few exceptions, like cefotiam and tobramycin. Many antibiotic class-dependent changes in drug metabolism and excretion are reported, with an increased total body clearance for ss-lactam antibiotics, aminoglycosides, fluoroquinolones, and trimethoprim. We, therefore, recommend following class-specific guidelines for CF, mostly resulting in higher dosages per kg bodyweight in CF compared to non-CF controls. Higher local antibiotic concentrations in the airways can be obtained by inhalation therapy, with which eradication of bacteria may be achieved while minimizing systemic exposure and risk of toxicity.

Aims Dried blood spot (DBS) home sampling allows monitoring creatinine levels and tacrolimus trough levels as an alternative for blood sampling in the hospital, which is important in kidney transplant patient follow-up. This study aims to assess whether DBS home sampling results in decreased patient travel burden and lower societal costs. Methods In this single-centre randomized controlled hybrid implementation trial, adult kidney transplant patients were enrolled. The intervention group (n = 25) used DBS home sampling on top of usual care in the first 6 months after transplantation. The control group (n = 23) received usual care only. The primary endpoint was the number of outpatient visits. Other endpoints were costs per patient, patient satisfaction and implementation. Results There was no statistically significant difference in the average number of outpatient visits between the DBS group (11.2, standard deviation: 1.7) and the control group (10.9, standard deviation: 1.4; P = .48). Average costs per visit in the DBS group were not significantly different (€542, 95% confidence interval €316-990) compared to the control group (€533, 95% confidence interval €278-1093; P = .66). Most patients (n = 19/23, 82.6%) were willing to perform DBS home-sampling if this would reduce the number of hospital visits. Only 55.9% (n = 143/256) of the expected DBS samples were received and 1/5 analysed on time (n = 52/256). Conclusion Adult kidney transplant patients are willing to perform DBS home sampling. However, to decrease patient travel burden and costs in post-transplant care, optimization of the logistical process concerning mailing and analysis of DBS samples is crucial.

INTRODUCTION: In the field of forensic toxicology, many unexpected deaths are investigated as to whether toxicological substances may have caused or contributed to someone's death. One of the factors that makes interpretation of the results of quantitative analysis in postmortem toxicology challenging, is that measured postmortem drugs levels may vary according to the sampling site and the interval between death and specimen collection. These site- and time-dependent variations are caused by 'postmortem redistribution' (PMR). Literature shows that there are several factors that determine the degree of PMR, such as cell and tissue changes after death, decomposition and the physicochemical characteristics of drugs. Blood from peripheral sites seems to be less affected by PMR than cardiac blood. Therefore, the ratio of cardiac blood concentration/peripheral blood concentration (C/P) of a drug is often used as a marker of the extent of postmortem redistribution. In this study, we investigated the relationship between different potentially important variables and the C/P ratio of morphine in humans in order to provide new insights that might assist in the interpretation of quantitative results in forensic casework.METHOD: Toxicological results of all morphine positive postmortem cases investigated by the Netherlands Forensic Institute between January 1, 2010 and July 31, 2020 were reviewed. Morphine was quantified in both femoral and cardiac blood in a total of 103 cases. The C/P ratios were determined for all selected cases. To collect data for this study, all corresponding files were reviewed. C/P ratios were compared between subgroups by performing either a Mann-Whitney U test or a Kruskal-Wallis test, followed by a post-hoc Mann-Whitney U test. Bonferroni correction was performed to correct for the likelihood of a significant result by chance due to multiple testing. After Bonferroni correction, a p-value< 0.004 was considered statistically significant.RESULTS: The data suggests a relationship between grade of decomposition at autopsy, position of the corpse at discovery, route of administration, attempted resuscitation and the C/P ratio of morphine with p-values of 0.010, 0.026, 0.035 and 0.046, respectively.CONCLUSION: Grade of decomposition at autopsy, position of the corpse at discovery, route of administration and attempted resuscitation seem to be influencing the C/P ratio of morphine. Of these four variables, the route of administration seems to have the greatest impact.

Background Many antidepressants are substrates of P-glycoprotein, an efflux transporter in the blood-brain-barrier encoded by the ABCB1 gene. Genetic variations might influence the transport rate of antidepressants and hence their pharmacological effects. This study investigates the influence of eight polymorphisms in the ABCB1 gene on antidepressant treatment response. Method 152 patients were included from psychiatric departments of the Mental Health Research Institute in Tomsk. The difference in Hamilton-Depression-Rating-Scale (HAMD-17)-scores between baseline and week two, week two and four, and baseline and week four was used to estimate timing of improvement of depression. Associations between the ABCB1 gene-polymorphisms and reduction in HAMD-17 score were assessed using independent t-test and multiple linear regression. Results Tricyclic antidepressants were associated with a higher reduction of HAMD-17 score when compared to SSRIs. The SNP rs2235040 A-allele had a significant positive influence on the Delta HAMD-17((0 -> 2W)) score but a significant negative influence on the Delta HAMD-17((2 -> 4W)) score. The rs4148739 G-allele had a significant negative influence on the Delta HAMD-17((0 -> 2W)) score but a significant positive influence on the Delta HAMD-17((2 -> 4W)) score. The SNP rs2235015 T-allele is significant negatively related to the Delta HAMD-17((2 -> 4W)) score. Conclusion ABCB1 Genetic variations appear to affect speed but not magnitude of antidepressant drug response.

Background and Objectives: Uncertainty exists regarding the optimal dosing regimen for vancomycin in different patient populations, leading to a plethora of subgroup-specific pharmacokinetic models and derived dosing regimens. We aimed to investigate whether a single model for vancomycin could be developed based on a broad dataset covering the extremes of patient characteristics. Furthermore, as a benchmark for current dosing recommendations, we evaluated and optimised the expected vancomycin exposure throughout life and for specific patient subgroups. Methods: A pooled population-pharmacokinetic model was built in NONMEM based on data from 14 different studies in different patient populations. Steady-state exposure was simulated and compared across patient subgroups for two US Food and Drug Administration/European Medicines Agency-approved drug labels and optimised doses were derived. Results: The final model uses postmenstrual age, weight and serum creatinine as covariates. A 35-year-old, 70-kg patient with a serum creatinine level of 0.83 mg dL−1 (73.4 µmol L−1) has a V1, V2, CL and Q2 of 42.9 L, 41.7 L, 4.10 L h−1 and 3.22 L h−1. Clearance matures with age, reaching 50% of the maximal value (5.31 L h−1 70 kg−1) at 46.4 weeks postmenstrual age then declines with age to 50% at 61.6 years. Current dosing guidelines failed to achieve satisfactory steady-state exposure across patient subgroups. After optimisation, increased doses for the Food and Drug Administration label achieve consistent target attainment with minimal (± 20%) risk of under- and over-dosing across patient subgroups. Conclusions: A population model was developed that is useful for further development of age and kidney function-stratified dosing regimens of vancomycin and for individualisation of treatment through therapeutic drug monitoring and Bayesian forecasting., SCOPUS: ar.j, info:eu-repo/semantics/published

Background In the era of multiple daily dosing of systemic aminoglycosides, a circadian rhythm in the clearance of these vital antibiotics has been demonstrated in animals and healthy volunteers. Over the past decade, once-daily dosing regimens have been proved to be less nephrotoxic and were therefore adopted worldwide for most indications requiring treatment with an aminoglycoside. In this study, the effect of the time of administration on the pharmacokinetics of once-daily tobramycin in adults with cystic fibrosis (CF) experiencing a pulmonary exacerbation was investigated. Methods In this open randomized study, patients with CF received intravenous tobramycin at 8:00 or 22:00 hours. Pharmacokinetic and kidney function parameters were compared between the 2 groups. Results Twenty-five patients were included. The mean weight-corrected clearances of tobramycin were 1.46 versus 1.43 mL/h*kg (P = 0.50) and mean volumes of distribution were 0.25 versus 0.27 L/kg (P = 0.54) for the 8:00 and 22:00 groups, respectively. In addition, no significant differences were detected in changes in estimated clearances of creatinine or tobramycin on day 1 and day 8 in the 8:00 or 22:00 group, indicating that there was no decline in clearance over time. At day 8 of therapy, the increase in serum blood urea nitrogen in the 22:00 group was significantly higher than that in the 8:00 group (1.8 versus 0.2 mmol/L, P = 0.015). Conclusions The time of administration (8:00 versus 22:00) did not affect tobramycin pharmacokinetics in the adult CF population studied. The increase in serum blood urea nitrogen in the 22:00 group requires further investigation.

Online haemodiafiltration (HDF) is increasingly used in clinical practice as a routine intermittent dialysis modality. It is well known that renal impairment and renal replacement therapy can substantially affect the pharmacokinetic behaviour of several drugs. However, surprisingly few data are available on the need for specific dose adjustments during HDF. Due to convection, drug clearance may be increased during HDF as compared with standard haemodialysis. This may be of particular interest in patients undergoing anti-infective therapy, since under-dosing may compromise patient outcomes and promote the emergence of bacterial resistance. Drug clearance during HDF is determined by (i) dialysis characteristics, (ii) drug characteristics and (iii) patient characteristics. In this review, we will discuss these different determinants of drug clearance during HDF and advise on how to adjust the dose of antibacterial, antimycotic and antiviral agents in patients undergoing HDF. In addition, the possible added value of therapeutic drug monitoring is discussed. The review provides guidance for optimization of anti-infective dosing regimens in HDF patients.

Supplemental Digital Content is Available in the Text., Background: Darunavir is a second-generation protease inhibitor and is registered for the treatment of HIV-1 infection. The aim of this study was to develop and validate a darunavir population pharmacokinetic model based on data from daily practice. Methods: Data sets were obtained from 2 hospitals: ASST Fatebenefratelli Sacco University Hospital, Italy (hospital A), and University Medical Center Groningen, the Netherlands (hospital B). A pharmacokinetic model was developed using data from the largest data set using the iterative two-stage Bayesian procedure within the MWPharm software package. External validation was conducted using data from the smaller data set with Passing–Bablok regression and Bland–Altman analyses. Results: In total, data from 198 patients from hospital A and 170 patients from hospital B were eligible for inclusion. A 1-compartment model with first-order absorption and elimination resulted in the best model. The Passing–Bablok analysis demonstrated a linear correlation between measured concentration and predicted concentration with r2 = 0.97 (P < 0.05). The predicted values correlated well with the measured values as determined by a Bland–Altman analysis and were overestimated by a mean value of 0.12 mg/L (range 0.23–0.94 mg/L). A total of 98.2% of the predicted values were within the limits of agreement. Conclusions: A robust population pharmacokinetic model was developed, which can support therapeutic drug monitoring of darunavir in daily outpatient settings.

INTRODUCTION: Contrasting findings have been published regarding the effect of human immunodeficiency virus (HIV) on tuberculosis (TB) drug pharmacokinetics (PK). OBJECTIVES: The aim of this systematic review was to investigate the effect of HIV infection on the PK of the first-line TB drugs (FLDs) rifampicin, isoniazid, pyrazinamide and ethambutol by assessing all published literature. METHODS: Searches were performed in MEDLINE (through PubMed) and EMBASE to find original studies evaluating the effect of HIV infection on the PK of FLDs. The included studies were assessed for bias and clinical relevance. PK data were extracted to provide insight into the difference of FLD PK between HIV-positive and HIV-negative TB patients. This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement and its protocol was registered at PROSPERO (registration number CRD42017067250). RESULTS: Overall, 27 studies were eligible for inclusion. The available studies provide a heterogeneous dataset from which consistent results could not be obtained. In both HIV-positive and HIV-negative TB groups, rifampicin (13 of 15) and ethambutol (4 of 8) peak concentration (Cmax) often did not achieve the minimum reference values. More than half of the studies (11 of 20) that included both HIV-positive and HIV-negative TB groups showed statistically significantly altered FLD area under the concentration-time curve and/or Cmax for at least one FLD. CONCLUSIONS: HIV infection may be one of several factors that reduce FLD exposure. We could not make general recommendations with respect to the role of dosing. There is a need for consistent and homogeneous studies to be conducted.

OBJECTIVES: Currently there is no data about a liquid chromatography tandem mass spectrometry (LC-MS/MS) assay including ganciclovir and acyclovir using stable-isotopically labeled internal standards.METHODS: LC-MS/MS assay for measurement of ganciclovir and acyclovir using deuterated standards: ganciclovir-[2H5] and acyclovir-[2H4] was developed. The selectivity and sensitivity, linearity, accuracy and precision, recovery, matrix effect, stability, total process efficiency, carry-over and dilution integrity were validated based on EMA and FDA guidelines.RESULTS: The retention time for ganciclovir was 1.1 min and for acyclovir 1.35 min. Calibration curves were linear over a range of 0.1 to 20 mg/L and the correlation coefficient (R2) was 0.99912 for ganciclovir and 0.99945 for acyclovir. The calculated accuracy was –2.0% to 3.1% for ganciclovir and –1.0% to 6.4% for acyclovir. Within-day precision ranged from 1.8% to 6.6% for ganciclovir and 1.6 % to 6.5% for acyclovir and between-day precision 0% to 9.6% for ganciclovir and 0% to 7.9% for acyclovir.CONCLUSIONS: A rapid and validated LC-MS/MS method was developed for measurement of ganciclovir and acyclovir in human serum which can be used in routine patient care and clinical research.

Background: Regular therapy for schizophrenia includes maintenance antipsychotic treatment. Unfortunately, antipsychotics also have a spectrum of side effects, including metabolic, endocrine, cardiovascular, and movement disorders. One of the common side effects of these drugs is hyperprolactinemia (HPRL) [1]. This side effect is attributed to blockade of dopamine D2 receptors on the membranes of lactotroph cells within the pituitary gland. Certain antipsychotic drugs, e.g. risperidone, are more likely to induce HPRL because of relative accumulation within the adenohypophysis. The strong prolactin-elevating effect of risperidone reflects its relatively high blood/brain concentration ratio, a consequence of it being a substrate for the p-glycoprotein (P-gp, also known as ABCB1) pump [2]. Therefore, P-gp genotypes with altered functional activity might influence the potential of risperidone to cause HPRL as the changed blood/brain concentration ratio would lead to an altered vulnerability for CNS side effects like parkinsonism. Such side effects are expected to make dose adaptations necessary, which would also decrease exposure of lactrotroph dopamine D2 receptors. Aims: The present study aimed to investigate the influence of polymorphisms of the P-glycoprotein gene (ABCB1 gene) on the prevalence of antipsychotic-induced hyperprolactinemia in patients with schizophrenia. Methods: We studied the association between polymorphisms of the P-gp gene (ABCB1 gene) and antipsychotic drug-induced hyperprolactinemia in patients with schizophrenia from Siberia. Evaluation of serum prolactin was performed by ELISA using reagents set PRL Test System (USA). Genotyping was carried out on 8 polymorphic variants of the P-glycoprotein gene (rs1045642, rs2032582, rs4148739, rs28401781, rs2235040, rs9282564, rs2235015, and rs2032583). Associations between HPRL and polymorphisms of P-gp gene were established using logistic regression accounting for covariates (age, sex, duration of the disease, and CPZeq). An additive genetic model was tested and the analysis was carried out both in the total sample and in subgroups stratified by the use of risperidone/paliperidone (N = 76) or sulpiride/amisulpride (N = 13). Bonferroni correction was applied assuming 5 independent tests estimated via the correlation between the SNPs. Results: 446 Russian patients with schizophrenia were examined, including 225 women and 221 men [3]. The average age of patients was 42.1 ± 1.4 years. No statistically significant associations were obtained in the total sample after correction for multiple-testing. However, the rs2032582 variant appeared to be protective against HPRL in the subgroup of patients using risperidone or paliperidone (OR = 0.17, 95% CI = 0.04–0.79, adjusted p = 0.041). Discussion: Our finding supports the hypothesis that a variant of P-gp gene may influence the likelihood of inducing HPRL in patients using risperidone or paliperidone (i.e. 9-hydroxy-risperidone). This may be related to affecting the blood/brain concentration ratio of the risperidone moiety. In the total sample the association was significant but did not survive correction for multiple testing. Moreover, another variant, rs4148739, was associated to a larger extent than rs2032582. Hence, the variant may affect the affinity of the risperidone moiety specifically without having consequences for the binding and transport of other antipsychotic drugs. Conclusion: Rs2032582 of the P-gp is negatively associated with risperidone/paliperidone-induced HPRL, but not with HPRL induced by other antipsychotic drugs. References [1] Peuskens, J., Pani, L., Detraux, J., De Hert, M., 2014. The effects of novel and newly approved antipsychotics on serum prolactin levels: a comprehensive review. CNS Drugs 28, 421–453. [2] Ejsing, T., Pedersen, A., Linnet, K., 2005. P-glycoprotein interaction with risperidone and 9-OH-risperidone studied in vitro, in knock-out mice and in drug-drug interaction experiments. Hum Psychopharmacol 20, 493–500. [3] Ivanova, S.A., Osmanova, D.Z., Freidin, M.B., Fedorenko, O.Y., Boiko, A.S., Pozhidaev, I.V., Semke, A.V., Bokhan, N.A., Agarkov, A.A., Wilffert, B., Loonen, A.J.M., 2017. Identification of 5-hydroxytryptamine receptor gene polymorphisms modulating hyperprolactinaemia in antipsychotic drug-treated patients with schizophrenia. World J Biol Psychiatry 18, 239–246. Keywords: Schizophrenia: clinical Pharmacokinetics Neuroendocrinology

Haloperidol decanoate is a typical antipsychotic drug used as maintenance therapy for schizophrenia and mood disorders formulated as an ester for intramuscular injection. Cases of oral haloperidol decanoate intoxications have not been described in literature. In this report, we present for the first time a case of an oral ingestion of haloperidol decanoate of a young woman who presented to the emergency department following an intentional oral ingestion of 1 ampoule of haloperidol decanoate 100mg. At presentation, she had a bilateral rest tremor of both hands and mild hypothermia. No other obvious signs of an intoxication were observed. She was treated with a single dose of activated charcoal and laxative and was admitted to the intensive care for rhythm monitoring and observation. During the night the QTc interval increased to 453ms, but stayed within the normal range. Haloperidol plasma levels increased as well, but also stayed within therapeutic ranges. These findings indicate that treatment with oral activated charcoal was sufficient to prevent any serious events.

Background: Current gentamicin dosing algorithms in adult populations target a high peak concentration (Cmax) assuring efficacy and a drug-free period (concentration ,0.5 mg/L) preventing toxicity. In contrast, gentamicin-based regimens in neonatal sepsis often aim for lower peak levels and trough concentrations of 0.5-2.0 mgL21. The latter concentrations are associated with an increased risk of aminoglycoside-related toxicity. Therefore, the primary aim of this study was to assess the target attainment of a simple and practical dosing regimen designed to attain drug-free periods in newborns. Methods: The study was of prospective observational design. Neonates admitted to a level II neonatal nursery diagnosed with (suspected) early-onset sepsis and commencing intravenous gentamicin therapy of 5 mgkg21 every 36 hours were eligible for inclusion. Gentamicin dosing was guided by drug concentration monitoring targeting Cmax values .8 mgL21 and estimated trough concentrations ,0.5 mgL21. Relationships between body weight (BW), gestational age (GA), postnatal age, and pharmacokinetic parameters were analyzed using the Pearson correlation test, and univariate and multivariate logistic regression analyses were performed to identify covariates predictive of target attainment failure. Results: A total of 184 patients were included. 90.4% of patients (n = 166) achieved a Cmax value .8 mgL21 with a Cmin value ,0.5 mgL21. Subsequently, significant correlations were found between GA and Cmax (r = 0.58, P , 0.001) between GA and Cmin (r = 0.44, P , 0.001), between BW and Cmax (r = 0.50, P , 0.001), and between BW and Cmin (r = 0.42, P , 0.001). Correlations between area under the curve (AUC) and GA (r = 0.064, P = 0.4), and between AUC and BW (r = 0.028, P = 0.7) were not significant. During multivariate analysis, only GA (P , 0.001) was retained as an independent predictor of underexposure. Conclusions: Extended interval dosing of gentamicin resulted in high target attainment rates in neonates admitted to a level II unit. In line with previous reports, low GA and BW were predictive of subtherapeutic peak and toxic trough levels. The AUC, however, was unaffected by the interpatient variation in GA and BW. Since AUC-guided dosing is gaining interest worldwide, the latter finding deserves further exploration in other neonatal cohorts.

Azithromycin maintenance therapy results in improvement of respiratory function in patients with cystic fibrosis (CF). In azithromycin maintenance therapy, several dosing schemes are applied. In this review, we combine current knowledge about azithromycin pharmacokinetics with the dosing schedules used in clinical trials in order to come to a dosing advise which could be generally applicable. We used data from a recently updated Cochrane meta analysis (2011), the reports of clinical trials and pharmacokinetic studies. Based on these data, it was concluded that a dose level of 22-30 mg/kg/week is the lowest dose level with proven efficacy. Due to the extended half-life in patients with CF, the weekly dose of azithromycin can be divided in one to seven dosing moments, depending on patient preference and gastro-intestinal tolerance. No important side effects or interactions with other CF-related drugs have been documented so far.

Maximum a posteriori Bayesian (MAPB) pharmacokinetic parameter estimation is an accurate and flexible method of estimating individual pharmacokinetic parameters using individual blood concentrations and prior information. In the past decade, many studies have developed optimal sampling strategies to estimate pharmacokinetic parameters as accurately as possible using either multiple regression analysis or MAPB estimation. This has been done for many drugs, especially immunosuppressants and anticancer agents. Methods of development for optimal sampling strategies (OSS) are diverse and heterogeneous. This review provides a comprehensive overview of OSS development methodology using MAPB pharmacokinetic parameter estimation, determines the transferability of published OSSs, and compares sampling strategies determined by MAPB estimation and multiple regression analysis. OSS development has the following components: 1) prior distributions; 2) reference value determination; 3) optimal sampling time identification; and 4) validation of the OSS. Published OSSs often lack all data necessary for the OSS to be clinically transferable. MAPB estimation is similar to multiple regression analysis in terms of predictive performance but superior in flexibility.

The development of a new drug is characterized by distinct developmental stages, usually described as phases I to IV. Dose tolerance and dose response exploration studies are undertaken in phase II or III. Pharmacokinetic studies are often involved in these phases, but frequently only as an objective of minor importance. The usefulness of therapeutic drug monitoring (TDM) is not consequently investigated for new drugs. Usually the need for TDM is only discovered much later, when the drug is already on the market. TDM is particularly valuable under the following circumstances: (i) if there is a stronger relationship between the drug concentration and effect than between the dose and effect; (ii) if there is no simple and clear clinical parameter available to evaluate the clinical efficacy of the drug; (iii) if the therapeutic window is small; (iv) to document interactions; (v) to monitor drug compliance; and (vi) if there is large intra- and interindividual variability and unpredictability in pharmacokinetic parameters. Our recommendation is that randomized concentration controlled trials should be performed during the early stages of drug development and that it should be obligatory for drug licensing.

The amount of drug clearance during online hemodiafiltration (HDF) is determined by (1) the pharmacokinetic properties of a drug defined by its absorption, distribution, metabolism and elimination (ADME) characteristics, (2) dialysis characteristics, including membrane properties, treatment time and blood-, dialysate- and ultrafiltration flow rates, and (3) patient factors. For several drugs, especially those within the middle molecular weight range, with low protein binding and neutrally or positively charged, clearance may be substantially higher during HDF as compared to conventional low flux hemodialysis. Based on drug characteristics, the expected additional effect of a high ultrafiltration rate, as indicated by a high convection volume, can be estimated. This is shown for anticoagulants, antibiotics and antiviral drugs. For drugs with an expected additional effect of convection and for drugs with a narrow therapeutic window, therapeutic drug monitoring may be advisable. Comparative data from clinical studies is scarce. Hence, for an individual patient it may be relevant to calculate the total amount of a drug excreted during an HDF session. This can easily be performed in routine clinical practice and may guide the clinician to estimate the dose of the drug needed for suppletion upon completion of HDF treatment. Examples are provided how to calculate drug suppletion after HDF. Collectively, this chapter is intended as a guidance to optimize pharmacotherapy in online HDF patients.

Quality control in TB drug measurement is essential for the development of new drugs and for patient care http://ow.ly/KxWNc

Hemocue leuco+diff and DBS are two recent technological advances that can beneficially affect clozapine treatment in the near future. 1. Hemocue Leuco+diff is a new point of care instrument that provides both a total white blood cel count as that of the five most common types of leucytes (neutrophils, lymphocytes, monocytes, eosinophils and basophils). In an open study in 70 patients on clozapine maintenance treatment, 39 clinical and 31 out-patients, the tolerability and the (dis-), advantages of the two methods of blood sampling, venous versus point-of care, were compared. In four consecutive monthly measurements, the method of blood sampling alternated monthly from point-of-care to venous and the other way around, from venous sampling to point-of-care. In those patients who indicated a preference, point of care method was preferred because it is less burdensome (no travelling involved, no waiting time) and immediate access to the results. 2. The dried blood spot (DBS) is a method of measurement of drug plasma levels in a drop of dried blood on standardized paper card. DBS has been validated for antibiotic therapy of fungal infections and the treatment of tuberculosis. In a study of 15 outpatients on clozapine maintenance therapy we studied the non-inferiority of clozapine monitoring with DBS compared with venous blood sampling. We will present the first results and the possible implications of the outcome for clinical practice.

Aims The objectives of the present investigation were: (a) to determine the correlation between lignocaine and midazolam pharmacokinetics following intravenous administration in healthy volunteers, (b) to determine the effects of treatment with an inhibitor of CYP3A4 (erythromycin) on this correlation and (c) to assess the precision of the MEGX-test as a sole predictor of lignocaine and midazolam pharmacokinetics. Methods The study was conducted in four male and four female healthy volunteers, aged between 21 and 26 years, who received 1 mg kg−1 lignocaine HCl i.v. on days 1, 3, 5, 9 and 10 of the investigation. On days 5 and 10 they also received midazolam, 0.075 mg kg−1 i.v. and from days 6–10 they took erythromycin 500 mg orally, four times daily. Following administration of lignocaine and midazolam, frequent venous blood samples were obtained for determination of the concentrations of lignocaine, MEGX and midazolam. Results In the absence of erythromycin a statistically significant linear correlation was observed between the clearance of lignocaine and midazolam (CLmidazolam= 0.41×CLlignocaine+1.2; r2 = 0.857; P

INTRODUCTION: The clinical application of continuous infusion (CoI) of vancomycin has gained interest in recent years. Since no international guidelines on initial dosing of vancomycin CoI exist, there is a need for methods to facilitate the switch from intermittent to continuous vancomycin dosing algorithms in clinically infected populations. Therefore, the aim of this study was to design and validate an a priori dosing schedule for CoI of vancomycin in clinical practice.METHODS: A dosing table for CoI of vancomycin based on estimated glomerular filtration rate (eGFR) was developed by simulation of continuous infusion of vancomycin using pharmacokinetic (PK) software and a PK population model designed from historical within-population data in intermittently dosed patients. The target range for the first vancomycin serum concentrations drawn approximately 24 h after start of infusion' (C24) was set at 15-20 mg/L corresponding with an area under the curve (AUC) of at least 350 mg·h·L(-1). The performance of the dosing schedule was primarily assessed by describing the percentages of patients attaining the predefined target.RESULTS: An eGFR-derived dosing schedule for CoI of vancomycin was established and implemented in clinical practice. Prospective assessment in 35 general ward and 45 intensive care unit patients showed that the C24 target was reached in 69 and 63 % and the AUC target was attained in 80 and 72 % of patients, respectively.CONCLUSIONS: An easy method to design and validate an eGFR-derived dosing algorithm for the continuous infusion of vancomycin to switch from intermittent to continuous dosing of vancomycin was developed.

The objective of this study was to evaluate and compare the pharmacokinetics of meropenem in premature neonates, both after the first dose and during steady state at day 5, after a 1-minute intravenous administration to evaluate the possibility of twice-daily administration. Seven premature neonates received 15 mg/kg meropenem twice daily on clinical grounds as a 1-minute infusion. After the first dose and during steady state at day 5, serum levels of meropenem were measured for 12 hours after intravenous administration. Meropenem pharmacokinetics at the first dose were studied in seven children (mean birth weight 925 g, mean postnatal age 21 days). Serum concentration-time curves could be described with a one-compartment model. Mean total body clearance was 0.157 L/kg per hour, volume of distribution was 0.74 L/kg, and half-life was 3.4 hours. At day 5 at steady state, pharmacokinetic properties did not differ significantly. No side effects were noted. A 1-minute intravenous administration is feasible. Pharmacokinetic properties are comparable at day 5 compared with the first dose, and half-life is such that twice-daily administration of 15 mg/kg produces adequate serum concentrations.

Background: Ertapenem is a parenteral carbapenem. In patients undergoing hemodialysis a dosage reduction of 50%, as a dose of 0.5 gram once daily, is advised. Hospital admission or specialised home care is needed to administer ertapenem. As these patients are already visiting the hospital 3 times a week a more patient friendly dosage regime would be favorable. This study is to determine whether this regime is a viable alternative to current daily administration. Methods: The study enrolled chronic hemodialysis patients with a proven infection caused by ertapenem-susceptible bacteria. The minimal inhibitory concentration (MIC) was determined. Patients received a dose of 1 g ertapenem 3 times a week, administerd immediately after hemodialysis. Ertapenem peak an trough levels, before and after dialysis, were measured at 2 consecutive dialysis sessions. Total ertapenem concentrations were measured using a validated LC-MS-MS method. Treatment efficacy was evaluated, based on a decrease of CRP-levels. The data were analyzed (MW/Pharm). Results: Ten patients were included, 5 female and 5 male, with an average age of 68 years. The ertapenem trough level at 68 hours was 3.7 mg/L (range, 0.5-9.6 mg/L) and exceeded the individual MIC values during the 68 hour dosing interval, and are well above the known MIC90 for most gram-negative bacteria. The overall clinical success rate was 8 out of 10. Treatment failure in patient 3 could be explained by a decreased tissue perfusion at the infection site. The treatment was well tolerated; no severe adverse reports were reported. The pharmacokinetic parameters were calculated for the investigated population. The half life (t1/2) of ertapenem was 19.9 ± 5.1 hours and the volume of distribution (Vd) 0.16 L/kg. The increased Vd and t1/2 compared to literature values could be explained by the infectious state and a severe renal insufficiency in our population. Conclusions: Ertapenem administered to chronic hemodialysis patients as a thrice weekly dosage gives adequate serum levels during the 68 hours interdialytic interval. This dosage regime is a practical, patient-friendly and effective alternative to current daily administration of ertapenem.

Background: Observational data sets can be used for population pharmacokinetic (PK) modeling. However, these data sets are generally less precisely recorded than experimental data sets. This article aims to investigate the influence of erroneous records on population PK modeling and individual maximum a posteriori Bayesian (MAPB) estimation.Methods: A total of 1123 patient records of neonates who were administered vancomycin were used for population PK modeling by iterative 2-stage Bayesian (ITSB) analysis. Cut-off values for weighted residuals were tested for exclusion of records from the analysis. A simulation study was performed to assess the influence of erroneous records on population modeling and individual MAPB estimation. Also the cut-off values for weighted residuals were tested in the simulation study.Results: Errors in registration have limited the influence on outcomes of population PK modeling but can have detrimental effects on individual MAPB estimation. A population PK model created from a data set with many registration errors has little influence on subsequent MAPB estimates for precisely recorded data. A weighted residual value of 2 for concentration measurements has good discriminative power for identification of erroneous records.Conclusions: ITSB analysis and its individual estimates are hardly affected by most registration errors. Large registration errors can be detected by weighted residuals of concentration.

Azithromycin maintenance therapy results in improvement of respiratory function in patients with cystic fibrosis (CF). In azithromycin maintenance therapy, several dosing schemes are applied. In this review, we combine current knowledge about azithromycin pharmacokinetics with the dosing schedules used in clinical trials in order to come to a dosing advise which could be generally applicable. We used data from a recently updated Cochrane meta analysis (2011), the reports of clinical trials and pharmacokinetic studies. Based on these data, it was concluded that a dose level of 22-30 mg/kg/week is the lowest dose level with proven efficacy. Due to the extended half-life in patients with CF, the weekly dose of azithromycin can be divided in one to seven dosing moments, depending on patient preference and gastro-intestinal tolerance. No important side effects or interactions with other CF-related drugs have been documented so far.

Background hospitalized patients with serious infections treated with aminoglycosides are at risk of developing nephrotoxicity. Previous clinical studies have shown that the pharmacokinetics of aminoglycosides in humans follow a circadian rhythm. Therefore, the time of administration could have important clinical implications with respect to the risk of developing aminoglycoside-associated nephrotoxicity in patients treated with once daily dosing regimens. Objective To examine the effect of the time period of administration on aminoglycoside exposure and the incidence of nephrotoxicity in a large population of hospitalized patients with serious infections. Setting General ward and intensive care unit of a teaching hospital. Method In this retrospective cohort study, patients treated with intravenous tobramycin or gentamicin were eligible for inclusion. Patients were divided into three groups by time of administration: morning, afternoon and night. Main outcome measure Pharmacokinetic parameters and the incidences of nephrotoxicity were compared between the morning, afternoon and evening groups. Results 310 general ward and 411 intensive care unit patients were included. No significant differences were found in patient characteristics between the morning, afternoon and night groups. The time period of administration did not affect aminoglycoside pharmacokinetics or the incidence of nephrotoxicity. Conclusion The time of administration has no effect on the pharmacokinetics or nephrotoxicity of once daily dosed aminoglycosides in hospitalized patients. Consequently, we advise aminoglycosides to be administered as soon as possible in case of (suspected) severe hospital-acquired infections and subsequent dosages to be based on therapeutic drug monitoring to optimize the efficacy/toxicity balance.

The objectives of the present investigation were: (a) to determine the correlation between lignocaine and midazolam pharmacokinetics following intravenous administration in healthy volunteers, (b) to determine the effects of treatment with an inhibitor of CYP3A4 (erythromycin) on this correlation and (c) to assess the precision of the MEGX-test as a sole predictor of lignocaine and midazolam pharmacokinetics.The study was conducted in four male and four female healthy volunteers, aged between 21 and 26 years, who received 1 mg kg-1 lignocaine HCl i.v. on days 1, 3, 5, 9 and 10 of the investigation. On days 5 and 10 they also received midazolam, 0.075 mg kg-1 i.v. and from days 6-10 they took erythromycin 500 mg orally, four times daily. Following administration of lignocaine and midazolam, frequent venous blood samples were obtained for determination of the concentrations of lignocaine, MEGX and midazolam.In the absence of erythromycin a statistically significant linear correlation was observed between the clearance of lignocaine and midazolam (CL(midazolam)= 0.41 x CL(lignocaine)+ 1.2; r(2) = 0.857; P0.001). Erythromycin cotreatment resulted in a loss of the correlation between the two clearances (r(2) = 0.39; P = 0.1). Erythromycin caused a statistically significant reduction in midazolam clearance from the original value of 3.8 to 2.5 (95% CI for the difference -2.27, -0.35) ml kg-1 min-1. Interestingly there was no significant change in the clearance of lignocaine (6.4 vs 5.8 (95% CI for the difference -2.74, -1.51) ml kg-1 min-1). Furthermore no correlation at all was observed between the MEGX-test and lignocaine or midazolam clearances. Considering the data on day 1, 3 and 5 the intra-individual coefficient of variation in the MEGX-test was 45.3% at 15 min and 23.5% at 30 min, respectively.It is concluded that there is a significant correlation between lignocaine and midazolam clearances but this correlation is lost after CYP3A4 inhibition by erythromycin. The MEGX-test is of no value in assessing intra- and inter-individual variability in midazolam clearance.