Influence of Age, Heart Failure and ACE Inhibitor Treatment on Plasma Renin Activity in Children: Insights from a Systematic Review and the European LENA Project.

BACKGROUND: Plasma renin activity (PRA) has gained relevance as prognostic marker in adults with heart failure. The use of PRA as a clinically meaningful parameter in children and children with heart failure requires a thorough knowledge of the factors that influence PRA to correctly assess PRA levels. We aim to evaluate the influence of age, heart failure and angiotensin-converting enzyme inhibitor (ACEi) on PRA levels in children. METHODS: We conducted a systematic literature search to identify studies on PRA levels in healthy children and in children with heart failure. In addition, we analysed PRA data measured before (n = 35, aged 25 days-2.1 years), 4 hours after (n = 34) and within the first 8 days of enalapril treatment (n = 29) in children with heart failure from the European project Labeling of Enalapril from Neonates up to Adolescents (LENA). RESULTS: Age has a profound effect on PRA levels in healthy children, as PRA levels in the literature are up to about 7 times higher in neonates than in older children. Children with heart failure younger than 6 months showed 3-4 times higher PRA levels than healthy peers in both the literature and the LENA studies. In the LENA studies, the ACEi enalapril significantly increased median predose PRA by a factor of 4.5 in children with heart failure after 4.7 ± 1.6 days of treatment (n = 29, p < 0.01). Prior to treatment with enalapril, LENA subjects with symptomatic heart failure (Ross score ≥3) had a significantly higher PRA than LENA subjects with asymptomatic heart failure of comparable age (Ross score ≤2, p < 0.05). CONCLUSIONS: Age, heart failure and ACEi treatment have a notable influence on PRA and must be considered when assessing PRA as a clinically meaningful parameter. CLINICAL TRIAL REGISTRATION: The trials are registered on the EU Clinical Trials Register (https://www.clinicaltrialsregister.eu). TRIAL REGISTRATION NUMBERS: EudraCT 2015-002335-17, EudraCT 2015-002396-18.

EMDIA Case Series-Effective Medication Therapy Management (MTM) for Diabetes Type 2 Patients-A Proof of Concept Study.

Background: A 2016 meta-analysis of pharmaceutical care for patients with diabetes mellitus showed that the following four components were most effective: (a) individual goal setting, (b) sending feedback to the physician, (c) reviewing the medication, and (d) reviewing blood glucose measurements. Methods: To formulate a hypothesis regarding the effect of these four pharmaceutical care components on glycemic control in patients with diabetes mellitus and the feasibility of these components in practice. Ten patients with type 2 diabetes were included in the case series and received medication therapy management over four months. Results: The four care components were feasible in everyday practice and could be implemented within one patient visit. The average visits were 49 and 28 min at the beginning and end of the study, respectively. The glycated hemoglobin values did not change over the study period, though the fasting blood glucose decreased from 142 to 120 mg/dl, and the number of unsolved drug-related problems decreased from 6.9 to 1.9 per patient by the study end. Conclusions: This case series supports the hypothesis that community pharmacists can implement structured pharmaceutical care in everyday pharmacy practice for patients with type 2 diabetes mellitus.

Development and evaluation of a physiologically based pharmacokinetic model to predict carvedilol-paroxetine metabolic drug-drug interaction in healthy adults and its extrapolation to virtual chronic heart failure patients for dose optimization.

Purpose: The metabolic drug-drug interactions (mDDIs) are one of the most important challenges faced by the pharmaceutical industry during the drug development stage and are frequently associated with labeling restrictions and withdrawal of drugs. The capacity of physiologically based pharmacokinetic (PBPK) models to absorb and upgrade with the newly available information on drug and population-specific parameters, makes them a preferred choice over the conventional pharmacokinetic models for predicting mDDIs.Method: A PBPK model capable of predicting the stereo-selective disposition of carvedilol after administering paroxetine by incorporating mechanism (time) based inhibition of CYP2D6 and CYP3A4 was developed by using the population-based absorption, distribution, metabolism and elimination (ADME) simulator, Simcyp®.Results: The model predictions for both carvedilol enantiomers were in close agreement with the observed PK data, as the ratios for observed/predicted PK parameters were within the 2-fold error range. The developed PBPK model was successful in capturing an increase in exposures of R and S-carvedilol, due to the time-based inhibition of CYP2D6 enzyme caused by paroxetine.Conclusion: The developed model can be used for exploring complex clinical scenarios, where multiple drugs are given concurrently, particularly in diseased populations where no clinical trial data is available.

Pharmacology of enalapril in children: a review.

Enalapril is an angiotensin-converting enzyme (ACE) inhibitor that is used for the treatment of (paediatric) hypertension, heart failure and chronic kidney diseases. Because its disposition, efficacy and safety differs across the paediatric continuum, data from adults cannot be automatically extrapolated to children. This review highlights paediatric enalapril pharmacokinetic data and demonstrates that these are inadequate to support with certainty an age-related effect on enalapril/enalaprilat pharmacokinetics. In addition, our review shows that evidence to support effective and safe prescribing of enalapril in children is limited, especially in young children and heart failure patients; studies in these groups are either absent or show conflicting results. We provide explanations for observed differences between age groups and indications, and describe areas for future research.

Zidovudine and lamivudine reach higher concentrations in ventricular than in lumbar human cerebrospinal fluid.

OBJECTIVE: For the treatment of HIV-1-related brain disease and for the prevention of the brain becoming a viral reservoir, it is important that antiretroviral agents reach sufficient concentrations in the CNS. To date, human brain pharmacokinetic data are solely derived from lumbar cerebrospinal fluid (CSF) and mostly originate from single samples. DESIGN: We determined concentrations of antiretroviral drugs in serial samples of ventricular CSF and compared these to the concentrations in serum and lumbar CSF of these patients. METHODS: Two treatment-naïve HIV-1-infected patients received external ventricular drainage for obstructive hydrocephalus. Starting with a combination antiretroviral regimen (cART), ventricular CSF, and subsequently lumbar CSF, with parallel serum, was frequently collected. Drug concentrations were determined and CSF-to-serum ratios were calculated. RESULTS: High concentrations, resulting in high CSF-to-serum ratios, were found in the ventricular CSF of the three substances zidovudine, lamivudine and indinavir, whereas this was not observed for stavudine, ritonavir, saquinavir and efavirenz. Concentrations of zidovudine and lamivudine were up to four times greater in CSF from the ventricles than in lumbar CSF of the same patient. The zidovudine concentrations in the ventricular CSF exceeded serum concentrations by a factor of 1.4. CONCLUSION: Unexpectedly high concentrations of some antiretrovirals in the ventricular CSF, the site close to the brain parenchyma where HIV is located, should be considered when the cART regimen is aiming at CNS viral replication.

Simulation Training to Improve Informed Consent and Pharmacokinetic/Pharmacodynamic Sampling in Pediatric Trials.

Background: Pediatric trials to add missing data for evidence-based pharmacotherapy are still scarce. A tailored training concept appears to be a promising tool to cope with critical and complex situations before enrolling the very first patient and subsequently to ensure high-quality study conduct. The aim was to facilitate study success by optimizing the preparedness of the study staff shift. Method: An interdisciplinary faculty developed a simulation training focusing on the communication within the informed consent procedure and the conduct of the complex pharmacokinetic/pharmacodynamic (PK/PD) sampling within a simulation facility. Scenarios were video-debriefed by an audio-video system and manikins with artificial blood simulating patients were used. The training was evaluated by participants' self-assessment before and during trial recruitment. Results: The simulation training identified different optimization potentials for improved informed consent process and study conduct. It facilitated the reduction of avoidable errors, especially in the early phase of a clinical study. The knowledge gained through the intervention was used to train the study teams, improve the team composition and optimize the on-ward setting for the FP-7 funded "LENA" project (grant agreement no. 602295). Self-perceived ability to communicate core elements of the trial as well as its correct performance of sample preparation increased significantly (mean, 95% CI, p ≤ 0.0001) from 3 (2.5-3.5) to four points (4.0-4.5), and from 2 (1.5-2.5) to five points (4.0-5.0). Conclusion: An innovative training concept to optimize the informed consent process and study conduct was successfully developed and enabled high-quality conduct of the pediatric trials as of the very first patient visit.

Simultaneous Semi-Mechanistic Population Pharmacokinetic Modeling Analysis of Enalapril and Enalaprilat Serum and Urine Concentrations From Child Appropriate Orodispersible Minitablets.

Enalapril is recommended as the first line of therapy and is proven to improve survival rates for treatment of Pediatric Heart Failure; however, an approved drug and child appropriate dosage formulation is still absent. The present analysis was conducted to perform a detailed model informed population pharmacokinetic analysis of prodrug enalapril and its active metabolite enalaprilat in serum and urine. Further, a model informed dosage form population-pharmacokinetic analysis was conducted to evaluate differences in pharmacokinetics of enalapril and its active metabolite enalaprilat when prodrug was administered to 24 healthy adults in a crossover, two periods, two treatments, phase I clinical trial using child-appropriate orodispersible mini-tablets (ODMT) and reference (Renitec®) dosage formulation. A simultaneous semi-mechanistic population-pharmacokinetic model was developed using NONMEM software, which predicted full profile serum and urine concentrations of enalapril and enalaprilat. First-order conditional estimation with interaction was used for parameter estimation. Transit compartments added using Erlang distribution method to predicted enalapril absorption and enalaprilat formation phases. Normalized body weight was identified as covariate related to enalapril volume of distribution. Visual predictive check (VPC) plots and conducted bootstrap analysis validated the model. The data from the two formulations were pooled for population-pharmacokinetic analysis and covariate effect of the formulation was found on mean transit time (MTT1) of enalapril absorption. In addition, data of each formulation were modeled separately and the estimated parameters of each individual administered both formulations were correlated using paired samples Wilcoxon rank test (p < 0.05 = significant) which also showed only a significant difference (p = 0.03) in MTT1 i.e., 5 min early appearance of enalapril from ODMT compared to reference tablets. No difference in the pharmacokinetics of active enalaprilat was found from the ODMT compared to the reference formulation. The population pharmacokinetic analysis provided detailed information about the pharmacokinetics of enalapril and enalaprilat, which showed that the ODMT formulation might have similar pharmacodynamic response compared to the reference formulation.

Pharmacotherapy in paediatric heart failure: a Delphi process.

BACKGROUND: Little evidence exists to support pharmacotherapeutic strategies for heart failure management in paediatrics. A recent Europe-wide survey suggests that this translates into substantial variability in clinical practice. OBJECTIVE: To conduct a formal discussion among an expert group of paediatric cardiology physicians on controversial aspects regarding the pharmacotherapy of children heart failure, facilitate consensus, and highlight areas of agreement and disagreement. METHODS: A two-round modified Delphi process was conducted between July and August 2015. Topics addressed were predominantly selected from the results of a previous Europe-wide survey. Fourteen statements were presented for discussion grouped under three categories; Angiotensin-converting-enzyme-inhibitors: Considerations for optimal dosage; Angiotensin-converting-enzyme-inhibitors for the management of CHDs; Neurohumoral antagonists for the management of dilated cardiomyopathy-related heart failure. RESULTS: A total of 13 paediatricians dedicated to cardiology from across Europe and the United States of America completed the study; of them, 92% had a working experience in the field of more than 10 years and were working in a specific paediatric cardiology unit. Agreement on the acceptance/rejection of 11 statements was achieved. Results show agreement on the importance of a set of topics relevant to the standardisation of the therapy as well as consensus upon specific therapeutic attitudes. CONCLUSIONS: We have found areas of common thinking and motivation, which can provide a means of triggering scientific collaboration. Our results might also contribute to disseminate available paediatric evidence and promote reducing unjustified variability in everyday practice. Until solid evidence is available, other research methods can contribute to advancing the goal of safe and effective paediatric heart failure pharmacotherapy.

Orodispersible minitablets of enalapril for use in children with heart failure (LENA): Rationale and protocol for a multicentre pharmacokinetic bridging study and follow-up safety study.

INTRODUCTION: Treatment of paediatric heart failure is based on paradigms extensively tested in the adult population assuming similar underlying pathophysiological mechanisms. Angiotensin converting enzyme inhibitors (ACEI) like enalapril are one of the cornerstones of treatment and commonly used off-label in children. Dose recommendations have been extrapolated from adult experience, but the relationship between dose and pharmacokinetics (PK) in (young) children is insufficiently studied. Furthermore, appropriate paediatric formulations are lacking. Within the European collaborative project LENA, a novel formulation of enalapril orodispersible minitablets (ODMT), suitable for paediatric administration, will be tested in (young) children with heart failure due to either dilated cardiomyopathy or congenital heart disease in two pharmacokinetic bridging studies. Paediatric PK data of enalapril and its active metabolite enalaprilat will be obtained. In a follow-up study, the safety of enalapril ODMTs will be demonstrated in patients on long-term treatment of up to 10 months. Furthermore, additional information about pharmacodynamics (PD) and ODMT acceptability will be collected in all three studies. METHODS AND ANALYSIS: Phase II/III, open-label, multicentre study. Children with dilated cardiomyopathy (DCM) (n = 25; 1 month to less than 12 years) or congenital heart disease (CHD) (n = 60; 0 to less than 6 years) requiring or already on ACEI will be included. Exclusion criteria include severe heart failure precluding ACEI use, hypotension, renal impairment, hypersensitivity to ACEI. For those naïve to ACEI up-titration to an optimal dose will be performed, those already on ACEI will be switched to an expected equivalent dose of enalapril ODMT and optimised. In the first 8 weeks of treatment, a PK profile will be obtained at the first dose (ACEI naïve patients) or when an optimal dose is reached. Furthermore, population PK will be done with concentrations detected over the whole treatment period. PD and safety data will be obtained at least at 2-weeks intervals. Subsequently, an intended number of 85 patients will be followed-up up to 10 months to demonstrate long-term safety, based on the occurrence of (severe) adverse events and monitoring of vital signs and renal function. ETHICS AND DISSEMINATION: Clinical Trial Authorisation and a favourable ethics committee opinion were obtained in all five participating countries. Results of the studies will be submitted for publication in a peer-reviewed journal. TRIAL REGISTRATION NUMBERS: EudraCT 2015-002335-17, EudraCT 2015-002396-18, EudraCT 2015-002397-21.

[Pharmacokinetic and pharmacodynamic modelling in paediatric drug development with a focus on physiology-based pharmacokinetic simulations]. / Pharmakokinetische und pharmakodynamische Modellierung bei Kinderarzneimitteln: Schwerpunkt Physiologie-basiertes pharmakokinetisches Simulieren.

Pharmacokinetic and pharmacodynamic models are mandatory for dosing and the safe use of drugs in the paediatric population. Different modelling methods allow for the development of dosing regimens for children requiring only a small number of blood samples or none at all. The medicines regulatory authorities recommend using these methods for paediatric drug development programs. Taking sildenafil as an example, the least invasive method of physiology-based pharmacokinetic simulation for the development of dosing regimens in the paediatric population is presented.

Pharmacotherapeutic management of paediatric heart failure and ACE-I use patterns: a European survey.

OBJECTIVE: To characterise heart failure (HF) maintenance pharmacotherapy for children across Europe and investigate how angiotensin-converting enzyme inhibitors (ACE-I) are used in this setting. METHODS: A Europe-wide web-based survey was conducted between January and May 2015 among European paediatricians dedicated to cardiology. RESULTS: Out of 200-eligible, 100 physicians representing 100 hospitals in 27 European countries participated. All participants reported prescribing ACE-I to treat dilated cardiomyopathy-related HF and 97% in the context of congenital heart defects; 87% for single ventricle physiology. Twenty-six per cent avoid ACE-I in newborns. Captopril was most frequently selected as first-choice for newborns (73%) and infants and toddlers (66%) and enalapril for children (56%) and adolescents (58%). Reported starting and maintenance doses varied widely. Up to 72% of participants follow formal creatinine increase limits for decision-making when up-titrating; however, heterogeneity in the cut-off points selected existed. ACE-I formulations prescribed by 47% of participants are obtained from more than a single source. Regarding symptomatic HF maintenance therapy, 25 different initial drug combinations were reported, although 79% select a regimen that includes ACE-I and diuretic (thiazide and/or loop), 61% ACE-I and aldosterone antagonist; 44% start with beta-blocker, 52% use beta-blockers as an add-on drug. Of the 89 participants that prescribe pharmacotherapy to asymptomatic patients, 40% do not use ACE-I monotherapy or ACE-I-beta-blocker two-drug only combination. CONCLUSIONS: Despite some reluctance to use them in newborns, ACE-I seem key in paediatric HF treatment strategies. Use in single ventricle patients seems frequent, in apparent contradiction with current paediatric evidence. Disparate dosage criteria and potential formulation-induced variability suggest significant differences may exist in the risk-benefit profile children are exposed to. No uniformity seems to exist in the drug regimens in use. The information collected provides relevant insight into real-life clinical practice and may facilitate research to identify the best therapeutic options for HF children.

Model-dependent pharmacokinetic analysis of enalapril administered to healthy adult volunteers using orodispersible minitablets for use in pediatrics.

INTRODUCTION: Comparative pharmacokinetic (PK) data analysis of drugs administered using developed child-appropriate and market authorized dosage formulation is sparse and is important in pediatric drug development. OBJECTIVES: To compare and evaluate any differences in PK of enalapril administered using two treatments of child-appropriate orodispersible minitablets (ODMTs) and market authorized reference tablet formulation (Renitec®) using PK compartment model and validated least square minimization method (LSMM) of parameter estimation. METHODS: Full profile data sets were obtained from a phase I clinical trial, whereby three treatments of enalapril, ie, reference tablets with 240 mL water (treatment A), child-appropriate ODMTs with 240 mL (treatment B), and ODMTs dispersed in the mouth with 20 mL water (treatment C), were administered to 24 healthy adult volunteers. Virtual validation analysis was conducted using R program to select accurate and precise LSMM of parameter estimation. For the selection of PK model and estimation of parameters, enalapril data were fitted with one-and two-compartment models with first order of absorption and elimination, with and without incorporated lag time parameter (tlag). The log-transformed PK parameters were statistically compared by the two-sided paired t-test with the level of significance of P<0.05. RESULTS: One-compartment model with first-order absorption and elimination and incorporated lag time adequately predicted concentrations of enalapril. Reciprocal of predicted concentration using iteratively reweighted LSMM was selected as the most appropriate method of parameter estimation. Comparison of PK parameters including rate constant of absorption and elimination, volume of distribution, and tlag between the three treatments showed significant difference (P=0.018) in tlag between treatments B and A only. CONCLUSION: Compared with reference formulation, enalapril administered from child-appropriate ODMTs administered with 240 mL water appeared 4 minutes earlier in serum. No other differences were observed in absorption, elimination, and relative bioavailability of drug between the three treatment arms.

LC-MS/MS method for screening of intoxication and drug adherence of angiotensin-converting enzyme inhibitors in plasma.

Aim: Intentional and accidental drug intoxication as well as medication adherence require sensitive and reliable analytical screening methods. Such methods are often lacking in children and adults, therefore, a reliable analytical method has been developed by using low plasma volume. Materials & methods: Sample preparation from plasma was achieved by solid-phase extraction process. LC-MS in positive ion mode was performed using X-select CSH™ C18 column. The mobile phase consisted of water and acetonitrile acidified with 1% formic acid using a gradient method with total run time of 10 min. Results: The method showed repeatability for all analytes. The linearity range from 0.78 to 100 ng/ml per analyte was established with recoveries ≥87% and matrix effect for all analytes was within guideline limits. Conclusion: The screening method was successfully validated for monitoring of intoxication and medication adherence of ten analytes in 50 µl residual plasma samples of children and adults.

Optimizing the Clinical Use of Carvedilol in Liver Cirrhosis Using a Physiologically Based Pharmacokinetic Modeling Approach.

BACKGROUND AND OBJECTIVE: Liver cirrhosis is a complex pathophysiological condition that can affect the pharmacokinetics (PK) and hereby dosing of administered drugs. The physiologically based pharmacokinetic (PBPK) models are a valuable tool to explore PK of drugs in cirrhosis patients. The objective of this study was to develop and evaluate a PBPK-carvedilol-cirrhosis model with the available clinical data in liver cirrhosis patients and to recommend model-based drug dosing after exploring the underlying differences in unbound and total (bound and unbound) systemic carvedilol concentrations with the different disease stages. METHODS: A whole body PBPK model was developed using the population-based PBPK simulator, Simcyp®. After model development and evaluation in healthy adults, system parameters were modified according to the pathophysiological changes that occur in liver cirrhosis, and predictions were compared to available experimental data from liver cirrhosis Child-Pugh [CP]-C patients. A two-fold error range for the observed/predicted ratios (ratioObs/Pred) of the pharmacokinetic parameters was used for model evaluation. Simulations were then extended to cirrhosis CP-A and CP-B populations were no experimental data that are available to explore changes in drug disposition in these patients. Finally, drug unbound and total (bound and unbound) exposure were predicted in cirrhotic patients of different disease severity, and the results were compared to those of healthy adults. RESULTS: The developed model has successfully described carvedilol PK in healthy and cirrhosis CP-C patients. The model predictions showed that, there was an ~13-fold increase in unbound and ~7-fold increase in total (bound and unbound) systemic exposure of carvedilol between healthy and CP-C populations. To have comparable predicted unbound drug exposure in cirrhosis CP-A, CP-B, and CP-C populations as in healthy subjects receiving a dose of 25 mg, reductions of administered doses to 9.375 mg in CP-A, 4.68 mg in CP-B, and 2.34 mg in CP-C population were recommended. CONCLUSION: The presented model-generated data can guide the optimization of carvedilol therapy on the basis of differences in unbound and total drug exposures with respect to disease severity and can help improve the design of some necessary clinical studies in the drug development process.

Predicting Stereoselective Disposition of Carvedilol in Adult and Pediatric Chronic Heart Failure Patients by Incorporating Pathophysiological Changes in Organ Blood Flows-A Physiologically Based Pharmacokinetic Approach.

Chronic heart failure (CHF) is a systemic low perfusion syndrome resulting from impairment in the pumping function of the heart. The decrease in blood supply to body organs can potentially affect the pharmacokinetics (PK) of the drugs being administered. Carvedilol is administered as a racemic mixture and undergoes extensive stereoselective first pass metabolism. For such a drug, the pathophysiological changes occurring in CHF can have a profound impact on PK, and thus the resulting pharmacodynamic response, of both enantiomers. The aim of the current work was to predict stereoselective disposition of carvedilol after incorporating the pathophysiological changes in CHF into a whole-body physiologically based PK model using Simcyp, and to scale that model to pediatric CHF patients on a physiologic basis to investigate whether the same changes in the adult model can also be adopted for children. The developed model has successfully described PK of carvedilol enantiomers in healthy adults and in patients after the incorporation of reduced organ blood flows, as seen by the visual predictive checks and the calculated observed/predicted ratios for all PK parameters of interest. In contrast to adults, pediatric patients up to 12 years of age were better described without the reductions in organ blood flow, whereas older pediatric patients were better described after incorporating organ blood flow reductions. These findings indicate that the incorporated blood flow reductions in the adult model cannot be directly adopted in pediatrics, at least for the young ones; however, to draw definite conclusions, more data are still needed.

Diabetes Stewardship ­ Pharmaceutical care of adolescents with type 1 diabetes mellitus provided by community pharmacists. / Pharmazeutische Betreuung von Jugendlichen mit Diabetes mellitus Typ 1 Zeit für "Diabetes Stewardship"?

Diabetes mellitus Type 1 is one of the most common diseases in childhood. Severe, secondary diseases like hypertension or blindness are results of micro- and macrovascular complications caused by insufficient glycaemic control. Especially adolescent patients with type 1 diabetes have a lower adherence rate. The DIADEMA trial proved that community pharmacist in collaboration with diabetologists and diabetes advisors can have a positive impact on the therapy of adolescents with type 1 diabetes. This article highlights and explains which components of the pharmacist intervention caused the preferable adjustments and improved the insulin therapy of the patients.

Pharmaceutical care of an adolescent with type 1 diabetes. / Wie betreuen wir als Apotheker einen Jugendlichen mit Diabetes mellitus Typ 1? Ein Beispiel aus der klinischen Praxis.

This article describes the pharmaceutical care of an adolescent with type 1 diabetes mellitus, who took part in the DIADEMA study. Diabetes was diagnosed for three years and his baseline HbA1c-value was 9.3 %. In the DIADEMA study adolescents received pharmaceutical care provided by community pharmacists in addition to usual care provided by diabetologists and diabetes educators. Patients in the intervention group received monthly scheduled visits with the community pharmacists and on-demand telephone calls. Fundamental contents of the pharmacistá¾½s interventions were in particular self-monitoring of blood glucose, prevention of acute and long-term diabetes complications and conscientious consumption of alcohol. Furthermore difficulties in individual insulin therapy and current life conditions were addressed.

Pharmaceutical care of adolescents with diabetes mellitus type 1: the DIADEMA study, a randomized controlled trial.

BACKGROUND: Physiological and psychological changes during puberty and a low adherence to complex treatment regimens often result in poor glycemic control in adolescents with type 1 diabetes mellitus (T1DM). The benefit of pharmaceutical care in adults with diabetes mellitus type 2 has been explored; however, evidence in adolescents with T1DM is scarce. OBJECTIVE: To evaluate the impact of pharmaceutical care in adolescents with T1DM provided by pharmacists, in collaboration with physicians and diabetes educators on important clinical outcomes (e.g., HbA1c and severe hypoglycemia) SETTING: At the outpatient Helios Paediatric Clinic and at the 12 regular community pharmacies of the study patients with 14 pharmacists in the Krefeld area, Germany, and at the University Pediatric Clinic with one clinical pharmacist on-site in Sarajevo, Bosnia-Herzegovina. METHODS: A randomized, controlled, prospective, multicenter study in 68 adolescents with T1DM. The intervention group received monthly structured pharmaceutical care visits delivered by pharmacists plus supplementary visits and phone calls on an as needed basis, for 6 months. The control group received usual diabetic care. Data were collected at baseline and after 3 and 6 months. MAIN OUTCOME MEASURES: The between-group difference in the change from baseline in glycosylated hemoglobin (HbA1c) and the number of severe hypoglycemic events in both groups. RESULTS: The improvement from baseline in HbA1c was significantly greater in the intervention group than in the control group after 6 months (change from baseline -0.54 vs. +0.32%, p = 0.0075), even after adjustment for country-specific variables (p = 0.0078). However, the effect was more pronounced after only 3 months (-1.09 vs. +0.23%, p = 0.00002). There was no significant between-group difference in the number of severe hypoglycemia events. (p = 0.1276). CONCLUSION: This study suggests that multidisciplinary PhC may add value in the management of T1DM in adolescents with inadequate glycemic control. However, the optimal methods on how to achieve sustained, long-term improvements in this challenging population require further study.

A physiologically based pharmacokinetic drug-disease model to predict carvedilol exposure in adult and paediatric heart failure patients by incorporating pathophysiological changes in hepatic and renal blood flows.

BACKGROUND AND OBJECTIVE: Chronic diseases are associated with pathophysiological changes that could have profound impacts on drug pharmacokinetic behaviour, with a potential need to modify the administered drug therapy. It is important to acknowledge that most patients with chronic illnesses do not have a single, predominant condition but suffer from multiple comorbidities. The rapid advancement in physiologically based pharmacokinetic (PBPK) modelling, as well as the increasing quantitative knowledge of disease-related pathophysiological changes, facilitate building of drug-disease models. However, there are only a few published examples of PBPK models incorporating the pathophysiological changes that occur with chronic diseases. The objective of this study was to develop PBPK models that incorporate the haemodynamic changes in hepatic and renal blood flows occurring in chronic heart failure (CHF) and to evaluate these changes in adults and children, using carvedilol as a model drug. METHODS: After a comprehensive literature search to select the model input parameters, two PBPK models were developed. Model 1 was based on human liver and intestinal microsome clearances, and model 2 was based on clearance by specific cytochrome P450 enzymes. After evaluation of both models in healthy adults, the reduced hepatic and renal blood flows were incorporated into the developed models to predict carvedilol exposure in the adult CHF population. The adult carvedilol models were scaled down to children by using Simcyp(®) (Simcyp Ltd, Sheffield, UK). In order to show the impact of reduced organ blood flows on carvedilol disposition, the predictions in the CHF population were made with and without reductions in organ blood flows. RESULTS: The predictions made by both models in healthy adults were comparable and within the 2-fold error range. In adults with CHF, the mean observed/predicted ratio [ratio(Obs/Pred)] for oral clearance (CL/F) without reductions in organ blood flows was outside the 2-fold error range, i.e. 0.34 (95 % confidence interval [CI] 0.31-0.37), with use of both models. The mean CL/F ratio(Obs/Pred) values after incorporation of reduced organ blood flows were 1.0 (95 % CI 0.92-1.08) and 0.95 (95 % CI 0.88-1.03) with use of models 1 and 2, respectively. The mean ratio(Obs/Pred) values for the pharmacokinetic parameters were not improved after incorporation of reduced blood flows in paediatric patients, except in those above 17 years of age, who were categorized according to the New York Heart Association classification of CHF, where the CL/F ratio(Obs/Pred) values in two patients were closer to unity. CONCLUSION: There was a strong connection between a decrease in hepatic clearance of carvedilol and an increase in the severity of CHF, especially in adults and in paediatric patients above 17 years of age. The incorporated reductions in hepatic and renal blood flows occurring in moderate and severe CHF patients resulted in improved predictions of carvedilol exposure. The developed models can be extended to predict exposures of drugs with high hepatic extraction in the CHF population.