In patients with chronic heart failure (CHF), the use of angiotensin-converting enzyme inhibitors, including ramipril, is recommended to reduce the risk of heart failure worsening, hospitalisation, ...and death. Our aim was to investigate the influence of body composition on the pharmacokinetics of ramipril and its active metabolite ramiprilat and to evaluate the changes in pharmacokinetics after prolonged therapy. Twenty-three patients with CHF who were on regular therapy with ramipril participated at the first study visit ( median age 77 years, 65 % male, and 70 % New York Heart Association Class II); 19 patients attended the second study visit and the median time between the two visits was 8 months. Pharmacokinetics were assessed using a nonlinear mixed-effects parent-metabolite model comprising two compartments for ramipril and one compartment for ramiprilat. The influence of body size and composition was best described by an allometric relationship with fat-free mass. In addition, ramipril clearance was related to patient age and daily ramipril dose, while clearance of ramiprilat was influenced by glome rular filtration rate and daily ramipril dose. There were no clinically relevant changes in the pharmacokinetics of ramipril and ramiprilat between the study visits. Due to the relatively stable pharmacokinetics of ramipril, regular outpatient visits at 6-month intervals seem appropriate to evaluate ramipril therapy.
The aim of this study was to externally validate the predictive performance of published population pharmacokinetic models of gentamicin in all paediatric age groups, from preterm newborns to ...adolescents. We first selected published population pharmacokinetic models of gentamicin developed in the paediatric population with a wide age range. The parameters of the literature models were then re-estimated using the PRIOR subroutine in NONMEM
. The predictive ability of the literature and the tweaked models was evaluated. Retrospectively collected data from a routine clinical practice (512 concentrations from 308 patients) were used for validation. The models with covariates characterising developmental changes in clearance and volume of distribution had better predictive performance, which improved further after re-estimation. The tweaked model by Wang 2019 performed best, with suitable accuracy and precision across the complete paediatric population. For patients treated in the intensive care unit, a lower proportion of patients would be expected to reach the target trough concentration at standard dosing. The selected model could be used for model-informed precision dosing in clinical settings where the entire paediatric population is treated. However, for use in clinical practice, the next step should include additional analysis of the impact of intensive care treatment on gentamicin pharmacokinetics, followed by prospective validation.
: Patients with schizophrenia are often exposed to polypharmacotherapy, which may lead to drug-drug interactions. The aim of the study was to investigate the prevalence of potential drug-drug ...interactions (pDDIs) in hospitalized patients with schizophrenia spectrum disorders and to identify factors associated with pDDIs and manifested symptoms and signs.
: This cross-sectional observational study included 311 inpatients admitted to a psychiatric hospital. The LexiComp drug interaction program was used to identify pDDIs in 2014. Factors associated with the prevalence of pDDIs and factors related to clinically observed symptoms and signs were assessed using multivariable regression. In addition, replicate analysis of pDDI was performed using 2021 program updates.
The prevalence of pDDIs was 88.7%. Our study showed that more than half of the patients received at least one drug combination that should be avoided. The most common pDDIs involved combinations of two antipsychotics or combinations of antipsychotics and benzodiazepines, which can lead to cardio-respiratory depression, sedation, arrhythmias, anticholinergic effects, and neuroleptic malignant syndrome. The number of prescribed drugs was a risk factor for pDDIs (OR 2.85; 95% CI 1.84-5.73). All groups of clinically observed symptoms and signs were associated with the number of drugs. In addition, symptoms and signs characteristic of the nervous system and psychiatric disorders were associated with antipsychotic dosage (IRR 1.33; 95% CI 1.12-1.58), which could contribute to the development of extrapyramidal syndrome, insomnia, anxiety, agitation, and bipolar mania. The 2021 version of the drug interaction program showed a shift in drug interactions toward a lower risk rating, implying less severe patient management and possibly less alert fatigue.
Patients with schizophrenia spectrum disorders are at high risk of developing drug-drug interactions. Optimization of drug therapy, patient monitoring, and use of drug interaction programs could help to prevent pDDIs and subsequent adverse drug events.
Immunosuppressive therapy is the cornerstone of successful kidney transplantation. Frequently used immunosuppressives are cyclosporine, tacrolimus, sirolimus and mycophenolic acid. These drugs have ...narrow therapeutic index and show high pharmacokinetic variability. In order to maintain the balance between efficacy and safety, dosing is based on measured drug concentrations. Proper identification, quantification and understanding the sources of variability in measured concentrations facilitate routine dose adjustment in clinical practice. Classical pharmacokinetic studies have limited use in transplant patients attributable to design with intense sampling in a small, relatively homogenous population, and identification of only single variability factor per study. Population approach is a powerful tool for analysing sparse data, identifying factors that influence drug pharmacokinetics and estimating variability. In this report we reviewed available population pharmacokinetic models for cyclosporine, tacrolimus, sirolimus and mycophenolic acid in adult kidney transplant patients. The major focus was to describe various demographic factors, biochemical parameters, genetic polymorphisms of metabolic enzymes and transporters and drug-drug interactions, which have been identified as an important concern of pharmacokinetic variability in kidney transplant patients.
Dodeca-2E,4E,8Z,10E/Z-tetraenoic isobutylamide (tetraene) is the main component of Echinacea angustifolia DC. lipophilic extract, the bioavailability and immunomodulatory effect after oral ...administration in soft gel capsules in healthy volunteers of which we have already demonstrated. In the present work, we assessed the transdermal administration as an alternative route of administration of such an alkamide. The first step, therefore, encompassed the preparation of a drug-in-adhesive patch with an area of 868 mm2 and containing a dose of 0.64 mg of tetraene. In vitro skin permeation studies in Franz-type diffusion chambers resulted in a tetraene flux of (103 ± 10) ng × cm−2 × h−1 with a very good linearity (r = 0.99). The relatively low lag time of just 13 min indicates low binding and the accumulation of tetraene in the skin. Finally, the patch was administered to six healthy volunteers, and the pharmacokinetic analysis was performed by nonlinear mixed effects modelling with soft gel oral capsules serving as the reference formulation. The in vivo results correlated well with the in vitro permeation and indicated an initial burst tetraene absorption from the patch that was in parallel with the zero-order kinetics of absorption. The rate of the latter process was in good agreement with the one estimated in vitro. The tetraene absorption rate was therefore slow and prolonged with time, resulting in a bioavailability of 39% relative to the soft gel capsules and a very flat plasma concentration profile.
Ustekinumab is a monoclonal antibody used in Crohn’s disease (CD). Dose optimization in case of non-response and the role of pharmacokinetic–pharmacodynamic (PK-PD) monitoring remain unresolved ...dilemmas in clinical practice. We aimed to develop a population PK-PD model for ustekinumab in CD and simulate efficacy of alternative dosing regimens. We included 57 patients and recorded their characteristics during 32 weeks after starting with ustekinumab therapy. Serum ustekinumab concentration was prospectively measured and fecal calprotectin (FC) concentration was used to monitor the disease activity. Ustekinumab PK-PD was described by a two-compartment target-mediated drug disposition model linked to an indirect response model. Lower fat-free mass, higher serum albumin, previous non-exposure to biologics, FCGR3A-158 V/V variant and lower C-reactive protein were associated with higher ustekinumab exposure. Model-based simulation suggested that 41.9% of patients receiving standard dosing achieve biochemical remission at week 32. In patients not achieving remission with standard dosing at week 16, transition to 4-weekly subcutaneous maintenance dosing with or without intravenous reinduction resulted in comparably higher remission rates at week 32 (51.1% vs. 49.2%, respectively). Our findings could be used to guide stratified ustekinumab treatment in CD, particularly in patients with unfavorable characteristics, who might benefit from early transition to 4-weekly maintenance dosing.
A simple, sensitive, accurate, precise and inexpensive HPLC method with fluorescence detection, suitable for routine therapeutic drug monitoring (TDM) of an antiepileptic drug topiramate, was ...developed and validated. The determination of plasma topiramate concentration was carried out after precolumn derivatization, using 4-chloro-7-nitrobenzofurazan as a fluorescent labeling agent and bendroflumethiazide as an internal standard. The standard calibration curve was linear over the concentration range of 0.01-24 μg/mL (r² > 0.9998). The intra- and inter-day accuracies expressed as bias were from 1.4 to 9.9% and from 1.9 to 10.2%, respectively. The intra- and inter-day precisions were below 7.9% and 2.7%, respectively. The validated method was applied for the measurement of plasma topiramate concentrations in patients with epilepsy. The reported method is appropriate for TDM of topiramate as well as for pharmacokinetic and bioequivalence studies.
Background
Body wasting and cachexia change body composition and organ function, with effects on drug pharmacokinetics. The aim of this study was to investigate how cancer and cancer cachexia modify ...liver metabolism and renal drug elimination in rats.
Methods
Nine male Wistar‐Han rats received a single oral dose of midazolam and propranolol (markers of hepatic metabolism), and 10 rats received single intravenous dose of iohexol, a marker of glomerular filtration rate. After drug delivery, multiple dried blood samples were obtained within 2 h post‐dose to evaluate drug pharmacokinetic profiles. After baseline sampling (D0), rats were injected with tumour cells. Drug application and blood sampling were repeated when rats developed tumours (Day 5—D5), and when rats were severely cachectic (Day 10—D10). Clearance (CL) and volume of distribution (Vd) of drugs were assessed with non‐linear mixed effects modelling. Weight and body composition were measured on D0 and D10 and were related to pharmacokinetic parameters.
Results
All three drugs showed non‐significant trend towards increased CL and Vd on D5. On D10, midazolam and propranolol CL and midazolam Vd significantly decreased from baseline (−80.5%, −79.8%, and −72.0%, respectively, P < 0.05 for all). Iohexol CL decreased by 29.8% from baseline value on D10, which was related to body weight loss (Pearson's r = 0.837, P = 0.019).
Conclusions
Hepatic metabolism and renal drug elimination are significantly reduced in cachexia, which could increase risk of dose‐related adverse events.
An assay comprising two simple, selective and isocratic HPLC methods with UV detection was developed and validated for measuring warfarin enantiomers and all five warfarin monohydroxylated ...metabolites in patient blood plasma. Following liquid/liquid extraction from 1 ml of blood plasma a baseline separation of analytes was achieved on chiral (alpha(1) acid glycoprotein - AGP) and achiral (C(18)) column. Both methods were consistent (R.S.D.<6.9% for warfarin enantiomers and<8.9% for monohydroxylated metabolites) and linear (r>0.998). The limits of detection were 25 ng/ml for warfarin enantiomers, 25 ng/ml for 4'-, 10-, 6- and 7-hydroxywarfarin, 35 ng/ml for 8-hydroxywarfarin and 50 ng/ml for racemic warfarin. In a clinical study in 204 patients, it was confirmed that the assay is appropriate for evaluation of influences of genetic polymorphisms, demographic factors and concomitant drug treatment on warfarin metabolism.
The application of artificial neural networks in the pharmaceutical sciences is broad, ranging from drug discovery to clinical pharmacy. In this study, we explored the applicability of ...counter-propagation artificial neural networks (CPANNs), combined with genetic algorithm (GA) for prediction of topiramate (TPM) serum levels based on identified factors important for its prediction.
The study was performed on 118 TPM measurements obtained from 78 adult epileptic patients. Patients were on stable TPM dosing regimen for at least 7 days; therefore, steady-state was assumed. TPM serum concentration was determined by high performance liquid chromatography with fluorescence detection. The influence of demographic, biochemical parameters and therapy characteristics of the patients on TPM levels were tested. Data analysis was performed by CPANNs. GA was used for optimal CPANN parameters, variable selection and adjustment of relative importance.
Data for training included 88 measured TPM concentrations, while remaining were used for validation. Among all factors tested, TPM dose, renal function (eGFR) and carbamazepine dose significantly influenced TPM level and their relative importance were 0.7500, 0.2813, 0.0625, respectively. Relative error and root mean squared relative error (%) and their corresponding 95% confidence intervals for training set were 2.14 (-2.41) - 6.70 and 21.5 18.5 - 24.1; and for test set were -6.21 (-21.2) - 8.77 and 39.9 31.7 - 46.7, respectively.
Statistical parameters showed acceptable predictive performance. Results indicate the feasibility of CPANNs combined with GA to predict TPM concentrations and to adjust relative importance of identified variability factors in population of adult epileptic patients.
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