Evaluation of adherence to abiraterone therapy in prostate cancer patients based on a population pharmacokinetic model.

AIMS: Abiraterone treatment requires regular drug intake under fasting conditions due to pronounced food effect, which may impact patient adherence. The aim of this prospective study was to evaluate adherence to abiraterone treatment in patients with prostate cancer. To achieve this aim, an abiraterone population pharmacokinetic model was developed and patients' adherence has been estimated by comparison of measured levels of abiraterone with population model-based simulations. METHODS: A total of 1469 abiraterone plasma levels from 83 healthy volunteers collected in a bioequivalence study were analysed using a nonlinear mixed-effects model. Monte Carlo simulation was used to describe the theoretical distribution of abiraterone pharmacokinetic profiles at a dose of 1000 mg once daily. Adherence of 36 prostate cancer patients treated with abiraterone was then evaluated by comparing the real abiraterone concentration measured in each patient during follow-up visit with the theoretical distribution of profiles based on simulations. Patients whose abiraterone levels were ˂5th or ˃95th percentile of the distribution of simulated profiles were considered to be non-adherent. RESULTS: Based on this evaluation, 13 patients (36%) have been classified as non-adherent. We observed significant association (P = .0361) between richness of the breakfast and rate of non-adherence. Adherent patients reported significantly better overall condition in self-assessments (P = .0384). A trend towards a higher occurrence of adverse effects in non-adherent patients was observed. CONCLUSIONS: We developed an abiraterone population pharmacokinetic model and proposed an advanced approach to medical adherence evaluation. Due to the need for administration under fasting conditions, abiraterone therapy is associated with a relatively high rate of non-adherence.

Vancomycin loading dose individualization in a population of obese patients undergoing haemodialysis based on population pharmacokinetic model.

This study aimed to develop a vancomycin population pharmacokinetic model in obese adult patients treated with intermittent haemodialysis and propose a model-based loading dose strategy ensuring attainment of newly recommended AUC-based PK/PD target. Retrospective cross-sectional analysis was performed among obese haemodialysis dependent adult patients treated with intravenous vancomycin. A pharmacokinetic population model was developed using a nonlinear mixed-effects modelling approach and Monte Carlo simulations were used to identify the optimal loading dose for PK/PD target attainment during the first 48 h of treatment. Therapeutic drug monitoring data from 27 patients with a BMI of 30.2-52.9 kg/m2 were analysed. Among all tested variables, only LBM as a covariate of vancomycin Vd significantly improved the model, while vancomycin CL did not correlate with any of the tested variables. The median (IQR) value from the conditional mean of individual estimates of Vd and CL was 68.4 (56.6-84.2) L and 0.86 (0.79-0.90) L/h, respectively. To ensure optimal vancomycin exposure during the first 48 h of therapy, the vancomycin loading dose of 1500, 1750, 2000, 2250, 2500 and 2750 mg should be administered to obese patients with a lean body mass of ˂50, 50-60, 60-70, 70-80, 80-85 and >85 kg, respectively.

Vancomycin population pharmacokinetics and dosing proposal for the initial treatment in obese adult patients.

Aim: The aim of this study was to develop a vancomycin population pharmacokinetic model in adult obese patients and propose covariate-based dosing individualization in order to maximize the achievement of the newly recommended PK/PD target, according to a revised consensus guideline from 2020. Methods: Therapeutic drug monitoring data from initial vancomycin therapy (first 3 days of treatment) in adult obese (BMI ≥ 30 kg/m2) patients from 2013 to 2022 were analyzed using a non-linear mixed-effects modeling method, and Monte Carlo simulations were then used to find the optimal dosage maximizing the PK/PD target attainment. Results: A total of 147 vancomycin serum levels obtained from 138 patients were included in the analysis. Based on the covariate model diagnosis among all tested variables, no reliable predictor of vancomycin volume of distribution (Vd) was identified, while clearance (CL) was positively correlated with eGFR and lean body mass. Creatinine-based eGFR predicted vancomycin CL better than cystatin C-based eGFR. The median (interquartile range) value from conditional modes of individual estimates of Vd, CL, and elimination half-life in our population was 74.0 (70.5-75.4) L, 6.65 (4.95-8.42) L/h, and 7.7 (6.0-10.0) h, respectively. Conclusion: We proposed dosing individualization based on the covariate found in order to maximize the achievement of the newly recommended PK/PD target of the AUC/MIC ratio of 400-600. Clinical pharmacy/pharmacology interventions may lead to an improvement in vancomycin dosing with a reflection in PK/PD target attainment.

Development of immediate-release formulation with reliable absorption of rivaroxaban in various meal regimes.

The bioavailability of rivaroxaban at the higher doses (15 and 20 mg) is considerably reduced when the drug is administered on an empty stomach. This can lead to inadequate anticoagulant effect, and therefore, it is recommended to use the higher doses at fed state. However, proper posology may represent a barrier for some patients. Therefore, the aim of this study was to evaluate innovative rivaroxaban-containing formulations designed to eliminate the food effect to ensure reliable absorption and thus to improve patient adherence with the treatment. Three prototypes (Cocrystal, HPMCP and Kollidon) with rivaroxaban were developed and their bioavailability and food effect in comparison to the reference product was tested in open label, randomized, single oral dose, crossover studies, where test products were administered under fasting and fed conditions and the reference product was administered under fed conditions. Comparable bioavailability for all tested prototypes both under fed and fasting conditions was demonstrated as the 90% confidence intervals of the geometric mean ratios for area under the concentration-time curve remained within the standard acceptance range of 80.00%-125.00%. An innovative immediate release form of rivaroxaban with no food effect on drug bioavailability has been developed, which may represent an important step toward increasing adherence, improving treatment outcome and reducing health care costs.

Evidence for Therapeutic Drug Monitoring of Atypical Antipsychotics.

Second-generation antipsychotics (SGAs), also known as atypical antipsychotics, are a newer class of antipsychotic drugs used to treat schizophrenia, bipolar disorder, and related psychiatric conditions. The plasma concentration of antipsychotic drugs is a valid measure of the drug at its primary target structure in the brain, and therefore determines the efficacy and safety of these drugs. However, despite the well-known high variability in pharmacokinetics of these substances, psychiatric medication is usually administered in uniform dosage schedules. Therapeutic drug monitoring (TDM), as the specific method that can help personalised medicine in dose adjustment according to the characteristics of the individual patient, minimizing the risk of toxicity, monitoring adherence, and increasing cost-effectiveness in the treatment, thus seems to be an elegant tool to solve this problem. Non-response to therapeutic doses, uncertain adherence to medication, suboptimal tolerability, or pharmacokinetic drug-drug interactions are typical indications for TDM of SGAs. This review aims to summarize an overview of the current knowledge and evidence of the possibilities to tailor the dosage of selected SGAs using TDM, including the necessary pharmacokinetic parameters for personalised pharmacotherapy.

A novel dosing approach for rituximab in glomerular diseases based on a population pharmacokinetic analysis.

OBJECTIVES: Rituximab is being increasingly prescribed for the treatment of autoimmune glomerular diseases. While it is highly effective for some diseases, the response is less predictable for others, which may be due to differing requirements in terms of the dosing according to the disease type and variations concerning exposure to the drug. METHODS: We compiled novel rituximab dosing schedules according to pharmacokinetic analysis of data gathered from rituximab treated patients in a tertiary referral nephrology centre between May 2020 and June 2023. The population-pharmacokinetic analysis was based on the rituximab dosing, the patients' characteristics, rituximab levels and anti-rituximab antibodies. RESULTS: The analysis, which was based on data from 185 patients, clearly highlighted differing rituximab dosing requirements for patients with ANCA associated vasculitis and minimal change disease compared to those with membranous nephropathy, focal-segmental glomerulosclerosis and lupus nephritis. This corresponded to the good treatment response of the first two diseases and the unreliable efficacy for the others. The model predicts the rituximab pharmacokinetics with high degree of accuracy when body weight, proteinuria, type of glomerulonephritis, treatment length and anti-rituximab antibodies formation are used as covariates. We proposed a dosing schedule with shortened dosing intervals for difficult-to-treat diagnoses with high proteinuria. CONCLUSION: In order to ensure reliable and comparable exposure of rituximab with respect to the full range of glomerular diseases, the dosing schedule should be adjusted for membranous nephropathy, focal-segmental glomerulosclerosis and lupus nephritis. This is largely, but not solely, due to the enhanced level of unselective proteinuria in these diseases.

Ivacaftor pharmacokinetics and lymphatic transport after enteral administration in rats.

Background: Ivacaftor is a modern drug used in the treatment of cystic fibrosis. It is highly lipophilic and exhibits a strong positive food effect. These characteristics can be potentially connected to a pronounced lymphatic transport after oral administration. Methods: A series of studies was conducted to describe the basic pharmacokinetic parameters of ivacaftor in jugular vein cannulated rats when dosed in two distinct formulations: an aqueous suspension and an oil solution. Additionally, an anesthetized mesenteric lymph duct cannulated rat model was studied to precisely assess the extent of lymphatic transport. Results: Mean ± SD ivacaftor oral bioavailability was 18.4 ± 3.2% and 16.2 ± 7.8%, respectively, when administered as an aqueous suspension and an oil solution. The relative contribution of the lymphatic transport to the overall bioavailability was 5.91 ± 1.61% and 4.35 ± 1.84%, respectively. Conclusion: Lymphatic transport plays only a minor role in the process of ivacaftor intestinal absorption, and other factors are, therefore, responsible for its pronounced positive food effect.

Population pharmacokinetics and covariate-based dosing individualization of voriconazole in lung transplant recipients.

This study aimed to explore pharmacokinetics of voriconazole and its covariates in lung transplant recipients using population approach in order to propose dosing individualization. Data from routine therapeutic drug monitoring in adult lung transplant recipients treated with oral voriconazole were analysed with a three-stage population pharmacokinetic model using nonlinear mixed-effects modelling. Monte Carlo simulations based on final voriconazole pharmacokinetic model were used to generate the theoretical distribution of pharmacokinetic profiles at various dosing regimens. A total of 78 voriconazole serum concentrations collected from 40 patients were included in pharmacokinetic analysis. The only significant covariate was age for voriconazole clearance. Population voriconazole apparent clearance started at 32.26 L/h and decreased by 0.021 L/h with each year of patient's age, while population apparent volume of distribution was 964.46 L. Based on this model, we have proposed an easy-to-use dosing regimen consisting of a loading dose of 400 mg every 12 h for the first 48 h of treatment followed by maintenance dose of 300 mg every 12 h in patients aged up to 59 years, or by maintenance dose of 200 mg every 12 h in patients aged above 59 years.

Disposition of levobupivacaine during intraoperative continuous caudal epidural analgesia in a preterm neonate.

BACKGROUND: Continuous caudal epidural analgesia used intraoperatively in children is an effective and safe technique. However, in preterm neonates, developmental factors may significantly affect levobupivacaine disposition, leading to variable pharmacokinetics, pharmacodynamics, and potential large-variable systemic toxicity of local anesthetics. OBJECTIVE: To our knowledge, this is the first case report describing the disposition of levobupivacaine used for intraoperative caudal epidural analgesia in a preterm neonate treated for the postoperative pain profile. METHOD: 4-days old neonate (postmenstrual age 35+5, weight 2140 g) with congenital anal atresia received continuous caudal epidural long-term analgesia (loading dose 1.694 mg/kg, initial infusion 0.34 mg/kg/hour) before correction surgery. The blood samples were obtained at 1.0, 1.5, 6.5, 12, and 36.5 h after the start of epidural infusion. The pharmacokinetic profile of levobupivacaine was determined by using the Stochastic Approximation Expectation Maximization algorithm. COMFORT and NIPS pain scores were used for the assessment of epidural analgesia. RESULTS: The levobupivacaine absorption rate constant, apparent volume of distribution, apparent clearance, and elimination half-life were 10.8 h-1, 0.9 L, 0.086 L/h, and 7.3 h, respectively. CONCLUSION: The results confirm our hypothesis of altered pharmacokinetics in the preterm neonate. Therefore, levobupivacaine therapy in these patients should be carefully monitored. Since therapeutic drug monitoring of levobupivacaine is not established in clinical routines, we suggest monitoring the intraoperative pain profile using validated scores. TRIAL REGISTRATION: EudraCT number: 2020-000595-37.

Pathogenesis of Collagen-Induced Arthritis: Role of Immune Cells with Associated Cytokines and Antibodies, Comparison with Rheumatoid Arthritis.

Collagen-induced arthritis is the most com-mon in vivo model of rheumatoid arthritis used for investigation of new potential therapies in preclinical research. Rheumatoid arthritis is a systemic inflammatory and autoimmune disease affecting joints, accompanied by significant extra-articular symptoms. The pathogenesis of rheumatoid arthritis and collagen-induced arthritis involves a so far properly unexplored network of immune cells, cytokines, antibodies and other factors. These agents trigger the autoimmune response leading to polyarthritis with cell infiltration, bone and cartilage degeneration and synovial cell proliferation. Our review covers the knowledge about cytokines present in the rat collagen-induced arthritis model and the factors affecting them. In addition, we provide a comparison with rheumatoid arthritis and a description of their important effects on the development of both diseases. We discuss the crucial roles of various immune cells (subtypes of T and B lymphocytes, dendritic cells, monocytes, macrophages), fibroblast-like synoviocy-tes, and their related cytokines (TNF-α, IL-1ß, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, IL-17, IL-23, GM-CSF, TGF-ß). Finally, we also focus on key antibodies (rheu-matoid factor, anti-citrullinated protein antibodies, anti-collagen II antibodies) and tissue-degrading enzymes (matrix metalloproteinases).

Demonstration of the Rationale for Therapeutic Drug Monitoring of Isavuconazole: A Case Report with a Lung Transplant Recipient.

Mucormycosis is a rare invasive fungal disease diagnosed in immunocompromised patients, including those with diabetes or iron overload, and in patients treated for hematological malignancies or after transplantation. Isavuconazole is a triazole antifungal effective against Mucorales with good tolerability, but with potential for relatively high interindividual variability in pharmacokinetics. This report demonstrates the case of a lung transplant recipient treated with isavuconasole that exhibits a very long elimination half-life of 159 hours, and discusses the practical implications of this finding for dosage adjustment and need for therapeutic drug monitoring.

The frequency of, and predisposing risk factors for, ciprofloxacin-induced neuro-psychiatric adverse drug reactions.

OBJECTIVES: Ciprofloxacin induces rare neuro-psychiatric adverse drug reactions (ADRs) that are, as yet, not possible to predict due to unknown predisposition factors. BACKGROUND: The aim of the analysis was to assess the frequency of neuro-psychiatric ADRs and to identify potential risk factors that predisposed patients to ciprofloxacin neurotoxicity. METHODS: This observational retrospective study involved the evaluation of the medical records of patients in the Nephrology department and 3rd Internal Clinic of the General University Hospital in Prague. RESULTS: The overall incidence of neurological ADRs was 3.6 %. No neurological ADRs developed in patients aged less than 70 years. The covariates that were significantly more prevalent in the patients who developed neuropsychiatric ADRs were as follows: higher age, a history of neuropsychiatric disorders and the use of anticonvulsants. The administration of drugs from other ATC groups, gender, weight, body mass index, body surface area, renal functions, level of C-reactive protein at the beginning of treatment and the total daily dose/kg did not differ significantly between the two groups. CONCLUSION: Ciprofloxacin neuropsychiatric ADRs are more frequent in older patients with a history of neurologic or psychiatric disorders. No other tested covariates were proven to predispose patients to neuropsychiatric ADRs during treatment with ciprofloxacin (Tab. 2, Ref. 20).

Dasatinib anhydrate containing oral formulation improves variability and bioavailability in humans.

Dasatinib monohydrate indicated for the treatment of chronic myeloid leukemia displays pH-dependent solubility. The aim of reported development program of novel dasatinib anhydrate containing formulation was to demonstrate improved absorption and lower pharmacokinetic variability compared to dasatinib monohydrate. In a bioavailability study comparing formulations containing 110.6 mg and 140 mg of dasatinib as anhydrate and monohydrate, respectively, both Cmax and AUC of dasatinib were within standard 80.00-125.00% range, while the intra- and inter-subject variability for AUC0-inf after the test product was approximately 3-fold and 1.5-fold less than after the reference, respectively.In a drug-drug interaction study, omeprazole 40 mg reduced the mean AUC0-inf of dasatinib by 19%, when the test was ingested 2 h before the 5th omeprazole dose. This decrease of exposure is clinically irrelevant and substantially less than after the reference. Co-prescription analysis supports the importance of pH-dependent solubility of dasatinib, as >21% of patients were treated concomitantly with a PPI and dasatinib despite warnings against this co-medication in the SmPC.The novel dasatinib anhydrate containing formulation demonstrated improved absorption and less pharmacokinetic variability compared to dasatinib monohydrate product, which may translate into improved clinical outcomes, although this needs to be proven by an appropriate trial.

Therapeutic Drug Monitoring of Protein Kinase Inhibitors in the Treatment of Non-small Cell Lung Cancer.

Targeted therapy with protein kinase inhibitors (PKIs) represents one of the important treatment options for non-small cell lung cancer (NSCLC). It has contributed to improve patients' survival and quality of life significantly. These anticancer drugs are administrated orally in flat-fixed doses despite the well-known large interpatient pharmacokinetic variability and the possible need for dose individualization. To optimize and individualize dosing of PKIs, and thereby increasing the effectiveness and safety of the treatment, therapeutic drug monitoring (TDM) is the most frequently mentioned method. Unlike other areas of medicine, TDM has been rather exceptional in oncological practise since there is a little evidence or no data for concentration-effect relationships of PKIs. Therefore, the aim of this review is to summarize the pharmacokinetic characteristics of PKIs and provide the evidence supporting the use of TDM for personalised treatment of patients with NSCLC.

Effects of Cannabidiol in Inflammation: A Review of Pre-clinical and Clinical Findings.

Cannabidiol (CBD) is the second most abundant component of the plant Cannabis sativa. Currently, CBD is approved for Lennox-Gastaut and Dravet syndrome and newly for tuberous sclerosis complex. However, based on the available data, CBD migth have a broad spectrum of potential therapeutic uses. Therefore, the aim of this review was to summarize the evidence on the effects of CBD on pain and inflammation of various causes. PubMed and Web of Science databases were searched until January 2023. The medical keyword term "cannabidiol" was combined with "pain", "arthritis", and "inflammation". Based on the initial search for these terms, 9, 5, and 5 relevant publications have been selected. Based on the available data, it is not possible to draw a clear conclusion about the effect of CBD to releave pain, because each study used a different route of administration or treatment regimen. The studies also differed in etiopathogenesis of pain (chronic, neuropathic, and possibly inflammatory pain), and in general included only small number of subjects. In case of anti-inflammatory qualities of CBD, its effect on the intestinal system is negligible. On the other hand, positive treatment results were observed in all publications dealing with the effect of CBD on arthritis.

Dosing Optimization of Posaconazole in Lung-Transplant Recipients Based on Population Pharmacokinetic Model.

Although posaconazole tablets show relatively low variability in pharmacokinetics (PK), the proportion of patients achieving the PK/PD target at the approved uniform dose for both prophylaxis and therapy is not satisfactory. The aim of this study was to develop a posaconazole population PK model in lung-transplant recipients and to propose a covariate-based dosing optimization for both prophylaxis and therapy. In this prospective study, 80 posaconazole concentrations obtained from 32 lung-transplant patients during therapeutic drug monitoring were analyzed using nonlinear mixed-effects modelling, and a Monte Carlo simulation was used to describe the theoretical distribution of posaconazole PK profiles at various dosing regimens. A one-compartment model with both linear absorption and elimination best fit the concentration-time data. The population apparent volume of distribution was 386.4 L, while an apparent clearance of 8.8 L/h decreased by 0.009 L/h with each year of the patient's age. Based on the covariate model, a dosing regimen of 200 mg/day for prophylaxis in patients ˃60 years, 300 mg/day for prophylaxis in patients ˂60 years and for therapy in patients ˃60 years, and 400 mg/day for therapy in patients ˂60 years has been proposed. At this dosing regimen, the PK/PD target for prophylaxis and therapy is reached in 95% and 90% of population, respectively, representing significantly improved outcomes in comparison with the uniform dose.

Dose Optimization and Targeting Strategies of Anti-Infective Agents.

Most drugs are currently developed, approved and marketed based on their effect on the majority of the population [...].

Population pharmacokinetic model-based dosing proposal for ampicillin prophylaxis in cardiac surgery patients with cardiopulmonary bypass.

The aim of this study was to describe and quantify pharmacokinetics of ampicillin used prophylactically in cardiac surgery both with and without cardiopulmonary bypass (CPB) using population pharmacokinetic analysis in order to propose an optimal dosing strategy. Adult patients undergoing cardiac surgery and treated with prophylactic dose of 2 g ampicillin were enrolled to this prospective study. Blood samples were collected according to the study protocol and ampicillin plasma concentrations were measured using HPLC/UV system. A three-stage population pharmacokinetic model using nonlinear mixed-effects modelling approach was developed. Totally 273 blood samples obtained from 20 patients undergoing cardiac surgery with the use of the CPB and 20 patients without CPB use were analyzed. Two-comparmental model best fits ampicillin concentration-time data. Mean ± SD body weight-normalized ampicillin central and peripheral volume of distribution was 0.12 ± 0.02 L/kg and 0.15 ± 0.03 L/kg, respectively, while mean ± SD ampicillin clearance in typical patient with eGFR of 1.5 mL/s/1.73 m2 was 1.17 ± 0.05 L/h. The use of CPB did not significantly affect the pharmacokinetics of ampicillin. When administering 2 g of ampicillin before surgery, an additional dose should be administered to reach the PK/PD target of fT > MIC = 50% if the operation lasts longer than 430 min in patients with moderate to severe renal impairment, 320 min in patients with mild renal impairment, 220 min in patients with normal renal function status or 140 min in patients with an augmented renal clearance.

Plasma concentrations of levobupivacaine in neonates during caudal epidural analgesia maintained over 48 hours.

BACKGROUND: Differences in neonatal pharmacokinetics are known to cause systemic accumulation of levobupivacaine with adverse effects during epidural analgesia. Therefore, it is not recommended to surpass 48 hours of administration in neonates. Free and total levobupivacaine levels are considered as predictors of toxicity. OBJECTIVE: The aim of the LEVON pilot study was to detect the accumulation of levobupivacaine during epidural analgesia exceeding 48 hours in neonates. METHODS: Ten neonates received a loading dose of levobupivacaine (1.25 mg/kg) followed by a continuous infusion (0.2 mg/kg/hour) epidurally. Free and total levobupivacaine concentrations were measured 0.5, 1, 6, 12, 36, 72 and 144 hours after the start of infusion. Cumulative doses of levobupivacaine, pain scores and clinical signs of toxicity were used for assessing efficacy and safety. RESULTS: The median concentrations of total levobupivacaine were 586.0, 563.0, 837.5, 957.0, 1930.0, 708.5 and 357.5 ng/ml. The median concentrations of free levobupivacaine were 4.0, 3.6, 5.5, 3.6, 5.5, 0.8 and 0.0 ng/ml. Three patients reached concerning concentrations of total levobupivacaine. Levels of free levobupivacaine remained low. No signs of toxicity were observed. CONCLUSION: Caudal epidural analgesia with levobupivacaine lasting longer than 48 hours appears to be safe providing that free levobupivacaine levels are below the presumed threshold for toxicity (Tab. 1, Fig. 1, Ref. 29). Text in PDF www.elis.sk Keywords: free levobupivacaine, total levobupivacaine, neonate, caudal continuous epidural analgesia, postoperative pain.