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.

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.

Superiority of ceftazidime off-label high-dose regimen in PK/PD target attainment during treatment of extensively drug-resistant Pseudomonas aeruginosa infections in cancer patients.

AIM: The objective of this study was to evaluate off-label high-dose ceftazidime population pharmacokinetics in cancer patients with suspected or proven extensively drug-resistant (XDR) Pseudomonas aeruginosa infections and then to compare the achievement of the pharmacokinetic/pharmacodynamic (PK/PD) target after standard and off-label high-dose regimens using population model-based simulations. A further aim was to clinically observe the occurrence of adverse effects during the off-label high-dose ceftazidime treatment. METHODS: In patients treated with off-label high-dose ceftazidime (3 g every 6 h), blood samples were collected and ceftazidime serum levels measured using LC-MS/MS. A pharmacokinetic population model was developed using a nonlinear mixed-effects modelling approach and Monte Carlo simulations were then used to compare standard and high-dose regimens for PK/PD target attainment. RESULTS: A total of 14 cancer patients with serious infection suspected of XDR P. aeruginosa aetiology were eligible for PK analysis. XDR P. aeruginosa was confirmed in 10 patients as the causative pathogen. Population ceftazidime volume of distribution was 13.23 L, while clearance started at the baseline of 1.48 L/h and increased by 0.0076 L/h with each 1 mL/min/1.73 m2 of eGFR. High-dose regimen showed significantly higher probability of target attainment (i.e., 86% vs. 56% at MIC of 32 mg/L). This was translated into a very low mortality rate of 20%. Only one case of reversible neurological impairment was observed. CONCLUSION: We proved the superiority of the ceftazidime off-label high-dose regimen in PK/PD target attainment with very low occurrence of adverse effects. The off-label high-dose regimen should be used to optimize treatment of XDR P. aeruginosa infections.

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).

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.

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.

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.

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.

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).

Pharmacokinetic principles of dose adjustment of mTOR inhibitors in solid organ transplanted patients.

WHAT IS KNOWN AND OBJECTIVES: mTOR inhibitors possess narrow therapeutic range and substantial pharmacokinetic variability and the consequences from suboptimal dosing are serious. The aim of this review is to summarize the current knowledge about the factors influencing mTOR inhibitors pharmacokinetics and the possibility of using these relationships in order to improve its therapy individualization in solid organ transplanted patients. METHODS: Literature search from Pubmed and Web of Science databases were performed using Boolean search operators in order to identify relevant studies. RESULTS AND DISCUSSION: A total of 701 reports were identified from the initial literature search. Out of which 40 studies dealt with relationships between various factors and pharmacokinetics of mTOR inhibitors and with relevance of these associations for dosage optimization. WHAT IS NEW AND CONCLUSION: The overview of the current covariates for pharmacokinetic variability of mTOR inhibitors has been provided on the level of absorption, distribution and elimination, and consequences of these relationships for dosing optimization has been summarized.

Factors Affecting Drug Exposure after Inhalation.

Administration of drugs by inhalation is mainly used to treat lung diseases and is being investigated as a possible route for systemic drug delivery. It offers several benefits, but it is also fraught with many difficulties. The lung is a complex organ with complicated physiology and specific pharmacokinetic processes. Therefore, the exposure and subsequently efficacy of a drug after inhalation is affected by a number of factors. In this review, we summarize the main variables that may affect drug fate after inhalation delivery, such as physicochemical properties of the drug, pulmonary clearance and metabolism, pathophysiological factors and inhalation device. Factors that have impact on pharmacokinetic processes need to be considered during development as their correct setting can lead to new effective inhaled drugs.

Changes in Rosuvastatin Pharmacokinetics During Postnatal Ontogenesis in Rats.

PURPOSE: Statin therapy should be considered in children with familial hypercholesterolemia and sustained high LDL-C levels. There are no data on rosuvastatin exposure in patients <6 years and efficacy/safety can only be derived from case reports. Our aim was to examine developmental changes in pharmacokinetics of rosuvastatin in rats in vivo as a basis for clinical development of formulations for patients < 6 years. METHODS: Rosuvastatin pharmacokinetics was examined in rats aged 1, 4, 7, 10, 14, 21, 28, 35 and 42 days (from birth to sexual maturity). After intraperitoneal dose of 5 mg/kg, blood samples to determine serum rosuvastatin levels were taken at 0.5, 3 and 5 hours. Pharmacokinetic parameters (Vd, CL, AUClast, AUC0-∞) were calculated using pharmacokinecic simulations. RESULTS: Both rosuvastatin CL and Vd started to increase systematically between 2 - 3 weeks of age, which was reflected by decreased total drug exposure. The AUC was up to 13 times higher in the age groups ≤14 days compared with the value at 42 days. CONCLUSIONS: Based on interspecies scaling, a dose reduction could be a feasible way, how to develop appropriate dosing schedule and formulations for children aged 2 - 6 years. However, confirmation in clinical development studies will be needed.

Sufentanil Disposition and Pharmacokinetic Model-Based Dosage Regimen for Sufentanil in Ventilated Full-Term Neonates.

INTRODUCTION: Sufentanil is a potent synthetic opioid used for analgesia in neonates; however, data concerning drug disposition of sufentanil and dosage regimen are sparse in this population. Therefore, the aim of the study was to explore sufentanil disposition and to propose optimal loading and maintenance doses of sufentanil in ventilated full-term neonates. METHODS: Individual sufentanil pharmacokinetic parameters were calculated based on therapeutic drug monitoring data using a 2-compartmental model. Linear regression models were used to explore the covariates. RESULTS: The median (IQR) central volume of distribution (Vdc) and clearance (CL) for sufentanil were 4.7 (4.1-5.4) L/kg and 0.651 (0.433-0.751) L/h/kg, respectively. Linear regression models showed relationship between Vdc (L) and GA (r2 = 0.3436; p = 0.0452) as well as BW (r2 = 0.4019; p = 0.0268). Median optimal sufentanil LD and MD were 2.13 (95% CI: 1.78-2.48) µg/kg and 0.29 (95% CI: 0.22-0.37) µg/kg/h, respectively. Median daily COMFORT-B (IQR) scores ranged from 6 to 23 while no significant relationship between pharmacokinetic parameters and COMFORT-B scores was found. DISCUSSION/CONCLUSION: Body weight and gestational age were found as weak covariates for sufentanil distribution, and the dosage regimen was developed for a prospective trial.

Impact of haemolysis on vancomycin disposition in a full-term neonate treated with extracorporeal membrane oxygenation.

INTRODUCTION: Extracorporeal membrane oxygenation (ECMO) is a lifesaving support technology for potentially reversible neonatal cardiac and/or respiratory failure. Pharmacological consequences of ECMO-induced haemolysis in neonates are not well understood. CASE REPORT: We report a case report of a full-term neonate treated for congenital diaphragmatic hernia and sepsis with ECMO and with vancomycin. While the population elimination half-life of 7 h was estimated, fitting of the simulated population pharmacokinetic profile to truly observed drug concentration points resulted in the personalized value of 41 h. DISCUSSION: The neonate developed ECMO-induced haemolysis with subsequent acute kidney injury resulting in prolonged drug elimination. Whole blood/serum ratio of 0.79 excluded possibility of direct increase of vancomycin serum concentration during haemolysis. CONCLUSION: Vancomycin elimination may be severely prolonged due to ECMO-induced haemolysis and acute kidney injury, while hypothesis of direct increase of vancomycin levels by releasing the drug from blood cells during haemolysis has been disproved.

Therapeutic Drug Monitoring of Protein Kinase Inhibitors in Breast Cancer Patients.

Protein kinase inhibitors (PKIs) represent up-to-date therapeutic approach in breast cancer treatment. Although cancer is a rapidly progressive disease, many substances, including PKIs, are usually used at fixed doses without regard to each patient's individuality. Therapeutic drug monitoring (TDM) is a tool that allows individualization of therapy based on drug plasma levels. For TDM conduct, exposure-response relationships of drug substances are required. The pharmacokinetic data and exposure-response evidence supporting the use of TDM for 6 PKIs used in breast cancer treatment, one of the most common female tumour diseases, are discussed in this review.

Lymphatic Transport of Drugs after Intestinal Absorption: Impact of Drug Formulation and Physicochemical Properties.

PURPOSE: To provide a comprehensive and up-to-date overview focusing on the extent of lymphatic transport of drugs following intestinal absorption and to summarize available data on the impact of molecular weight, lipophilicity, formulation and prandial state. METHODS: Literature was searched for in vivo studies quantifying extent of lymphatic transport of drugs after enteral dosing. Pharmacokinetic data were extracted and summarized. Influence of molecular weight, log P, formulation and prandial state was analyzed using relative bioavailability via lymph (FRL) as the parameter for comparison. The methods and animal models used in the studies were also summarized. RESULTS: Pharmacokinetic data on lymphatic transport were available for 103 drugs. Significantly higher FRL [median (IQR)] was observed in advanced lipid based formulations [54.4% (52.0)] and oil solutions [38.9% (60.8)] compared to simple formulations [2.0% (27.1)], p < 0.0001 and p = 0.004, respectively. Advanced lipid based formulations also provided substantial FRL in drugs with log P < 5, which was not observed in simple formulations and oil solutions. No relation was found between FRL and molecular weight. There were 10 distinct methods used for in vivo testing of lymphatic transport after intestinal absorption so far. CONCLUSION: Advanced lipid based formulations provide superior ability to increase lymphatic absorption in drugs of various molecular weights and in drugs with moderate to low lipophilicity.

Post-mortem Redistribution of Alprazolam in Rats.

The post-mortem toxicological findings may be misinterpreted, if the drug undergoes substantial post-mortem redistribution. As alprazolam is one of the most frequently evaluated drug for legal/forensic reasons in drug-related fatalities, we studied possible changes in alprazolam distribution after death in a rat model. Rats were sacrificed 30 minutes after alprazolam administration. Blood and tissue samples from 8 animals per sampling time were collected at 0, 2, 6, and 24 h after death. The experimental samples were assayed for alprazolam using validated UHPLC-PDA method. Median blood alprazolam concentrations increased approximately 2 times compared with ante-mortem levels due to the redistribution during early post-mortem phase and then slowly decreased with a half-life of 60.7 h. The highest alprazolam tissue concentrations were found in fat and liver and the lowest levels were observed in lungs and brain. The median amount of alprazolam deposited in the lungs was relatively stable over the 24-h post-mortem period, while in heart, liver and kidney the deposited proportion of administered dose increased by 43-48% in comparison with ante-mortem values indicating continuous accumulation of alprazolam into these tissues. These results provide evidence needed for the interpretation of toxicological results in alprazolam-related fatalities and demonstrate modest alprazolam post-mortem redistribution.

Sufentanil pharmacokinetics in a full-term neonate treated with extracorporeal membrane oxygenation: a case report.

INTRODUCTION: Sufentanil is a potent analgesic drug used for pain management. A few studies describe the pharmacokinetics of sufentanil in neonates; however, no pharmacokinetic data about sufentanil during extracorporeal membrane oxygenation have been published yet. CASE REPORT: A 1-day-old neonate with moderate hypoxic-ischemic encephalopathy received veno-arterial extracorporeal membrane oxygenation support for refractory respiratory and circulatory failure. Sufentanil plasma concentrations were determined during both extracorporeal membrane oxygenation (n = 14) and non-extracorporeal membrane oxygenation (n = 17) period. Based on these measurements, individual sufentanil pharmacokinetic parameters were calculated. DISCUSSION: We observed increased sufentanil volume of distribution (11.6 vs 5.6 L/kg) and decreased sufentanil clearance (0.535 vs 0.746 L/h/kg) in extracorporeal membrane oxygenation period. The increment of volume of distribution was attributed to ECMO influence, while difference in clearance was probably due to drug interaction. CONCLUSIONS: This is the first description of sufentanil pharmacokinetics in neonate treated with extracorporeal membrane oxygenation. We observed considerably larger volume of distribution during extracorporeal membrane oxygenation period in comparison with non-extracorporeal membrane oxygenation period.

Pharmacokinetics of Dasatinib.

Tyrosine kinase inhibitors have recently become an essential tool in management of chronic myeloid leukaemia (CML). Dasatinib, a representative of those drugs, acts by inhibiting key proteins included in CML development, predominantly Bcr-Abl and Src. Its advantage is that it shows activity in many cases where other agents bring no improvement due to resistance. Pharmacokinetics of dasatinib has specific characteristics that may play an important role in achieving sufficient exposure in patients. Therefore, the key pharmacokinetic properties are summarized in this report. For example, dasatinib absorption is significantly influenced by gastric pH and its modulation can be a source of serious interactions, as well as simultaneous administration of drugs affecting cytochrome P450.

Gastric pH in Rats: Key Determinant for Preclinical Evaluation of pH-dependent Oral Drug Absorption.

Data on gastric pH in rats to be used in preclinical models for pH-dependent drug absorption are still limited or contradictory. The aim of this study was to describe gastric pH in rats at fasted state and to evaluate its changes induced by pentagastrin or omeprazole in order to mimic gastric pH at fasted and fed human subjects. Twenty Wistar rats, fasting for 12 h, were randomly assigned into four treatment groups (n=5): control, pre-treated with omeprazole 2 h before pH measurement, pre-treated with omeprazole 12 h before pH measurement, and pre-treated with pentagastrin 20 min before pH measurement. An incision on the stomach wall was made in anesthetized animals, and pH of gastric juice was measured. The observed pH values were significantly different among groups (p=0.0341), with the median (IQR) values of gastric pH of 3.5 (2.7-4.2), 6.7 (4.7-7.0), 5.6 (3.5-6.4) and 2.2 (1.6-3.1) in control, omeprazole 2 h, omeprazole 12 h and pentagastin group, respectively. We recommend using short interval pentagastrin and 2 h omeprazole pre-treatment in fasting animals to model similar gastric pH as is expected in human fasted and fed state pharmacokinetic studies, respectively.