Publisher: Adis   (Total: 21 journals)   [Sort by number of followers]

Showing 1 - 21 of 21 Journals sorted alphabetically
American J. of Clinical Dermatology     Full-text available via subscription   (Followers: 28, SJR: 1.542, CiteScore: 3)
Applied Health Economics and Health Policy     Full-text available via subscription   (Followers: 20, SJR: 0.991, CiteScore: 2)
BioDrugs     Full-text available via subscription   (Followers: 4, SJR: 1.038, CiteScore: 3)
Clinical Drug Investigation     Full-text available via subscription   (Followers: 6, SJR: 0.719, CiteScore: 2)
Clinical Pharmacokinetics     Full-text available via subscription   (Followers: 16, SJR: 1.482, CiteScore: 4)
CNS Drugs     Full-text available via subscription   (Followers: 10, SJR: 1.635, CiteScore: 4)
Drug Safety     Full-text available via subscription   (Followers: 81, SJR: 1.447, CiteScore: 3)
Drugs     Full-text available via subscription   (Followers: 146, SJR: 1.547, CiteScore: 5)
Drugs & Aging     Full-text available via subscription   (Followers: 9, SJR: 1.072, CiteScore: 3)
Drugs & Therapy Perspectives     Full-text available via subscription   (Followers: 9, SJR: 0.115, CiteScore: 0)
Drugs in R & D     Full-text available via subscription   (Followers: 2, SJR: 0.881, CiteScore: 2)
Giornale Italiano di Health Technology Assessment     Full-text available via subscription  
High Blood Pressure & Cardiovascular Prevention     Full-text available via subscription   (Followers: 2, SJR: 0.524, CiteScore: 1)
Inpharma Weekly     Full-text available via subscription   (Followers: 2)
Pediatric Drugs     Full-text available via subscription   (Followers: 3, SJR: 0.814, CiteScore: 2)
Pharmaceutical Medicine     Full-text available via subscription   (Followers: 4, SJR: 0.187, CiteScore: 0)
PharmacoEconomics     Full-text available via subscription   (Followers: 21, SJR: 1.998, CiteScore: 3)
PharmacoEconomics & Outcomes News     Full-text available via subscription  
PharmacoEconomics German Research Articles     Full-text available via subscription  
Sports Medicine     Full-text available via subscription   (Followers: 40, SJR: 3.367, CiteScore: 7)
The Patient - Patient-Centered Outcomes Research     Full-text available via subscription   (Followers: 11, SJR: 1.095, CiteScore: 3)
Similar Journals
Journal Cover
Clinical Pharmacokinetics
Journal Prestige (SJR): 1.482
Citation Impact (citeScore): 4
Number of Followers: 16  
 
  Full-text available via subscription Subscription journal
ISSN (Print) 0312-5963 - ISSN (Online) 1179-1926
Published by Adis Homepage  [21 journals]
  • Utilising Endogenous Biomarkers in Drug Development to Streamline the
           Assessment of Drug–Drug Interactions Mediated by Renal Transporters: A
           Pharmaceutical Industry Perspective

    • Free pre-print version: Loading...

      Abstract: Abstract The renal secretion of many drugs is facilitated by membrane transporters, including organic cation transporter 2, multidrug and toxin extrusion protein 1/2-K and organic anion transporters 1 and 3. Inhibition of these transporters can reduce renal excretion of drugs and thereby pose a safety risk. Assessing the risk of inhibition of these membrane transporters by investigational drugs remains a key focus in the evaluation of drug–drug interactions (DDIs). Current methods to predict DDI risk are based on generating in vitro data followed by a clinical assessment using a recommended exogenous probe substrate for the individual drug transporter. More recently, monitoring plasma-based and urine-based endogenous biomarkers to predict transporter-mediated DDIs in early phase I studies represents a promising approach to facilitate, improve and potentially avoid conventional clinical DDI studies. This perspective reviews the evidence for use of these endogenous biomarkers in the assessment of renal transporter-mediated DDI, evaluates how endogenous biomarkers may help to expand the DDI assessment toolkit and offers some potential knowledge gaps. A conceptual framework for assessment that may complement the current paradigm of predicting the potential for renal transporter-mediated DDIs is outlined.
      PubDate: 2024-06-13
       
  • Dose-Response Study of Norepinephrine Infusion for Maternal Hypotension in
           Preeclamptic Patients Undergoing Cesarean Delivery Under Spinal Anesthesia
           

    • Free pre-print version: Loading...

      Abstract: Background and Objective Spinal anesthesia remains the preferred mode of anesthesia for preeclamptic patients during cesarean delivery. We investigated the incidence of maternal hypotension under spinal anesthesia during cesarean delivery, by comparing different prophylactic infusion rates of norepinephrine with normal saline. Methods We randomly allocated 180 preeclamptic patients (45 in each groups) aged 18–45 scheduled for cesarean delivery to receive one of four prophylactic norepinephrine infusions at doses of 0 (normal saline group), 0.025 (0.025 group), 0.05 (0.05 group), or 0.075 (0.075 group) µg/kg/min following spinal anesthesia. The primary endpoint was the incidence of maternal hypotension (systolic blood pressure < 80% of baseline). Results The incidence of maternal hypotension was reduced with different prophylactic infusion rates of norepinephrine (26.7%, 15.6%, and 6.7%) compared with normal saline (37.8%) with a significant decreasing trend (p = 0.002). As the infusion doses of norepinephrine increased, there is a significant decreasing trend in deviation of systolic blood pressure control (median performance error; median absolute performance error) from baseline (p < 0.001; p < 0.001) and need for rescue norepinephrine boluses (p = 0.020). The effective dose 50 and effective dose 90 of prophylactic norepinephrine infusion were − 0.018 (95% confidence interval − 0.074, 0.002) µg/kg/min and 0.065 (95% confidence interval 0.048, 0.108) µg/kg/min, respectively. Conclusions Prophylactic infusion of norepinephrine, as compared to no preventive measures, can effectively reduce the incidence of maternal hypotension in preeclamptic patients under spinal anesthesia during cesarean delivery, without increasing other adverse events for either the mother or neonate. Registration: Clinical trials.gov identifier number NCT04556370.
      PubDate: 2024-06-13
       
  • Pharmacogenetic Testing or Therapeutic Drug Monitoring: A Quantitative
           Framework

    • Free pre-print version: Loading...

      Abstract: Background Pharmacogenetic profiling and therapeutic drug monitoring (TDM) have both been proposed to manage inter-individual variability (IIV) in drug exposure. However, determining the most effective approach for estimating exposure for a particular drug remains a challenge. This study aimed to quantitatively assess the circumstances in which pharmacogenetic profiling may outperform TDM in estimating drug exposure, under three sources of variability (IIV, inter-occasion variability [IOV], and residual unexplained variability [RUV]). Methods Pharmacokinetic models were selected from the literature corresponding to drugs for which pharmacogenetic profiling and TDM are both clinically considered approaches for dose individualization. The models were used to simulate relevant drug exposures (trough concentration or area under the curve [AUC]) under varying degrees of IIV, IOV, and RUV. Results Six drug cases were selected from the literature. Model-based simulations demonstrated that the percentage of patients for whom pharmacogenetic exposure prediction is superior to TDM differs for each drug case: tacrolimus (11.0%), tamoxifen (12.7%), efavirenz (49.2%), vincristine (49.6%), risperidone (48.1%), and 5-fluorouracil (5-FU) (100%). Generally, in the presence of higher unexplained IIV in combination with lower RUV and IOV, exposure was best estimated by TDM, whereas, under lower unexplained IIV in combination with higher IOV or RUV, pharmacogenetic profiling was preferred. Conclusions For the drugs with relatively low RUV and IOV (e.g., tamoxifen and tacrolimus), TDM estimated true exposure the best. Conversely, for drugs with similar or lower unexplained IIV (e.g., efavirenz or 5-FU, respectively) combined with relatively high RUV, pharmacogenetic profiling provided the most accurate estimate for most patients. However, genotype prevalence and the relative influence of genotypes on the PK, as well as the ability of TDM to accurately estimate AUC with a limited number of samples, had an impact. The results could be used to support clinical decision making when considering other factors, such as the probability for severe side effects.
      PubDate: 2024-06-06
       
  • Development of a Physiologically Based Pharmacokinetic Population Model
           for Diabetic Patients and its Application to Understand
           Disease-drug–drug Interactions

    • Free pre-print version: Loading...

      Abstract: Introduction The activity changes of cytochrome P450 (CYP450) enzymes, along with the complicated medication scenarios in diabetes mellitus (DM) patients, result in the unanticipated pharmacokinetics (PK), pharmacodynamics (PD), and drug–drug interactions (DDIs). Physiologically based pharmacokinetic (PBPK) modeling has been a useful tool for assessing the influence of disease status on CYP enzymes and the resulting DDIs. This work aims to develop a novel diabetic PBPK population model to facilitate the prediction of PK and DDI in DM patients. Methods First, mathematical functions were constructed to describe the demographic and non-CYP physiological characteristics specific to DM, which were then incorporated into the PBPK model to quantify the net changes in CYP enzyme activities by comparing the PK of CYP probe drugs in DM versus non-DM subjects. Results The results show that the enzyme activity is reduced by 32.3% for CYP3A4/5, 39.1% for CYP2C19, and 27% for CYP2B6, while CYP2C9 activity is enhanced by 38% under DM condition. Finally, the diabetic PBPK model was developed through integrating the DM-specific CYP activities and other parameters and was further used to perform PK simulations under 12 drug combination scenarios, among which 3 combinations were predicted to result in significant PK changes in DM, which may cause DDI risks in DM patients. Conclusions The PBPK modeling applied herein provides a quantitative tool to assess the impact of disease factors on relevant enzyme pathways and potential disease-drug–drug-interactions (DDDIs), which may be useful for dosing regimen optimization and minimizing the DDI risks associated with the treatment of DM. Graphical
      PubDate: 2024-05-31
       
  • Application of Physiologically Based Pharmacokinetic Modeling to
           Characterize the Effects of Age and Obesity on the Disposition of
           Levetiracetam in the Pediatric Population

    • Free pre-print version: Loading...

      Abstract: Background Levetiracetam is an antiseizure medication used for several seizure types in adults and children aged 1 month and older; however, due to a lack of data, pharmacokinetic (PK) variability of levetiracetam is not adequately characterized in certain populations, particularly neonates, children younger than 2 years of age, and children older than 2 years of age with obesity. Objective This study aimed to address the gap by leveraging PK data from two prospective standard-of-care pediatric trials (n = 88) covering an age range from 1 month to 19 years, including those with obesity (64%), and applying a physiologically based PK (PBPK) modeling framework. Methods A published PBPK model of levetiracetam for children aged 2 years and older was extended to pediatric patients younger than 2 years of age and patients older than 2 years of age with obesity by accounting for the obesity and age-related changes in PK using PK-Sim® software. The prospective pediatric data, along with the literature data for neonates and children younger than 2 years of age, were used to evaluate the extended PBPK models. Results Overall, 82.4% of data fell within the 90% interval of model-predicted concentrations, with an average fold error within twofold of the accepted criteria. PBPK modeling revealed that children with obesity had lower weight-normalized clearances (0.053 L/h/kg) on average than children without obesity (0.063 L/h/kg). The effect of maturation was well-characterized, resulting in comparable PBPK-simulated, weight-normalized clearances for neonates and children younger than 2 years of age reported from the literature. Conclusions PBPK modeling simulations revealed that the current US FDA-labeled pediatric dosing regimen listed in the prescribing information can produce the required exposure of levetiracetam in these target populations with dose adjustments for children with obesity aged 4 years to younger than 16 years.
      PubDate: 2024-05-30
       
  • Together or Apart' Revealing the Impact of Dietary Interventions on
           Bioavailability of Quinolones: A Systematic Review with Meta-analyses

    • Free pre-print version: Loading...

      Abstract: Background and Objective Managing drug-food interactions is essential for optimizing the effectiveness and safety profile of quinolones. Following PRISMA guidelines, we systematically reviewed the influence of dietary interventions on the bioavailability of 22 quinolones. Methods All studies describing or investigating the impact of food, beverages, antacids, and mineral supplements on pharmacokinetic parameters or pharmacokinetic/pharmacodynamic indices of orally taken quinolones were considered for inclusion. We excluded reviews, in vitro and in silico studies, studies performed on animals, and those involving alcohol. We performed the search in Medline (via PubMed), Embase, and Cochrane Library, covering reports from database inception to December 2022. We used the following tools to assess the risk of bias: version 2 of the Cochrane risk-of-bias tool for parallel trials, the Cochrane risk-of-bias tool for cross-over studies, and the NIH quality assessment tool for before-after studies. We performed quantitative analyses for each quinolone if two or more food-effect studies with specified and comparable study designs were available. If meta-analyses were not applicable, we qualitatively summarized the results. Results We included 109 studies from 101 reports. Meta-analyses were conducted for 12 antibiotics and qualitative synthesis was employed for the remaining drugs. Of the studies, 60.5% were open-label, cross-over, as recommended by FDA. We judged 46% of studies as having a high risk of bias and only 4% of having a low risk of bias. Among 19 quinolones with available food impact data, 14 (74%) had potentially clinically important interactions. For nalidixic acid, oxolinic acid, and tosufloxacin, food exerted a high positive impact on bioavailability (AUC or Cmax increased by > 45%), whereas, for all the remaining drugs, postprandial absorption was lower. The most significant negative influence of food (AUC or Cmax decreased by > 40%) occurred for delafloxacin capsules and norfloxacin, whereas the moderate influence (AUC or Cmax decreased by 30–40%) occurred for nemonoxacin and rufloxacin. All 14 analysed quinolones showed a substantial reduction in bioavailability when co-administered with antacids and mineral supplements, except for calcium preparations. The impact of beverages was evaluated for 10 quinolones, with 50% experiencing significantly reduced absorption in the presence of milk (the highest negative impact for ciprofloxacin). Moreover, both ciprofloxacin and levofloxacin demonstrated compromised bioavailability when consumed with orange juice, particularly calcium-fortified. Discussion Several factors may influence interactions, including the physicochemical characteristics of quinolones, the type of intervention, drug formulation, and the patient’s health status. We assessed the quality of evidence as low due to the poor actuality of included studies, their methodological diversity, and uneven data availability for individual drugs. Graphical
      PubDate: 2024-05-28
       
  • Drugs in Human Milk Part 1: Practical and Analytical Considerations in
           Measuring Drugs and Metabolites in Human Milk

    • Free pre-print version: Loading...

      Abstract: Abstract Human milk is a remarkable biofluid that provides essential nutrients and immune protection to newborns. Breastfeeding women consuming medications could pass the drug through their milk to neonates. Drugs can be transferred to human milk by passive diffusion or active transport. The physicochemical properties of the drug largely impact the extent of drug transfer into human milk. A comprehensive understanding of the physiology of human milk formation, composition of milk, mechanisms of drug transfer, and factors influencing drug transfer into human milk is critical for appropriate selection and use of medications in lactating women. Quantification of drugs in the milk is essential for assessing the safety of pharmacotherapy during lactation. This can be achieved by developing specific, sensitive, and reproducible analytical methods using techniques such as liquid chromatography coupled with mass spectrometry. The present review briefly discusses the physiology of human milk formation, composition of human milk, mechanisms of drug transfer into human milk, and factors influencing transfer of drugs from blood to milk. We further expand upon and critically evaluate the existing analytical approaches/assays used for the quantification of drugs in human milk.
      PubDate: 2024-05-15
       
  • Comment on: “CYP3A4*22 Genotype‑Guided Dosing of Kinase Inhibitors in
           Cancer Patients”

    • Free pre-print version: Loading...

      PubDate: 2024-05-11
       
  • The Effect of Various Degrees of Renal or Hepatic Impairment on the
           Pharmacokinetic Properties of Once-Weekly Insulin Icodec

    • Free pre-print version: Loading...

      Abstract: Background and Objective Icodec is a once-weekly insulin being developed to provide basal insulin coverage in diabetes mellitus. This study evaluated the effects of renal or hepatic impairment on icodec pharmacokinetics. Methods Two open-label, parallel-group, single-dose (1.5 U/kg subcutaneously) trials were conducted. In a renal impairment trial, 58 individuals were allocated to normal renal function (measured glomerular filtration rate ≥ 90 mL/min), mild (60 to < 90 mL/min), moderate (30 to < 60 mL/min) or severe (< 30 mL/min) renal impairment or end-stage renal disease. In a hepatic impairment trial, 25 individuals were allocated to normal hepatic function or mild (Child-Pugh Classification grade A), moderate (grade B) or severe (grade C) hepatic impairment. Blood was sampled frequently for a pharmacokinetic analysis until 35 days post-dose. Results The shape of the icodec pharmacokinetic profile was not affected by renal or hepatic impairment. Total icodec exposure was greater for mild (estimated ratio [95% confidence interval]: 1.12 [1.01; 1.24]), moderate (1.24 [1.12; 1.37]) and severe (1.28 [1.16; 1.42]) renal impairment, and for end-stage renal disease (1.14 [1.03; 1.28]), compared with normal renal function. It was also greater for mild (1.13 [1.00; 1.28]) and moderate (1.15 [1.02; 1.29]) hepatic impairment versus normal hepatic function. There was no statistically significant difference between severe hepatic impairment and normal hepatic function. Serum albumin levels (range 2.7–5.1 g/dL) did not statistically significantly influence icodec exposure. Conclusions The clinical relevance of the slightly higher icodec exposure with renal or hepatic impairment is limited as icodec should be dosed according to individual need. No specific icodec dose adjustment is required in renal or hepatic impairment. Clinical Trial Registration ClinicalTrials.gov identifiers: NCT03723785 and NCT04597697.
      PubDate: 2024-05-09
       
  • Population Pharmacokinetics of Intravenous Lidocaine in Adults: A
           Systematic Review

    • Free pre-print version: Loading...

      Abstract: Background The establishment of optimal dosing regimens for intravenous (IV) lidocaine in the perioperative setting, aiming to balance effective pain relief with minimisation of potential side effects, is a topic of ongoing debate. This discussion stems from the significant variability in lidocaine’s pharmacokinetic (PK) parameters and its relatively narrow safety margin. Population pharmacokinetic (popPK) modelling has emerged as a valuable tool for understanding the factors contributing to this observed variability in drug kinetics. Objectives This systematic review compiles the existing knowledge on lidocaine’s PK properties and published popPK models, with a focus on significant covariates. Methods A systematic search on Cochrane CENTRAL, Medline, and EMBASE was performed from inception to June 2023. Original clinical studies that administered IV lidocaine to adults and performed PK analyses using a nonlinear mixed effects modelling approach were included. The quality of the included studies was assessed by compliance with the Clinical Pharmacokinetics (ClinPK) statement checklist. Results Seven studies were included, which involved a diverse adult population, including both volunteers and patients with various comorbidities. Lidocaine PK was primarily characterised by a two- or three-compartment model. The volume of distribution at steady state ranged from 66 to 194 L, and the total clearance ranged from 22 to 49 L/h. Despite adjusting for significant covariates like heart failure status, alpha-1-acid glycoprotein, duration of lidocaine infusion, and body weight, each study revealed substantial variability in PK parameters. The potential impact of hepatic or renal function biomarkers on these PK parameters calls for further investigation. Incomplete reporting of key aspects of developed models may hinder the models’ reliability and clinical application. Conclusion The findings emphasise the importance of tailoring drug dosage to ensure the safe and effective use of intravenous lidocaine. Optimal design methodologies may be incorporated for a more efficient identification of important covariates. Utilising contemporary model evaluation methods like visual predictive checks and bootstrapping would enhance the robustness of popPK models and the reliability of their predictions. This comprehensive review advances our understanding of lidocaine's pharmacokinetics and lays the groundwork for further research in this critical area of perioperative pain management. Review protocol registered on 25 August 2023 in PROSPERO (CRD42023441113). This work was supported by the Fundamental Research Grant Scheme, the Ministry of Higher Education, Malaysia (FRGS/1/2020/SKK01/UM/02/2).
      PubDate: 2024-05-04
       
  • Correction: Relative Bioavailability of Dolutegravir (DTG) and
           Emtricitabine/Tenofovir Alafenamide Fumarate (F/TAF) Administered as
           Paediatric Tablet Formulations in Healthy Volunteers

    • Free pre-print version: Loading...

      PubDate: 2024-05-02
       
  • Predictions of Bedaquiline Central Nervous System Exposure in Patients
           with Tuberculosis Meningitis Using Physiologically based Pharmacokinetic
           Modeling

    • Free pre-print version: Loading...

      Abstract: Background and Objective The use of bedaquiline as a treatment option for drug-resistant tuberculosis meningitis (TBM) is of interest to address the increased prevalence of resistance to first-line antibiotics. To this end, we describe a whole-body physiologically based pharmacokinetic (PBPK) model for bedaquiline to predict central nervous system (CNS) exposure. Methods A whole-body PBPK model was developed for bedaquiline and its metabolite, M2. The model included compartments for brain and cerebrospinal fluid (CSF). Model predictions were evaluated by comparison to plasma PK time profiles following different dosing regimens and sparse CSF concentrations data from patients. Simulations were then conducted to compare CNS and lung exposures to plasma exposure at clinically relevant dosing schedules. Results The model appropriately described the observed plasma and CSF bedaquiline and M2 concentrations from patients with pulmonary tuberculosis (TB). The model predicted a high impact of tissue binding on target site drug concentrations in CNS. Predicted unbound exposures within brain interstitial exposures were comparable with unbound vascular plasma and unbound lung exposures. However, unbound brain intracellular exposures were predicted to be 7% of unbound vascular plasma and unbound lung intracellular exposures. Conclusions The whole-body PBPK model for bedaquiline and M2 predicted unbound concentrations in brain to be significantly lower than the unbound concentrations in the lung at clinically relevant doses. Our findings suggest that bedaquiline may result in relatively inferior efficacy against drug-resistant TBM when compared with efficacy against drug-resistant pulmonary TB.
      PubDate: 2024-05-01
       
  • Personalized Antifungal Therapy Through Model-Informed Precision Dosing of
           Posaconazole

    • Free pre-print version: Loading...

      Abstract: Background and Objective Posaconazole is a pharmacotherapeutic pillar for prophylaxis and treatment of invasive fungal diseases. Dose individualization is of utmost importance as achieving adequate antifungal exposure is associated with improved outcome. This study aimed to select and evaluate a model-informed precision dosing strategy for posaconazole. Methods Available population pharmacokinetic models for posaconazole administered as a solid oral tablet were extracted from the literature and evaluated using data from a previously published prospective study combined with data collected during routine clinical practice. External evaluation and selection of the most accurate and precise model was based on graphical goodness-of-fit and predictive performance. Measures for bias and imprecision included mean percentage error (MPE) and normalized relative root mean squared error (NRMSE), respectively. Subsequently, the best-performing model was evaluated for its a posteriori fit-for-purpose and its suitability in a limited sampling strategy. Results Seven posaconazole models were evaluated using 764 posaconazole plasma concentrations from 143 patients. Multiple models showed adequate predictive performance illustrated by acceptable goodness-of-fit and MPE and NRMSE below ± 10% and ± 25%, respectively. In the fit-for-purpose analysis, the selected model showed adequate a posteriori predictive performance. Bias and imprecision were lowest in the presence of two prior measurements. Additionally, this model showed to be useful in a limited sampling strategy as it adequately predicted total posaconazole exposure from one (non-)trough concentration. Conclusion We validated an MIPD strategy for posaconazole for its fit-for-purpose. Thereby, this study is an important first step towards MIPD-supported posaconazole dosage optimization with the goal to improve antifungal treatment in clinical practice.
      PubDate: 2024-05-01
       
  • Development of a Weight-Band Dosing Approach for Vosoritide in Children
           with Achondroplasia Using a Population Pharmacokinetic Model

    • Free pre-print version: Loading...

      Abstract: Background and Objective Vosoritide is a recently approved therapy for achondroplasia, the most common form of disproportionate short stature, that has been shown to be well tolerated and effective in increasing linear growth. This study aimed to develop a population pharmacokinetic (PPK) model to characterize pharmacokinetics (PK) of vosoritide and establish a weight-band dosing regimen. Methods A PPK model was developed using data from five clinical trials in children with achondroplasia (aged 0.95−15 years) who received daily per-kg doses of vosoritide. The model was used to simulate expected exposures in children with a refined weight-band dosing regimen. Simulated exposure was compared with the observed exposure from the pivotal clinical trial to evaluate appropriateness of the weight-band dosing regimen. Results A one-compartment model with a change-point first-order absorption and first-order elimination accurately described PK of vosoritide in children with achondroplasia. Body weight was found to be a predictor of vosoritide’s clearance and volume of distribution. Additionally, it was observed that dosing solution concentration and duration of treatment influenced bioavailability. The weight-band dosing regimen resulted in simulated exposures that were within the range demonstrated to be well tolerated and effective in the pivotal clinical trial and showed improved consistency in drug exposure across the achondroplasia population. Conclusions The weight-band dosing regimen reduced the number of recommended dose levels by body weight and is expected to simplify dosing for children with achondroplasia and their caregivers. Clinical Trial Registration NCT02055157, NCT02724228, NCT03197766, NCT03424018, and NCT03583697.
      PubDate: 2024-04-23
       
  • Time-Varying Clearance in Milrinone Pharmacokinetics from Premature
           Neonates to Adolescents

    • Free pre-print version: Loading...

      Abstract: Background and Objectives Milrinone is an inotrope and vasodilator used for prophylaxis or treatment of low cardiac output syndrome after weaning from cardiopulmonary bypass (CPB). It is renally eliminated and has an acceptable therapeutic range of 100–300 μg/L, but weight-based dosing alone is associated with poor target attainment. We aimed to develop a population pharmacokinetic model for milrinone from premature neonates to adolescents, and to evaluate how age, renal function and recovery from CPB may impact dose selection. Methods Fifty paediatric patients (aged 4 days to 16 years) were studied after undergoing cardiac surgery supported by CPB. Data from 29 premature neonates (23–28 weeks’ postmenstrual age) treated for prophylaxis of low systemic blood flow were available for a pooled pharmacokinetic analysis. Population parameters were estimated using non-linear mixed effects modelling (NONMEM 7.5.1). Results There were 369 milrinone measurements available for analysis. A one-compartment model with zero-order input and first-order elimination was used to describe milrinone disposition. Population parameters were clearance 17.8 L/70 kg [95% CI 15.8–19.9] and volume 20.4 L/h/70 kg [95% CI 17.8–22.1]. Covariates included size, postmenstrual age and renal function for clearance, and size and postnatal age for volume. Milrinone clearance is reduced by 39.5% [95% CI 24.0–53.7] immediately after bypass, and recovers to baseline clearance with a half-time of 12.0 h [95% CI 9.7–15.2]. Milrinone volume was 2.07 [95% CI 1.87–2.27] times greater at birth than the population standard and decreased over the first days of life with a half-time of 0.977 days [95% CI 0.833–1.12]. Conclusion Milrinone is predominately renally eliminated and so renal function is an important covariate describing variability in clearance. Increasing clearance over time likely reflects increasing cardiac output and renal perfusion due to milrinone and return to baseline following CPB.
      PubDate: 2024-04-13
       
  • Pharmacokinetics of Monoclonal Antibodies Throughout Pregnancy: A
           Systematic Literature Review

    • Free pre-print version: Loading...

      Abstract: Background and Objective Although little information is available on the pharmacokinetics (PK) of monoclonal antibodies (mAbs) during pregnancy, multiple mAbs are being used during pregnancy for various indications. The aim of this systematic literature review was to characterize the PK of mAbs throughout pregnancy. Methods A systematic literature search was carried out in PubMed and Embase on 21 April 2023. Articles were included when information on PK or exposure parameters of mAbs in pregnant women was available. Results A total of 42 relevant articles were included, of which eight discussed adalimumab, three certolizumab pegol, five eculizumab, one golimumab, 12 infliximab (IFX), two natalizumab, one canakinumab, one omalizumab, five tocilizumab, eight ustekinumab, and five vedolizumab. One of the 42 studies reported information on clearance (CL) and volume of distribution (VD) of IFX; all other studies only reported on serum concentrations in the pre-pregnancy state, different trimesters, and the postpartum period. For all of the assessed mAbs except IFX, serum concentrations were similar to concentrations in the pre-pregnancy state or modestly decreased. In contrast, IFX trough concentrations generally increased in the second and third trimesters in comparison to the non-pregnant state. Conclusion Available information suggests that the anatomical and physiological changes throughout pregnancy may have meaningful effects on the PK of mAbs. For most mAbs (not IFX), modestly higher dosing (per mg) maybe needed during pregnancy to sustain a similar serum exposure compared to pre-pregnancy.
      PubDate: 2024-04-07
       
  • Tacrolimus Variability and Clinical Outcomes in the Early Post-lung
           

    • Free pre-print version: Loading...

      Abstract: Background and Objective High variability in tacrolimus pharmacokinetics directly after lung transplantation (LuTx) may increase the risk for acute kidney injury (AKI) and transplant rejection. The primary objective was to compare pharmacokinetic variability in patients receiving tacrolimus orally versus intravenously early after LuTx. Methods Pharmacokinetic and clinical data from 522 LuTx patients transplanted between 2010 and 2020 in two university hospitals were collected to compare orally administered tacrolimus to intravenous tacrolimus early post-transplantation. Tacrolimus blood concentration variability, measured as intrapatient variability (IPV%) and  percentage of time within the therapeutic range (TTR%), was analyzed within the first 14 days after LuTx. Secondary outcomes were AKI, acute rejection, length of stay in the intensive care unit (ICU), and mortality in the ICU and during hospital admission. Results We included 224 patients in the oral and 298 in the intravenous group. The mean adjusted IPV% was 10.8% (95% confidence interval [CI] 6.9–14.6; p < 0.001) higher in the oral group (27.2%) than the intravenous group (16.4%). The mean TTR% was 7.3% (95% CI − 11.3 to − 3.4; p < 0.001) lower in the oral group (39.6%) than in the intravenous group (46.9%). The incidence of AKI was 46.0% for oral and 42.6% for intravenous administration (adjusted odds ratio [OR] 1.2; 95% CI 0.8–1.8; p = 0.451). The frequencies of clinically diagnosed acute rejection in the oral and intravenous groups were nonsignificant (24.6% vs 17.8%; OR 1.5 [95% CI 1.0–2.3; p = 0.059]). ICU and hospital mortality rate and ICU length of stay were similar. Conclusions Administering tacrolimus orally directly after LuTx leads to a higher variability in blood concentrations compared to intravenous administration. There was no difference in the occurrence of AKI or transplant rejection.
      PubDate: 2024-04-06
       
  • Population Pharmacokinetics of Sacituzumab Govitecan in Patients with
           Metastatic Triple-Negative Breast Cancer and Other Solid Tumors

    • Free pre-print version: Loading...

      Abstract: Background and Objective Sacituzumab govitecan (SG) is an antibody–drug conjugate composed of an antibody with affinity for Trop-2 coupled to SN-38 via hydrolyzable linker. SG is approved for patients with metastatic triple-negative breast cancer (mTNBC) who have received two or more prior chemotherapies (at least one in a metastatic setting) and for patients with pretreated hormone receptor positive (HR+)/human epidermal growth factor receptor 2 negative (HER2–) metastatic breast cancer. Methods In these analyses, the pharmacokinetics of SG, free SN-38, and total antibody (tAB) were characterized using data from 529 patients with mTNBC or other solid tumors across two large clinical trials (NCT01631552; ASCENT, NCT02574455). Three population pharmacokinetic models were constructed using non-linear mixed-effects modeling; clinically relevant covariates were evaluated to assess their impact on exposure. Models for SG and tAB were developed independently whereas free SN-38 was sequentially generated via a first-order release process from SG. Results Pharmacokinetics of the three analytes were each described by a two-compartment model with estimated body weight-based scaling exponents for clearance and volume. Typical parameter estimates for clearance and steady-state volume of distribution were 0.133 L/h and 3.68 L for SG and 0.0164 L/h and 4.26 L for tAB, respectively. Mild-to-moderate renal impairment, mild hepatic impairment, age, sex, baseline albumin level, tumor type, UGT1A1 genotype, or Trop-2 expression did not have a clinically relevant impact on exposure for any of the three analytes. Conclusions These analyses support the approved SG dosing regimen of 10 mg/kg as intravenous infusion on days 1 and 8 of 21-day cycles and did not identify a need for dose adjustment based on evaluated covariates or disease characteristics.
      PubDate: 2024-04-05
       
  • Comment on “Population Pharmacokinetics of Total and Unbound
           Isavuconazole in Critically Ill Patients: Implications for Adaptive Dosing
           Strategies” and “High Variability in Isavuconazole Unbound Fraction in
           Clinical Practice: A Call to Reconsider Pharmacokinetic/Pharmacodynamic
           Targets and Breakpoints”

    • Free pre-print version: Loading...

      PubDate: 2024-04-04
       
  • Relative Bioavailability of Dolutegravir (DTG) and Emtricitabine/Tenofovir
           Alafenamide Fumarate (F/TAF) Administered as Paediatric Tablet
           Formulations in Healthy Volunteers

    • Free pre-print version: Loading...

      Abstract: Background and objective Within the UNIVERSAL project (RIA2019PD-2882) we aim to develop a paediatric dolutegravir (DTG)/emtricitabine (FTC or F)/tenofovir alafenamide (TAF) fixed-dose combination. To inform dosing of this study, we undertook a relative bioavailability (RBA) study in healthy volunteers to investigate a potential pharmacokinetic effect when paediatric formulations of DTG and F/TAF are taken together. Methods Participants received all of the following treatments as paediatric formulations in randomised order: a single dose of 180/22.5 mg F/TAF; a single dose of 30 mg DTG; a single dose of 180/22.5 mg F/TAF plus 30 mg DTG. Blood concentrations of DTG, FTC, TAF, and tenofovir (TFV) were measured over 48 h post-dose. If the 90% confidence intervals (CIs) of the geometric least squares mean (GLSM) ratios of area under the curve (AUC) and maximum concentration (Cmax) of each compound were within 0.70–1.43, we considered this as no clinically relevant PK interaction. Results A total of 15 healthy volunteers were included. We did not observe a clinically relevant PK interaction between the paediatric DTG and F/TAF formulations for the compounds DTG, FTC, and TFV. For TAF, the lower boundaries of the 90% CIs of the GLSM ratios of the AUC0–∞ and Cmax fell outside our acceptance criteria of 0.70–1.43. Conclusions Although TAF AUC and Cmax 90% CIs fell outside the pre-defined criteria (0.62–1.11 and 0.65–1.01, respectively), no consistent effect on TAF PK was observed, likely due to high inter-subject variability. Moreover, there are several reasons to rely on TFV exposure as being more clinically relevant than TAF exposure. Therefore, we found no clinically relevant interactions in this study.
      PubDate: 2024-04-04
       
 
JournalTOCs
School of Mathematical and Computer Sciences
Heriot-Watt University
Edinburgh, EH14 4AS, UK
Email: journaltocs@hw.ac.uk
Tel: +00 44 (0)131 4513762
 


Your IP address: 44.220.44.148
 
Home (Search)
API
About JournalTOCs
News (blog, publications)
JournalTOCs on Twitter   JournalTOCs on Facebook

JournalTOCs © 2009-
JournalTOCs
 
 

Publisher: Adis   (Total: 21 journals)   [Sort by number of followers]

Showing 1 - 21 of 21 Journals sorted alphabetically
American J. of Clinical Dermatology     Full-text available via subscription   (Followers: 28, SJR: 1.542, CiteScore: 3)
Applied Health Economics and Health Policy     Full-text available via subscription   (Followers: 20, SJR: 0.991, CiteScore: 2)
BioDrugs     Full-text available via subscription   (Followers: 4, SJR: 1.038, CiteScore: 3)
Clinical Drug Investigation     Full-text available via subscription   (Followers: 6, SJR: 0.719, CiteScore: 2)
Clinical Pharmacokinetics     Full-text available via subscription   (Followers: 16, SJR: 1.482, CiteScore: 4)
CNS Drugs     Full-text available via subscription   (Followers: 10, SJR: 1.635, CiteScore: 4)
Drug Safety     Full-text available via subscription   (Followers: 81, SJR: 1.447, CiteScore: 3)
Drugs     Full-text available via subscription   (Followers: 146, SJR: 1.547, CiteScore: 5)
Drugs & Aging     Full-text available via subscription   (Followers: 9, SJR: 1.072, CiteScore: 3)
Drugs & Therapy Perspectives     Full-text available via subscription   (Followers: 9, SJR: 0.115, CiteScore: 0)
Drugs in R & D     Full-text available via subscription   (Followers: 2, SJR: 0.881, CiteScore: 2)
Giornale Italiano di Health Technology Assessment     Full-text available via subscription  
High Blood Pressure & Cardiovascular Prevention     Full-text available via subscription   (Followers: 2, SJR: 0.524, CiteScore: 1)
Inpharma Weekly     Full-text available via subscription   (Followers: 2)
Pediatric Drugs     Full-text available via subscription   (Followers: 3, SJR: 0.814, CiteScore: 2)
Pharmaceutical Medicine     Full-text available via subscription   (Followers: 4, SJR: 0.187, CiteScore: 0)
PharmacoEconomics     Full-text available via subscription   (Followers: 21, SJR: 1.998, CiteScore: 3)
PharmacoEconomics & Outcomes News     Full-text available via subscription  
PharmacoEconomics German Research Articles     Full-text available via subscription  
Sports Medicine     Full-text available via subscription   (Followers: 40, SJR: 3.367, CiteScore: 7)
The Patient - Patient-Centered Outcomes Research     Full-text available via subscription   (Followers: 11, SJR: 1.095, CiteScore: 3)
Similar Journals
Similar Journals
A  B  C  D  E  F  G  H  I  J  K  L  M  N  O  P  Q  R  S  T  U  V  W  X  Y  Z  All
HOME > Browse the 3359 Publishers covered by JournalTOCs 1 2 3 4 5 6 7 8  
PublisherTotal Journals
1 2 3 4 5 6 7 8  
 
JournalTOCs
School of Mathematical and Computer Sciences
Heriot-Watt University
Edinburgh, EH14 4AS, UK
Email: journaltocs@hw.ac.uk
Tel: +00 44 (0)131 4513762
 


Your IP address: 44.220.44.148
 
Home (Search)
API
About JournalTOCs
News (blog, publications)
JournalTOCs on Twitter   JournalTOCs on Facebook

JournalTOCs © 2009-