Therapeutic Plasma Concentrations Research Articles

Exposure effects of synthetic glucocorticoid drugs on skeletal developmental and immune cell function in zebrafish

Synthetic glucocorticoids (GCs) are used to treat a wide range of human health conditions and as such are frequently detected in the aquatic environment. This, together with the highly conserved nature of the glucocorticoid system across vertebrates means that the potential for biological effects of GCs in fish is relatively high. Here, we found that exposure of zebrafish (Danio rerio) to environmentally relevant concentrations of 4 of the most widely used synthetic GCs (beclomethasone dipropionate, budesonide, fluticasone propionate, and prednisolone), from 0 to 4 days post fertilisation (dpf), resulted in no effects on embryo-larval development or bone and cartilage formation. However, after exposure to equivalents of human therapeutic plasma levels, developmental abnormalities were observed that included pericardial oedema, blood pooling and alterations in jaw cartilage. Furthermore, using a double transgenic zebrafish osteoblast and chondrocyte reporter line, exposure up to 10 dpf resulted in alterations to lower jaw cartilage and bone development for all compounds at, and above, human therapeutic plasma concentrations. In the case of beclomethasone dipropionate, a reduction in lower jaw intercranial distance was observed at the environmentally relevant concentration of 0.1 μg/L. Using further transgenic reporter lines with fluorescently tagged neutrophils and macrophages, we also show exposure of embryo-larvae (0–4 dpf) to the GCs tested resulted in altered immune cell migration, but only at relatively high exposure concentrations. Collectively, our findings show GC exposure impacts embryo-larval zebrafish development, immune function, and skeletal formation, but predominantly at concentrations greater than those currently reported for the aquatic environment. Despite this, however, it is suggested that studies with longer exposure times, and to mixtures of multiple GCs (many GCs act via the same mechanism of action) are warranted before we can confidently assert that these commonly detected contaminants do not pose a risk to fish in the wild.

Sub- and supratherapeutic efavirenz plasma concentrations with risk for HIV therapy failure are mainly genetically explained in Ugandan children: The prospective GENEFA cohort study.

Interindividual variations in efavirenz (EFV) plasma concentrations are extensive, but paediatric data on its consequences for viral control are scarce. The aim of this study was to explore the role of genetic variation in achieving therapeutic efavirenz plasma concentrations in a cohort of Ugandan children and the linkage between genetic CYP2B6 variants, EFV plasma variability, viral resistance and viral outcome. Ninety-nine treatment-naïve children, aged 3-12 years and living with HIV, were followed for 24 weeks after ART initiation assessing mid-dose efavirenz plasma concentrations, HIV RNA, HIV drug resistance and adherence. Polymorphisms in genes coding for drug-metabolizing enzymes were genotyped. Efavirenz concentrations were determined by liquid chromatography coupled with high-resolution tandem mass spectrometry. Metabolizer phenotype was predicted from composite genotypes of CYP2B6 (c.516G>T and c.983 T>C). A mixed effects restricted maximum likelihood regression model was used to identify important factors for efavirenz exposure. Efavirenz plasma concentrations were below the therapeutic interval (1000-4000 mg/mL) in 12-17% and above in 21-24% of measurements. Eight children had persisting subtherapeutic concentrations, five of which failed virologically and three acquired at least one new resistant mutation. Multivariate modelling explained 70% of interindividual variation in plasma concentration, with treatment duration, adherence, CYP2B6c.136A>G, and metabolizer phenotype as independent predictors of EFV concentration. In univariate analysis, metabolizer phenotype explained 50% of interindividual variation. Metabolizer phenotype explained 50% of interindividual variation in efavirenz plasma concentration. Autoinduction was not confirmed and >33% of the concentrations were outside the therapeutic interval. Subtherapeutic concentrations worsened virological resistance and outcomes. Genotype-based dosing may help avert both sub- and supratherapeutic efavirenz plasma concentrations in Ugandan children.

Monitoring the efficiency of reversal on anti-Xa direct oral anticoagulants using point-of-care viscoelastic testing

Bleeding events in patients receiving direct oral anticoagulation (DOAC) can be life-threatening even at therapeutic DOAC plasma concentrations, as anticoagulation impairs hemostasis and should therefore be identified immediately after hospital admission. The anticoagulatory effects of DOAC are typically not measurable in standard coagulation tests, such as PT or aPTT. Specific calibrated anti-FXa-tests allow specific drug monitoring, but they are too time-consuming for critical bleeding events and are commonly not available for 24 h/7 days in routine care. However, recent advances in point-of-care (POC) viscoelastic testing (VET) have shown a promising approach for rapid and quantitative detection of DOAC plasma concentrations using the Russell viper venom factor V activator (RVV for FXa-inhibitors) test or the ecarin clotting time (thrombin inhibitors). In acute bleeding situations, direct FXa inhibitors can be reversed by specific antidote andexanet alfa or hemostasis can be improved by prothrombin complex factor concentrates (PCCs). After reversal, confirmation of reversal efficacy is often requested, but no routine assays are currently available. Thus, the emergency management of bleeding DOAC patients is usually “blinded” with regard to reversal efficacy. POC VET laboratory assays might therefore also be helpful for measuring DOAC effects after reversal. We present a case series demonstrating the usefulness of RVV-clotting time post-DOAC reversal with andexanet alfa.

Imipramine in Dogs: A Pharmacokinetic Study Following Oral Administration under Fasted and Fed Conditions

This study investigates the pharmacokinetics (PK) of imipramine, a tricyclic antidepressant used in human psychiatric disorders and increasingly considered in veterinary medicine. Despite its longstanding use in canines, prior research on imipramine's PK in dogs is lacking. This study aimed to determine the PK of imipramine in dogs in regards to feeding conditions, and to ascertain whether desipramine (active metabolite) is formed or not. In this study, six male Labrador dogs underwent oral administration (1.5mg/kg) of imipramine tablets (10mg each; Tofranil®, Novartis) in both fasted and fed conditions. Dogs were randomly allocated to one of two treatment groups, employing an open, single-dose, two-treatment, two-phase, cross-over design, with a washout period of one week. Blood was drawn from the left cephalic vein to heparinized tubes at 0, 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, 10, 24, and 48hr. Plasma concentrations were quantified using a validated HPLC method, and the data were analyzed using PKanalixTM software with a non-compartmental approach.Concentrations of imipramine remained quantifiable up to 1.5hr after administration under both conditions. Desipramine, in both feeding states, was detectable for a short duration, but not quantifiable. No significant differences were observed in the PK parameters of imipramine between the fasting and fed states. The rapid attainment of maximum concentration (Cmax) occurred within 0.25hr, indicating a swift absorption rate. Notably, the terminal half-life in dogs was remarkably short at 0.25hr, prompting a re-evaluation of dosing strategies. Considering the recommended therapeutic plasma concentrations in humans, the administered dose might result in effective levels for a brief period of time. Future research should explore intravenous administration, multiple-dose studies, and metabolic investigations to further elucidate imipramine's PK in dogs.

Comparison of gepant effects at therapeutic plasma concentrations: connecting pharmacodynamics and pharmacokinetics

BackgroundOrally administered second-generation gepants are effective for the treatment of migraine. The intranasal administration of the third-generation gepant zavegepant might have additional benefits including a rapid onset of action, but it is not clear yet to which extent this has clinical relevance.MethodsWe examined the effect of zavegepant on the relaxations induced by calcitonin gene-related peptide (CGRP) in human isolated middle meningeal arteries. Furthermore, we connected the pharmacodynamics and pharmacokinetics of gepants by combining data from clinical and basic research.ResultsWe showed that 10 nM zavegepant potently antagonized the functional response to CGRP. We also showed that all gepants are effective at inhibiting functional responses to CGRP at their therapeutic plasma concentrations.ConclusionsThe relatively low predicted potency of zavegepant to inhibit CGRP-induced relaxation at therapeutic systemic plasma concentrations may point to the relevance of local delivery to the trigeminovascular system through intranasal administration. This approach may have additional benefits for various groups of patients, including overweight patients.

Cefepime trough levels and clinical outcomes in patients undergoing universal therapeutic drug monitoring: A prospective cohort study

BackgroundCefepime is an essential beta-lactam antibiotic for which therapeutic drug monitoring (TDM) is not performed routinely in many centers. Current literature on cefepime levels consists of retrospective reports of TDM applied selectively by clinicians, i.e., in the setting of suspected toxicity. In an effort to capture and define therapeutic plasma concentration thresholds, this prospective study applied TDM uniformly to consecutive inpatients with suspected or confirmed bacterial infections and observed their ensuing 30-day clinical course. MethodsThis single-center prospective observational study included adult patients hospitalized in the hematology, intermediate- or intensive-care units of Geneva University Hospitals between January 2019 and December 2021. Participants in steady state (receiving cefepime for ≥24 hours) uniformly underwent TDM at least once and thereafter were assessed for the primary and secondary outcomes of occurrence of adverse events and clinical response, respectively, through 30 days. ResultsAmong 151 included patients, 104 had at least one trough level. Most (95/104, 91%) experienced clinical success. Six (6%) experienced an adverse event possibly related to cefepime; no neurotoxicity was observed. Median trough level was 8.5 mg/L (IQR 5.8-13.3); trough levels of those with or without adverse events and those with or without clinical success did not differ significantly. Trough levels increased significantly with renal insufficiency and age. ConclusionCefepime TDM conducted uniformly in hospitalized patients with severe infections reveals lower trough levels than previously reported. Toxicity is rare and clinical effectiveness is high, such that the determination of a strict therapeutic range remains elusive.

Pharmacokinetics, Fecal Output, and Grimace Scores in Rabbits Given Long-acting Buprenorphine or Fentanyl for Postsurgical Analgesia.

The New Zealand white rabbit (Oryctolagus cuniculus) is a frequently used surgical model. Pain management after surgery is a critical aspect of animal welfare. Recently, a long-acting buprenorphine formulation (Ethiqa XR; EXR) was approved for use in rats and mice but has not yet been investigated in rabbits. The current study aimed to determine whether a single subcutaneous dose of 0.15mg/kg of EXR could achieve and maintain therapeutic buprenorphine plasma concentrations (0.1ng/mL) for 72h in male and female rabbits. We also evaluated the safety profiles of EXR and the fentanyl patch (FP) by assessing fecal output after surgery, because opioids are known to decrease intestinal motility. Behavior and pain scores were compared for rabbits that received either EXR or the FP after undergoing an annulus puncture procedure to induce osteoarthritis. EXR at 0.15mg/kg SC provided a shorter time to onset and sustained analgesia for 72h in male and female rabbits, whereas the FP provided suboptimal analgesia after 48h. Both EXR and FP reduced fecal output after surgery. Output returned to baseline levels within 72h for the EXR group and remained slightly below baseline at 96h after surgery for the fentanyl group. Grimace pain scores revealed no significant difference between treatment groups. These results suggest that EXR is a safe and effective option for postoperative pain management in rabbits.

Subcutaneous administration of ceftazidime at 20 and 40 mg/kg produces theoretically therapeutic plasma concentrations for at least 120 hours in red-eared sliders (Trachemys scripta elegans).

To evaluate and compare the pharmacokinetic parameters of SC ceftazidime administered at 20 and 40 mg/kg to red-eared sliders. 8 adult red-eared sliders (Trachemys scripta elegans). In a sequential, 2-period study with a 3-week washout period between treatments, ceftazidime was administered SC to turtles at 20 and 40 mg/kg. Blood samples were collected from the subcarapacial sinus at 0, 24, 48, 72, 96, and 120 hours after ceftazidime administration. Plasma ceftazidime concentrations were quantified using reversed-phase HPLC. Mean plasma half-life after 20- and 40-mg/kg dosing was 39.75 ± 8.0 hours and 33.03 ± 6.56 hours, respectively. Mean maximum plasma concentration after 20- and 40-mg/kg dosing was 71.0 ± 15.93 µg/mL and 120.0 ± 30.62 µg/mL, respectively. Mean plasma ceftazidime concentrations remained ≥ 8 µg/mL, the theoretical MIC for various reptile pathogens for all time points. Results indicate that ceftazidime dosed at either 20 or 40 mg/kg produces plasma concentrations exceeding the theoretical MIC of various reptile pathogens for at least 120 hours. An ideal dosing interval could not be determined, as all plasma concentrations remained above the threshold of interest for all time points. Follow-up studies should focus on establishing a dosing interval and more rigorous monitoring for potential adverse effects.

Differential inhibition of sildenafil and macitentan on saxagliptin metabolism

The development of diabetes mellitus (DM) is generally accompanied by erectile dysfunction (ED) and pulmonary arterial hypertension (PAH), which increases the use of combination drug therapy and the risk of drug-drug interactions. Saxagliptin for the treatment of DM, sildenafil for the treatment of ED and PAH, and macitentan for the treatment of PAH are all substrates of CYP3A4, which indicates their potential involvement in drug-drug interactions. Therefore, we investigated potential pharmacokinetic interactions between saxagliptin and sildenafil/macitentan. We investigated this speculation both in vitro and in vivo, and explored the underlying mechanism using in vitro hepatic metabolic models and molecular docking assays. The results showed that sildenafil substantially inhibited the metabolism of saxagliptin by occupying the catalytic site of CYP3A4 in a competitive manner, leading to the alterations in the pharmacokinetic properties of saxagliptin in terms of increased maximum plasma concentration (Cmax), area under the plasma concentration–time curve from time 0 to 24 h (AUC(0-t)), area under the plasma concentration–time curve from time 0 extrapolated to infinite time (AUC(0-∞)), decreased clearance rate (CLz/F), and prolonged terminal half-life (t1/2). In contrast, a slight inhibition was observed in saxagliptin metabolism when concomitantly used with macitentan, as no pharmacokinetic parameters were altered, except for CLz/F. Thus, dosage adjustment of saxagliptin may be required in combination with sildenafil to achieve safe therapeutic plasma concentrations and reduce the risk of potential toxicity, but it is not necessary for co-administration with macitentan.

Pharmacokinetic/pharmacodynamic evaluation of gamithromycin against rabbit pasteurellosis

BackgroundGamithromycin is an effective therapy for bovine and swine respiratory diseases but not utilized for rabbits. Given its potent activity against respiratory pathogens, we sought to determine the pharmacokinetic profiles, antimicrobial activity and target pharmacokinetic/pharmacodynamic (PK/PD) exposures associated with therapeutic effect of gamithromycin against Pasteurella multocida in rabbits.ResultsGamithromycin showed favorable PK properties in rabbits, including high subcutaneous bioavailability (86.7 ± 10.7%) and low plasma protein binding (18.5–31.9%). PK analysis identified a mean plasma peak concentration (Cmax) of 1.64 ± 0.86 mg/L and terminal half-life (T1/2) of 31.5 ± 5.74 h after subcutaneous injection. For P. multocida, short post-antibiotic effects (PAE) (1.1–5.3 h) and post-antibiotic sub-inhibitory concentration effects (PA-SME) (6.6–9.1 h) were observed after exposure to gamithromycin at 1 to 4× minimal inhibitory concentration (MIC). Gamithromycin demonstrated concentration-dependent bactericidal activity and the PK/PD index area under the concentration-time curve over 24 h (AUC24h)/MIC correlated well with efficacy (R2 > 0.99). The plasma AUC24h/MIC ratios of gamithromycin associated with the bacteriostatic, bactericidal and bacterial eradication against P. multocida were 15.4, 24.9 and 27.8 h in rabbits, respectively.ConclusionsSubcutaneous administration of 6 mg/kg gamithromycin reached therapeutic concentrations in rabbit plasma against P. multocida. The PK/PD ratios determined herein in combination with ex vivo activity and favorable rabbit PK indicate that gamithromycin may be used for the treatment of rabbit pasteurellosis.

First evidence of a biomarker-based dose-response relationship in chronic pain using physiological closed-loop spinal cord stimulation

Background and objectivesIn spinal cord stimulation (SCS) therapy, electricity is the medication delivered to the spinal cord for pain relief. In contrast to conventional medication where dose is determined by...

CYCLODEXTRIN IN NOVEL FORMULATIONS AND SOLUBILITY ENHANCEMENT TECHNIQUES: A REVIEW

Using cyclodextrin helps make different dosage forms more soluble. The oligosaccharide class known as cyclodextrins (CDs) is made up of glucose units bound together in a ring. CDs have the promising ability to assemble into complexes with drug molecules and improve their physicochemical properties without the need for molecular modifications. Generally, drug-CD complexes have a stoichiometry of 1:1. However, natural CDs have a tendency to self-assemble and form aggregates in aqueous media, which can reduce the solubility of the CDs by aggregating. One can increase their complexation capacity and solubility through derivative formation, but the final outcome depends on the kind and extent of substitution. Drug penetration through biological membranes can be improved by the formation of water-soluble drug-CD complexes. Solubility is the property of a solid dissolving into a liquid phase to form a homogenous system. Solubility is a crucial component in obtaining the right drug concentration in the systemic circulation for the optimal pharmacological response. Orally administered poorly soluble drugs often require high dosages to reach therapeutic plasma concentrations. Their low solubility in water is one of the primary problems with creating new chemical entities through formulation. The BCS classification system places these medications in class II, which is characterized by high permeability and poor solubility. To greatly improve these medications, it is possible to make them more bioavailable and soluble.

Assessment of Quinidine-Induced Torsades de Pointes Risks Using a Whole-Body Physiologically Based Pharmacokinetic Model Linked to Cardiac Ionic Current Inhibition.

The lethality of torsades de pointes (TdP) by drugs is one of main reasons that some drugs were withdrawn from the market. In order to assess drug-induced TdP risks, a model of cardiac ionic current suppression in human ventricular myocytes (ToR-ORd model), combined with the maximum effective free therapeutic plasma concentration or the maximum effective free therapeutic myocyte concentration was often used, with the latter proved to be more relevant and more accurate. We aimed to develop a whole-body physiologically-based pharmacokinetic (PBPK) model, incorporated with a human cardiomyocyte pharmacodynamic (PD) model, to provide a comprehensive assessment of drug-induced TdP risks in normal and specific scenarios. Quinidine served as an example to validate the PBPK-PD model via predicting plasma quinidine concentrations and quinidine-induced changes in QT interval (ΔQTc). The predicted plasma quinidine concentrations and ΔQTc values following oral administration or intravenous administration of quinidine were comparable to clinic observations. Visual predictive checks showed that most of the observed plasma concentrations and ΔQTc values fell within the 5th and 95th percentiles of simulations. The validated PBPK-PD model was further applied to assess the TdP risks using frequencies of early afterdepolarization and long-QT syndrome occurrence in 4 scenarios, such as therapeutic dose, supra-therapeutic dose, alkalosis, and hyperkalemia in 200 human subjects. In conclusion, the developed PBPK-PD model may be applied to predict the quinidine pharmacokinetics and quinidine-induced TdP risks in healthy subjects, but also simulate quinidine-induced TdP risks under disease conditions, such as hypokalemia and alkalosis.

Analysis of cardiohemodynamic and electrophysiological effects of morphine along with its toxicokinetic profile using the halothane-anesthetized dogs.

Although morphine has been used for treatment-resistant dyspnea in end-stage heart failure patients, information on its cardiovascular safety profile remains limited. Morphine was intravenously administered to halothane-anesthetized dogs (n=4) in doses of 0.1, 1 and 10 mg/kg/10 min with 20 min of observation period. The low and middle doses attained therapeutic (0.13 µg/mL) and supratherapeutic (0.97 µg/mL) plasma concentrations, respectively. The low dose hardly altered any of the cardiovascular variables except that the QT interval was prolonged for 10-15 min after its start of infusion. The middle dose reduced the preload and afterload to the left ventricle for 5-15 min, then decreased the left ventricular contractility and mean blood pressure for 10-30 min, and finally suppressed the heart rate for 15-30 min. Moreover, the middle dose gradually but progressively prolonged the atrioventricular conduction time, QT interval/QTcV, ventricular late repolarization period and ventricular effective refractory period without altering the intraventricular conduction time, ventricular early repolarization period or terminal repolarization period. A reverse-frequency-dependent delay of ventricular repolarization was confirmed. The high dose induced cardiohemodynamic collapse mainly due to vasodilation in the initial 2 animals by 1.9 and 3.3 min after its start of infusion, respectively, which needed circulatory support to treat. The high dose was not tested further in the remaining 2 animals. Thus, intravenously administered morphine exerts a rapidly appearing vasodilator action followed by slowly developing cardiosuppressive effects. Morphine can delay the ventricular repolarization possibly through IKr inhibition in vivo, but its potential to develop torsade de pointes will be small.

Understanding pharmaceutical exposure and the potential for effects in marine biota: A survey of bonefish (Albula vulpes) across the Caribbean Basin

Most research on pharmaceutical presence in the environment to date has focused on smaller scale assessments of freshwater and riverine systems, relying mainly on assays of water samples, while studies in marine ecosystems and of exposed biota are sparse. This study investigated the pharmaceutical burden in bonefish (Albula vulpes), an important recreational and artisanal fishery, to quantify pharmaceutical exposure throughout the Caribbean Basin. We sampled 74 bonefish from five regions, and analyzed them for 102 pharmaceuticals. We assessed the influence of sampling region on the number of pharmaceuticals, pharmaceutical assemblage, and risk of pharmacological effects. To evaluate the risk of pharmacological effects at the scale of the individual, we proposed a metric based on the human therapeutic plasma concentration (HTPC), comparing measured concentrations to a threshold of 1/3 the HTPC for each pharmaceutical. Every bonefish had at least one pharmaceutical, with an average of 4.9 and a maximum of 16 pharmaceuticals in one individual. At least one pharmaceutical was detected in exceedance of the 1/3 HTPC threshold in 39% of bonefish, with an average of 0.6 and a maximum of 11 pharmaceuticals exceeding in a Key West individual. The number of pharmaceuticals (49 detected in total) differed across regions, but the risk of pharmacological effects did not (23 pharmaceuticals exceeded the 1/3 HTPC threshold). The most common pharmaceuticals were venlafaxine (43 bonefish), atenolol (36), naloxone (27), codeine (27), and trimethoprim (24). Findings suggest that pharmaceutical detections and concentration may be independent, emphasizing the need to monitor risk to biota regardless of exposure diversity, and to focus on risk quantified at the individual level. This study supports the widespread presence of pharmaceuticals in marine systems and shows the utility of applying the HTPC to assess the potential for pharmacological effects, and thus quantify impact of exposure at large spatial scales.

Do NSAIDs and Other Pain Relief Drugs Can Inhibit the Growth of Lactobacillaceae?

Non-steroidal anti-inflammatory drugs (NSAIDs) commonly used in clinical practice may cause gastrointestinal injuries and influence the gut microbiota. This study investigated the effects of various NSAIDs and some analgesics on the viability of Lactobacillaceae strains (including probiotic strains) in vitro. It was found that diclofenac, ibuprofen, ketoprofen, dexketoprofen, flurbiprofen, and acetylsalicylic acid inhibited the growth of lactobacilli at a concentration of 0.05-3.2 mg/ml. These MICs of NSAIDs are well above therapeutic plasma concentrations achieved in humans, indicating that the tested drugs should not inhibit the growth of lactobacilli in the human digestive tract.

Green Alternatives in Pharmaceutical and Bioanalytical Analysis of TDM Required Drugs: Procainamide.

In drug analysis, using non-hazardous solvents instead of the ones harmful to humans and the environment is a green strategy to protect analysts and environmental health. Procainamide (PCA) is an antiarrhythmic drug requiring therapeutic drug monitoring (TDM) because of its narrow therapeutic window and serious side effects. The aim of this study is to develop validated green HPLC methods to be used in drug quality control and TDM analysis for PCA, thus indicating the further applicability in the analysis of TDM-required drugs, such as immunosuppressants, anti-cancer drugs, and psychiatric drugs. Human-friendly ethanol was selected as an organic solvent in the mobile phase. PCA was eluted from NUCLEODUR 100-5 C8 ec (5 μm, 150 x 4.6 mm) column by a mobile phase containing ethanol and 50 mM NaH2PO4 buffer (5:95, v/v). The mobile phase flow rate was 1.0 ml min-1, the column temperature was 35 °C, and the wavelength at the PDA detector was 278 nm. Retention time for PCA was 5.0 min and 7.7 min for paracetamol as an internal standard (IS). In the green HPLC method for pharmaceutical analysis, the highest relative standard deviation (RSD) and mean recovery values were 1.32% and 98.89%, respectively. In the analysis of plasma, the sample preparation step was only smooth protein precipitation by ethanol. Thus, the bioanalytical method was fully green having a limit of detection (LOD) of 0.3 μg ml-1 and a limit of quantification (LOQ) of 0.8 μg ml-1. The therapeutic plasma concentration for PCA was reported in the range of 4-12 μg ml-1. As a result, the green HPLC methods developed and validated in this study were selective, accurate, precise, reproducible, and trustable and have the quality for the application in pharmaceutical and TDM analysis of PCA, thus encouraging green HPLC analysis of other TDM required drugs.

Clinical Guidance for Dosing and Monitoring Oral Antihormonal Drugs in Patients with Breast Cancer After Roux-en-Y Gastric Bypass.

Obesity is associated with an increased risk of cancers, such as breast cancer. Roux-en-Y gastric bypass (RYGB) is a common surgical intervention used to induce weight loss, reduce comorbidities, and improve overall survival. Due to alterations in the gastrointestinal tract, RYGB is associated with changes in oral drug disposition, which can affect treatment outcomes. Oral antihormonal agents were monitored in 9 patients who previously underwent RYGB. The results of therapeutic drug monitoring and estradiol concentrations were analyzed, and a review of the relevant literature was performed. As only 1 of the 6 patients prescribed tamoxifen achieved a therapeutic endoxifen concentration with the standard dose of 20 mg/d, a higher starting dose of 40 mg/d was recommended to increase the probability of attaining a therapeutic plasma concentration. All patients with decreased CYP2D6 metabolic activity could not achieve therapeutic plasma concentrations; therefore, CYP2D6 genotyping was recommended before the initiation of tamoxifen therapy to identify patients who should be switched to aromatase inhibitors. Anastrozole and letrozole exposure in patients who underwent RYGB patients appeared sufficient, with no dose adjustment required. However, until more data become available, monitoring aromatase inhibitor efficacy is recommended. Monitoring the drug concentrations is a viable option; however, only indicative data on therapeutic drug monitoring are available. Therefore, estradiol concentrations should be measured.

Pharmacokinetics of meloxicam in pre-ruminant calves after intravenous, oral, and subcutaneous administration.

Meloxicam is routinely used for pain alleviation in pre-ruminant calves during husbandry procedures. The pharmacokinetics of a single dose (0.5 mg/kg) of meloxicam was investigated after intravenous (IV), subcutaneous (SC), and oral (PO) administration in 30 pre-ruminant calves. Each group included 10 calves. Oral meloxicam was administered at least 1 h after feeding. Plasma samples were collected for up to 168 h, and the meloxicam concentration was analysed with liquid chromatography and mass spectrometry, followed by a noncompartmental pharmacokinetic analysis. The maximum meloxicam concentrations in plasma were 1.91 ± 0.27 μg/mL and 1.77 ± 0.16 μg/mL after SC and PO routes, respectively. The time of maximum concentration was 7.6 ± 2.8 h after SC and 10.0 ± 5.7 h after PO administration. The approximate bioavailability of meloxicam was 97% for SC and PO routes. The elimination half-lives were 79.2 ± 12.4, 84.6 ± 24.8, and 84.8 ± 22.3 h after IV, SC, and PO routes, respectively. The results suggest that the therapeutic meloxicam concentrations in plasma that are required for pain relief in other species, such as horses, may be maintained for several days following a single dose (0.5 mg/kg) administered IV, SC, or PO in calves.

Predicting clozapine dose required to achieve a therapeutic plasma concentration - A comparison of a population algorithm and three algorithms based on gene variant models.

Clozapine is the most effective antipsychotic but requires careful titration to therapeutic blood levels. Methods to predict therapeutic doses are based on population data. We aimed to construct a model based on genetic variants which accurately predicted plasma levels for clozapine. We measured clozapine plasma levels in patients on a stable dose of clozapine who were known to be fully compliant. Measured plasma levels were adjusted for sampling time and dose. Hepatic enzyme variants were analysed and models were constructed to predict the required dose. These predictions were compared with a standard population-based algorithm. We measured plasma clozapine concentrations in 18 adherent patients on stable doses of clozapine and recorded the exact timing of sampling. For the algorithm-predicted dose, the mean difference was -49.9 mg/day ((SD 155.9), r = 0.36) from the actual dose required to give a plasma concentration of 0.35 ng/ml. The gene variant activity score predicted a dose for which the mean difference was -43.5 mg/day ((SD 140.1), r = 0.55). For the gene variant activity score with omeprazole correction predicted dose, the mean difference was -31.0 mg/day ((SD 140.8), r = 0.54), and with the gene variant CYP1A2 inducibility predicted dose the mean difference was 44.9 mg/day ((SD 160.8), r = 0.32). Our gene variant activity score with omeprazole correction gave the best estimate of the clozapine dose required to achieve a minimum therapeutic plasma concentration. The use of this model will allow safer titration of clozapine and may reduce the need for plasma-level monitoring during titration.