Measured Plasma Concentrations Research Articles

Loading Dose of Ceftazidime Needs to Be Increased in Critically Ill Patients: A Retrospective Study to Evaluate Recommended Loading Dose with Pharmacokinetic Modelling.

To rapidly achieve ceftazidime target concentrations, a 2 g loading dose (LD) is recommended before continuous infusion, but its adequacy in critically ill patients, given their unique pharmacokinetics, needs investigation. This study included patients from six ICUs in Saint-Etienne and Paris, France, who received continuous ceftazidime infusion with plasma concentration measurements. Using MONOLIX and R, a pharmacokinetic (PK) model was developed, and the literature on ICU patient PK models was reviewed. Simulations calculated the LD needed to reach a 60 mg/L target concentration and assessed ceftazidime exposure for various regimens. Among 86 patients with 223 samples, ceftazidime PK was best described by a one-compartment model with glomerular filtration rate explaining clearance variability. Typical clearance and volume of distribution were 4.45 L/h and 88 L, respectively. The literature median volume of distribution was 37.2 L. Simulations indicated that an LD higher than 2 g was needed to achieve 60 mg/L in 80% of patients, with a median LD of 4.9 g. Our model showed a 4 g LD followed by 6 g/day infusion reached effective concentrations within 1 h, while a 2 g LD caused an 18 h delay in achieving target steady state.

Pharmacokinetic, bioequivalence, and safety assessments of two brands of 30-mg nifedipine controlled-release formulations in Chinese healthy subjects.

This study aimed to analyze the pharmacokinetic (PK) characteristics, safety, and bioequivalence (BE) of a test (T) preparation of a nifedipine controlled-release tablet and the reference (R) drug (Adalat GTIS) in Chinese study participants in the context of fasting and postprandial states. An open-label, single-center, randomized, single-dose, two-period study was designed including two separate arms, one with administration under fasting conditions and one with administration under postprandial conditions (high-fat, high-calorie breakfast). After oral administration, the nifedipine concentrations in plasma were quantitatively analyzed using liquid chromatography-tandem mass spectrometry (LC-MS/MS) at regular intervals. Primary PK parameters, including the area under the concentration curve from 0 to infinity (AUC0-∞), the area under the concentration profile from 0 to the last measurable concentration time (AUC0-t), and maximal measured plasma concentration (Cmax) were log-transformed with BE limits of 80-125% to evaluate BE. All adverse events (AEs) were wholly supervised. The PK profiles of the T and R formulations were comparable to each other under both fasting and postprandial conditions. The 90% confidence intervals (CIs) of the AUC0-∞, AUC0-t, and Cmax were 92.69-106.06%, 93.32-107.05%, and 99.53-116.71%, respectively, under the fasting state. The 90% CIs of the AUC0-∞, AUC0-t, and Cmax were 105.05-117.40%, 105.43-117.82%, and 102.66-116.30%, respectively, in the postprandial arm. 47 cases of drug-associated AEs were noted in the entire research. Under both the fasting and postprandial states, the two nifedipine controlled-release formulations were bioequivalent and safe in healthy Chinese subjects.

Study of risk factors and clinical management of patients with clinical non-response due to low plasma levels of anti-tubercular drugs.

This study was carried out to assess the role of therapeutic drug monitoring of crucial first-line anti-tubercular drugs: rifampicin (R) and isoniazid (H) among 75 non-responding proven drug-sensitive tuberculosis patients on treatment followed by intervention in field conditions. The intervention was done in the form of either an increase in the dosage of R and H in patients with minimally low drug levels or a modification of the regimen in a certain group of patients with significantly low drug levels by augmenting it with three or four second-line drugs in addition to standard first-line drugs. This study also aimed to determine the relationship between the measured plasma concentration of anti-tubercular drugs and various demographic, microbiological, radiological, and malabsorption factors and the presence of co-morbidities affecting them. The study also focused on the clinical impact of the intervention for low plasma levels of anti-TB drugs on TB treatment outcomes. In our study overall, 85.5% of patients had low levels of any drug. In 85.3% of patients, R levels were low, and in 39.1%, H levels were low. On univariate analysis, low body mass index (BMI), hypoalbuminemia, bilateral disease on chest X-rays, and the presence of cavities were found to be significantly associated with low drug levels, while none of the factors were independently significantly associated. Low BMI, pulmonary tuberculosis and disseminated tuberculosis, far-advanced disease and bilateral disease on chest X-ray, presence of cavities, and only low R levels were associated with unfavorable outcomes, with none of the factors found to be significant on multivariate analysis. In our study, it was seen that the treatment outcome was favorable in 59.6% of patients in whom this intervention was done by augmenting the treatment regimen with three/four second-line drugs along with increasing the dose of R and H. To conclude, various factors may be associated with low plasma levels of anti-tubercular drugs. If such patients show clinical non-response after >6 months of treatment and have significantly low drug levels, with an absence of drug resistance, their treatment regimen may need augmentation with three/four second-line drugs along with an increase in the dose of R and H, which may lead to a favorable outcome.

Quantification of the Plasma Concentration of Vadadustat by High-Performance Liquid Chromatography with Ultraviolet Detection and Ultra-Performance Liquid Chromatography-Tandem Mass Spectrometry.

An inexpensive, simple, and accurate plasma concentration measurement system is needed to actively conduct pharmacokinetic and pharmacodynamic analyses of vadadustat, hypoxia-inducible factor-prolyl hydroxylase inhibitor, in clinical settings. In this study, the authors aimed to develop a method for measuring vadadustat in human plasma that could be applied for therapeutic drug monitoring using high-performance liquid chromatography with ultraviolet detection (HPLC-UV) in a clinical setting. Plasma samples (100 μL) were pretreated with acetonitrile using butyl paraoxybenzoate as an internal standard. Chromatographic separation was performed on a SunShell PFP C18 column (2.6 μm, 4.6 mm × 150 mm). The mobile phase consisted of (A) 20 mM of phosphate buffer (pH 2.4) and (B) acetonitrile (60:40, v/v), delivered isocratically at a flow rate of 1 mL/min. The analytes were detected by UV absorbance at a wavelength of 220 nm, and the column temperature was 40°C. To evaluate the applicability of HPLC-UV in a clinical setting, blood samples were collected at 19 time points from 7 patients who had been taking vadadustat. The calibration curve was linear over the concentration range of 0.2-150 mcg/mL (R2 > 0.99). Intra-assay and interassay accuracy, precision, and stability met the Food and Drug Administration recommendations. The vadadustat plasma concentrations of patients analyzed using the current HPLC-UV method were almost equal to those measured using ultra-performance liquid chromatography-tandem mass spectrometry (mean difference: 0.13 mcg/mL). Large variability in the dose-adjusted plasma concentrations of vadadustat at 12 hours after administration was observed between patients (coefficient of variation = 57.6%). This HPLC-UV method is a simple, accurate quantification method for evaluating plasma concentrations in patients taking vadadustat in a clinical setting.

Plasma concentrations of buprenorphine administered via matrix-type transdermal patches applied at three different anatomical locations in healthy adult horses.

Anatomical location-dependent differences in transdermal opioid penetration are well described in human patients. Although this has been investigated in horses with fentanyl, there is no literature available on location-dependent plasma buprenorphine concentrations when administered as a transdermal matrix-type patch. This study aims to compare the plasma concentrations achieved from the matrix-type transdermal buprenorphine patches placed at different anatomical sites (metacarpus, gaskin, and ventral tail base) in healthy adult horses. This is a randomized experimental study with a Latin square design. Six adult horses were given each of three treatments with a minimum 10-day washout period. For each treatment, two 20 μg h-1 matrix-type buprenorphine patches were applied to the ventral aspect of the tail base (TailTDP), metacarpus region (MetacarpusTDP), or gaskin region (GaskinTDP). Whole blood samples (for determination of buprenorphine concentration) and physiological variables were collected before (0 h) and at 0.5, 2, 4, 6, 8, 10, 12, 16, 24, 32, 48, 56, 72, 96 and 120 h after patches were applied. The patches were removed 96 h following placement and were analyzed for residual buprenorphine content. Buprenorphine concentrations were measured in plasma by LC-MS/MS. A mixed-effects model was used to analyze the physiological variables. Between the three treatment groups, there was no change in physiological variables across timepoints as compared to baseline and when compared to each other in a single horse and between horses (p > 0.3). When comparing all three locations, the buprenorphine uptake was observed to be more consistent with respect to measurable plasma concentrations >0.1 ng ml-1 when applied to the ventral aspect of the tail base. In the TailTDP group, the mean plasma buprenorphine concentrations were >0.1 ng ml-1 from 2 to 32 h. The highest group mean was 0.25 ng ml-1 noted at 4 h. The metacarpal and gaskin regions presented more erratic and inconsistent buprenorphine uptake and plasma concentrations as compared to the ventral aspect of the tail base. Further research must be directed at investigating the optimal dose, achievable duration of analgesia, change in measurable plasma concentrations, and behavioral and systemic effects.

Plasma epinephrine and norepinephrine responses to extreme heat exposures in young and older adults.

Hyperthermia is known as a hyperadrenergic state, yet there is a lack of data on the sympathetic responses to ambient heat stress in humans. Therefore, we investigated the plasma epinephrine and norepinephrine concentrations of healthy young and older adults exposed to 3 h of very hot and dry, as well as hot and humid, heat, both with accompanying activities of daily living. We hypothesized that older adults, compared with young adults, would have augmented increases in epinephrine and norepinephrine concentrations secondary to increased thermal strain. Young (n = 20) and older (n = 18) participants underwent two 3-h heat exposures on different days: very hot and dry [47°C and 15% relative humidity (RH)] and hot and humid (41°C and 40% RH). To mimic heat generation comparable to activities of daily living, participants performed seven 5-min bouts of light cycling (approximately 3 METS) dispersed throughout the heat exposure. We measured plasma concentrations of epinephrine and norepinephrine at baseline, end, and 2-h postheat exposure. There was a group-wide increase in epinephrine from baseline to the end of the heat exposure (Δ19 ± 27 pg/mL; P < 0.001) in the hot and humid condition, but not in the very hot and dry condition (Δ6 ± 19 pg/mL; P = 0.10). There were group-wide decreases in norepinephrine concentrations from baseline to the end of the heat exposure in both the very hot and dry (Δ-131 ± 169 pg/mL; P < 0.001) and the hot and humid (Δ-138 ± 157 pg/mL; P < 0.001) conditions, with both returning to near baseline at 2-h postexposure. These data suggest that ambient heating with accompanying bouts of light intermittent exercise may lead to decreases in circulating concentrations of norepinephrine.NEW & NOTEWORTHY Herein we present plasma epinephrine and norepinephrine concentrations to 3 h of very hot and dry, as well as hot and humid, heat exposures with accompanying activities of daily living in young and older participants. We found 1) increased plasma concentrations of epinephrine in young and older adults following the hot and humid, but not the very hot and dry exposures and 2) decreased concentrations of norepinephrine in both groups following exposure to both conditions.

Population pharmacokinetics of TLD-1, a novel liposomal doxorubicin, in a phase I trial.

TLD-1 is a novel pegylated liposomal doxorubicin (PLD) formulation aiming to optimise the PLD efficacy-toxicity ratio. We aimed to characterise TLD-1's population pharmacokinetics using non-compartmental analysis and nonlinear mixed-effects modelling. The PK of TLD-1 was analysed by performing a non-compartmental analysis of longitudinal doxorubicin plasma concentration measurements obtained from a clinical trial in 30 patients with advanced solid tumours across a 4.5-fold dose range. Furthermore, a joint parent-metabolite PK model of doxorubicinentrapped, doxorubicinfree, and metabolite doxorubicinol was developed. Interindividual and interoccasion variability around the typical PK parameters and potential covariates to explain parts of this variability were explored. Medians standard deviations of dose-normalised doxorubicinentrapped+free Cmax and AUC0-∞ were 0.342 0.134mg/L and 40.1 18.9mg·h/L, respectively. The median half-life (95h) was 23.5h longer than the half-life of currently marketed PLD. The novel joint parent-metabolite model comprised a one-compartment model with linear release (doxorubicinentrapped), a two-compartment model with linear elimination (doxorubicinfree), and a one-compartment model with linear elimination for doxorubicinol. Body surface area on the volumes of distribution for free doxorubicin was the only significant covariate. The population PK of TLD-1, including its release and main metabolite, were successfully characterised using non-compartmental and compartmental analyses. Based on its long half-life, TLD-1 presents a promising candidate for further clinical development. The PK characteristics form the basis to investigate TLD-1 exposure-response (i.e., clinical efficacy) and exposure-toxicity relationships in the future. Once such relationships have been established, the developed population PK model can be further used in model-informed precision dosing strategies. ClinicalTrials.gov-NCT03387917-January 2, 2018.

The efficacy of wound catheter infusion with local anesthetics for the treatment of postoperative pain in children: A systematic review

AbstractWound catheter infusion (WCI) with local anesthetics (LA) is a regional anesthesia technique, which has shown to produce effective postoperative analgesia in adults, without any adverse effects on wound healing. To investigate the efficacy and safety of WCI with LA for the treatment of postoperative pain in children, we conducted a systematic review of literature published until 2020. The literature search included articles concerning subcutaneous WCI with LA, in the surgical wound, as treatment of postoperative pain, in children &lt;18 years of age. Exclusion criteria were studies describing peripheral nerve blocks, intercostal, abdominal or thoracic wall blocks and single local anesthetic infiltration of the surgical wound. The articles were appraised for quality and only randomized controlled trials with a Jadad score ≥3 were included for evaluation of results concerning postoperative pain scores and opioid use. All relevant original studies, including observational studies and case reports, were assessed for adverse events and measurements of LA plasma concentrations during WCI. A total of 1907 articles were found, leading to 92 relevant abstracts selected for further review. After exclusion of articles of which full texts could not be retrieved or because of exclusion criteria, 28 articles remained. Thirteen articles described randomized controlled trials, of which 10 were assessed as good or excellent in quality. Due to the small number and heterogeneity of the studies, the data could not be pooled. Instead, results were described per type of procedure: abdominal surgery, extremity surgery, thoracic surgery and iliac crest bone harvesting. Reduced pain scores and opioid needs were demonstrated after abdominal and extremity surgery. In five studies, plasma levels of LA were measured, which all remained below toxic thresholds. In all relevant studies, no serious adverse events concerning the use of WCI were reported.

Pharmacokinetics and Bioequivalence of Two Formulations of Azithromycin Tablets: A Randomized, Single-Dose, Three-Period, Crossover Study in Healthy Chinese Volunteers Under Fasting and Fed Conditions.

Azithromycin is the first azalide antibiotic that is related to the macrolide family of antibiotics. Bioequivalence studies in China are initiated by the National Medical Products Administration (NMPA), which supports a generic consistency evaluation program for ensuring that generic products manufactured in China meet the required standards and provide equivalent therapeutic effects to their reference products. This study aimed to assess the bioequivalence of two azithromycin tablets under both fasting and fed conditions in healthy Chinese volunteers. This was a single-center, open-label, single-dose, randomized, three-way crossover trial with two independent groups (fasting group and fed group). A total of 72 healthy Chinese subjects (36 subjects in the fasting state and 36 subjects in the fed state) were enrolled and randomized to treatment. Blood samples were collected from 0 to 120 h after a single oral dose of a 250-mg generic azithromycin tablet (test, T) or branded azithromycin tablet (reference, R). The plasma concentrations of azithromycin were determined by high-performance liquid chromatography-tandem mass spectrometry (HPLC‒MS/MS). A non-compartmental analysis method was used to estimate the pharmacokinetic parameters. Adverse events were documented. In a fasting state, the bioequivalence of maximum plasma concentration (Cmax) was evaluated using the reference-scaled average bioequivalence (RSABE) approach (within-subject standard deviation, SWR >0.294), and the bioequivalence of area under the concentration-time curve from time 0 to the time of the last measurable plasma concentration (AUC0-t) and area under the concentration-time curve from time 0 extrapolated to infinity (AUC0-∞) were evaluated by the average bioequivalence (ABE) method (SWR < 0.294). The geometric mean ratio (GMR) of T/R for Cmax was 106.49%, while the 95% upper confidence bound was < 0. The GMRs of AUC0-t and AUC0-∞ were 103.34% and 101.28%, and the 90% confidence intervals (CIs) of the test/reference were 95.90-111.35%/94.85-108.15%, respectively. In the fed state, the RSABE approach was applied to estimate the bioequivalence of Cmax (SWR >0.294), and the ABE approach was applied to estimate the bioequivalence of AUC0-t and AUC0-∞ (SWR < 0.294). The GMR for Cmax was 99.80%, while the 95% upper confidence bound value was < 0. The GMRs of AUC0-t and AUC0-∞ were 97.07% and 98.15%, and the 90% CIs of the T/R were 90.02-104.68% and 90.66-106.25%, respectively. All adverse events were mild and transient. The trial indicated that the test and the reference azithromycin tablets were bioequivalent and well tolerated in healthy Chinese volunteers under both fasting and fed conditions. Clinicaltrials, ChiCTR2300071630 (retrospectively registered in 19/05/2023).

Synergizing pharmacometrics and pharmacovigilance for medication error management: the case of secukinumab.

To demonstrate the effective integration of pharmacometrics and pharmacovigilance in managing medication errors, highlighted by a case involving secukinumab in a patient with hidradenitis suppurativa. We present the case of a 41-year-old male with progressive hidradenitis suppurativa, unresponsive to multiple antibiotic regimens and infliximab treatment. Due to a medication error, the patient received 300 mg of secukinumab daily for 4 days instead of weekly, totaling 1200 mg. The regional pharmacovigilance center assessed potential toxicity, and a pharmacometric analysis using a population pharmacokinetic model was performed to inform dosing adjustments. Clinical data indicated that the received doses were within a non-toxic range. No adverse effects were observed. Pharmacometric simulations revealed a risk of underexposure due to the dosing error. Based on these simulations, it was recommended to restart monthly secukinumab injections on day 35 after the initial dose. Measured plasma concentrations before re-administration confirmed the model's accuracy. This case highlights the crucial collaboration between clinical services, pharmacovigilance, and pharmacometrics in managing medication errors. Such interdisciplinary efforts ensure therapeutic efficacy and patient safety by maintaining appropriate drug exposure levels.

Study protocol for ADAPT-TDM: A beta-lactam antibiotic Dose AdaPtation feasibility randomised controlled Trial using Therapeutic Drug Monitoring

IntroductionCritically ill patients are at risk of suboptimal beta-lactam antibiotic (beta-lactam) exposure due to the impact of altered physiology on pharmacokinetics. Suboptimal concentrations can lead to treatment failure or toxicity....

Therapeutic Drug Monitoring Characteristics in a City Hospital for a Year.

Therapeutic drug monitoring (TDM) involves the measurement of drug concentrations in serum, plasma, whole blood, or other biologic fluids. This study focused on evaluating the TDM requests of a city hospital over a period of one year, retrospectively. The study retrospectively analyzed TDM requests for carbamazepine, cyclosporine-A, digoxin (DIGOX), lithium (LITH), methotrexate (MTX), phenitoin, tacrolimus, and valproic acid (VALP) from June 1, 2022, to June 1, 2023. Parameters such as the age and the gender of patients, the requesting departments, the measurement results, and the turnaround time (TAT) were assessed. Drug concentrations below the reference values were classified as subtherapeutic, whereas concentrations above the reference values were considered supratherapeutic. In total, 10,913 drug concentration measurement records were analyzed. The gender distribution was 51.6% male and 48.4% female. Pediatric samples comprised 6.2% and elderly samples 8.6% of the total. Notably, DIGOX, LITH, and VALP levels showed a significant correlation with age (p = < 0.0001, p = < 0.0001, and p = 0.0002, respectively). TAT was maintained at 360 minutes (6 hours) for all tests. The study found significant correlations between age and DIGOX, LITH, and VALP levels. TDM plays a critical role in the elderly population, necessitating careful management of these drugs.

Beta-glucan intake with energy and carbohydrate restricted meals: impact on subjective appetite and gastrointestinal appetite hormones in overweight adults

Energy restriction is commonly used as body weight-loss interventions (1). However, it modifies secretion of gastrointestinal appetite hormones, which might be expected to upregulate appetite and thus impair the ability to comply with prescribed intervention(1). Supplementation with soluble fibre may potentially counteract this matter (2). This study aimed to investigate whether addition of β- glucan to energy and carbohydrate-restricted meals impacts postprandial responses of gastrointestinal appetite hormones and subjective appetite in overweight adults.Twenty-three sedentary individuals living with overweight or obesity (age: 36 ± 8.5 years, BMI: 31.12 ± 4.04 kg/m2) participated in a double-blind randomised crossover study with two experimental arms, each lasting over two days. On day 1, participants consumed Counterweight PRO800 meal replacement shakes/soups for breakfast and dinner at home, each providing ~200 kcal and a carbohydrate-restricted lunch providing 35% of their habitual energy intake. On day 2, participants attended the metabolic investigation room where they consumed the same breakfast and lunch as on day 1. On both days, each meal was taken with either 3g β-glucan (Oat Well) or cellulose (Comprecel) as placebo. On Day 2, fasting and postprandial appetite scores were recorded, and fasting and postprandial blood samples were obtained for the measurements of plasma concentration of acylated ghrelin, PYY, and GLP-1. The study is registered at www.clinicaltrials.gov as NCT05981404.Two-way ANOVA showed that the postprandial concentrations of acylated ghrelin (β-glucan arm, 383 ± 23 pg/ml; placebo arm, 428 ± 23 pg/ml, P=0.02, treatment effect) and composite appetite scores (P=0.003, treatment effect) were significantly lower and PYY concentrations (β-glucan arm, 132 ± 5 pg/ml; Placebo arm, 110 ± 4 pg/ml, P= 0.003, treatment effect) significantly higher in the β- glucan arm than in the Placebo arm. The concentrations of GLP-1 were not different between arms (β-glucan arm, 29 ± 1 pM; placebo arm, 28 ± 0.9 pM, P=0.36, treatment effect).The obtained data suggests that consuming β -glucan with energy and carbohydrate-restricted meals can be expected to attenuate reduction in satiety and diminish increase in hunger. Therefore, supplementation with β-glucan during energy restriction intervention applied to body weight loss might lead to improve compliance and reduce discomfort of negative energy balance.

How to verify the analytical and clinical performance of ELISA immunoanalysis in the real laboratory practice. PCSK9 as an example

BackgroundManufacturers and diagnostic companies often recommend on-site verification of analytical performance in the clinical laboratory. The validation process used by manufacturers is rarely described in detail, and certain information on analytical performance is missing from the product sheet, especially for immunoanalytical methods. We describe an approach to the detailed validation of an ELISA method for the measurement of proprotein convertase subtilisin/kexin type 9 (PCSK9) plasma concentrations. We compared manufacturers' claims of analytical performance with data obtained in the field laboratory using several approaches. MethodsWe used the Human Proprotein Convertase 9/PCSK9 Quantikine ELISA diagnostic kit (R&D systems, Bio-Techne Ltd., Abingdon Science Park, Abingdon, UK) and three levels of quality control solution Quantikine Immunoassay Control Group 235 (R&D systems, Bio-Techne Ltd., Abingdon Science Park, Abingdon, UK) to verify precision. We measured the concentration of PCSK9 using the DS2 ELISA Reader (Dynex Technologies GmbH, Denkendorf, Germany). We used analysis of variance (ANOVA) and the R statistical package (R core team, version 1.4.5). Statistical analysis and terminology were performed according to protocol CLSI EP15-A3, and the reference interval was checked according to CLSI/IFCC C28-A3c. ResultsWe found a significant difference between the manufacturer's claims of analytical performance and real data measured in the routine clinical laboratory. The calculated CV (%) for repeatability (calculated by simple estimation of the mean and SD, as used by the manufacturer) was between 5.5% and 7.4%, but the manufacturer's claim was between 4.1% and 6.5%. Using ANOVA, the true repeatability was between 5.0% and 6.9%. Similarly, ANOVA revealed values of CV (%) for within-laboratory imprecision between 6.5% and 9.1%, while the manufacturer's claims were between 4.1% and 5.9%. The recovery ranged from 105.5% to 121.8%. The manufacturer's recommended reference interval was checked and we didn't find any significant difference between men and women. ConclusionsWe describe a comprehensive approach to verify the analytical performance of an ELISA method using the measurement of PCSK9 plasma concentration as an example. We found differences between the results of this approach based on the CLSI EP15-A3 protocol and data provided by the manufacturer. We recommend the verification of analytical performance by more complex statistical tools in laboratory practice.

Using the fish plasma model to evaluate potential effects of pharmaceuticals in effluent from a large urban wastewater treatment plant

Several pharmaceuticals and personal care products (PPCPs) were evaluated using the fish plasma model (FPM) for juvenile Chinook salmon exposed to effluent from a large urban wastewater treatment plant. The FPM compares fish plasma concentrations to therapeutic values determined in human plasma as an indication of potential adverse effects. We used human Cmax values, which are the maximum plasma concentration for a minimum therapeutic dose. Observed and predicted plasma concentrations from juvenile Chinook salmon exposed to a dilution series of whole wastewater effluent were compared to 1%Cmax values to determine Response Ratios (RR) ([plasma]/1%Cmax) for assessment of possible adverse effects. Several PPCPs were found to approach or exceed an RR of 1, indicating potential effects in fish. We also predicted plasma concentrations from measured water concentrations and determined that several of the values were close to or below the analytical reporting limit (RL) indicating potential plasma concentrations for a large number of PPCPs that were below detection. Additionally, the 1%Cmax was less than the RL for several analytes, which could impede predictions of possible effect concentrations. A comparison of observed and predicted plasma concentrations found that observed values were frequently much higher than values predicted with water concentrations, especially for low log10Dow compounds. The observed versus predicted values using the human volume of distribution (Vd), were generally much closer in agreement. These data appear to support the selection of whole-body concentrations to predict plasma values, which relies more on estimating simple partitioning within the fish instead of uptake via water. Overall, these observations highlight the frequently underestimated predicted plasma concentrations and potential to cause adverse effects in fish. Using measured plasma concentrations or predicted values from whole-body concentrations along with improved prediction models and reductions in analytical detection limits will foster more accurate risk assessments of pharmaceutical exposure for fish.

Determination of meropenem in capillary plasma microsamples using LC-MS/MS.

Background: The measurement of meropenem plasma concentrations is employed for dosing regimen individualization. The aim of this study was to develop and validate a LC-MS/MS assay for quantification of meropenem in capillary plasma microsamples. Methods: Samples were prepared by protein precipitation with acetonitrile, followed by clean-up with dichloromethane. The method was validated and applied to 12 paired samples of venous and capillary plasma. Results: The method was linear in the range of 0.5-50μg/ml. Matrix effects were minimal. Inter-and intra-assay were 3.8-7.9% and 2.7-5.5%, respectively, while accuracy was 91.7-100.6%. Concentrations in capillary and venous plasma were highly correlated. Conclusion: An assay for the quantification of meropenem in capillary plasma microsamples was fully validated, showing potential for clinical application.

Physiologically based pharmacokinetic modeling of imatinib and N-desmethyl imatinib for drug-drug interaction predictions.

The first-generation tyrosine kinase inhibitor imatinib has revolutionized the development of targeted cancer therapy and remains among the frontline treatments, for example, against chronic myeloid leukemia. As a substrate of cytochrome P450 (CYP) 2C8, CYP3A4, and various transporters, imatinib is highly susceptible to drug-drug interactions (DDIs) when co-administered with corresponding perpetrator drugs. Additionally, imatinib and its main metabolite N-desmethyl imatinib (NDMI) act as inhibitors of CYP2C8, CYP2D6, and CYP3A4 affecting their own metabolism as well as the exposure of co-medications. This work presents the development of a parent-metabolite whole-body physiologically based pharmacokinetic (PBPK) model for imatinib and NDMI used for the investigation and prediction of different DDI scenarios centered around imatinib as both a victim and perpetrator drug. Model development was performed in PK-Sim® using a total of 60 plasma concentration-time profiles of imatinib and NDMI in healthy subjects and cancer patients. Metabolism of both compounds was integrated via CYP2C8 and CYP3A4, with imatinib additionally transported via P-glycoprotein. The subsequently developed DDI network demonstrated good predictive performance. DDIs involving imatinib and NDMI were simulated with perpetrator drugs rifampicin, ketoconazole, and gemfibrozil as well as victim drugs simvastatin and metoprolol. Overall, 12/12 predicted DDI area under the curve determined between first and last plasma concentration measurements (AUClast) ratios and 12/12 predicted DDI maximum plasma concentration (Cmax) ratios were within twofold of the respective observed ratios. Potential applications of the final model include model-informed drug development or the support of model-informed precision dosing.

Evaluation of physical variables, thermal nociceptive threshold testing and pharmacokinetics during placement of transdermal buprenorphine matrix-type patch in healthy adult horses.

Matrix type transdermal buprenorphine patches have not been investigated in horses and may provide an effective means of providing continuous pain control for extended period and eliminating venous catheterization. Assessment of the physiological variables (heart rate, respiratory rate, body temperature) and thermal nociceptive threshold testing, and describing the pharmacokinetic profile of transdermal buprenorphine matrix-type patch (20 μg h-1 and 40 μg h-1 dosing) in healthy adult horses. Randomised experimental study with a Latin-square design. Six adult healthy horses received each of the three treatments with a minimum 10 day washout period. BUP0 horses did not receive a patch (control). BUP20 horses received one patch (20 μg h-1) applied on the ventral aspect of the tail base resulting in a dose of 0.03-0.04 μg kg-1 h-1. BUP40 horses received two patches placed alongside each other (40 μg h-1) on the tail base resulting in a dose of 0.07-0.09 μg kg-1 h-1. Whole blood samples (for determination of buprenorphine concentration), physiological variables and thermal threshold testing were performed before (0 h) and at 2, 4, 8, 12, 16, 24, 32, 40, 48, 56, 64, 72, and 96 h after patch application. The patches were removed 72 h following placement and were analyzed for residual buprenorphine content. Between the three groups, there was no change in physiological variables across timepoints as compared to baseline (p > 0.1). With the higher dose, there was a significant increase in thermal thresholds from baseline values from 2 h until 48 h and these values were significantly higher than the group receiving the lower patch dose for multiple timepoints up to 40 h. 40 μg h-1 patch led to consistent measurable plasma concentrations starting at 2 h up to 96 h, with the mean plasma concentrations of > 0.1 ng/ml from 4 h to 40 h. 20 μg h-1 and 40 μg h-1 patch doses were well tolerated by all horses. At higher dose, plasma buprenorphine concentrations were more consistently measurable and blunted thermal thresholds for 48 h vs. 32 h with 20 μg h-1 dosing as compared to control.

Depot medroxyprogesterone acetate concentrations in patients with and without the use of antiseizure medications

ObjectivesTo measure plasma concentrations of medroxyprogesterone acetate (MPA) in users with epilepsy treated with anti-seizure medications and compare these to MPA concentrations in those without epilepsy. MethodsFor this multi-site cross-sectional study, we obtained a single blood sample from those with epilepsy treated with various anti-seizure medications (n=18) within the week before their next depot medroxyprogesterone (DMPA) injection. Among the participants without epilepsy (n=20), 10 similarly were scheduled within the week prior to the next injection, and 10 were scheduled at earlier intervals to attempt to balance the time intervals between groups. MPA concentrations were determined by a validated assay. ResultsMPA concentrations were similar among those with epilepsy and controls, and between groups with and without use of enzyme-inducing medications. The lowest MPA concentrations, under 0.07 ng/mL, were observed among two of eight using enzyme-inducing anti-seizure medications; one of 10 using non-inducing medications, and one of 19 controls had concentrations below 0.2 ng/mL. ConclusionsIn this exploratory study, lower MPA concentrations in some participants using enzyme-inducing anti-seizure medications suggest a potential interaction that could reduce DMPA efficacy.

Demonstrating Bioequivalence for Two Dose Strengths of Niraparib andAbiraterone AcetateDual-Action Tablets Versus Single Agents: Utility of Clinical Study Data Supplemented with Modeling and Simulation.

The combination of niraparib and abiraterone acetate (AA) plus prednisone is under investigation for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) and metastatic castration-sensitive prostate cancer (mCSPC). Regular-strength (RS) and lower-strength (LS) dual-action tablets (DATs), comprising niraparib 100 mg/AA 500 mg and niraparib 50 mg/AA 500 mg, respectively, were developed to reduce pill burden and improve patient experience. A bioequivalence (BE)/bioavailability (BA) study was conducted under modified fasting conditions in patients with mCRPC to support approval of the DATs. This open-label randomized BA/BE study (NCT04577833) was conducted at 14 sites in the USA and Europe. The study had a sequential design, including a 21-day screening phase, a pharmacokinetic (PK) assessment phase comprising three periods [namely (1) single-dose with up to 1-week run-in, (2) daily doseon days 1-11, and (3) daily dose ondays 12-22], an extension where both niraparib and AA as single-agent combination (SAC; reference) or AA alone was continued from day 23 until discontinuation, and a 30-day follow-up phase. Patients were randomly assigned in a parallel-group design (four-sequence randomization) to receive a single oral dose of niraparib 100 mg/AA 1000 mg as a LS-DAT or SAC in period 1, and patients continued as randomized into a two-way crossover design during periods 2 and 3 where they received niraparib 200 mg/AA 1000 mg once daily as a RS-DAT or SAC. The design was powered on the basis of crossover assessment of RS-DAT versus SAC. During repeated dosing (periods 2 and 3, and extension phase), all patients also received prednisone/prednisolone 5 mg twice daily. Plasma samples were collected for measurement of niraparib and abiraterone plasma concentrations. Statistical assessment of the RS-DAT and LS-DAT versus SAC was performed on log-transformed pharmacokinetic parameters data from periods 2 and 3 (crossover) and from period 1 (parallel), respectively. Additional paired analyses and model-based bioequivalence assessments were conducted to evaluate the similarity between the LS-DAT and SAC. For the RS-DAT versus SAC, the 90% confidence intervals (CI) of geometric mean ratios (GMR) for maximum concentration at a steady state (Cmax,ss) and area under the plasma concentration-time curve from 0-24 h at a steady state (AUC 0-24h,ss) were respectively 99.18-106.12% and 97.91-104.31% for niraparib and 87.59-106.69 and 86.91-100.23% for abiraterone. For the LS-DAT vs SAC, the 90% CI of GMR for AUC0-72h of niraparib was 80.31-101.12% in primary analysis, the 90% CI of GMR for Cmax,ss and AUC 0-24h,ss of abiraterone was 85.41-118.34% and 86.51-121.64% respectively, and 96.4% of simulated LS-DAT versus SAC BE trials met the BE criteria for both niraparib and abiraterone. The RS-DAT met BE criteria (range 80%-125%) versus SAC based on 90% CI of GMR for Cmax,ss and AUC 0-24h,ss. The LS-DAT was considered BE to SAC on the basis of the niraparib component meeting the BE criteria in the primary analysis for AUC 0-72h; abiraterone meeting the BE criteria in additional paired analyses based on Cmax,ss and AUC 0-24h,ss; and the percentage of simulated LS-DAT versus SAC BE trials meeting the BE criteria for both. NCT04577833.