Prediction of steady-state plasma concentrations of olanzapine in Chinese Han in patients based on a retrospective population pharmacokinetic model

Purpose: To develop robust methods of establishing a population pharmacokinetics (Pop-PK) model of olanzapine, using existing hospital in-patient information, in order to predict the steady-state plasma concentration of olanzapine tablets in Chinese Han inpatients, thus providing guidance for individualized therapy for mental disorders.Methods: A retrospective study analyzing and predicting the steady-state plasma olanzapineconcentration was performed using nonlinear mixed-effect modeling (Phoenix® NLME8). The effects of ten potential covariates, including age, gender, Body Mass Index, fasting lipid, family history, alcohol and smoking status in 107 Chinese Han patients with steady-state plasma olanzapine concentration were collected from the hospital information system (HIS) in Wuhan Mental Health Center from Feb 2017 to Jul 2019.Results: The final model was validated using bootstrap and visual predictive check (VPC) and was found to fit the one-compartment mixed error model. Smoking status was found to be the only factor affecting olanzapine tablets clearance. The standard Pop-PK parameters apparent volume of distribution (VL/F) and clearance (CL/F) were 223 L and 12.4 Lꞏh-1, respectively.Conclusion: The Pop-PK model for olanzapine established with the data from HIS is effective inpredicting the plasma olanzapine tablets concentration of individual Chinese in-patients. This Pop-PK model approach can now be adapted to optimize other antipsychotic drugs.

New In Vitro Methodology for Kinetics Distribution Prediction in the Brain. An Additional Step towards an Animal-Free Approach

The development of new drugs or formulations for central nervous system (CNS) diseases is a complex pharmacologic and pharmacokinetic process; it is important to evaluate their access to the CNS through the blood−brain barrier (BBB) and their distribution once they have acceded to the brain. The gold standard tool for obtaining this information is the animal microdialysis technique; however, according to 3Rs principles, it would be better to have an “animal-free” alternative technique. Because of that, the purpose of this work was to develop a new formulation to substitute the brain homogenate in the in vitro tests used for the prediction of a drug’s distribution in the brain. Fresh eggs have been used to prepare an emulsion with the same proportion in proteins and lipids as a human brain; this emulsion has proved to be able to predict both the unbound fraction of drug in the brain (fu,brain) and the apparent volume of distribution in the brain (Vu,brain) when tested in in vitro permeability tests. The new formulation could be used as a screening tool; only the drugs with a proper in vitro distribution would pass to microdialysis studies, contributing to the refinement, reduction and replacement of animals in research.

Analysis of Pharmacokinetic Parameters of Acetylsalicylic Acid for Prediction of Potential Nephrotoxic Effects

Nonsteroidal anti-inflammatory drugs, including acetylsalicylic acid, can have a dose-dependent nephrotoxic effect. The study of the pharmacokinetics of acetylsalicylic acid products will contribute to timely detection and correction of side effects caused by this medicinal product.The aim of the study was to evaluate potential nephrotoxic effects following a single oral administration of 75 mg of acetylsalicylic acid, based on the analysis of the pharmacokinetic parameters.Materials and methods: the study involved 24 healthy volunteers who received 75 mg of acetylsalicylic acid (tablets) once orally. The measurement of the active metabolite of acetylsalicylic acid—salicylic acid—in blood plasma was performed by HPLC/MS using an Agilent 1200 liquid chromatography system coupled to an Agilent 6140 tandem mass spectrometer. Agilent Eclipse XDB-C18 column (4.6 mm×150 mm; 5.0 μm) was used for chromatographic separation. The test procedure used in the study was validated. The results obtained were used to calculate the pharmacokinetic parameters: Cmax (maximum concentration), Tmax (time to maximum concentration), T1/2 (half-life of the drug), AUC0-t (area under the pharmacokinetic curve from 0 to the last time point of the curve), AUC0-∞ (total area under the pharmacokinetic curve from 0 to ∞), MRT (mean residence time of the drug in the blood), Kel (elimination rate constant), Cl/F (total clearance), Vd/F (apparent volume of distribution). The Statistics (22.0.0.0) software was used for statistical processing of the results.Results: T1/2 of salicylic acid in blood plasma was determined to be 1.6 ± 0.5 h, Cmax was 4523.0 ± 725.0 ng/mL, and Tmax was 0.98 ± 0.4 h. AUC0–t was equal to 16183.0 ± 3823.0 ng×h/m, Vd/F was 12.0 ± 3.1 L/kg, and MRT was 2.9 ± 0.6 h.Conclusions: the analysis of the pharmacokinetic parameters demonstrated a high absorption rate, intensive distribution, and moderate elimination rate of salicylic acid (the main metabolite of acetylsalicylic acid), indicating a low risk of nephrotoxic effects associated with the studied dose of the drug.

Population Pharmacokinetic and Concentration-QTc Analysis of Delamanid in Pediatric Participants with Multidrug-Resistant Tuberculosis

A population pharmacokinetic analysis of delamanid and its major metabolite DM-6705 was conducted to characterize the pharmacokinetics of delamanid and DM-6705 in pediatric participants with multidrug-resistant tuberculosis (MDR-TB). Data from participants between the ages of 0.67 to 17 years old, enrolled in 2 clinical trials, were utilized for the analysis. The final dataset contained 634 delamanid and 706 DM-6705 valid plasma concentrations from 37 children. A transit model with three compartments best described the absorption of delamanid. Two compartment models for each component with linear elimination were selected to characterize the disposition of delamanid and DM-6705, respectively. The covariates included in the model were body weight on apparent volume of distribution and apparent clearance (for both delamanid and DM-6705); formulation (dispersible vs film coated tablet) on mean absorption time; age, formulation, and dose on bioavailability of delamanid; age on the fraction of delamanid metabolized to DM-6705. Based on the simulations, doses for participants within different age/weight groups that result in delamanid exposure comparable to that in adults following the approved adult dose were calculated. By concentration-QTc (QTcB, QT corrected by Bazett’s' formula) analysis, a significant positive correlation was detected with concentrations of DM-6705. However, the model-predicted upper bounds of the 90% confidence intervals of ΔQTc value were less than 10 ms at the simulated Cmax of DM-6705 following administration of maximum doses simulated. This suggests that the effect on the QT interval following the proposed dosing is unlikely to be clinically meaningful in children with MDR-TB who receive delamanid.

1098. A Phase 1 Safety and Tolerability of Single Ascending Doses of a Novel Engineered Cationic Peptide, PLG0206, in Healthy Subjects

Background PLG0206 is a novel engineered cationic antimicrobial peptide being evaluated for treatment of prosthetic joint infections (PJI). This abstract presents the results from the first in human study to evaluate the safety, tolerability and pharmacokinetic (PK) profile of PLG0206 when administered as an intravenous (IV) infusion. Methods 6 cohorts of 8 participants were planned to receive escalating single 1-hour IV infusions of PLG0206 at 0.05, 0.125, 0.25, 0.5, 1, 2 and 3 mg/kg dose or placebo. Participants were randomized to receive either PLG0206 (6 per cohort) or placebo (2 per cohort). At each dose level, there were 2 sentinel participants (1 active, 1 placebo) who were dosed at least 48 hours in advance of the other participants in their group. Serial pharmacokinetic samples were taken prior to infusion and up to 48 post infusion. Safety and tolerability was assessed throughout the study. There was at least a 7-day period after dosing at each of the dose levels before dose escalation. Results PLG0206 was safe and well tolerated when administered to healthy volunteers at doses ranging from 0.05 and 1 mg/kg. Therapeutic exposures were achieved at 1 mg/kg. The 2 and 3 mg/kg cohorts were not studied. The incidence of treatment emergent adverse events related to study drug administration was low and most events mild (Grade 1) in severity and was similar between the PLG0206 treatment and placebo groups. There were no SAEs, life-threatening events or deaths throughout the study. IV PLG0206 exhibited linear PK over the dose range of 0.05 to 1.0 mg/kg. The median terminal half-life (t½) ranged from 7.37 to 19.97 hours. AUC0-∞ increased with increasing PLG0206 dose ranging between 1581.41 and 21141.52 ng.hr/mL. Cmax ranged between 256 and 2653 ng/mL. The mean apparent volume of distribution (Vz) increased was between 25.49 and 94.2 L, mean clearance (CL) were similar across all and ranged from 2.42 to 4.18 L/hour. Conclusion Following single IV infusion to healthy volunteers, PLG0206 was safe and well tolerated at doses ranging from 0.05 to 1 mg/kg. IV PLG0206 exhibits linear PK over the dose range. These findings support the ongoing development of IV PLG0206 and will inform dosing regimens in future studies to investigate its utility as an antimicrobial agent. Disclosures David Huang, MD, PhD, Peptilogics (Employee) Despina Dobbins, BS, Peptilogics (Employee) Parviz Ghahramani, PhD, PharmD, MSc, MBA, Peptilogics (Consultant) Jonathan Steckbeck, PhD, Peptilogics (Employee)

Pharmacokinetic/Pharmacodynamic Model of Neutropenia in Real-Life Palbociclib-Treated Patients

Palbociclib is an oral CDK4/6 inhibitor indicated in HR+/HER2- advanced or metastatic breast cancer in combination with hormonotherapy. Its main toxicity is neutropenia. The aim of our study was to describe the kinetics of circulating neutrophils from real-life palbociclib-treated patients. A population pharmacokinetic (popPK) model was first constructed to describe palbociclib pharmacokinetic (PK). Individual PK parameters obtained were then used in the pharmacokinetic/pharmacodynamic (PK/PD) model to depict the relation between palbociclib concentrations and absolute neutrophil counts (ANC). The models were built with a population of 143 patients. Palbociclib samples were routinely collected during therapeutic drug monitoring, whereas ANC were retrospectively retrieved from the patient files. The optimal popPK model was a mono-compartmental model with a first-order absorption constant of 0.187 h−1 and an apparent clearance Cl/F of 57.09 L (32.8% of inter individuality variability (IIV)). The apparent volume of distribution (1580 L) and the lag-time (Tlag: 0.658 h) were fixed to values from the literature. An increase in creatinine clearance and a decrease in alkaline phosphatase led to an increase in palbociclib Cl/F. To describe ANC kinetics during treatment, Friberg’s PK/PD model, with linear drug effect, was used. Parameters estimated were Base (2.92 G/L; 29.6% IIV), Slope (0.0011 L/µg; 28.8% IIV), Mean Transit Time (MTT; 5.29 days; 17.9% IIV) and γ (0.102). The only significant covariate was age on the initial ANC (Base), with lower ANC in younger patients. PK/PD model-based simulations show that the higher the estimated CressSS (trough concentration at steady state), the higher the risk of developing neutropenia. In order to present a risk lower than 20% to developing a grade 4 neutropenia, the patient should show an estimated CressSS lower than 100 µg/L.

The Pharmacokinetics of Buserelin after Intramuscular Administration in Pigs and Cows

Background: Buserelin is a LHRH agonist used for the treatment of hormone-dependent diseases in males and females. However, the pharmacokinetics of buserelin in pigs and cows are not clearly understood. This study was designed to develop a sensitive method to determine the concentration of buserelin and to investigate the pharmacokinetic parameters after intramuscular (i.m.) administration in pigs and cows. Results: A sensitive and rapid stability method based on ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) was developed. The pharmacokinetic parameters of buserelin after i.m. administration were studies in five pigs and five cows at a single dose of 1 mg per pig and 3 mg per cow. The plasma kinetics were analyzed by WinNonlin 8.1.0 software using a non-compartmental model. The mean concentration area under the curve (AUC0-t) was 25.02 ± 6.93 h·ng/mL for pigs and 5.63 ±1.86 h·ng/mL for cows. The maximum plasma concentration (Cmax) and time to reach the maximum concentration (tmax) were 10.99 ± 2.04 ng/mL and 0.57 ± 0.18 h for pigs and 2.68 ± 0.36 ng/mL and 1.05 ±0.27 h for cows, respectively. The apparent volume of distribution (Vz) in pigs and cows was 80.49 ± 43.88 L and 839.88 ± 174.77 L, respectively. The elimination half-time (t1/2λz), and clearance (CL) were 1.29 ± 0.40 h and 41.15 ± 11.18 L/h for pigs and 1.13 ± 0.3 h and 545.04 ± 166.40 L/h for cows, respectively. No adverse effects were observed in any of the animals. Conclusion: This study extends previous studies describing the pharmacokinetics of buserelin following i.m. administration in pigs and cows. Further studies investigating other factors were needed to establish therapeutic protocol in pigs and cows and to extrapolate these parameters to others economic animals.

Disposition Kinetics of Amitraz in Lactating Does

Amitraz, a member of the formamidine pesticide family, commonly used for ectoparasite control, is applied as a dip or low-pressure hand spray to cattle and swine, and the neck collar on dogs. Data on amitraz were generated mainly on laboratory animals, hens, dogs, and baboons. The data on the toxicity and disposition of amitraz in animals and its residues in the milk are inadequate. Therefore, the present study was intended to analyze the disposition kinetics of amitraz and its pattern of elimination in the milk of lactating does after a single dermal application at a concentration of 0.25%. Blood at predetermined time intervals and milk twice daily were collected for eight days post application. The drug concentration was assayed by high-performance liquid chromatography (HPLC). Amitraz was detected in whole blood as early as 0.5 h, which attained a peak concentration at 12 ± 5 h, followed by a steady decline; however, detection persisted until 168 h. Amitraz was present in the blood at its 50% Cmax even after 48 h, and was still detectable after 7 days. The disposition after a single dermal application was best described non-compartmentally. The mean terminal half-life (t1/2), mean residence time (MRT), and area under the curve (AUC0–t) were 111 ± 31 h, 168 ± 39 h, and 539 ± 211 µg/mL/h, respectively. The apparent volume of distribution (Vdarea) was 92 ± 36 mL/g with an observed clearance (Cl) of 0.57 ± 0.33 mL/kg/h. Thus, the drug was well absorbed, widely distributed and slowly eliminated from the animal body. Amitraz achieved milk concentration approximating 0.2 per cent of the total dose after a single exposure and the steady-state elimination of amitraz in milk above the recommended maximum residue limit (MRL) of 0.01 mg/kg can act as a source of public health concern when applied on lactating animals.

Distribution, excretion and metabolic pathways of a single parenteral administration of kappa-opioid receptor agonist RU-1205

Introduction: The purpose was to study the pharmacokinetic properties of RU-1205 with the previously identified kappa-agonistic and analgesic effects after parenteral administration. Materials and methods: Pharmacokinetic parameters of RU-1205 after intravenous and subcutaneous administration at doses of 10 mg/kg and 50 mg/kg, respectively, were investigated, using the method of high-performance liquid chromatography with measurement of the compound according to a pre-established calibration curve. The indices of the area under the pharmacokinetic curve, clearance, half-life, residence time of the drug molecule in the body, total (apparent) volume of distribution, as well as the indicator of absolute bioavailability for subcutaneous administration were calculated. Tissue distribution and excretion of RU-1205 were also studied. Evaluation of metabolism of RU-1205 was conducted in silico, using the PALLAS 3.00 software, with the use of specific tests with CYP 450 substrates and by studying the ability of RU-1205 to form conjugates with endogenous acids. Results and discussion: It was found that after a single intravenous administration, the investigated substance was determined in the blood for 12 h; the half-life was 8.49 hours. The absolute bioavailability after subcutaneous administration is 57.35%. RU-1205 is eliminated within 3–4 days. The main route of excretion is extrarenal. The biotransformation of the substance probably proceeds mainly with the formation of oxidized forms of the initial molecule according to the reactions of the first phase of metabolic transformation, so the chance to observe phase 2 of the metabolism could be very low. Conclusion: The test substance undergoes a long process of elimination, has the highest tropism to the elimination organs and undergoes active biotransformation processes in the body of animals.