Plasma Drug Concentrations Research Articles

Risperidone plasma level, and its correlation with CYP2D6 gene polymorphism, clinical response and side effects in chronic schizophrenia patients

BackgroundTo explore the influence of CYP2D6 genetic polymorphism on risperidone metabolism, thereby affecting risperidone’s effects and safeties in patients with chronic schizophrenia.MethodsSixty-nine subjects with chronic schizophrenia treated with risperidone were recruited. CYP2D6 genotypes was determined using targeted sequencing and translated into phenotype using activity system. Risperidone plasma concentrations were measured using HPLC. Positive and Negative Symptom Scale (PANSS) and Brief Psychiatric Rating Scale (BPRS) were used to evaluate the existence and severity of psychiatric symptoms, Barnes Akathisia Scale (BAS) and Extrapyramidal Symptom Rating Scale (ESRS) for neurological side effects. Metabolic and endocrine status assess were also included.ResultsThe plasma drug concentrations varied hugely among individuals. Intermediate metabolizer (IM) group had higher plasma levels of RIP and dose corrected RIP concentration, RIP/9-OH-RIP ratio and C/D ratio than normal metabolizer (NM) group (p < 0.01). There was no statistic difference between responders and non-responders in dose-adjusted plasma concentrations and ratios of RIP/9-OH-RIP and C/D. The occurrence of EPS was related to active moiety levels in 4th week (p < 0.05). The prolactin (PRL) levels in two follow-ups were both significantly higher than baseline (p < 0.01). PRL change from baseline to week 4 and week 8 were both positively associated with active moiety concentration detected in week 4 (p < 0.05).ConclusionsThe risperidone plasma levels have great inter- and intraindividual variations, and are associated with the CYP2D6 phenotypes, as well as the changes in serum prolactin in patients diagnosed with chronic schizophrenia.

α-L-iduronidase fused with humanized anti-human transferrin receptor antibody (lepunafusp alfa) for mucopolysaccharidosis type I: A phase 1/2 trial

Mucopolysaccharidosis type I (MPS I) causes systemic accumulation of glycosaminoglycans due to a genetic deficiency of α-L-iduronidase (IDUA), which results in progressive systemic symptoms affecting multiple organs, including the central nervous system (CNS). Because the blood-brain barrier (BBB) prevents enzymes from reaching the brain, enzyme replacement therapy is effective only against the somatic symptoms. Hematopoietic stem cell transplantation can address the CNS symptoms, but the risk of complications limits its applicability. We have developed a novel genetically modified protein consisting of IDUA fused with humanized anti-human transferrin receptor antibody (lepunafusp alfa; JR-171), which has been shown in nonclinical studies to be distributed to major organs, including the brain, bringing about systemic reductions in heparan sulfate (HS) and dermatan sulfate concentrations. Subsequently, a first-in-human study was conducted to evaluate the safety, pharmacokinetics, and exploratory efficacy of JR-171 in 18 patients with MPS I. No notable safety issues were observed. Plasma drug concentration increased dose-dependently and reached its maximum approximately 4 hours after the end of drug administration. Decreased HS in the cerebrospinal fluid suggested successful delivery of JR-171 across the BBB, while suppressed urine and serum concentrations of the substrates indicated its somatic efficacy was comparable to that of laronidase.

Novel bioequivalent oral disintegrating tablet of aripiprazole prepared by direct compression technique with shortened disintegration time

Herein, we aimed to formulate a novel oral disintegrating tablet (ODT) of aripiprazole (ARP) capable of rapid disintegration using a direct compression technique. Different ODTs were fabricated with directly compressible excipients, and their disintegration time, wettability (water absorption ratio and wetting time), and mechanical properties (hardness and friability) were evaluated. The optimized ODT comprised F-Melt® type C, Prosolv® SMCC HD90, and Na croscarmellose (10 mg of ARP in a 130 mg tablet). The ODT with 3.1–5.2 kp hardness exhibited rapid disintegration (14.1–17.2 sec), along with appropriate mechanical strength (friability < 0.24%). In a bioequivalent study in Korean healthy subjects (randomized, single-dose, two-period crossover design, n = 37), the novel ODT offered the equivalent pharmacokinetic profile to that of a conventional immediate release tablet (Otsuka, Abilify®, Japan), despite different disintegration and dissolution profiles. The 90% confidence intervals of the geometric mean test to reference ratios considering the area-under-the-curve and maximum plasma drug concentrations were 1.0306–11051 and 0.9448–1.1063, respectively, satisfying FDA regulatory criteria for bioequivalence. The novel ART ODT was physicochemically stable under the accelerated storage condition (40 °C, RH75%) for 24 weeks. Therefore, the novel ARP-loaded ODT is expected to be an alternative to oral ARP therapy, providing improved patient adherence.

A physiologically based pharmacokinetic/pharmacodynamic model to determine dosage regimens and withdrawal intervals of aditoprim against Streptococcus suis.

Introduction: Streptococcus suis (S. suis) is a zoonotic pathogen threatening public health. Aditoprim (ADP), a novel veterinary medicine, exhibits an antibacterial effect against S. suis. In this study, a physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) model was used to determine the dosage regimens of ADP against S. suis and withdrawal intervals. Methods: The PBPK model of ADP injection can predict drug concentrations in plasma, liver, kidney, muscle, and fat. A semi-mechanistic pharmacodynamic (PD) model, including susceptible subpopulation and resistant subpopulation, is successfully developed by a nonlinear mixed-effect model to evaluate antibacterial effects. An integrated PBPK/PD model is conducted to predict the time-course of bacterial count change and resistance development under different ADP dosages. Results: ADP injection, administrated at 20mg/kg with 12 intervals for 3 consecutive days, can exert an excellent antibacterial effect while avoiding resistance emergence. The withdrawal interval at the recommended dosage regimen is determined as 18days to ensure food safety. Discussion: This study suggests that the PBPK/PD model can be applied as an effective tool for the antibacterial effect and safety evaluation of novel veterinary drugs.

Preparation, In-vitro, Ex-vivo, and Pharmacokinetic Study of Lasmiditan as Intranasal Nanoemulsion-based In Situ Gel.

Lasmiditan (LAS) is a recently developed antimigraine drug and was approved in October, 2019 for the treatment of acute migraines; however, it suffers from low oral bioavailability, which is around 40%. This study aimed to improve the LAS bioavailability via formulation as nanoemulsionbased in situ gel (NEIG) given intranasally and then compare the traditional aqueous-LASsuspension (AQS) with the two successful intranasal prepared formulations (NEIG 2 and NEIG 5) in order to determine its relative bioavailability (F-relative) via using rabbits. Two successfully prepared nanoemulsion (NE) formulas, a and b, were selected for the incorporation of different percentages of pH-sensitive in situ gelling polymer (Carbopol 934) to prepare NEIGs 1, 2, 3, 4, 5, and 6. The pH, gelation capacity, gel strength, and viscosity were predicted for the prepared NEIGs. The release (in vitro) and the nasal permeation (ex vivo) were determined for NEIG 2 and 5, and then both were subjected to pharmacokinetics in vivo studies. Eighteen male rabbits weighing 2.0 to 2.5 kg were employed in the parallel design study. The body surface area (BSA) normalization method was applied for LAS dose calculation. Serial blood samples were taken out and subjected to drug analysis using the HPLC method previously developed and validated by L. Santosh Kumar. Primary pharmacokinetics parameters, including maximum drug concentration in plasma (Cmax), time to reach C-max (T-max), and area under the concentration-time curve from time zero to affinity (AUCt0-∞) were calculated. Both NE (a and b), together with NEIG (2 and 5) formulas, were subjected to the stability study. Finally, a nasal ciliotoxicity study was carried out to evaluate the nasal toxicity of developed NEIGs 2 and 5. The results showed that NEIGs 2 and 5 could be selected as the optimized NEIGs as both achieved 100% permeation within 20 min and then released within 25 and 35 min, respectively, thus achieving 3.3 folds with higher permeation percentages as compared to the AQS. Both NEIGs 2 and 5 exerted comparable release and permeation values as the corresponding NE a and b with more residence time in order to overcome the normal nasal physiological clearance. The values of C-max, Tmax, and AUC0- ∞ for NEIG 2 and NEIG 5 were 8066±242 ng/ml, 0.75±0.05 h, 19616.86±589 ng. h/ml, and 7975.67±239 ng/ml, 1.0±0.05 h, 17912.36±537 ng. h/ml, respectively, compared to the traditional AQS, which is equal to 4181.09±125 ng/ml, 2±0.2 h, and 8852.27±266 ng. h/ml, respectively. It was discovered that NEIGs 2 and 5 had better intranasal delivery of LAS and could significantly (p<0.05) achieve a higher value of permeability coefficient (3.3 folds) and 2.5 folds improvement in bioavailability when compared to AQS. The NE a, NE b, NEIG2, and NEIG5 formulations showed good stability at various temperatures. According to the nasal ciliotoxicity study, the nasal mucosal membrane, which was treated with NEIG 5, showed irritation with a bit of damage. However, damage was not observed when it was treated with NEIG 2, indicating the biocompatibility of the last one to be selected as the optimum formula. NEIG 2 and NEIG 5 are promising new intranasal formulas with a faster onset of action and greater bioavailability than the oral dosage form (AQS). Finally, the selected optimum gold formula that will be ready for further clinical study is NEIG 2.

Intratympanic injections of emulsion-like dispersions to augment cinnarizine amount in a healthy rabbit inner ear model.

Aim: To investigate eutectic liquid-based emulsion-like dispersions for intratympanic injections to augment cinnarizine permeability across round window membrane in a healthy rabbit inner ear model.Methods: Two-tier systematic optimization was used to get the injection formula. The drug concentrations in perilymph and plasma were analyzed via. Ultra-performance liquid chromatography-tandem mass spectrometry method after 30-, 60-, 90- and 120-min post intratympanic injection time points in rabbits.Results: A shear-thinning behavior, immediate drug release (∼98.80%, 10min) and higher cell viability (>97.86%, 24h) were observed in dispersions. The cinnarizine level of 8168.57±1236.79ng/ml was observed in perilymph at 30min post intratympanic injection in rabbits.Conclusion: The emulsion-like dispersions can augment drug permeability through round window membrane.

Evidence for Therapeutic Drug Monitoring of Atypical Antipsychotics.

Second-generation antipsychotics (SGAs), also known as atypical antipsychotics, are a newer class of antipsychotic drugs used to treat schizophrenia, bipolar disorder, and related psychiatric conditions. The plasma concentration of antipsychotic drugs is a valid measure of the drug at its primary target structure in the brain, and therefore determines the efficacy and safety of these drugs. However, despite the well-known high variability in pharmacokinetics of these substances, psychiatric medication is usually administered in uniform dosage schedules. Therapeutic drug monitoring (TDM), as the specific method that can help personalised medicine in dose adjustment according to the characteristics of the individual patient, minimizing the risk of toxicity, monitoring adherence, and increasing cost-effectiveness in the treatment, thus seems to be an elegant tool to solve this problem. Non-response to therapeutic doses, uncertain adherence to medication, suboptimal tolerability, or pharmacokinetic drug-drug interactions are typical indications for TDM of SGAs. This review aims to summarize an overview of the current knowledge and evidence of the possibilities to tailor the dosage of selected SGAs using TDM, including the necessary pharmacokinetic parameters for personalised pharmacotherapy.

Pharmacokinetic profile of oral and subcutaneous administration of paracetamol in the koala (Phascolarctos cinereus) and prediction of its analgesic efficacy.

The pharmacokinetic profile of paracetamol in koalas is described when administered orally at 15 mg/kg; followed by the same dose, administered every 12 hours (hrs), repeated five times. After the initial oral administration, the median (range) maximal plasma concentration (Cmax), the time Cmax was reached (Tmax) and elimination half-life (t1/2) were 16.93 μg/mL (13.66 to 20.25 μg/mL); 4 hrs (4 to 8 hrs) and 5.54 hrs (4.66 to 7.67 hrs), respectively. When paracetamol was administered orally at 15 mg/mL every 12 hrs, the trough total plasma concentration range remained comparable to the therapeutic range in humans i.e. 4 to 20 μg/mL that is known to provide some analgesia. However, there is a smaller proportion of free drug (i.e. not bound to plasma proteins; and the active form) available in koala plasma (approximately 40% unbound) compared to human plasma (approximately 80% unbound). Consequently, even when there are similar total drug plasma concentrations in both koala and human plasma, the therapeutic efficacy may be reduced in koalas compared to humans. The initial oral dose and subsequent twice daily doses resulted in no obvious adverse effects in any koala. Haematology, plasma electrolyte and biochemical analyte values remained within their reference ranges eight hrs after the last dose but there was a significant change in alanine transaminase (ALT) levels (an increase), and in total protein (a decrease) (both p = 0.03). A dose of 15 mg/kg was also administered as a subcutaneous injection, diluted 50:50 with saline, to two koalas. As the oral formulation and the subcutaneous administration resulted in comparable absorption, the study focused on the oral profile. Based on these results there is an argument to recommend a slight increase in the oral paracetamol dose for the koala, however further investigation is required to confirm whether repeated administration of a slightly higher dose may be associated with more severe or additional significant changes in haematology, electrolytes or biochemical analytes. However, a preferable recommendation would be to administer this dosage of paracetamol in combination with another analgesic such as tramadol, as a subcutaneous injection, to improve efficacy.

Paclitaxel and Therapeutic Drug Monitoring with Microsampling in Clinical Practice.

Paclitaxel is an anticancer agent efficacious in various tumors. There is large interindividual variability in drug plasma concentrations resulting in a wide variability in observed toxicity in patients. Studies have shown the time the concentration of paclitaxel exceeds 0.05 µM is a predictive parameter of toxicity, making dose individualization potentially useful in reducing the adverse effects. To determine paclitaxel drug concentration, a venous blood sample collected 24 h following the end of infusion is required, often inconvenient for patients. Alternatively, using a microsampling device for self-sampling would facilitate paclitaxel monitoring regardless of the patient's location. We investigated the feasibility of collecting venous and capillary samples (using a Mitra® device) from cancer patients to determine the paclitaxel concentrations. The relationship between the venous plasma and whole blood and venous and capillary blood (on Mitra®) paclitaxel concentrations, defined by a Passing-Bablok regression, were 0.8433 and 0.8569, respectively. Demonstrating a clinically acceptable relationship between plasma and whole blood paclitaxel concentration would reduce the need to establish new target concentrations in whole blood. However, in this study, comparison of venous and capillary blood using Mitra® for sampling displayed wide confidence intervals suggesting the results from the plasma and whole blood on this device may not be interchangeable.

Evaluating the bioequivalence and safety of liraglutide injection versus Victoza® in healthy Chinese subjects: a randomized, open, two-cycle, self-crossover phase I clinical trial.

Background: Liraglutide is an acylated glucagon-like peptide-1 (GLP-1) analog, and its pharmacokinetic and pharmacodynamic properties as a GLP-1 receptor (GLP-1R) agonist make it an important therapeutic option for many patients with type 2 diabetes mellitus. This study compared the bioequivalence and safety of liraglutide with the originator product in healthy Chinese adult subjects. Methods: Subjects (N = 36, both sexes) were randomized in a 1:1 ratio into two groups (18 cases each) for a two-cycle, self-crossover trial. Each cycle involved a single subcutaneous injection of the test and reference drugs, with a washout period of 14days. The plasma drug concentration was quantified by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The main pharmacokinetic parameters were statistically analyzed to assess drug bioequivalence. Furthermore, the safety of the drugs was assessed throughout the trial. Results: The geometric mean ratios of Cmax, AUC0-t, and AUC0-∞ were 103.73%, 103.01%, and 103.03%, respectively, and their 90% confidence intervals (CIs) were consistent with the range of 80.00%-125.00%, indicating that the two formulations had similar pharmacokinetics. Meanwhile, safety results showed that both drugs were well tolerated. Conclusion: Studies have shown that the test drug has similar bioequivalence and safety to the reference drug. Clinical trial registration: (http://www.chinadrugtrials.org.cn/index.html), identifier (CTR20171303).

Therapeutic Drug Monitoring and Pharmacogenetic Testing as Guides to Psychotropic Drug Dose Adjustment: An Observational Study.

To avoid the failures in therapy with psychotropic drugs, treatments can be personalized by applying the results of therapeutic drug monitoring and pharmacogenetic testing. The objective of the present single-center observational study was to describe the changes in psychotropic drug management prompted by therapeutic drug monitoring and pharmacogenetic testing, and to compare the effective drug concentration based on metabolic status with the dose predicted using an in silico decision tool for drug-drug interactions. The study was conducted in psychiatry wards at Lille University Hospital (Lille, France) between 2016 and 2020. Patients with data for at least one therapeutic drug monitoring session or pharmacogenetic test were included. Blood tests were performed for 490 inpatients (mainly indicated by treatment monitoring or failure) and mainly concerned clozapine (21.4%) and quetiapine (13.7%). Of the 617 initial therapeutic drug monitoring tests, 245 (40%) complied with good sampling practice. Of the patients, 51% had a drug concentration within the therapeutic range. Regardless of the drug concentration, the drug management did not change in 83% of cases. Thirty patients underwent pharmacogenetic testing (twenty-seven had also undergone therapeutic drug monitoring) for treatment failure; the plasma drug concentration was outside the reference range in 93% of cases. The patient's metabolic status explained the treatment failure in 12 cases (40%), and prompted a switch to a drug metabolized by another CYP450 pathway in 5 cases (42%). Of the six tests that could be analyzed with the in silico decision tool, all of the drug concentrations after adjustment were included in the range estimated by the tool. Knowledge of a patient's drug concentration and metabolic status (for CYD2D6 and CYP2C19) can help clinicians to optimize psychotropic drug adjustment. Drug management can be optimized with good sampling practice, support from a multidisciplinary team (a physician, a geneticist, and clinical pharmacist), and decision support tools.

Design and Development of a Lipid-Based Self-Nano Emulsifying Drug Delivery System of Rosuvastatin Calcium

The work aimed at design and development of a self-nanoemulsifying drug delivery system to increase the solubility and further to evaluate pharmacokinetic parameters of Rosuvastatin calcium (SNEDDS).A unique High Performance Liquid Chromatography technique was used to measure drug concentration in albino rat blood plasma, optimized Self-Nano emulsified formulation had greater absorption than the drug suspension. Lab solutions software were used to analyse the plasma drug concentration data.

Preparation, in vitro and in vivo evaluation of a novel mitiglinide microemulsions

This study aimed to prepare an o/w mitiglinide microemulsion (MTGME) to improve the drug solubility and bioavailability. The formulation of o/w MTGME was optimized by the solubility study of drug, pseudo-ternary phase diagram and Box-Behnken design successively. MTGME was characterized by dynamic laser light scattering (DLS), zeta potential and transmission electron microscopy (TEM), moreover, the storage stability, pharmacodynamics and pharmacokinetics were investigated. The optimal prescription for MTGME consisted of Maisine 35–1 (oil), Cremophor EL (surfactant) and propylene glycol (PG, cosurfactant). MTGME with a spherical dimension of 58.1 ± 5.86 nm was stable when stored at 4 °C for 3 months. The blood glucose levers (BGL) of diabetic mice were uniformly and significantly decreased by intragastric (i.g.) administration of 1–4 mg/kg MTGME, in which BGL (i.g. 4 mg/kg MTGME) was reduced by 69% during 24 h. The pharmacokinetics study of MTGME (i.g., 20 mg/kg) in Wistar rats showed higher plasma drug concentration (Cmax, 2.9 folds), larger area under curve (AUC, 4.6 folds) and oral bioavailability than those of MTG suspensions. Generally, the MTGME (o/w) showed good effect on controlling hyperglycemia. Therefore, microemulsion can be used as an effective oral drug delivery system to improve the bioavailability of MTG.

Physiologically Based Pharmacokinetic Modeling in Neonates: Current Status and Future Perspectives.

Rational drug use in special populations is a clinical problem that doctors and pharma-cists must consider seriously. Neonates are the most physiologically immature and vulnerable to drug dosing. There is a pronounced difference in the anatomical and physiological profiles be-tween neonates and older people, affecting the absorption, distribution, metabolism, and excretion of drugs in vivo, ultimately leading to changes in drug concentration. Thus, dose adjustments in neonates are necessary to achieve adequate therapeutic concentrations and avoid drug toxicity. Over the past few decades, modeling and simulation techniques, especially physiologically based pharmacokinetic (PBPK) modeling, have been increasingly used in pediatric drug development and clinical therapy. This rigorously designed and verified model can effectively compensate for the deficiencies of clinical trials in neonates, provide a valuable reference for clinical research design, and even replace some clinical trials to predict drug plasma concentrations in newborns. This review introduces previous findings regarding age-dependent physiological changes and pathological factors affecting neonatal pharmacokinetics, along with their research means. The application of PBPK modeling in neonatal pharmacokinetic studies of various medications is also reviewed. Based on this, we propose future perspectives on neonatal PBPK modeling and hope for its broader application.

SLIC-Occ: functional segmentation of occupancy images improves precision of EC50 images

BackgroundDrug occupancy studies with positron emission tomography imaging are used routinely in early phase drug development trials. Recently, our group introduced the Lassen Plot Filter, an extended version of the standard Lassen plot to estimate voxel-level occupancy images. Occupancy images can be used to create an EC50 image by applying an Emax model at each voxel. Our goal was to apply functional clustering of occupancy images via a clustering algorithm and produce a more precise EC50 image while maintaining accuracy.MethodA digital brain phantom was used to create 10 occupancy images (corresponding to 10 different plasma concentrations of drug) that correspond to a ground truth EC50 image containing two bilateral local “hot spots” of high EC50 (region-1: 25; region-2: 50; background: 6–10 ng/mL). Maximum occupancy was specified as 0.85. An established noise model was applied to the simulated occupancy images and the images were smoothed. Simple Linear Iterative Clustering, an existing k-means clustering algorithm, was modified to segment a series of occupancy images into K clusters (which we call “SLIC-Occ”). EC50 images were estimated by nonlinear estimation at each cluster (post SLIC-Occ) and voxel (no clustering). Coefficient of variation images were estimated at each cluster and voxel, respectively. The same process was also applied to human occupancy data produced for a previously published study.ResultsVariability in EC50 estimates was reduced by more than 80% in the phantom data after application of SLIC-Occ to occupancy images with only minimal loss of accuracy. A similar, but more modest improvement was achieved in variability when SLIC-Occ was applied to human occupancy images.ConclusionsOur results suggest that functional segmentation of occupancy images via SLIC-Occ could produce more precise EC50 images and improve our ability to identify local “hot spots” of high effective affinity of a drug for its target(s).

Measurement uncertainty estimation of free drug concentrations in clinical laboratories using equilibrium dialysis.

Developing procedures based on equilibrium dialysis (ED) that allow measuring the free drug concentration in plasma improves therapeutic drug monitoring (TDM) in those cases where its measurement is justified. However, this procedure requires specific sample preparation and presents different pitfalls, which are not error-free. As withany result provided by a clinical laboratory, this one should be as accurate as possible to allow a correct clinical interpretation. The measurement uncertainty (MU) is a parameter that enables the accuracy of results to be known, and that is mandated by ISO 15189. Herein, this study suggests how the MU for the results of the free drug concentrations in serum could be estimated when an ED isused. A combination of the top-down and bottom-up approaches was used to estimate the MU based on the ISO/TS 20914:2019 and JCGM 100:2008 guidelines, including the concentration of free phenytoin in serum, as an example. Different scenarios were incorporated considering or not asignificant bias related to the primary drawbacks of ED: thenon-specific binding, the volume shift effect and the Gibbs-Donnan effect. The expanded uncertainties estimated ranged between 13.0 and 30.9 %. The highest MU corresponded to the free drug concentrations in serum results when significant biases related to the volume shift and Gibbs-Donnan effects exist. A detailed estimation of MU for free drug concentrations is presented using ED, considering different scenarios. This study could stimulate clinical laboratories to perform MU studies and its application in TDM.

A first-in-human study of Brozopentyl Sodium, following single and multiple ascending intravenous infusion in Chinese healthy volunteers

BackgroundBrozopentyl Sodium (BZP), a novel agent for ischemic stroke, has shown promising results in preclinical pharmacological studies, prompting the initiation of the first-in-human investigation. PurposeThis study aimed to assess the safety, tolerability, and pharmacokinetic (PK) characteristics of BZP in Chinese healthy volunteers. MethodsThe study consisted of two parts. Part I was a single-center, randomized, single-blinded, placebo-controlled, single-ascending study with six BZP dose cohorts (SAD: 25, 50, 100, 200, 300, and 400 mg). Part II was a single-center, randomized, single-blinded, placebo-controlled, multi-dose- and dose-elevated study with three BZP dose cohorts (MAD: 50, 100, and 200 mg). Doses were administered once daily on days 1 and 7 and twice daily on days 2–6. The PK properties of BZP and its bioactive metabolites, BNBP, were assessed. Safety and tolerability evaluations were also conducted. ResultsIn the SAD study, BZP reached peak plasma concentrations (Tmax) at the end of administration, with median Tmax values ranging from 1 to 1.03 h, while BNBP reached Tmax between 1.25 to 1.38 h. The terminal half-lives (T1/2) were approximately 8 h for BZP and 15 h for BNBP. In the MAD study, steady-state plasma concentrations of BZP were reached by day 5. There was minimal accumulation of both BZP and BNBP after 7 days of administration. The area under the plasma concentration-time curve from 0 to time of the last measurable concentration (AUC0-t) and maximum plasma drug concentration (Cmax) showed dose-proportional increases for BZP but not for BNBP in both study parts. Single and multiple doses of BZP demonstrated a good safety profile and were well-tolerated. ConclusionBZP displayed safety, good tolerability and predictable PK characteristics following both single and multiple ascending intravenous administrations. These findings provide a basis for further clinical development of BZP for ischemic stroke patients.

Assessment of CYP3A-mediated drug interaction via cytokine (IL-6) elevation for mosunetuzumab using physiologically-based pharmacokinetic modeling.

Mosunetuzumab is a CD3/CD20 bispecific antibody. As an on-target effect, transient elevation of interleukin-6 (IL-6) occurs in early treatment cycles. A physiologically-based pharmacokinetic (PBPK) model was developed to assess potential drug interaction caused by IL-6 enzyme suppression on cytochrome P450 3A (CYP3A) during mosunetuzumab treatment. The model's performance in predicting IL-6 CYP3A suppression and subsequent drug-drug interactions (DDIs) was verified using existing clinical data of DDIs caused by chronic and transient IL-6 elevation. Sensitivity analyses were performed for a complete DDI risk assessment. The IL-6 concentration- and time-dependent CYP3A suppression during mosunetuzumab treatment was simulated using PBPK model with incorporation of invitro IL-6 inhibition data. At clinically approved doses/regimens, the DDI at maximum CYP3A suppression was predicted to be a midazolam maximum drug concentration in plasma (Cmax ) and area under the plasma drug concentration-time curve (AUC) ratio of 1.17 and 1.37, respectively. At the 95th percentile of IL-6 concentration level or when gut CYP3A suppression was considered, the predicted DDI risk for mosunetuzumab remained low (<2-fold). The PBPK-based DDI predictions informed the mosunetuzumab product label to monitor, in early cycles, the concentrations and toxicities for sensitive CYP3A substrates with narrow therapeutic windows.

Impact of the physical-chemical properties of poly(lactic acid)–poly(ethylene glycol) polymeric nanoparticles on biodistribution

Nanoparticle (NP) formulations are inherently polydisperse making their structural characterization and justification of specifications complex. It is essential, however, to gain an understanding of the physico-chemical properties that drive performance in vivo. To elucidate these properties, drug-containing poly(lactic acid) (PLA)–poly(ethylene glycol) (PEG) block polymeric NP formulations (or PNPs) were sub-divided into discrete size fractions and analyzed using a combination of advanced techniques, namely cryogenic transmission electron microscopy, small-angle neutron and X-ray scattering, nuclear magnetic resonance, and hard-energy X-ray photoelectron spectroscopy. Together, these techniques revealed a uniquely detailed picture of PNP size, surface structure, internal molecular architecture and the preferred site(s) of incorporation of the hydrophobic drug, AZD5991, properties which cannot be accessed via conventional characterization methodologies. Within the PNP size distribution, it was shown that the smallest PNPs contained significantly less drug than their larger sized counterparts, reducing overall drug loading, while PNP molecular architecture was critical in understanding the nature of in vitro drug release. The effect of PNP size and structure on drug biodistribution was determined by administrating selected PNP size fractions to mice, with the smaller sized NP fractions increasing the total drug-plasma concentration area under the curve and reducing drug concentrations in liver and spleen, due to greater avoidance of the reticuloendothelial system. In contrast, administration of unfractionated PNPs, containing a large population of NPs with extremely low drug load, did not significantly impact the drug's pharmacokinetic behavior - a significant result for nanomedicine development where a uniform formulation is usually an important driver. We also demonstrate how, in this study, it is not practicable to validate the bioanalytical methodology for drug released in vivo due to the NP formulation properties, a process which is applicable for most small molecule-releasing nanomedicines. In conclusion, this work details a strategy for determining the effect of formulation variability on in vivo performance, thereby informing the translation of PNPs, and other NPs, from the laboratory to the clinic.

Abstract A140: A physiologically based pharmacokinetic modeling approach for predicting the exposure of irinotecan and its active metabolite (SN-38) in cancer patients

Abstract Introduction: Irinotecan is an inhibitor of the topoisomerase I enzyme that is essential in DNA transcription, replication, and repair. It is considered a “backbone” regime in colorectal cancer in adults and in pediatric gliomas to which other antineoplastic agents are added to improve the outcome. It is used as well in the treatment of many other types of adult and pediatric cancers. Irinotecan acts as a prodrug of SN-38 which has approximately 100-1000-fold greater cytotoxic activity. The metabolic and pharmacokinetic behavior of irinotecan is very complex and currently not completely elucidated. Clinical data have shown high variability in treated patients in the efficacy, toxicity, and pharmacokinetic profile of the drug. To increase safety and efficacy, a physiologically based pharmacokinetic modeling (PBPK) approach was used to predict the optimal dose for treatment initiation. Methods: Clinical data were used in combination with measured physicochemical and blood-binding data to inform the model. Hence a middle-out approach was used to build the parent model for a population of adult cancer patients. While the default Sim-Cancer population available within the Simcyp Simulator (v21) was used, the unbound fraction in plasma for the healthy population was incorporated into the PBPK model. By using the reverse translational tool and a retrograde approach, the irinotecan metabolism was described by incorporating CYP3A (Km 14.4±1.6 μM, Vmax 14.7± 0.6 pmol/min/mg protein) and an additional clearance. This additional clearance was then explained by scaled esterases (CES1 and CES2) enzyme kinetic from in vitro data. Besides the clinical study that was used to build the model, other independent intravenously administered irinotecan studies were used for verification. Results: The model predicted the plasma concentration of the parent drug and its metabolite (SN-38) in good agreement with observed data from the clinical study that was used to build the model, as well as from several clinical studies that were not used to build the initial model, covering a dose range of 50-750 mg/m2. Conclusion: We developed a PBPK model that accurately predicts the pharmacokinetic behavior of irinotecan and its metabolite (SN-38) in an adult cancer population. Future directions involve the adaption of the model to the pediatric cancer population to predict the optimal dose for initiation of first-in-human Phase I studies and to identify potential drug interactions and unanticipated toxicities when this “backbone” regimen is combined with other investigated anticancer agents. This will then lead to an increase in individualized treatment. Citation Format: Kristina Zoran Denic, Sibylle Neuhoff, Joel Reid, Rachel Kudget. A physiologically based pharmacokinetic modeling approach for predicting the exposure of irinotecan and its active metabolite (SN-38) in cancer patients [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A140.