Clinical Pharmacokinetics Research Articles

Metformin (The Miracle Drug) Kinetics in Different Diseases such as Cancer

: Metformin, a miracle drug that was introduced a century ago, could be considered for various aspects of diseases such as diabetes (type 1 and 2), cancer prevention or chemotherapy, metabolic and neurodegenerative disease. It is well known that the frequency of cancer is higher in patients with type 2 diabetes mellitus. This review aims to provide updated information regarding clinical pharmacokinetics and the mechanism of action of Metformin in different diseases such as cancer. Diabetes type 1 is another chronic autoimmune disease detected usually in early childhood due to immune-mediated devastation of insulin-producing pancreatic beta-cells. Because of the lack of effective therapeutic approaches, its prevalence is increasing. Regarding cancer, an estimated 19.3 million new cancer cases and almost 10.0 million cancer deaths were reported in 2020 worldwide. By 50-60% bioavailability, the main route of metformin excretion is through urine. Its mechanism of action is based on 1) initiation of adenosine monophosphate-activated kinase, 2) block proinflammatory paths in perivascular adipose tissue, 3) decrease in monocyte-to-macrophage differentiation in vascular tissues, and 4) improvement in endothelial function. Metformin induces adenosine monophosphate-activated protein kinase signaling and suppresses gluconeogenesis. Antitumor properties of Metformin include a decrease in reactive oxygen species generation and inducing autophagy. In addition to glucose-lowering effects, Metformin has moderate anti-inflammatory and antioxidative effects. It could improve lipid profile and reduce overweight individuals' body mass and arterial blood pressure. In type 1 diabetes, Metformin reduces the requirement for daily insulin and improves glycemia. Its long-term use decreases cardiovascular events. In addition to inhibiting the synthesis of lipids via a reduction in oxidative stress, Metformin inhibits inflammation and increases energy metabolism. Finally, by reducing micro- and macro-vascular consequences, mortality-related diabetes and cancer decline by metformin administration. Therefore, in addition to diabetes, Metformin could reduce the proliferation of cancer cells and the possibility of malignancies in different types of cancer.

Impact of real-world off-label dose of Apixaban on long-term clinical outcomes in patients with atrial fibrillation and chronic kidney disease

Abstract Background Apixaban represent one of the cornerstone treatments to prevent cardioembolic events in patients with nonvalvular atrial fibrillation (NVAF). However, the choices of Apixaban dose guided by the decision-making process of the physician, which considers specific according to kidney functions are inconsistent in the real-world practice. Objective The objective of the present study is to evaluate the effects of real-world Off-label dose of Apixaban on long-term clinical outcomes in NVAF patients with chronic kidney disease (CKD). Methods Our database of AF patients diagnosed with CKD from 2018 to 2023 was used to obtain laboratory, echocardiography, electrocardiogram (ECG), and clinical outcomes data. Inclusion criteria were all AF patients with CKD using Apixaban. And we compared bleeding, systemic thrombotic events including stroke/systemic embolism and death according to off-label real -world dose of Apixaban. Results Among 635 patients with AF and CKD (76.9±10.4 years), 335 (52.8%) patients took off-label underdosed Apixaban. Difference in the baseline characteristics was not observed among patients including CHA2DS2 VASc score and HASBLED score. During the median 18-month follow-up, a lower incidence of bleeding events (P=0.001) was observed in the off-label underdosed Apixaban group compared to those with standard dose or off-label overdosed Apixaban. However, there was no significant difference of systemic thrombotic events including stroke/systemic embolism and death according to off-label real-world dose of Apixaban (off-label underdose vs. standard dose, P=1.000; off-label overdose vs. standard dose, P=1.000; off-label underdose vs. off-label overdose, P=0.609). In multivariate analysis, HASBLED score was independent risk factors for bleeding events (OR 9.650; CI 1.998-46.622; P=0.005). Conclusions Compared with standard or off-label overdose of Apixaban, off-label underdose of Apixaban was associated with a lower risk of bleeding in patients with AF and CKD, with no difference in the risk of stroke/systemic embolism or death, supporting the apixaban dosing tailored to specific clinical features and drug pharmacokinetics of the Asian patients.

Efficacy and safety of the ustekinumab biosimilar ABP 654 in patients with moderate-to-severe plaque psoriasis: a randomized, double-blinded, active-controlled, comparative clinical study over 52 weeks.

ABP 654 is a biosimilar to ustekinumab reference product (RP). ABP 654 has been shown to have an amino acid sequence identical to ustekinumab RP and they are similar in structure, purity, and potency as well as clinical pharmacokinetics and safety in healthy volunteers. This randomized, double-blinded, active-controlled, single-transition, comparative clinical study (ClinicalTrials.gov ID NCT04607980) was conducted to compare the efficacy, safety, and immunogenicity of ABP 654 and ustekinumab RP in patients with moderate-to-severe plaque psoriasis. Patients were randomized in a 1:1 ratio to receive ABP 654 or ustekinumab RP at a weight-based dose of 45 mg or 90 mg administered subcutaneously on day 1 (week 0), week 4, and week 16. At week 28, patients with a ≥75% improvement in Psoriasis Area and Severity Index (PASI) were re-randomized such that those initially randomized to ABP 654 continued to receive ABP 654 and those initially randomized to ustekinumab RP were re-randomized to either continue on ustekinumab RP or transition to ABP 654. The primary efficacy endpoint was PASI percent improvement from baseline to week 12. Secondary endpoints included additional efficacy measurements as well as an assessment of adverse events and antidrug antibodies. At week 12, the observed mean (SD) PASI percent improvement from baseline was 81.9 (19.9) and 81.9 (19.6) for the ABP 654 and ustekinumab RP treatment groups, respectively. The point estimate of the mean difference in PASI percent improvement from baseline to week 12 between the treatment groups was 0.14 with a 2-sided 90% confidence interval (CI) of (-2.6, 2.9), well within the prespecified similarity margin of (-10, +10). In addition, throughout the study, secondary efficacy analyses and safety and immunogenicity profiles were similar across the treatment groups. These results indicate that ABP 654 and ustekinumab RP are clinically similar in efficacy, safety, and immunogenicity in patients with moderate-to-severe plaque psoriasis. Further, a single transition from ustekinumab RP to ABP 654 at week 28 had no impact on the efficacy, safety, or immunogenicity results for the remainder of the 52-week study, supporting a conclusion of no clinically meaningful differences between ABP 654 and ustekinumab RP.

Establishing a physiologically based pharmacokinetic framework for aldehyde oxidase and dual aldehyde oxidase-CYP substrates.

Aldehyde oxidase (AO) contributes to the clearance of many approved and investigational small molecule drugs, which are often dual substrates of AO and drug-metabolizing enzymes such as cytochrome P450s (CYPs). As such, the lack of established framework for quantitative translation of the clinical pharmacologic correlates of AO-mediated clearance represents an unmet need. This study aimed to evaluate the utility of physiologically based pharmacokinetic (PBPK) modeling in the development of AO and dual AO-CYP substrates. PBPK models were developed for capmatinib, idelalisib, lenvatinib, zaleplon, ziprasidone, and zoniporide, incorporating invitro functional data from human liver subcellular fractions and human hepatocytes. Prediction of metabolic elimination with/without the additional empirical scaling factors (ESFs) was assessed. Clinical pharmacokinetics, human mass balance, and drug-drug interaction (DDI) studies with CYP3A4 modulators, where available, were used to refine/verify the models. Due to the lack of clinically significant AO-DDIs with known AO inhibitors, the fraction metabolized by AO (fmAO) was verified indirectly. Clearance predictions were improved by using ESFs (GMFE ≤1.4-fold versus up to fivefold with physiologically-based scaling only). Observed fmi from mass balance studies were crucial for model verification/refinement, as illustrated by capmatinib, where the fmAO (40%) was otherwise underpredicted up to fourfold. Subsequently, independent DDI studies with ketoconazole, itraconazole, rifampicin, and carbamazepine verified the fmCYP3A4, with predicted ratios of the area under the concentration-time curve (AUCR) within 1.5-fold of the observations. In conclusion, this study provides a novel PBPK-based framework for predicting AO-mediated pharmacokinetics and quantitative assessment of clinical DDI risks for dual AO-CYP substrates within a totality-of-evidence approach.

Model-Informed Drug Development-Based Approval of Intravenous Secukinumab for the Treatment of Adult Patients with Active Psoriatic Arthritis, Active Ankylosing Spondylitis, and Active Non-Radiographic Axial Spondyloarthritis.

On October 6, 2023, the US Food and Drug Administration (FDA) approved an intravenous (IV) formulation and dosage of Cosentyx® (secukinumab), for the treatment of adult patients with active psoriatic arthritis (PsA), active ankylosing spondylitis (AS), and active non-radiographic axial spondyloarthritis (nr-axSpA) with objective signs of inflammation. Clinical pharmacokinetics (PK), efficacy, and short-term placebo-controlled safety data were available from clinical studies (NCT04156620 and NCT04209205) with the to-be-marketed IV formulation using a maintenance dosage 3 mg/kg every 4 weeks (q4w), which was different from the dose approved (1.75 mg/kg q4w). The IV dosage of 3 mg/kg utilized in these two trials resulted in exposures (Cmax,ss) significantly higher than those for the approved subcutaneous (SC) regimens. Further, there is limited long-term safety information available for this 3 mg/kg q4w IV dose. To address this important limitation, a model-informed drug development (MIDD) approach was employed to leverage available clinical PK, efficacy, and safety data from the secukinumab development program to identify a maintenance IV dosing regimen, 1.75 mg/kg IV q4w, that better approximated the relevant SC secukinumab exposures for which efficacy and safety have been established. The MIDD analyses were used to support approval of this IV dosing regimen not directly studied in the indications sought for licensure, PsA, AS, and nr-AxSpA.

Establishing a Relationship between In Vitro Potency in Cell-Based Assays and Clinical Efficacious Concentrations for Approved GLP-1 Receptor Agonists.

Background: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) play an important role in the treatment of type 2 diabetes (T2D) and obesity. The relationship between efficacy and dosing regimen has been studied extensively for this class of molecules. However, a comprehensive analysis of the translation of in vitro data to in vivo efficacious exposure is still lacking. Methods: We collected clinical pharmacokinetics for five approved GLP-1RAs to enable the simulation of exposure profiles and compared published clinical efficacy endpoints (HbA1c and body weight) with in-house in vitro potency values generated in different cell-based assays. Additionally, we investigated the correlation with target coverage, expressed as a ratio between the steady state drug exposure and unbound potency, body weight, or HbA1c reduction in patients with T2D. Results: We found that the best correlation with in vivo efficacy was seen for in vitro potency data generated in cellular assays performed in the absence of any serum albumin or using ovalbumin. Residual variability was larger using in vitro potency data generated in endogenous cell lines or in the presence of human serum albumin. For the human receptor assay with no albumin, exposures above 100-fold in vitro EC50 resulted in >1.5% point HbA1c reduction, while a 5% BW reduction was related to approximately 3× higher exposures. A similar relationship was seen in the ovalbumin assay. Conclusions: Overall, the relationship established for in vitro potency and in vivo efficacy will help to increase confidence in human dose prediction and trial design for new GLP-1RAs in the discovery and early clinical phases.

Clinical Pharmacokinetics of Atropine Administered Ocularly Using an Ultrasensitive Bioanalytical Assay.

Purpose: Previous pharmacokinetic studies conducted on atropine sulfate ophthalmical solution have utilized bioanalytical assays that lacked sufficient sensitivity to fully characterize the complete pharmacokinetic profile. To address these limitations, Pharma Medica Research Inc. has developed and validated an ultrasensitive bioanalytical method capable of accurately quantifying the active enantiomer, L-hyoscyamine, with a very low limit of quantitation of 0.500 pg/mL. The objective of this study was to evaluate the pharmacokinetics of L-hyoscyamine in healthy subjects using a highly sensitive bioanalytical assay. Methods: Ten subjects were administered 0.3 mg of Isopto Atropine solution into the conjunctival sac of the eye. Blood samples were taken as early as 2 min and up to 24 h following administration. The plasma samples were assayed for L-hyoscyamine using a chiral method with an analytical range of 0.500-500 pg/mL. The pharmacokinetic parameters were estimated using both a noncompartmental and compartmental approach. Results: The pharmacokinetics of L-hyoscyamine were fully characterized as there were no samples that were below the limit of quantitation following dosing. Using noncompartmental analysis, the mean Cmax was 467.9 ± 159.4 pg/mL with a median (range) Tmax of 0.5 (0.08-1) h. The mean area under the concentration-time curve was 1668.96 ± 436.02 h·pg/mL and the mean half-life was 3.91 ± 1.16 h. Overall, the study drug was well tolerated and no serious adverse events were reported. Conclusion: Through the utilization of a proprietary ultrasensitive bioanalytical method, a comprehensive investigation into the pharmacokinetics of L-hyoscyamine has been successfully conducted. This advanced method offers significant potential for optimizing study designs and facilitating in-depth examinations of the pharmacokinetics of ocularly administered atropine formulations.

Physiology-based pharmacokinetic model with relative transcriptomics to evaluate tissue distribution and receptor occupancy of anifrolumab.

Type I interferons contribute to the pathogenesis of several autoimmune disorders, including systemic lupus erythematosus (SLE), systemic sclerosis, cutaneous lupus erythematosus, and myositis. Anifrolumab is a monoclonal antibody that binds to subunit 1 of the type I interferon receptor (IFNAR1). Results of phase IIb and phase III trials led to the approval of intravenous anifrolumab 300 mg every 4 weeks (Q4W) alongside standard therapy in patients with moderate-to-severe SLE. Here, we built a population physiology-based pharmacokinetic (PBPK) model of anifrolumab by utilizing the physiochemical properties of anifrolumab, binding kinetics to the Fc gamma neonatal receptor, and target-mediated drug disposition properties. A novel relative transcriptomics approach was employed to determine IFNAR1 expression in tissues (blood, skin, gastrointestinal tract, lungs, and muscle) using mRNA abundances from bioinformatic databases. The IFNAR1 expression and PBPK model were validated by testing their ability to predict clinical pharmacokinetics over a large dose range from different clinical scenarios after subcutaneous and intravenous anifrolumab dosing. The validated PBPK model predicted high unbound local concentrations of anifrolumab in blood, skin, gastrointestinal tract, lungs, and muscle, which exceeded its IFNAR1 dissociation equilibrium constant values. The model also predicted high IFNAR1 occupancy with subcutaneous and intravenous anifrolumab dosing. The model predicted more sustained IFNAR1 occupancy ≥90% with subcutaneous anifrolumab 120 mg once-weekly dosing vs. intravenous 300 mg Q4W dosing. The results informed the dosing of phase III studies of anifrolumab in new indications and present a novel approach to PBPK modeling coupled with relative transcriptomics in simulating pharmacokinetics of therapeutic monoclonal antibodies.

Population pharmacokinetic analysis and dosing optimization of colistin sulphate in lung transplant recipients with pneumonia: A prospective study

ObjectiveCurrently, there is a lack of information on the clinical pharmacokinetics (PK), effectiveness, and safety of colistin sulphate (CS) in lung transplant recipients. This study aims to improve CS dosing regimens and evaluate its population PK in lung transplant recipients. MethodsThis study evaluated the clinical efficacy, microbiological efficacy, and adverse events of CS in lung transplant recipients. The NONMEM program was employed to construct the population PK model, and Monte Carlo simulations were executed to establish dosing regimens according to the probability of target attainment (PTA). ResultsThe study included 146 CS concentrations, spanning from 0.05 to 4.18 mg/L from 39 lung transplant recipients with multidrug-resistant Gram-negative bacteria. 26 (66.67%) patients successfully eradicated bacteria, and 30 (76.92%) patients had clinical cure or improvement. Additionally, only 2 (5.13%) patients developed CS-related nephrotoxicity. The PK profile was effectively represented by a one-compartmental model with linear elimination. Creatinine clearance and concomitant furosemide use were recognized as covariates influencing the clearance of CS. Based on the PTA results, a daily dosage of 1.5 million IU, divided into 2–3 administrations, could attain a PTA exceeding 90% for MIC ≤ 1 µg/mL at creatinine clearance of about 110 mL/min. However, this regimen would lead to insufficient exposure for MIC ≥ 2 µg/mL. ConclusionsThe clearance of CS is significantly influenced by concomitant furosemide use and renal function. The currently recommended dosing regimens by label sheet may result in subtherapeutic exposure for MIC exceeding 1 mg/L in lung transplant recipients.

Efficacy and Safety of Biosimilar SCT510 Compared with Bevacizumab for the First-Line Treatment of Advanced Non-Squamous Non-Small Cell Lung Cancer: A Randomized, Double-Blind, Phase III Study.

SCT510 is a biosimilar to bevacizumab (Avastin) reference product (RP) that is approved for various metastatic cancers. In this study, we aimed to demonstrate the equivalence of SCT510 and bevacizumab in terms of efficacy, safety, immunogenicity and pharmacokinetics (PK) in patients with advanced non-squamous non-small cell lung cancer (NSCLC). Patients with non-squamous NSCLC were randomized equally to the SCT510 group (comprising SCT510, paclitaxel, and carboplatin) and the bevacizumab group (comprising bevacizumab, paclitaxel, and carboplatin) for 4-6 cycles, followed by maintenance monotherapy with SCT510. The primary endpoint was the objective response rate (ORR) at week 12. Secondary endpoints included 18-week ORR, disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), overall survival (OS), and 1-year survival rate, as well as assessments of safety, immunogenicity, and multi-dose PK analysis. Between March 29, 2019, and April 27, 2021, 989 patients were screened and 567 eligible patients were randomly assigned to the SCT510 group (285 patients) and the bevacizumab group (282 patients). The ORR at week 12 was 52.6% [95% confidence interval (CI) 46.66-58.55%] in the SCT510 group and 52.5% (95% CI 46.47-58.47%) in the bevacizumab group. The ORR at week 18 was 55.4% (95% CI 49.46-61.30%) for SCT510 and 55.7% (95% CI 49.68-61.62%) for bevacizumab. The ORR risk ratio (RR) at weeks 12 and 18 was 0.99 (90% CI 0.873-1.133) and 0.99 (90% CI 0.872-1.114), respectively, both within the pre-specified equivalence margin of 0.75-1.33. There were no differences between the two groups in relation to other secondary endpoints, specifically DCR, DOR, PFS, OS, and 1-year survival rate. The overall safety findings were similar between the two treatment groups, and both SCT510 and bevacizumab RP exhibited low immunogenicity. SCT510 is similar to bevacizumab in clinical efficacy, safety, immunogenicity, and PK in patients with advanced non-squamous NSCLC. The totality of the evidence supports the clinical equivalence of SCT510 and bevacizumab. NCT03792074.

Ocular Pharmacology.

Treatment of ocular diseases presents unique challenges and opportunities for the clinician and for the clinical pharmacologist. Ophthalmic pharmaceuticals, typically given as liquids, require consideration of solubility, physiological pH, and osmolarity, as well as sterility and stability, which in turn requires optimal pharmaceutics. Ocular tissue levels are challenging to obtain in humans, and the clinical pharmacokinetics is typically blood levels, which are primarily related to safety, rather than efficacy. The eye is a closed compartment with multiple physiological barriers with esterases and transporters, but relatively little cytochrome oxidases. Delivery routes include topical, intravitreal, and systemic. Patient dosing involves not only adherence issues common to all chronic diseases, but also performance requirements on eye drop instillation. Therapeutically, ocular diseases and their pharmacological treatments include both those analogous to systemic diseases (e.g., inflammation, infection, and neuronal degeneration) and those unique to the eye (e.g., cataract and myopia).

Comparative clinical efficacy and safety of biosimilar ABP 959 and eculizumab reference product in patients with paroxysmal nocturnal hemoglobinuria.

ABP 959 is a biosimilar to the eculizumab reference product (RP), which is approved for the treatment of patients with paroxysmal nocturnal hemoglobinuria (PNH). This multicenter, randomized, double-blind, active-controlled, two-period crossover study randomized eculizumab RP-treated patients with PNH to one of two treatment sequences (ABP 959/eculizumab RP or eculizumab RP/ABP 959) to evaluate the clinical similarity of ABP 959 when compared with eculizumab RP. This study evaluated the efficacy of ABP 959 when compared with eculizumab RP based on control of intravascular hemolysis as measured by lactate dehydrogenase (LDH) and by the time-adjusted area under the effect curve of LDH. Secondary outcomes included safety, pharmacokinetics, and immunogenicity. Forty-two patients were randomized (20 in the ABP 959/eculizumab RP group and 22 in the eculizumab RP/ABP 959 group) across 25 centers. Similarity of efficacy was established by a ratio of geometric least squares means of LDH (ABP 959/eculizumab RP) of 1.0628, with a one-sided 97.5% upper CI of 1.1576 at week 27, and a geometric means ratio of time-adjusted area under the effect curve (ABP 959 vs. eculizumab RP) of LDH of 0.981, with a 90% CI of 0.9403-1.0239 from week 13 to 27, week 39 to 53, and week 65 to 79. All secondary efficacy endpoints were comparable between treatment groups. No new safety concerns were identified. The results of this study in patients with PNH, along with previously demonstrated similarity of analytical, nonclinical, and clinical pharmacokinetics and pharmacodynamics in healthy volunteers support a demonstration of no clinically meaningful differences between ABP 959 and eculizumab RP. Clinical Trial Registration: NCT03818607.

First-in-Human Study of the Safety, Tolerability, Pharmacokinetics, Immunogenicity, and Pharmacodynamics of DS-7011a, an Anti-TLR7 Antagonistic Monoclonal Antibody for the Treatment of Systemic Lupus Erythematosus.

Toll-like receptor (TLR)7 is a pattern recognition receptor that critically contributes to the pathogenesis of systemic lupus erythematosus (SLE). DS-7011a is an anti-TLR7 monoclonal antibody that prevents TLR7 from signaling. The aim of this first-in-human, double-blind, randomized, and placebo-controlled study was to evaluate the safety, pharmacokinetics, immunogenicity, and pharmacodynamics of single ascending intravenous (IV) and subcutaneous (SC) doses of DS-7011a in healthy subjects (HS) (NCT05203692). On day 1, 80 HS received DS-7011a or placebo 6:2 in 10 cohorts (7 treated IV and 3 SC) of 8 each and were followed for 8 weeks until day 57. Safety was evaluated by recording treatment-emergent adverse events (TEAEs), pharmacokinetics by measuring plasma DS-7011a, immunogenicity by measuring plasma anti-drug antibodies (ADAs), and pharmacodynamics by evaluating the suppression of interleukin-6 production ex vivo in whole blood. DS-7011a was safe and well tolerated across all cohorts. TEAEs were mostly mild in severity and not drug-related. DS-7011a exposure increased with the dose but was not dose proportional, as the elimination of lower doses was accelerated by target-mediated drug disposition. Terminal half-life was about 15-17 days and Tmax upon SC administration was about 5 days. DS-7011a induced ADAs in about half of HS but with no impact on clinical findings and pharmacokinetics. Pharmacodynamic (PD) response also increased with the dose and at the higher doses was of large extent (>90%), early onset, and lasting duration. DS-7011a showed favorable safety, pharmacokinetics, immunogenicity, and PD properties that support its development for the treatment of SLE.

Physiologically Based Pharmacokinetic Model of OATP1B Substrates with a Nonlinear Mixed Effect Approach: Estimating Empirical In Vitro-to-In Vivo Scaling Factors.

Physiologically based pharmacokinetic (PBPK) models are valuable for translating in vitro absorption, distribution, metabolism, and excretion (ADME) data to predict clinical pharmacokinetics, and can enable discovery and early clinical stages of pharmaceutical research. However, in predicting pharmacokinetics of organic anion transporting polypeptide (OATP) 1B substrates based on in vitro transport and metabolism data, PBPK models typically require additional empirical in vitro-to-in vivo scaling factors (ESFs) in order to accurately recapitulate observed clinical profiles. As model simulation is very sensitive to ESFs, a critical evaluation of ESF estimation is prudent. Previously studies have applied classic 'two-stage' and 'naïve pooled data' approaches in identifying a set of compound independent ESFs. However, the 'two-stage' approach has the parameter identification issue in separately fitting data for individual compounds, while the 'naïve pooled data' approach ignores interstudy variability, leading to potentially biased ESF estimates. In this study, we have applied a nonlinear mixed-effect approach in estimating ESF of the PBPK model and incorporated additional data from 86 runs of in vitro uptake assay and 49 clinical studies of 12 training compounds in model development to further enhance the translation of in vitro data to predict the pharmacokinetics of OATP1B substrate drugs. To test predication accuracy of the model, a 'leave-one-out' analysis has been performed. The established model can reasonably describe the clinical observations, with both mean values and interstudy variabilities quantified for ESF and volume of distribution parameters. The mean estimates are largely consistent with values in the previous reports. The interstudy variabilities of these parameters are estimated to be at least 50% (as coefficient of variation). Most compounds can be reasonably predicted in the 'leave-one-out' analysis. This study improves the confidence in predicting the pharmacokinetics of OATP1B substrates in individual studies of small sample sizes, and quantifies the variability associated with the prediction.

Unveiling the electron-induced ionization cross sections and fragmentation mechanisms of 3,4-dihydro-2H-pyran.

The interactions of electrons with molecular systems under various conditions are essential to interdisciplinary research fields extending over the fundamental and applied sciences. In particular, investigating electron-induced ionization and dissociation of molecules may shed light on the radiation damage to living cells, the physicochemical processes in interstellar environments, and reaction mechanisms occurring in combustion or plasma. We have, therefore, studied electron-induced ionization and dissociation of the gas phase 3,4-dihydro-2H-pyran (DHP), a cyclic ether appearing to be a viable moiety for developing efficient clinical pharmacokinetics and revealing the mechanisms of biofuel combustion. The mass spectra in the m/z = 10-90 mass range were measured at several different energies of the ionizing electron beam using mass spectrometry. The mass spectra of DHP at the same energies were simulated using on-the-fly semi-classical molecular dynamics (MD) within the framework of the QCxMS formalism. The MD settings were suitably adjusted until a good agreement with the experimental mass spectra intensities was achieved, thus enabling a reliable assignment of cations and unraveling the plausible fragmentation channels. Based on the measurement of the absolute total ionization cross section of DHP (18.1 ± 0.9) × 10-16cm2 at 100eV energy, the absolute total and partial ionization cross sections of DHP were determined in the 5-140eV electron energy. Moreover, a machine learning algorithm that was trained with measured cross sections from 25 different molecules was used to predict the total ionization cross section for DHP. Comparison of the machine learning simulation with the measured data showed acceptable agreement, similar to that achieved in past predictions of the algorithm.

Actionable Predictions of Human Pharmacokinetics at the Drug Design Stage.

We present a novel computational approach for predicting human pharmacokinetics (PK) that addresses the challenges of early stage drug design. Our study introduces and describes a large-scale data set of 11 clinical PK end points, encompassing over 2700 unique chemical structures to train machine learning models. To that end multiple advanced training strategies are compared, including the integration of in vitro data and a novel self-supervised pretraining task. In addition to the predictions, our final model provides meaningful epistemic uncertainties for every data point. This allows us to successfully identify regions of exceptional predictive performance, with an absolute average fold error (AAFE/geometric mean fold error) of less than 2.5 across multiple end points. Together, these advancements represent a significant leap toward actionable PK predictions, which can be utilized early on in the drug design process to expedite development and reduce reliance on nonclinical studies.

A Data Driven Strategy and Case Study for Implementation of Singlicate Analysis in Ligand Binding Assays Used for PK Quantitation.

Duplicate analysis has been a conventional practice in the industry for ligand-binding assays (LBA), particularly for plate-based platforms like Enzyme-linked immunosorbent assay (ELISA) and Meso Scale Discovery (MSD) assays. Recent whitepapers and guidance have opened a door to exploring the implementation of single-well (singlicate) analysis approach for LBAs. Although the bioanalytical industry has actively investigated the suitability of singlicate analysis, applications in supporting regulated LBA bioanalysis are limited. The primary reason for this limitation is the absence of appropriate strategy to facilitate the transition from duplicate to singlicate analysis. In this paper we present the first case study with our data-driven approach to implement singlicate analysis in a clinical pharmacokinetics (PK) plate based LBA assay with ISR data. The central aspect of this strategy is a head-to-head comparison with Precision and Accuracy assessment in both duplicate and singlicate formats as the initial stage of assay validation. Subsequently, statistical analysis is conducted to evaluate method variability in both precision and accuracy. The results of our study indicated that there was no impactful difference between duplicate vs singlicate, affirming the suitability of singlicate analysis for the remaining steps of PK assay validation. The validation results obtained through singlicate analysis demonstrated acceptable assay performance characteristics across all validation parameters, aligning with regulatory guidance. The validated PK assay in singlicate has been employed to support a Phase I study. The appropriateness of singlicate analyses is further supported by initial Incurred Sample Reanalysis (ISR) data in which 90.1% of ISR samples fall within the acceptable criteria.

Modelling the nicotine pharmacokinetic profile for e-cigarettes using real time monitoring of consumers’ physiological measurements and mouth level exposure

Pharmacokinetic (PK) studies can provide essential information on abuse liability of nicotine and tobacco products but are intrusive and must be conducted in a clinical environment. The objective of the study was to explore whether changes in plasma nicotine levels following use of an e-cigarette can be predicted from real time monitoring of physiological parameters and mouth level exposure (MLE) to nicotine before, during, and after e-cigarette vaping, using wearable devices. Such an approach would allow an -effective pre-screening process, reducing the number of clinical studies, reducing the number of products to be tested and the number of blood draws required in a clinical PK study Establishing such a prediction model might facilitate the longitudinal collection of data on product use and nicotine expression among consumers using nicotine products in their normal environments, thereby reducing the need for intrusive clinical studies while generating PK data related to product use in the real world.An exploratory machine learning model was developed to predict changes in plasma nicotine levels following the use of an e-cigarette; from real time monitoring of physiological parameters and MLE to nicotine before, during, and after e-cigarette vaping. This preliminary study identified key parameters, such as heart rate (HR), heart rate variability (HRV), and physiological stress (PS) that may act as predictors for an individual’s plasma nicotine response (PK curve). Relative to baseline measurements (per participant), HR showed a significant increase for nicotine containing e-liquids and was consistent across sessions (intra-participant). Imputing missing values and training the model on all data resulted in 57% improvement from the original’learning’ data and achieved a median validation R2 of 0.70.The study is in its exploratory phase, with limitations including a small and non-diverse sample size and reliance on data from a single e-cigarette product. These findings necessitate further research for validation and to enhance the model's generalisability and applicability in real-world settings. This study serves as a foundational step towards developing non-intrusive PK models for nicotine product use.

Clinical Pharmacokinetics and Pharmacodynamics of Letermovir in Allogenic Hematopoietic Cell Transplantation.

Letermovir is a newly developed antiviral agent used for the prophylaxis of human cytomegalovirus infections in patients undergoing allogeneic hematopoietic cell transplantation. This novel anti-cytomegalovirus drug, used for the prophylaxis of cytomegalovirus reactivation until approximately 200 days after transplantation, effectively reduces the risk of clinically significant cytomegalovirus infection. No human counterpart exists for the terminase complex; letermovir is virus specific and lacks some toxicities previously observed with other anti-cytomegalovirus drugs, such as cytopenia and nephrotoxicity. The absolute bioavailability of letermovir in healthy individuals is estimated to be 94% based on a population-pharmacokinetic analysis. In contrast, oral administration of letermovir to patients undergoing hematopoietic cell transplantation results in lower exposure than that in healthy individuals. Renal or hepatic impairment does not influence the intrinsic clearance of letermovir. Co-administration of letermovir may alter the plasma concentrations of other drugs, including itself, as it acts as a substrate and inhibitor/inducer of several drug-metabolizing enzymes and transporters. In particular, attention should be paid to the drug-drug interactions between letermovir and calcineurin inhibitors or azole antifungal agents, which are commonly used in patients undergoing hematopoietic cell transplantation. This article reviews and summarizes the clinical pharmacokinetics and pharmacodynamics of letermovir, focusing on patients undergoing hematopoietic cell transplantation, healthy individuals, and specific patient subsets.

Inter-Antibody Variability in the Clinical Pharmacokinetics of Monoclonal Antibodies Characterized Using Population Physiologically Based Pharmacokinetic Modeling.

The objective of this work was to develop a population physiologically based pharmacokinetic (popPBPK) model to characterize the variability in the clinical PK of monoclonal antibodies (mAbs) following intravenous (IV) and subcutaneous (SC) administration. An extensive literature search was conducted and clinical PK data for FDA-approved as well as non-approved mAbs were collected. Training and validation datasets of 44 and 9 mAbs exhibiting linear pharmacokinetics were used for model development. The variability in antibody PK was captured by accounting for different rate constants of pinocytosis (CLup) and intracellular degradation (kdeg) for different mAbs. Typical values for CLup and kdeg and their respective inter-antibody variabilities (ωClup, ωKdeg) were estimated to be 0.32 L/h/L and 26.1 h-1 (73% and 46%). Varied absorption profiles following SC dosing were characterized by incorporating inter-antibody variability in local degradation (kSC) and rate of lymphatic uptake (S_Lu) of mAbs. Estimates for typical kSC and S_Lu values, and ωKsc,ωS_Lu, were found to be 0.0015 h-1 and 0.54 (193%, and 49%). FDA-approved mAbs showed less local degradation (0.0014 h-1 vs. 0.0038 h-1) compared with other clinically tested mAbs, whereas no substantial differences in physiological processes involved in disposition were observed. To evaluate the generalizability of estimated PK parameters and model validation, the final popPBPK model was used to simulate the range of expected PK for mAbs following SC administration of nine different mAbs that were not used for model-building purposes. The predicted PK of all nine mAbs was within the expected range specified a priori. Thus, the popPBPK model presented here may serve as a tool to predict the clinical PK of mAbs with linear disposition before administering them to humans. The model may also support preclinical-to-clinical translation and 'first-in-human' dose determination for mAbs.