-
Scientific Reports Jul 2023Cell-penetrating peptides (CPPs) have been used in basic and preclinical research in the past 30 years to facilitate drug delivery into target cells. However,...
Cell-penetrating peptides (CPPs) have been used in basic and preclinical research in the past 30 years to facilitate drug delivery into target cells. However, translation toward the clinic has not been successful so far. Here, we studied the pharmacokinetic (PK) and biodistribution profiles of Shuttle cell-penetrating peptides (S-CPP) in rodents, combined or not with an immunoglobulin G (IgG) cargo. We compared two enantiomers of S-CPP that contain both a protein transduction domain and an endosomal escape domain, with previously shown capacity for cytoplasmic delivery. The plasma concentration versus time curve of both radiolabelled S-CPPs required a two-compartment PK analytical model, which showed a fast distribution phase (tα ranging from 1.25 to 3 min) followed by a slower elimination phase (tβ ranging from 5 to 15 h) after intravenous injection. Cargo IgG combined to S-CPPs displayed longer elimination half-life, of up to 25 h. The fast decrease in plasma concentration of S-CPPs was associated with an accumulation in target organs assessed at 1 and 5 h post-injection, particularly in the liver. In addition, in situ cerebral perfusion (ISCP) of L-S-CPP yielded a brain uptake coefficient of 7.2 ± 1.1 µl g s, consistent with penetration across the blood-brain barrier (BBB), without damaging its integrity in vivo. No sign of peripheral toxicity was detected either by examining hematologic and biochemical blood parameters, or by measuring cytokine levels in plasma. In conclusion, S-CPPs are promising non-toxic transport vectors for improved tissue distribution of drug cargos in vivo.
Topics: Cell-Penetrating Peptides; Tissue Distribution; Drug Delivery Systems; Biological Transport; Endosomes
PubMed: 37422520
DOI: 10.1038/s41598-023-37280-0 -
Clinical Pharmacology and Therapeutics Dec 2023Coincidental with the intensified regulatory and industry focus on the design and conduct of human absorption, metabolism, and excretion (hAME) studies in the past... (Review)
Review
Coincidental with the intensified regulatory and industry focus on the design and conduct of human absorption, metabolism, and excretion (hAME) studies in the past 12 months, we have recently completed our 500th cohort involving radiolabeled test item administration to humans. Here, we build upon a recent industry white paper in this journal and share some of our own experiences as a Contract Research Organization based upon collaborations with numerous pharma companies and their differing approaches to design and timing, to add further context to the discussion regarding hAME studies and the pivotal role that drug metabolism and pharmacokinetics plays. In this article, we explore how both changing relationships within the industry and shifting regulatory guidelines are impacting strategies, and compare EU and US pre-study approval requirements, before evaluating the trends from over 500 studies conducted at our global facilities conducted over more than 30 years. We conclude with a review of how improved technical capabilities and strategies are influencing the design and conduct of hAME studies, before speculating on some of the driving factors which may shape the direction they take in the future.
Topics: Humans; Metabolic Clearance Rate; Data Analysis
PubMed: 37665689
DOI: 10.1002/cpt.3040 -
Carbohydrate Polymers Apr 2024Oral drug administration has become the most common and preferred mode of disease treatment due to its good medication adherence and convenience. For orally administered... (Review)
Review
Oral drug administration has become the most common and preferred mode of disease treatment due to its good medication adherence and convenience. For orally administered drugs, the safety, efficacy, and targeting ability requirements have grown as disease treatment research advances. It is difficult to obtain prominent efficacy of traditional drugs simply via oral administration. Numerous studies have demonstrated that cyclodextrins (CDs) can improve the clinical applications of certain orally administered drugs by enhancing their water solubility and masking undesirable odors. Additionally, deeper studies have discovered that CDs can influence disease treatment by altering the drug pharmacokinetics (PK) or pharmacodynamics (PD). This review highlights recent research progress on the PK and PD effects of CD-based oral drug delivery in disease therapy. Firstly, the review describes the characteristics of current drug delivery modes in oral administration. Besides, we minutely summarized the different CD-containing drugs, focusing on the impact of CD-based alterations in PK or PD of orally administered drugs in treating diseases. Finally, we deeply discussed current challenges and future opportunities with regard to PK and PD of CD-based oral drug delivery formulations.
Topics: Cyclodextrins; Pharmaceutical Preparations; Administration, Oral; Drug Delivery Systems; Biological Availability; Solubility
PubMed: 38286540
DOI: 10.1016/j.carbpol.2023.121763 -
The Brazilian Journal of Infectious... 2023Vancomycin is widely prescribed to treat or prevent Gram-positive infections in pediatric liver transplant recipients. The objective of this prospective cohort study is...
INTRODUCTION
Vancomycin is widely prescribed to treat or prevent Gram-positive infections in pediatric liver transplant recipients. The objective of this prospective cohort study is to describe vancomycin pharmacokinetics and to evaluate the therapeutic target attainment after initial dose regimen.
MATERIALS AND METHODS
Patients with previous renal injury were excluded. Vancomycin therapy started with 40‒60 mg/kg/day. The pharmacokinetic parameters were assessed using two steady-state blood samples and the first-order kinetic equations. Therapeutic target was defined as vancomycin 24-hour Area Under the Curve/Minimum Inhibitory Concentration (AUC/MIC) ≥ 400 and < 600.
RESULTS
Sixteen patients were included. The found vancomycin clearance, half-life, and volume of distribution were, respectively: 2.1 (1.3‒2.8) mL/kg/min, 3.3 (2.7‒4.4) hours, and 0.7 (0.5‒0.9) L/kg. With the initial dose, only 6 (37 %) patients reached the therapeutic target against Gram-positive pathogens with MIC 1 mg/L. After individual dose adjustments, all patients reached the target. The correlation between trough levels and AUC was low (R = 0.5).
CONCLUSIONS
Pediatric patients with preserved renal function after liver transplantation have an increased volume of distribution for vancomycin, and most patients present subtherapeutic levels after the standard initial dosing regimen. With the vancomycin AUC-guided monitoring and dosing, it is possible to improve therapeutic target attainment.
Topics: Humans; Child; Vancomycin; Anti-Bacterial Agents; Liver Transplantation; Prospective Studies; Retrospective Studies; Area Under Curve; Microbial Sensitivity Tests
PubMed: 37977199
DOI: 10.1016/j.bjid.2023.103688 -
International Journal of Biological... May 2024Carrageenan (CGN) is a typical sulfated polysaccharide widely applied in the food and pharmaceutical industries. Its in vivo behavior plays vital roles in understanding...
Carrageenan (CGN) is a typical sulfated polysaccharide widely applied in the food and pharmaceutical industries. Its in vivo behavior plays vital roles in understanding structural and biological functional relationships. The lack of UV chromophores in highly sulfated polysaccharides presents a challenge for their in vivo behavior studies. Therefore, this study aimed to develop a fast and effective quantitative fluorescence method for investigating the pharmacokinetics and tissue distribution of CGN. Fluorescence isothiocyanate labeling of CGN (FCGN) and microplate reader-based measurements were developed and validated to study its pharmacokinetics. These results showed that the FCGN concentration peaked at 3 h, the mean residence time was 36.6 h, and the clearance rate was 0.1 L/h/kg. Most of the FCGN was excreted in the feces, while 9.2 % was excreted in the urine, suggesting absorption and metabolism. The pharmacokinetic parameters indicated that the FCGN was absorbed quickly, eliminated slowly, and could remain in the body for a sustained profile. Moreover, ex vivo imaging and quantification of FCGN in tissues revealed that FCGN accumulated in the liver and kidney. Furthermore, oral administration of CGN or KOs for 14 days led to changes in liver and kidney indices. Histological analysis of significant organs revealed hepatocyte necrosis in the liver, renal tubular vacuolization in the kidney, and incomplete colonic epithelial cells. The KOs had a more significant effect on inflammatory cell infiltration than did CGNs. These in vivo findings laid the foundation for the study and application of CGN in food and pharmaceutical applications.
Topics: Animals; Carrageenan; Mice; Tissue Distribution; Administration, Oral; Male; Liver; Kidney
PubMed: 38490394
DOI: 10.1016/j.ijbiomac.2024.130725 -
Drug Metabolism and Disposition: the... Oct 2023Ipatasertib (GDC-0068) is a potent, highly selective, small-molecule inhibitor of protein kinase B (Akt) being developed by Genentech/Roche as a single agent and in...
Ipatasertib (GDC-0068) is a potent, highly selective, small-molecule inhibitor of protein kinase B (Akt) being developed by Genentech/Roche as a single agent and in combination with other therapies for the treatment of cancers. To fully understand the absorption, metabolism, and excretion of ipatasertib in humans, an open-label study using C-radiolabeled ipatasertib was completed to characterize the absolute bioavailability (period 1) and mass balance and metabolite profiling (period 2). In period 1, subjects were administered a 200 mg oral dose of ipatasertib followed by an 80 g (800 nCi) intravenous dose of [C]-ipatasertib. In period 2, subjects received a single oral dose containing approximately 200 mg (100 Ci) [C]-ipatasertib. In an integrated analytical strategy, accelerator mass spectrometry was applied to measure the C microtracer intravenous pharmacokinetics in period 1 and fully profile plasma radioactivity in period 2. The systemic plasma clearance and steady-state volume of distribution were 98.8 L/h and 2530 L, respectively. The terminal half-lives after oral and intravenous administrations were similar (26.7 and 27.4 hours, respectively) and absolute bioavailability of ipatasertib was 34.0%. After a single oral dose of [C]-ipatasertib, 88.3% of the administered radioactivity was recovered with approximately 69.0% and 19.3% in feces and urine, respectively. Radioactivity in feces and urine was predominantly metabolites with 24.4% and 8.26% of dose as unchanged parent, respectively; indicating that ipatasertib had been extensively absorbed and hepatic metabolism was the major route of clearance. The major metabolic pathway was -dealkylation mediated by CYP3A, and minor pathways were oxidative by cytochromes P450 and aldehyde oxidase. SIGNIFICANCE STATEMENT: The study provided definitive information regarding the absolute bioavailability and the absorption, metabolism, and excretion pathways of ipatasertib, a potent, novel, and highly selective small-molecule inhibitor of protein kinase B (Akt). An ultrasensitive radioactive counting method, accelerator mass spectrometry was successfully applied for C-microtracer absolute bioavailability determination and plasma metabolite profiling.
Topics: Humans; Biological Availability; Proto-Oncogene Proteins c-akt; Piperazines; Metabolic Clearance Rate; Feces; Administration, Oral
PubMed: 37524543
DOI: 10.1124/dmd.122.001175 -
Journal of Controlled Release :... Sep 2023The critical barrier for clinical translation of cancer nanomedicine stems from the inefficient delivery of nanoparticles (NPs) to target solid tumors. Rapid growth of...
The critical barrier for clinical translation of cancer nanomedicine stems from the inefficient delivery of nanoparticles (NPs) to target solid tumors. Rapid growth of computational power, new machine learning and artificial intelligence (AI) approaches provide new tools to address this challenge. In this study, we established an AI-assisted physiologically based pharmacokinetic (PBPK) model by integrating an AI-based quantitative structure-activity relationship (QSAR) model with a PBPK model to simulate tumor-targeted delivery efficiency (DE) and biodistribution of various NPs. The AI-based QSAR model was developed using machine learning and deep neural network algorithms that were trained with datasets from a published "Nano-Tumor Database" to predict critical input parameters of the PBPK model. The PBPK model with optimized NP cellular uptake kinetic parameters was used to predict the maximum delivery efficiency (DEmax) and DE at 24 (DE24) and 168 h (DE168) of different NPs in the tumor after intravenous injection and achieved a determination coefficient of R = 0.83 [root mean squared error (RMSE) = 3.01] for DE24, R = 0.56 (RMSE = 2.27) for DE168, and R = 0.82 (RMSE = 3.51) for DEmax. The AI-PBPK model predictions correlated well with available experimentally-measured pharmacokinetic profiles of different NPs in tumors after intravenous injection (R ≥ 0.70 for 133 out of 288 datasets). This AI-based PBPK model provides an efficient screening tool to rapidly predict delivery efficiency of a NP based on its physicochemical properties without relying on an animal training dataset.
Topics: Mice; Animals; Tissue Distribution; Artificial Intelligence; Models, Biological; Nanoparticles; Neoplasms
PubMed: 37499908
DOI: 10.1016/j.jconrel.2023.07.040 -
International Journal of Clinical... Nov 2023Lenvatinib is a tyrosine kinase inhibitor that helps prevent angiogenesis. In this study, we investigated the potential influencing factors on lenvatinib...
OBJECTIVE
Lenvatinib is a tyrosine kinase inhibitor that helps prevent angiogenesis. In this study, we investigated the potential influencing factors on lenvatinib pharmacokinetics to provide a reference for clinical application.
MATERIALS AND METHODS
All healthy participants received a single dose of 4 mg lenvatinib mesylate capsules with a high-fat meal or fasted conditions. Lenvatinib plasma concentrations were determined via high-performance liquid chromatography-mass spectrometry/mass spectrometry, and the pharmacokinetic parameters were calculated using WinNonlin 8.1 software. A mixed effect model analysis was adopted to explore the influence factor for the pharmacokinetic parameters of lenvatinib.
RESULTS
After a single oral dose of 4 mg lenvatinib mesylate, the pharmacokinetic parameters for the fasted and fed groups were as follows: t was 2.0 hours and 4.5 hours, C was 53.60 ng/mL and 45.54 ng/mL, AUC was 597.44 h×ng/mL and 561.51 h×ng/mL, CL was 6.82 L/h and 7.26 L/h, and Vd was 82.82 L and 94.04 L, respectively. Compared with those in the fasted group, decreased C and increased t were observed in the fed group. The geometric mean ratios of fed/fasted for C, AUC, and AUC were 86.9%, 94.0%, and 93.9%, respectively, and the pharmacokinetics of lenvatinib were significantly influenced by food intake. Gender influenced the pharmacokinetics of lenvatinib; females had higher C and AUC levels after 4 mg lenvatinib. Lenvatinib was well tolerated in healthy Chinese subjects.
CONCLUSION
High-fat diet altered the pharmacokinetic profile of lenvatinib, but not sufficient to significantly impact its clinical efficacy. Therefore, lenvatinib is suitable for administration under fasted or fed conditions.
Topics: Female; Humans; Biological Availability; Healthy Volunteers; East Asian People; Area Under Curve; Fasting; Cross-Over Studies; Administration, Oral
PubMed: 37644876
DOI: 10.5414/CP204440 -
Expert Opinion on Biological Therapy 2024This Phase I study compared the pharmacokinetic (PK) and pharmacodynamic (PD) similarity of GP2411 proposed denosumab biosimilar to reference denosumab (a monoclonal... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
This Phase I study compared the pharmacokinetic (PK) and pharmacodynamic (PD) similarity of GP2411 proposed denosumab biosimilar to reference denosumab (a monoclonal antibody for specific pro-resorptive conditions).
RESEARCH DESIGN AND METHODS
Healthy males (28-65 years, 50-90 kg) were randomized to a single sub-therapeutic subcutaneous injection of 35 mg GP2411, EU-Xgeva® or US-Xgeva®, and followed for 39 weeks. The primary endpoints were AUC, AUC, and C.
RESULTS
Four hundred ninety-two participants completed treatment. The 90% confidence intervals (CIs) (AUC, AUC, and C) and 95% CI of the geometric mean ratios of AUEC of % change from baseline in serum CTX were fully contained within the prespecified equivalence margins (0.80, 1.25), demonstrating similarity. The occurrence of treatment-emergent adverse events (TEAEs) with GP2411, EU-Xgeva® and US-Xgeva® was similar (72.9%, 76.0%, and 71.0% of participants, respectively). Most were Grade 1 or 2, <30% were treatment-related, and there was only one TEAE-related study discontinuation. Rates of positive anti-drug antibodies (ADAs) were similar (57.8%, 64.9%, and 69.1% of participants respectively), but immunogenicity was only borderline detectable and of very low magnitude. Ninety-nine percent of positive ADAs were transient.
CONCLUSION
GP2411 demonstrated similarity with EU-Xgeva® and US-Xgeva® in PK, PD, safety, and immunogenicity in this population.
CLINICAL TRIAL REGISTRATION
EudraCT 2019-001651-39.
Topics: Male; Humans; Denosumab; Biosimilar Pharmaceuticals; Therapeutic Equivalency; Healthy Volunteers; Antibodies, Monoclonal; Double-Blind Method
PubMed: 38269652
DOI: 10.1080/14712598.2024.2308645 -
Clinical Pharmacology in Drug... Sep 2023ABP 654 is a proposed biosimilar to ustekinumab reference product (RP) which works through antagonism of interleukin-12 and interleukin-23. Ustekinumab RP is used for... (Randomized Controlled Trial)
Randomized Controlled Trial
ABP 654 is a proposed biosimilar to ustekinumab reference product (RP) which works through antagonism of interleukin-12 and interleukin-23. Ustekinumab RP is used for the treatment of chronic inflammatory conditions, including some forms of plaque psoriasis, psoriatic arthritis, Crohn's disease, and ulcerative colitis. A randomized, double-blinded, single-dose, 3-arm, parallel-group study was conducted to assess the pharmacokinetic (PK) similarity of ABP 654 with ustekinumab RP sourced from the United States (US) and the European Union (EU); the PK similarity of ustekinumab US versus ustekinumab EU; and the comparative safety, tolerability, and immunogenicity of all 3 products. A total of 238 healthy subjects were randomized 1:1:1 and stratified by gender and ethnicity (Japanese versus non-Japanese) to receive a single 90 mg subcutaneous injection of ABP 654 or ustekinumab US or ustekinumab EU. PK similarity was established based on 90% confidence intervals (CIs) for the primary endpoints of area under the concentration-time curve from time 0 extrapolated to infinity (AUC ) and maximum observed serum concentration (C ) being contained within the prespecified margin of 0.8-1.25. No clinically meaningful differences in immunogenicity were found among the 3 products. Adverse events were similar between treatment groups and consistent with the safety profile of ustekinumab RP. Results indicate that ABP 654, ustekinumab US and ustekinumab EU share similar PK and safety profiles.
Topics: Humans; United States; Biosimilar Pharmaceuticals; Ustekinumab; Healthy Volunteers; Double-Blind Method; Therapeutic Equivalency
PubMed: 37415567
DOI: 10.1002/cpdd.1301