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14 pages, 3978 KiB

Open AccessArticle

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

by Alessandro Boianelli, Pär Nordell, Joseph Earl, Jacqueline Naylor, David Hornigold, Rasmus Jansson Löfmark and Monika Sundqvist

Pharmaceutics 2024, 16(10), 1310; https://doi.org/10.3390/pharmaceutics16101310 - 8 Oct 2024

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Abstract

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 [...] Read more.

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. Full article

(This article belongs to the Special Issue Role of Pharmacokinetics in Drug Development and Evaluation)

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16 pages, 1903 KiB

Open AccessArticle

Rutin and Physalis peruviana Extract: Population Pharmacokinetics in New Zealand Rabbits

by Gina Paola Domínguez Moré, Diana P. Rey, Ivonne H. Valderrama, Luis F. Ospina and Diana Marcela Aragón

Pharmaceutics 2024, 16(10), 1241; https://doi.org/10.3390/pharmaceutics16101241 - 24 Sep 2024

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Abstract

Background/Objectives: An extract of calyces from Physalis peruviana with hypoglycemic activity is being considered as a potential herbal medicine. Preclinical pharmacokinetics (PK) studies of the extract in rats, focusing on plasma concentrations of its main compound, rutin, and its metabolites, revealed PK interactions [...] Read more.

Background/Objectives: An extract of calyces from Physalis peruviana with hypoglycemic activity is being considered as a potential herbal medicine. Preclinical pharmacokinetics (PK) studies of the extract in rats, focusing on plasma concentrations of its main compound, rutin, and its metabolites, revealed PK interactions in the extract matrix that improved the absorption of rutin metabolites compared to the pure compound, among other PK effects. This research aimed to study the PK of rutin alone and in the extract and assess potential PK interactions in the extract matrix on the flavonoid and its metabolites in rabbits, a nonrodent species; Methods: Animals received pure rutin or extract orally and intravenously. The PK analysis used noncompartmental and population pharmacokinetics (popPK) methods, and simple allometry was applied to predict human PK parameters; Results: The rutin concentration–time profile fit a two-compartment model with first-order elimination, while its metabolites fit a double first-order absorption model. The extract matrix led to increased absorption, distribution, and elimination of rutin as well as increased bioavailability of its metabolites in rabbits; Conclusions: The popPK model defined the equations for PK parameters describing these findings, and the increased volume of distribution and clearance of rutin was maintained in human predictions. These results will support the development of a new herbal medicine. Full article

(This article belongs to the Special Issue Role of Pharmacokinetics in Drug Development and Evaluation)

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12 pages, 1289 KiB

Open AccessArticle

Analysis of Lipophilicity and Pharmacokinetic Parameters of Dipyridothiazine Dimers with Anticancer Potency

by Emilia Martula, Beata Morak-Młodawska, Małgorzata Jeleń and Patrick Nwabueze Okechukwu

Pharmaceutics 2024, 16(9), 1235; https://doi.org/10.3390/pharmaceutics16091235 - 23 Sep 2024

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Abstract

Lipophilicity is an essential parameter of a compound that determines the solubility and pharmacokinetic properties that determine the transport of the drug to the molecular target. Dimers of dipyridothiazines are diazaphenothiazine derivatives exhibiting diverse anticancer potential in vitro, which is related to their [...] Read more.

Lipophilicity is an essential parameter of a compound that determines the solubility and pharmacokinetic properties that determine the transport of the drug to the molecular target. Dimers of dipyridothiazines are diazaphenothiazine derivatives exhibiting diverse anticancer potential in vitro, which is related to their affinity for histone deacetylase. In this study, the lipophilicity of 16 isomeric dipyridothiazine dimers was investigated theoretically and experimentally by reversed-phase thin-layer chromatography (RP-TLC) in an acetone–TRIS buffer (pH = 7.4). The relative lipophilicity parameter R_M0 and specific hydrophobic surface area b were significantly intercorrelated, showing congeneric classes of dimers. The parameter R_M0 was transformed into parameter logP_TLC by use of the calibration curve. Molecular descriptors, ADMET parameters and probable molecular targets were determined in silico for analysis of the pharmacokinetic profile of the tested compounds showing anticancer activity. The analyzed compounds were tested in the context of Lipinski’s rule of five, Ghose’s rule and Veber’s rule, confirming their bioavailability. Full article

(This article belongs to the Special Issue Role of Pharmacokinetics in Drug Development and Evaluation)

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18 pages, 3667 KiB

Open AccessArticle

A Minimal PBPK/PD Model with Expansion-Enhanced Target-Mediated Drug Disposition to Support a First-in-Human Clinical Study Design for a FLT3L-Fc Molecule

by Iraj Hosseini, Brett Fleisher, Jennifer Getz, Jérémie Decalf, Mandy Kwong, Meric Ovacik, Travis W. Bainbridge, Christine Moussion, Gautham K. Rao, Kapil Gadkar, Amrita V. Kamath and Saroja Ramanujan

Pharmaceutics 2024, 16(5), 660; https://doi.org/10.3390/pharmaceutics16050660 - 15 May 2024

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Abstract

FLT3L-Fc is a half-life extended, effectorless Fc-fusion of the native human FLT3-ligand. In cynomolgus monkeys, treatment with FLT3L-Fc leads to a complex pharmacokinetic/pharmacodynamic (PK/PD) relationship, with observed nonlinear PK and expansion of different immune cell types across different dose levels. A minimal physiologically [...] Read more.

FLT3L-Fc is a half-life extended, effectorless Fc-fusion of the native human FLT3-ligand. In cynomolgus monkeys, treatment with FLT3L-Fc leads to a complex pharmacokinetic/pharmacodynamic (PK/PD) relationship, with observed nonlinear PK and expansion of different immune cell types across different dose levels. A minimal physiologically based PK/PD model with expansion-enhanced target-mediated drug disposition (TMDD) was developed to integrate the molecule’s mechanism of action, as well as the complex preclinical and clinical PK/PD data, to support the preclinical-to-clinical translation of FLT3L-Fc. In addition to the preclinical PK data of FLT3L-Fc in cynomolgus monkeys, clinical PK and PD data from other FLT3-agonist molecules (GS-3583 and CDX-301) were used to inform the model and project the expansion profiles of conventional DC1s (cDC1s) and total DCs in peripheral blood. This work constitutes an essential part of our model-informed drug development (MIDD) strategy for clinical development of FLT3L-Fc by projecting PK/PD in healthy volunteers, determining the first-in-human (FIH) dose, and informing the efficacious dose in clinical settings. Model-generated results were incorporated in regulatory filings to support the rationale for the FIH dose selection. Full article

(This article belongs to the Special Issue Role of Pharmacokinetics in Drug Development and Evaluation)

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15 pages, 2921 KiB

Open AccessArticle

Enhancing Paclitaxel Efficacy with Piperine-Paclitaxel Albumin Nanoparticles in Multidrug-Resistant Triple-Negative Breast Cancer by Inhibiting P-Glycoprotein

by Wenwen Xu, Yumeng Xiao, Liang Zheng, Mingyu Xu, Xuehua Jiang and Ling Wang

Pharmaceutics 2023, 15(12), 2703; https://doi.org/10.3390/pharmaceutics15122703 - 30 Nov 2023

Cited by 3 | Viewed by 1694

Abstract

Triple-negative breast cancer (TNBC) is a highly aggressive disease with rapid progression and poor prognosis due to multidrug resistance (MDR). Piperine (PIP) shows promise as a P-gp inhibitor, capable of sensitizing chemotherapeutic drugs and exhibiting antitumor properties. This study explores the inhibitory mechanism [...] Read more.

Triple-negative breast cancer (TNBC) is a highly aggressive disease with rapid progression and poor prognosis due to multidrug resistance (MDR). Piperine (PIP) shows promise as a P-gp inhibitor, capable of sensitizing chemotherapeutic drugs and exhibiting antitumor properties. This study explores the inhibitory mechanism of PIP on P-glycoprotein (P-gp) and its capacity to enhance the sensitivity of paclitaxel (PTX). We subsequently evaluated the efficacy and safety of albumin nanoparticles that co-encapsulate PTX and PIP (PP@AN). The results demonstrated that PIP enhanced the accumulation of PTX intracellularly, as determined with HPLC/MS/MS analysis. PIP was also found to increase cell sensitivity to PTX. Furthermore, we explored the inhibitory mechanism of PIP on P-gp, utilizing molecular docking simulations, RT-qPCR, and Western blot analysis. PIP appears to compete with the active paclitaxel binding site on P-gp, affecting ATPase activity and downregulating the MDR1 gene and P-gp expression. In summary, PIP could inhibit P-gp and act as a sensitizer in the treatment of TNBC with PTX. Moreover, stable and uniform PP@AN was successfully formulated, resulting in a significant increase in drug accumulation within cells as well as the downregulation of P-gp in tumors at the optimal ratio (PTX:PIP = 1:2). This led to an improvement in the antitumor effect in vivo while also reducing hepatotoxicity and hemototoxicity following chemotherapy. This study comprehensively investigated PIP’s inhibitory effect and mechanism on P-gp. We present a new approach for co-delivering PIP and PTX using albumin nanoparticles, which reduced toxicity and improved therapeutic efficacy both in vivo and in vitro. Full article

(This article belongs to the Special Issue Role of Pharmacokinetics in Drug Development and Evaluation)

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18 pages, 1557 KiB

Open AccessArticle

Quantitative Analysis of a Pilot Transwell Barrier Model with Automated Sampling and Mathematical Modeling

by Júlia Tárnoki-Zách, Szilvia Bősze and András Czirók

Pharmaceutics 2023, 15(11), 2646; https://doi.org/10.3390/pharmaceutics15112646 - 20 Nov 2023

Viewed by 1358

Abstract

In the preclinical phase of drug development, it is necessary to determine how the active compound can pass through the biological barriers surrounding the target tissue. In vitro barrier models provide a reliable, low-cost, high-throughput solution for screening substances early in the drug [...] Read more.

In the preclinical phase of drug development, it is necessary to determine how the active compound can pass through the biological barriers surrounding the target tissue. In vitro barrier models provide a reliable, low-cost, high-throughput solution for screening substances early in the drug candidate development process, thus reducing more complex and costly animal studies. In this pilot study, the transport properties of TB501, an antimycobacterial drug candidate, were characterized using an in vitro barrier model of VERO E6 kidney cells. The compound was delivered into the apical chamber of the transwell insert, and its concentration passing through the barrier layer was measured through the automated sampling of the basolateral compartment, where media were replaced every 30 min for 6 h, and the collected samples were stored for further spectroscopic analysis. The kinetics of TB501 concentration obtained from VERO E6 transwell cultures and transwell membranes saturated with serum proteins reveal the extent to which the cell layer functions as a diffusion barrier. The large number of samples collected allows us to fit a detailed mathematical model of the passive diffusive currents to the measured concentration profiles. This approach enables the determination of the diffusive permeability, the diffusivity of the compound in the cell layer, the affinity of the compound binding to the cell membrane as well as the rate by which the cells metabolize the compound. The proposed approach goes beyond the determination of the permeability coefficient and offers a more detailed pharmacokinetic characterization of the transwell barrier model. We expect the presented method to be fruitful in evaluating other compounds with different chemical features on simple in vitro barrier models. The proposed mathematical model can also be extended to include various forms of active transport. Full article

(This article belongs to the Special Issue Role of Pharmacokinetics in Drug Development and Evaluation)

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13 pages, 605 KiB

Open AccessArticle

Comprehensive Assessment of Pharmacokinetics, Pharmacodynamics, and Tolerability of Ligelizumab in Healthy Volunteers and Patients with Chronic Spontaneous Urticaria to Optimize Its Subcutaneous Delivery System

by Yan Ji, Claudio Calonder, Tiina Kirsilä, Alis Burciu, Matjaz Tisu, Yolandi Joubert, Nathalie Laurent, Eva Hua, Manmath Patekar, Anton Drollmann and Ralph Woessner

Pharmaceutics 2023, 15(9), 2266; https://doi.org/10.3390/pharmaceutics15092266 - 1 Sep 2023

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Abstract

Ligelizumab is a highly potent, humanized IgG1, anti-IgE monoclonal antibody. To explore its optimal subcutaneous delivery, the pharmacokinetics (PK), pharmacodynamics (PD), and tolerability of ligelizumab from two Phase 1 studies in healthy volunteers (HVs) and four Phase 2 and 3 studies in patients [...] Read more.

Ligelizumab is a highly potent, humanized IgG1, anti-IgE monoclonal antibody. To explore its optimal subcutaneous delivery, the pharmacokinetics (PK), pharmacodynamics (PD), and tolerability of ligelizumab from two Phase 1 studies in healthy volunteers (HVs) and four Phase 2 and 3 studies in patients with chronic spontaneous urticaria (CSU) were assessed. Using different injection volumes or durations of a liquid-in-vial (LIVI) formulation or different formulations (LIVI vs. prefilled syringe (PFS)), single-dose ligelizumab showed comparable PK exposure in HVs. Steady-state exposure of ligelizumab was also comparable between LIVI and PFS following multiple dosing in CSU patients. The total IgE level (a PD marker) and tolerability were similar between the two formulations in both HVs and patients. Furthermore, the PK, total IgE, and tolerability were comparable for PFS administered either by patients or healthcare providers (HCPs). Collective evidence demonstrated that the injection duration or volume, formulation, or administrator had no apparent impact on the PK, PD, and tolerability of ligelizumab, supporting no clinically relevant difference between LIVI and PFS, and that PFS can be administered by patients or HCPs. This report provides a comprehensive assessment based on data of multiple clinical endpoints from both HVs and patients to inform formulation development and commercial use of a monoclonal antibody. Full article

(This article belongs to the Special Issue Role of Pharmacokinetics in Drug Development and Evaluation)

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12 pages, 4014 KiB

Open AccessArticle

Systemic Protein Delivery via Inhalable Liposomes: Formulation and Pharmacokinetics

by Pranav Ponkshe, Yingzhe Wang and Chalet Tan

Pharmaceutics 2023, 15(7), 1951; https://doi.org/10.3390/pharmaceutics15071951 - 14 Jul 2023

Cited by 3 | Viewed by 1957

Abstract

The enormous and thin alveolar epithelium is an attractive site for systemic protein delivery. Considering the excellent biocompatibility of phospholipids with endogenous pulmonary surfactant, we engineered dimyristoylphosphatidylcholine (DMPC)-based liposomes for pulmonary administration, using Cy5.5-labeled bovine serum albumin (BSA-Cy5.5) as a model protein payload. [...] Read more.

The enormous and thin alveolar epithelium is an attractive site for systemic protein delivery. Considering the excellent biocompatibility of phospholipids with endogenous pulmonary surfactant, we engineered dimyristoylphosphatidylcholine (DMPC)-based liposomes for pulmonary administration, using Cy5.5-labeled bovine serum albumin (BSA-Cy5.5) as a model protein payload. The level of cholesterol (Chol) and surface modification with PEG in inhalable liposomes were optimized iteratively based on the encapsulation efficiency, the release kinetics in the simulated lung fluid, and the uptake in murine RAW 264.7 macrophages. The plasma pharmacokinetics of BSA-Cy5.5-encapsulated liposomes with the composition of DMPC/Chol/PEG at 85:10:5 (molar ratio) was studied in mice following intratracheal aerosolization, in comparison with that of free BSA-Cy5.5 solution. The biodisposition of BSA-Cy5.5 was continuously monitored using whole-body near-infrared (NIR) fluorescence imaging for 10 days. We found that the systemic bioavailability of BSA-Cy5.5 from inhaled liposomes was 22%, which was notably higher than that of inhaled free BSA-Cy5.5. The mean residence time of BSA-Cy5.5 was markedly prolonged in mice administered intratracheally with liposomal BSA-Cy5.5, which is in agreement with the NIR imaging results. Our work demonstrates the great promise of inhalable DMPC-based liposomes to achieve non-invasive systemic protein delivery. Full article

(This article belongs to the Special Issue Role of Pharmacokinetics in Drug Development and Evaluation)

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13 pages, 883 KiB

Open AccessArticle

Methylphenidate Multiphasic Release Tablet: Bioequivalence Assessment between Two Formulations Administered under Fasting and Fed Conditions

by Marcelo Gomes Davanço, Jessica Meulman, Thalita Martins da Silva, Fernando Costa, Karini Bruno Bellorio, Iram Moreira Mundim, Ana Carolina Costa Sampaio, Leonardo de Souza Teixeira and Celso Francisco Pimentel Vespasiano

Pharmaceutics 2023, 15(6), 1737; https://doi.org/10.3390/pharmaceutics15061737 - 14 Jun 2023

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Abstract

Methylphenidate hydrochloride is used to treat children, adolescents, and adults with attention deficit/hyperactivity disorder (ADHD). Multiphasic release formulation has been used to control drug levels, mainly during children’s school period. This study aimed to evaluate the bioequivalence between two methylphenidate hydrochloride extended-release tablets [...] Read more.

Methylphenidate hydrochloride is used to treat children, adolescents, and adults with attention deficit/hyperactivity disorder (ADHD). Multiphasic release formulation has been used to control drug levels, mainly during children’s school period. This study aimed to evaluate the bioequivalence between two methylphenidate hydrochloride extended-release tablets to meet regulatory requirements for registration in Brazil. Two independent studies (under fasting and fed conditions) designed as open-label, randomized, single-dose, two-period, two-way crossover trials were conducted in healthy subjects of both genders. Subjects were enrolled and randomly received a single dose of the test formulation methylphenidate hydrochloride 54 mg extended-release tablet (Consiv^®, Adium S.A., São Paulo, Brazil) or the reference formulation (Concerta^®, Janssen-Cilag Farmacêutica Ltd., São Paulo, Brazil), in each period, with a 7-day washout interval. Serial blood samples were collected up to 24 h post dose and methylphenidate plasma concentrations were obtained using a validated LC-MS/MS method. A total of 96 healthy subjects were enrolled in the fasting study, of which 80 completed the study. For the fed study, 52 healthy subjects were enrolled, and 46 subjects completed it. In both studies, 90% confidence intervals for Cmax, AUC_0–t, AUC_0–inf, and partial AUCs were within the acceptable limits of 80.00 to 125.00%. Thus, according to regulatory requirements, the test formulation (Consiv^®) was considered to be bioequivalent to the reference formulation (Concerta^®) in both conditions (fasting and fed) and, therefore, it can be considered interchangeable in clinical practice. Both formulations were safe and well tolerated in single-dose administration. Full article

(This article belongs to the Special Issue Role of Pharmacokinetics in Drug Development and Evaluation)

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13 pages, 4005 KiB

Open AccessArticle

Rapid In Vitro Assessment of Antimicrobial Drug Effect Bridging Clinically Relevant Pharmacokinetics: A Comprehensive Methodology

by Michael Nikolaou and Vincent H. Tam

Pharmaceutics 2023, 15(6), 1671; https://doi.org/10.3390/pharmaceutics15061671 - 7 Jun 2023

Cited by 1 | Viewed by 1254

Abstract

Rapid in vitro assessment of antimicrobial drug efficacy under clinically relevant pharmacokinetic conditions is an essential element of both drug development and clinical use. Here, we present a comprehensive overview of a recently developed novel integrated methodology for rapid assessment of such efficacy, [...] Read more.

Rapid in vitro assessment of antimicrobial drug efficacy under clinically relevant pharmacokinetic conditions is an essential element of both drug development and clinical use. Here, we present a comprehensive overview of a recently developed novel integrated methodology for rapid assessment of such efficacy, particularly against the emergence of resistant bacterial strains, as jointly researched by the authors in recent years. This methodology enables rapid in vitro assessment of the antimicrobial efficacy of single or multiple drugs in combination, following clinically relevant pharmacokinetics. The proposed methodology entails (a) the automated collection of longitudinal time–kill data in an optical-density instrument; (b) the processing of collected time–kill data with the aid of a mathematical model to determine optimal dosing regimens under clinically relevant pharmacokinetics for single or multiple drugs; and (c) in vitro validation of promising dosing regimens in a hollow fiber system. Proof-of-concept of this methodology through a number of in vitro studies is discussed. Future directions for the refinement of optimal data collection and processing are discussed. Full article

(This article belongs to the Special Issue Role of Pharmacokinetics in Drug Development and Evaluation)

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13 pages, 3251 KiB

Open AccessArticle

Immune Monitoring of Mycophenolate Mofetil Activity in Healthy Volunteers Using Ex Vivo T Cell Function Assays

by Aliede E. in ’t Veld, Manon A. A. Jansen, Marieke L. de Kam, Yalҫin Yavuz, Dirk Jan A. R. Moes, Kathalijne A. Oudhoff, Mariette I. E. van Poelgeest, Jacobus Burggraaf and Matthijs Moerland

Pharmaceutics 2023, 15(6), 1635; https://doi.org/10.3390/pharmaceutics15061635 - 31 May 2023

Cited by 1 | Viewed by 1912

Abstract

Mycophenolate mofetil (MMF) is part of the standard immunosuppressive treatment after transplantation and usually given as “one-dose-fits-all” together with a calcineurin inhibitor (CNI). Although drug concentrations are frequently monitored, there is still a group of patients who experience side effects related to excessive [...] Read more.

Mycophenolate mofetil (MMF) is part of the standard immunosuppressive treatment after transplantation and usually given as “one-dose-fits-all” together with a calcineurin inhibitor (CNI). Although drug concentrations are frequently monitored, there is still a group of patients who experience side effects related to excessive or insufficient immune suppression. We therefore aimed to identify biomarkers that reflect the overall immune status of the patient and might support individualized dosing. We previously studied immune biomarkers for CNIs and aimed to investigate whether these are also suitable to monitor MMF activity. Healthy volunteers received a single dose of MMF or placebo, after which IMPDH enzymatic activity, T cell proliferation, and cytokine production were measured and compared to MPA (MMF’s active metabolite) concentration in three different matrices (plasma, peripheral blood mononuclear cells, and T cells). MPA concentrations in T cells exceeded those in PBMCs, but all intracellular concentrations correlated strongly with plasma concentrations. At clinically relevant MPA concentrations, IL-2 and IFN-γ production was mildly suppressed, while MPA T cell proliferation was strongly inhibited. Based on these data, it is expected that monitoring of T cell proliferation in MMF-treated transplantation patients may be a valid strategy to avoid excessive immune suppression. Full article

(This article belongs to the Special Issue Role of Pharmacokinetics in Drug Development and Evaluation)

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12 pages, 1398 KiB

Open AccessArticle

Pharmacokinetic and Biomarker Quantification Studies on Vancomycin-Loaded PEGylated Liposomes and Its Potential to Reduce Vancomycin-Induced Kidney Injury: A Rat Study

by Medha D. Joshi, Paulina Iacoban and Marc H. Scheetz

Pharmaceutics 2023, 15(6), 1582; https://doi.org/10.3390/pharmaceutics15061582 - 24 May 2023

Cited by 2 | Viewed by 1713

Abstract

Vancomycin is a commonly used antibiotic in hospital settings, especially against Methicillin-resistant staphylococcus aureus (MRSA). One of the major adverse events of vancomycin use in adults is kidney injury. The drug concentration, specifically the area under the concentration curve, predicts kidney injury in [...] Read more.

Vancomycin is a commonly used antibiotic in hospital settings, especially against Methicillin-resistant staphylococcus aureus (MRSA). One of the major adverse events of vancomycin use in adults is kidney injury. The drug concentration, specifically the area under the concentration curve, predicts kidney injury in adults receiving vancomycin. To attempt to reduce vancomycin-induced nephrotoxicity, we have successfully encapsulated vancomycin in polyethylene glycol-coated liposomes (PEG-VANCO-lipo). We have previously carried out in vitro cytotoxicity studies on kidney cells using PEG-VANCO-lipo and found it to be minimally toxic compared to the standard vancomycin. In this study, we have dosed male adult rats with PEG-VANCO-lipo or vancomycin HCl and compared plasma vancomycin concentrations and KIM-1 as an injury biomarker in rat urine. Male Sprague Dawley rats (350 ± 10 g) were administered vancomycin (n = 6) or PEG-VANCO-lipo (n = 6) 150 mg/kg/day for three days using an IV infusion in the left jugular vein catheter. Blood was collected for plasma at 15, 30, 60, 120, 240, and 1440 min after the first and the last IV dose. Urine was collected 0–2, 2–4, 4–8, and 8–24 h after the first and the last IV infusions using metabolic cages. The animals were observed for three days after the last compound administration. Vancomycin was quantified in plasma by LC-MS/MS. Urinary KIM-1 analysis was done by using an ELISA kit. Three days after the last dose, under terminal anesthesia with IP ketamine (65–100 mg/kg) and xylazine (7–10 mg/kg), rats were euthanized. Vancomycin urine and kidney concentrations and KIM-1 were lower on day three in the PEG-Vanco-lipo group compared to the vancomycin group (p < 0.05, ANOVA and/or t-test). There was a significant reduction in plasma vancomycin concentration on day one and day three (p < 0.05, t-test) in the vancomycin group compared to the PEG-VANCO-lipo group. Vancomycin-loaded PEGylated liposomes resulted in lower levels of kidney injury, as noted by a decrease in KIM-1 values. Moreover, longer circulation in plasma with increased concentration in plasma as opposed to the kidney was observed with the PEG-VANCO-lipo group. The results indicate the high potential of PEG-VANCO-lipo in decreasing the nephrotoxicity of vancomycin clinically. Full article

(This article belongs to the Special Issue Role of Pharmacokinetics in Drug Development and Evaluation)

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15 pages, 1605 KiB

Open AccessArticle

A Physiologically Based Pharmacokinetic Model to Predict Determinants of Variability in Epirubicin Exposure and Tissue Distribution

by Radwan Ansaar, Robyn Meech and Andrew Rowland

Pharmaceutics 2023, 15(4), 1222; https://doi.org/10.3390/pharmaceutics15041222 - 12 Apr 2023

Cited by 3 | Viewed by 2549

Abstract

Background: Epirubicin is an anthracycline antineoplastic drug that is primarily used in combination therapies for the treatment of breast, gastric, lung and ovarian cancers and lymphomas. Epirubicin is administered intravenously (IV) over 3 to 5 min once every 21 days with dosing based [...] Read more.

Background: Epirubicin is an anthracycline antineoplastic drug that is primarily used in combination therapies for the treatment of breast, gastric, lung and ovarian cancers and lymphomas. Epirubicin is administered intravenously (IV) over 3 to 5 min once every 21 days with dosing based on body surface area (BSA; mg/m²). Despite accounting for BSA, marked inter-subject variability in circulating epirubicin plasma concentration has been reported. Methods: In vitro experiments were conducted to determine the kinetics of epirubicin glucuronidation by human liver microsomes in the presence and absence of validated UGT2B7 inhibitors. A full physiologically based pharmacokinetic model was built and validated using Simcyp^® (version 19.1, Certara, Princeton, NJ, USA). The model was used to simulate epirubicin exposure in 2000 Sim-Cancer subjects over 158 h following a single intravenous dose of epirubicin. A multivariable linear regression model was built using simulated demographic and enzyme abundance data to determine the key drivers of variability in systemic epirubicin exposure. Results: Multivariable linear regression modelling demonstrated that variability in simulated systemic epirubicin exposure following intravenous injection was primarily driven by differences in hepatic and renal UGT2B7 expression, plasma albumin concentration, age, BSA, GFR, haematocrit and sex. By accounting for these factors, it was possible to explain 87% of the variability in epirubicin in a simulated cohort of 2000 oncology patients. Conclusions: The present study describes the development and evaluation of a full-body PBPK model to assess systemic and individual organ exposure to epirubicin. Variability in epirubicin exposure was primarily driven by hepatic and renal UGT2B7 expression, plasma albumin concentration, age, BSA, GFR, haematocrit and sex. Full article

(This article belongs to the Special Issue Role of Pharmacokinetics in Drug Development and Evaluation)

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18 pages, 2268 KiB

Open AccessArticle

Neonatal Pharmacokinetics and Biodistribution of Polymeric Nanoparticles and Effect of Surfactant

by Nuo Xu, Megan Wong, Gabrielle Balistreri and Elizabeth Nance

Pharmaceutics 2023, 15(4), 1176; https://doi.org/10.3390/pharmaceutics15041176 - 7 Apr 2023

Viewed by 2079

Abstract

The development of therapeutics for pediatric use has advanced in the last few decades, yet the off-label use of adult medications in pediatrics remains a significant clinical problem. Nano-based medicines are important drug delivery systems that can improve the bioavailability of a range [...] Read more.

The development of therapeutics for pediatric use has advanced in the last few decades, yet the off-label use of adult medications in pediatrics remains a significant clinical problem. Nano-based medicines are important drug delivery systems that can improve the bioavailability of a range of therapeutics. However, the use of nano-based medicines for application in pediatric populations is challenged by the lack of pharmacokinetic (PK) data in this population. To address this data gap, we investigated the PK of polymer-based nanoparticles in term-equivalent neonatal rats. We used poly(lactic-co-glycolic acid)-poly(ethylene glycol) (PLGA-PEG) nanoparticles, which are polymer nanoparticles that have been extensively studied in adult populations but less commonly applied in neonates and pediatrics. We quantified the PK parameters and biodistribution of PLGA-PEG nanoparticles in term-equivalent healthy rats and revealed the PK and biodistribution of polymeric nanoparticles in neonatal rats. We further explored the effects of surfactant used to stabilize PLGA-PEG particles on PK and biodistribution. We showed that 4 h post intraperitoneal injection, nanoparticles had the highest accumulation in serum, at 54.0% of the injected dose for particles with Pluronic^® F127 (F127) as the stabilizer and at 54.6% of the injected dose for particles with Poloxamer 188 (P80) as the stabilizer. The half-life of the F127-formulated PLGA-PEG particles was 5.9 h, which was significantly longer than the 1.7 h half-life of P80-formulated PLGA-PEG particles. Among all organs, the liver had the highest nanoparticle accumulation. At 24 h after administration, the accumulation of F127-formulated PLGA-PEG particles was at 26.2% of the injected dose, and the accumulation of P80-formulated particles was at 24.1% of the injected dose. Less than 1% of the injected nanoparticles was observed in healthy rat brain for both F127- and P80-formulated particles. These PK data inform the use of polymer nanoparticle applications in the neonate and provide a foundation for the translation of polymer nanoparticles for drug delivery in pediatric populations. Full article

(This article belongs to the Special Issue Role of Pharmacokinetics in Drug Development and Evaluation)

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17 pages, 2434 KiB

Open AccessArticle

Developing a Formulation Strategy Coupled with PBPK Modeling and Simulation for the Weakly Basic Drug Albendazole

by Harsh Shah, Kushal Shah, Bhavin Gajera, Rutesh H. Dave and David R. Taft

Pharmaceutics 2023, 15(4), 1040; https://doi.org/10.3390/pharmaceutics15041040 - 23 Mar 2023

Cited by 2 | Viewed by 3532

Abstract

Albendazole (ABZ) is a weakly basic drug that undergoes extensive presystemic metabolism after oral administration and converts to its active form albendazole sulfoxide (ABZ_SO). The absorption of albendazole is limited by poor aqueous solubility, and dissolution is the rate-limiting step in the overall [...] Read more.

Albendazole (ABZ) is a weakly basic drug that undergoes extensive presystemic metabolism after oral administration and converts to its active form albendazole sulfoxide (ABZ_SO). The absorption of albendazole is limited by poor aqueous solubility, and dissolution is the rate-limiting step in the overall exposure of ABZ_SO. In this study, PBPK modeling was used to identify formulation-specific parameters that impact the oral bioavailability of ABZ_SO. In vitro experiments were carried out to determine pH solubility, precipitation kinetics, particle size distribution, and biorelevant solubility. A transfer experiment was conducted to determine the precipitation kinetics. A PBPK model for ABZ and ABZ_SO was developed using the Simcyp™ Simulator based on parameter estimates from in vitro experiments. Sensitivity analyses were performed to assess the impact of physiological parameters and formulation-related parameters on the systemic exposure of ABZ_SO. Model simulations predicted that increased gastric pH significantly reduced ABZ absorption and, subsequently, ABZ_SO systemic exposure. Reducing the particle size below 50 µm did not improve the bioavailability of ABZ. Modeling results illustrated that systemic exposure of ABZ_SO was enhanced by increasing solubility or supersaturation and decreasing the drug precipitation of ABZ at the intestinal pH level. These results were used to identify potential formulation strategies to enhance the oral bioavailability of ABZ_SO. Full article

(This article belongs to the Special Issue Role of Pharmacokinetics in Drug Development and Evaluation)

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13 pages, 1240 KiB

Open AccessArticle

Differential Preincubation Effects of Nicardipine on OATP1B1- and OATP1B3-Mediated Transport in the Presence and Absence of Protein: Implications in Assessing OATP1B1- and OATP1B3-Mediated Drug–Drug Interactions

by Ruhul Kayesh, Vishakha Tambe, Chao Xu and Wei Yue

Pharmaceutics 2023, 15(3), 1020; https://doi.org/10.3390/pharmaceutics15031020 - 22 Mar 2023

Cited by 3 | Viewed by 2468

Abstract

Impaired transport activity of hepatic OATP1B1 and OATP1B3 due to drug–drug interactions (DDIs) often leads to increased systemic exposure to substrate drugs (e.g., lipid-lowering statins). Since dyslipidemia and hypertension frequently coexist, statins are often concurrently used with antihypertensives, including calcium channel blockers (CCBs). [...] Read more.

Impaired transport activity of hepatic OATP1B1 and OATP1B3 due to drug–drug interactions (DDIs) often leads to increased systemic exposure to substrate drugs (e.g., lipid-lowering statins). Since dyslipidemia and hypertension frequently coexist, statins are often concurrently used with antihypertensives, including calcium channel blockers (CCBs). OATP1B1/1B3-related DDIs in humans have been reported for several CCBs. To date, the OATP1B1/1B3-mediated DDI potential of CCB nicardipine has not been assessed. The current study was designed to assess the OATP1B1- and OATP1B3-mediated DDI potential of nicardipine using the R-value model, following the US-FDA guidance. IC₅₀ values of nicardipine against OATP1B1 and OATP1B3 were determined in transporter-overexpressing human embryonic kidney 293 cells using [³H]-estradiol 17β-D-glucuronide and [³H]-cholecystokinin-8 as substrates, respectively, with or without nicardipine-preincubation in protein-free Hanks’ Balanced Salt Solution (HBSS) or in fetal bovine serum (FBS)-containing culture medium. Preincubation with nicardipine for 30 min in protein-free HBSS buffer produced lower IC₅₀ and higher R-values for both OATP1B1 and OATP1B3 compared to in FBS-containing medium, yielding IC₅₀ values of 0.98 and 1.63 µM and R-values of 1.4 and 1.3 for OATP1B1 and OATP1B3, respectively. The R-values were higher than the US-FDA cut-off value of 1.1, supporting that nicardipine has the potential to cause OATP1B1/3-mediated DDIs. Current studies provide insight into the consideration of optimal preincubation conditions when assessing the OATP1B1/3-mediated DDIs in vitro. Full article

(This article belongs to the Special Issue Role of Pharmacokinetics in Drug Development and Evaluation)

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13 pages, 3669 KiB

Open AccessArticle

Interplay of Breast Cancer Resistance Protein (Bcrp/Abcg2), Sex, and Fed State in Oral Pharmacokinetic Variability of Furosemide in Rats

by Sheena Sharma, Vijaya Saradhi Mettu and Bhagwat Prasad

Pharmaceutics 2023, 15(2), 542; https://doi.org/10.3390/pharmaceutics15020542 - 6 Feb 2023

Cited by 4 | Viewed by 2308

Abstract

Poor and variable oral bioavailability of furosemide (FUR) presents critical challenges in pharmacotherapy. We investigated the interplay of breast cancer resistance protein (Bcrp)-mediated transport, sex, and fed state on FUR pharmacokinetics (PK) in rats. A crossover PK study of FUR (5 mg/kg, oral) [...] Read more.

Poor and variable oral bioavailability of furosemide (FUR) presents critical challenges in pharmacotherapy. We investigated the interplay of breast cancer resistance protein (Bcrp)-mediated transport, sex, and fed state on FUR pharmacokinetics (PK) in rats. A crossover PK study of FUR (5 mg/kg, oral) was performed in Sprague-Dawley rats (3 males and 3 females), alone or with a Bcrp inhibitor, novobiocin (NOV) (20 mg/kg, oral), in both fed and fasted states. Co-administration of NOV significantly increased FUR extent (AUC) and rate (C_max) of exposure by more than two-fold, which indicates efficient Bcrp inhibition in the intestine. The female rats showed two-fold higher AUC and C_max, and two-fold lower renal clearance of FUR compared to the male rats. The latter was correlated with higher renal abundance of Bcrp and organic anion transporters (Oats) in the male rats compared to age-matched female rats. These findings suggest that the PK of Bcrp and/or Oat substrates could be sex-dependent in rats. Moreover, allometric scaling of rat PK and toxicological data of Bcrp substrates should consider species and sex differences in Bcrp and Oat abundance in the kidney. Considering that Bcrp is abundant in the intestine of rats and humans, a prospective clinical study is warranted to evaluate the effect of Bcrp inhibition on FUR PK. The potential confounding effect of the Bcrp transporter should be considered when FUR is used as a clinical probe of renal organic anion transporter-mediated drug–drug interactions. Unlike human data, no food-effect was observed on FUR PK in rats. Full article

(This article belongs to the Special Issue Role of Pharmacokinetics in Drug Development and Evaluation)

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11 pages, 1175 KiB

Open AccessArticle

Drug–Drug Interaction Study to Evaluate the Pharmacokinetics, Safety, and Tolerability of Ipatasertib in Combination with Darolutamide in Patients with Advanced Prostate Cancer

by Dhruvitkumar S. Sutaria, Grozdana Rasuo, Adam Harris, Ryan Johnson, Dale Miles, Jorge Daniel Gallo and Rucha Sane

Pharmaceutics 2022, 14(10), 2101; https://doi.org/10.3390/pharmaceutics14102101 - 1 Oct 2022

Cited by 4 | Viewed by 1904

Abstract

Ipatasertib is a selective, small molecule Akt inhibitor that is currently being developed for the treatment of metastatic castration-resistant prostate cancer. Darolutamide is an androgen receptor (AR) inhibitor that is approved for the treatment of non-metastatic castration-resistant prostate cancer. Ipatasertib is metabolized by [...] Read more.

Ipatasertib is a selective, small molecule Akt inhibitor that is currently being developed for the treatment of metastatic castration-resistant prostate cancer. Darolutamide is an androgen receptor (AR) inhibitor that is approved for the treatment of non-metastatic castration-resistant prostate cancer. Ipatasertib is metabolized by CYP3A4 to form a less active metabolite M1 (G-037720). Ipatasertib is also a weak time-dependent CYP3A4 inhibitor. Darolutamide is a mild CYP3A4 inducer and is metabolized into an active keto-darolutamide metabolite via CYP3A4. In this Phase 1b open-label, single sequence crossover study, ipatasertib pharmacokinetics safety and tolerability were evaluated in combination with darolutamide in metastatic castration-resistant prostate cancer (n = 15 patients). Specifically, the effect of 600 mg BID of darolutamide on 400 mg QD ipatasertib was evaluated in this study. Based on pharmacokinetic analysis, a mild reduction in ipatasertib AUC_{0–24 h,ss} and C_max,ss exposures was observed (~8% and ~21%, respectively) when administered in combination with darolutamide, which is considered not clinically meaningful. M1 exposures were similar with and without darolutamide administration. Darolutamide and keto-darolutamide exposures in combination with ipatasertib were similar to previously reported exposures for single agent darolutamide. Overall, the combination appears to be well-tolerated in the metastatic castration-resistant prostate cancer indication with very few AEs. Full article

(This article belongs to the Special Issue Role of Pharmacokinetics in Drug Development and Evaluation)

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Review

Jump to: Research

18 pages, 734 KiB

Open AccessReview

The Role of Pharmacogenetic-Based Pharmacokinetic Analysis in Precise Breast Cancer Treatment

by Xinyu Wu and Huihua Xiong

Pharmaceutics 2024, 16(11), 1407; https://doi.org/10.3390/pharmaceutics16111407 - 31 Oct 2024

Viewed by 675

Abstract

Given the high prevalence of breast cancer and the diverse genetic backgrounds of patients, a growing body of research emphasizes the importance of pharmacogenetic-based pharmacokinetic analysis in optimizing treatment outcomes. The treatment of breast cancer involves multiple drugs whose metabolism and efficacy are [...] Read more.

Given the high prevalence of breast cancer and the diverse genetic backgrounds of patients, a growing body of research emphasizes the importance of pharmacogenetic-based pharmacokinetic analysis in optimizing treatment outcomes. The treatment of breast cancer involves multiple drugs whose metabolism and efficacy are influenced by individual genetic variations. Genetic polymorphisms in drug-metabolizing enzymes and transport proteins are crucial in the regulation of pharmacokinetics. Our review aims to investigate the opportunities and challenges of pharmacogenomic-based pharmacokinetic analysis as a precision medicine tool in breast cancer management. Full article

(This article belongs to the Special Issue Role of Pharmacokinetics in Drug Development and Evaluation)

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14 pages, 1026 KiB

Open AccessReview

Application of Modelling and Simulation Approaches to Predict Pharmacokinetics of Therapeutic Monoclonal Antibodies in Pediatric Population

by Andrew Lim, Pradeep Sharma, Oleg Stepanov and Venkatesh Pilla Reddy

Pharmaceutics 2023, 15(5), 1552; https://doi.org/10.3390/pharmaceutics15051552 - 20 May 2023

Cited by 4 | Viewed by 3189

Abstract

Ethical regulations and limited paediatric participants are key challenges that contribute to a median delay of 6 years in paediatric mAb approval. To overcome these barriers, modelling and simulation methodologies have been adopted to design optimized paediatric clinical studies and reduce patient burden. [...] Read more.

Ethical regulations and limited paediatric participants are key challenges that contribute to a median delay of 6 years in paediatric mAb approval. To overcome these barriers, modelling and simulation methodologies have been adopted to design optimized paediatric clinical studies and reduce patient burden. The classical modelling approach in paediatric pharmacokinetic studies for regulatory submissions is to apply body weight-based or body surface area-based allometric scaling to adult PK parameters derived from a popPK model to inform the paediatric dosing regimen. However, this approach is limited in its ability to account for the rapidly changing physiology in paediatrics, especially in younger infants. To overcome this limitation, PBPK modelling, which accounts for the ontogeny of key physiological processes in paediatrics, is emerging as an alternative modelling strategy. While only a few mAb PBPK models have been published, PBPK modelling shows great promise demonstrating a similar prediction accuracy to popPK modelling in an Infliximab paediatric case study. To facilitate future PBPK studies, this review consolidated comprehensive data on the ontogeny of key physiological processes in paediatric mAb disposition. To conclude, this review discussed different use-cases for pop-PK and PBPK modelling and how they can complement each other to increase confidence in pharmacokinetic predictions. Full article

(This article belongs to the Special Issue Role of Pharmacokinetics in Drug Development and Evaluation)

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