The Uses and Advantages of Kirchhoff ’s Laws vs. Differential Equations in Pharmacology, Pharmacokinetics, and (Even) Chemistry
AbstractIn chemistry, rate processes are defined in terms of rate constants, with units of time−1, and are derived by differential equations from amounts. In contrast, when considering drug concentrations in biological systems, particularly in humans, rate processes must be defined in terms of clearance, with units of volume/time, since biological volumes, which are highly dependent on drug partition into biological tissues, cannot be easily determined. In pharmacology, pharmacokinetics, and in making drug dosing decisions, drug clearance and changes in drug clearance are paramount. Clearance is defined as the amount of ...
Source: The AAPS Journal - April 10, 2023 Category: Drugs & Pharmacology Source Type: research
Statistical Approaches for Establishing Appropriate Immunogenicity Assay Cut Points: Impact of Sample Distribution, Sample Size, and Outlier Removal
AbstractThe statistical assessments needed to establish anti-drug antibody (ADA) assay cut points (CPs) can be challenging for bioanalytical scientists. Poorly established CPs that are too high could potentially miss treatment emergent ADA or, when set too low, result in detection of responses that may have no clinical relevance. We evaluated 16 validation CP datasets generated with ADA assays at Regeneron ’s bioanalytical laboratory and compared results obtained from different CP calculation tools. We systematically evaluated the impact of various factors on CP determination including biological and analytical variabili...
Source: The AAPS Journal - April 4, 2023 Category: Drugs & Pharmacology Source Type: research
Dependence of Bioavailability on Mean Absorption Time: What Does It Tell Us?
AbstractThe extent and rate of bioavailability are fundamental measures to characterize the pharmacokinetics of drugs after oral administration. Together with bioavailability (F), the mean absorption time (MAT) can be used to define the rate of bioavailability, i.e., the rate of drug absorption. Previous results suggest thatF may depend onMAT. Estimates ofF andMAT were obtained from the input function (sum of two inverse Gaussian functions) used to model the oral absorption process. The estimation was performed by population analysis (nonlinear mixed-effects modeling) based on data from bioavailability studies in healthy v...
Source: The AAPS Journal - April 4, 2023 Category: Drugs & Pharmacology Source Type: research
Comparison of Pre-existing Anti-AAV8 Total Antibody Screening and Confirmatory Assays with a Cell-Based Neutralizing Assay in Normal Human Serum
This study is aimed at comparing total antibody assay (TAb) and cell-based NAb assay against AAV8 to help inform the best assay format for patient exclusion criteria. We developed a chemiluminescence-based enzyme-linked immunosorbent assay to analyze AAV8 TAb in human serum. The specificity of AAV8 TAb was determined using a confirmatory assay. A COS-7-based assay was used to analyze anti-AAV8 NAbs. The TAb screening cut point factor was determined to be 2.65, and the confirmatory cut point (CCP) was 57.1%. The prevalence of AAV8 TAb in 84 normal subjects was 40%, of which 24% were NAb positive and 16% were NAb negative. A...
Source: The AAPS Journal - April 3, 2023 Category: Drugs & Pharmacology Source Type: research
Correction: Preclinical In Vivo Data Integrated in a Modeling Network Informs a Refined Clinical Strategy for a CD3 T ‑Cell Bispecific in Combination with Anti‑PD‑L1
(Source: The AAPS Journal)
Source: The AAPS Journal - April 1, 2023 Category: Drugs & Pharmacology Source Type: research
Predicting Food Effects on Oral Extended-Release Drug Products: A Retrospective Evaluation
AbstractTheoretically, the risk of food effects for extended-release (ER) products compared to IR products may be less because: (1) postprandial physiological changes are usually transient and last for 2 –3 h only; and (2) the percentage of drug release from an ER product within the first 2–3 h post dose is usually small under both fasted and fed states. The major postprandial physiological changes that can affect oral absorption of ER drugs are delayed gastric emptying and prolonged intestina l transit. Oral absorption of ER drugs under fasted state mainly occurs in large intestine (colon and rectum) while the absor...
Source: The AAPS Journal - March 29, 2023 Category: Drugs & Pharmacology Source Type: research
Leveraging Prior Healthy Participant Pharmacokinetic Data to Evaluate the Impact of Renal and Hepatic Impairment on Ritlecitinib Pharmacokinetics
We present results from each study and two innovative approaches to utilizing available HP data as reference data for study 2: a statistical approach using analysis of variance and anin silico simulation of an HP cohort created using a population pharmacokinetics (POPPK) model derived from several ritlecitinib studies. For study 1, the observed area under the curve for 24-h dosing interval and maximum plasma concentration for HPs and their observed geometric mean ratios (participants with moderate hepatic impairmentvs HPs) were within 90% prediction intervals from the POPPK simulation-based approach, thereby validating t...
Source: The AAPS Journal - March 28, 2023 Category: Drugs & Pharmacology Source Type: research
Predicting Human Bioavailability of Subcutaneously Administered Fusion Proteins and Monoclonal Antibodies Using Human Intravenous Clearance or Antibody Isoelectric Point
In this study, we explored the relationships between human SC bioavailability and physicochemical or pharmacokinetic properties of 19 Fc- or albumin-fusion proteins and 98 monoclonal antibodies. An inverse linear correlation was observed between human SC bioavailability and intravenous clearance (CL) or isoelectric point (pI). Multivariate regression models were developed using intravenous CL and pI of a training set (N = 59) as independent variables. The predictive models of mAbs were validated with an independent test set (N = 33). Two linear regression models resulted in 24 (73%) and 27 (82%) among 33 prediction...
Source: The AAPS Journal - March 23, 2023 Category: Drugs & Pharmacology Source Type: research
Virtual Bioequivalence Assessment of Elagolix Formulations Using Physiologically Based Pharmacokinetic Modeling
AbstractIn lieu of large bioequivalence studies and exposing healthy postmenopausal women to additional drug exposure for elagolix coadministered with hormonal add-back therapy, physiologically based pharmacokinetic (PBPK) modeling was used within vitro dissolution data to test for virtual bioequivalence. For endometriosis, elagolix is approved at doses of 150 mg once daily and 200 mg twice daily as a tablet. As a combination therapy, two individual tablets, consisting of an elagolix tablet and an estradiol/norethindrone acetate 1/0.5 mg (E2/NETA) tablet, were utilized in Phase 3 endometriosis trials. However, the comm...
Source: The AAPS Journal - March 22, 2023 Category: Drugs & Pharmacology Source Type: research
Development of Drug Release Model for Suspensions in ESCAR (Emulator of SubCutaneous Absorption and Release)
The objective of this work was to investigate drug release behaviors of unmilled and milled suspensions in ESCAR. A mass transport-based model was developed to describe the multi-step drug release process, including drug dissolution, particle settling, drug distribution/partition, and drug permeation through the membrane(s). To address the particle settling effect, a correction factor was included in the model and its value was obtained by data fitting. It was found that, for both suspensions, (i) the experimental data of various dose/formulation combinations could be fit by the developed model; (ii) the dose effect on dru...
Source: The AAPS Journal - March 22, 2023 Category: Drugs & Pharmacology Source Type: research
The Prevalence of Several Treatments in Preventing the Back Conversion of Acyl Glucuronide Metabolites in Abbreviated New Drug Applications
The objective of this study was to investigate the impact of back conversion of acyl glucuronide metabolites on drug concentration measurement in bioequivalence (BE) studies submitted to Abbreviated New Drug Applications (ANDAs). The prevalence of several treatments for preventing the back conversion of acyl glucuronide metabolites and the results of incurred sample reanalysis (ISR) were analyzed. In total, 322 ANDAs for 26 drugs known to generate acyl glucuronide metabolites were surveyed. Many studies have applied multiple preventive treatments during the clinical and bioanalytical phases. More than two-thirds (67.2%) of...
Source: The AAPS Journal - March 1, 2023 Category: Drugs & Pharmacology Source Type: research
Ionic Liquid-Based Transcutaneous Peptide Antitumor Vaccine: Therapeutic Effect in a Mouse Tumor Model
In this study, we employed ionic liquids (ILs) for transcutaneous delivery of cancer antigen-derived peptides to obtain anticancer therapeutic effects in a needle-free manner. ILs successfully increased thein vitro skin permeability of a peptide from Wilms tumor 1 (WT1), one of the more promising cancer antigens, plus or minus an adjuvant, resiquimod (R848), a toll-like receptor 7 agonist.In vivo studies demonstrated that concomitant transcutaneous delivery of WT1 peptide and R848 by ILs induced WT1-specific cytotoxic T lymphocyte (CTL) in mice, resulting in tumor growth inhibition in Lewis lung carcinoma-bearing mice. Int...
Source: The AAPS Journal - February 17, 2023 Category: Drugs & Pharmacology Source Type: research
Novel Cell Quantification Method Using a Single Surrogate Calibration Curve Across Various Biological Samples
In this study, we aimed to establish a novel and robust ddPCR method capable of quantifying human cells across various mouse biological samples using a single surrogate calibration curve in combination with an external control gene and DNA recovery normalization. Acceptabl e accuracy and precision were observed for quality control samples from different tissues, indicating the excellent quantitative and versatile potential of the developed method. Furthermore, the established method enabled the evaluation of human CD8+ T cell biodistribution in immunodeficient mice. Our findings provide new insights into the use of ddPCR-b...
Source: The AAPS Journal - February 17, 2023 Category: Drugs & Pharmacology Source Type: research
Establishing the Safe Space via Physiologically Based Biopharmaceutics Modeling. Case Study: Fevipiprant/QAW039
AbstractPhysiologically based pharmacokinetic and absorption modeling has increasingly been implemented for biopharmaceutics applications to define the safe space for drug product quality attributes such as dissolution. For fevipiprant/QAW039, simulations were performed to assess the impact ofin vitro dissolution on thein vivo performance of immediate-release film-coated tablets during development and scaling up to commercial scale. A fevipiprant dissolution safe space was established using observed clinical intravenous and oral PK data from bioequivalent and non-bioequivalent formulations. Quality control dissolution prof...
Source: The AAPS Journal - February 14, 2023 Category: Drugs & Pharmacology Source Type: research
A Retrospective Review of Center for Biologics Evaluation and Research Advisory Committee Meetings in the Context of the FDA ’s Benefit-Risk Framework
AbstractThe US FDA Center for Biologics Evaluation and Research (CBER) is responsible for the regulation of biologically derived products. FDA has established Advisory Committees (AC) as vehicles to seek external expert advice on scientific and technical matters related to the development and evaluation of products regulated by the agency. We aimed to identify and evaluate common topics discussed in CBER AC meetings during the regulatory decision-making process for biological products and medical devices. We analyzed the content of 119 CBER-led AC meetings between 2009 and 2021 listed on the FDA AC webpage. We reviewed pub...
Source: The AAPS Journal - February 9, 2023 Category: Drugs & Pharmacology Source Type: research
