Nifurtimox for Treatment of Chagas Disease in Pediatric Patients: the Challenges of Applying Pharmacokinetic-Pharmacodynamic Principles to Dose Finding
AbstractThe
antiparasitic drug nifurtimox was approved in the USA in 2020 for the treatment of patients with Chagas disease aged less than 18 years and weighing at least 2.5 kg, based on outcomes from the phase 3 CHICO study. Accordingly, pediatric patients with Chagas disease take nifurtimox thrice daily with food at one of two body weight–adjusted dose ranges. We investigated possible relationships between pharmacokinetic (PK) data , and pharmacodynamic efficacy and safety data collected in an analysis population of 111 participants in CHICO, using a published population PK model to estimate nifurtimox exposure a...
Source: The AAPS Journal - August 24, 2022 Category: Drugs & Pharmacology Source Type: research
Determination of the Number of Tissue Groups of Kinetically Distinct Transit Time in Whole-Body Physiologically Based Pharmacokinetic (PBPK) Models I: Theoretical Consideration of Bottom-Up Approach of Lumping Tissues in Whole-Body PBPK
AbstractMinimal physiologically based pharmacokinetic (mPBPK) models, consisting of system-specific (e.g., tissue volume and blood flow) and drug-related (e.g., tissue-to-plasma partition coefficient) parameters, are practically useful for pharmacokinetic analyses. However, biopharmaceutical principles were not clear on how peripheral tissues, adopted in whole-body physiologically based pharmacokinetic (WB-PBPK) models, could be kinetically consolidated into one or two tissue groups in the mPBPK models. In this theoretical examination, we studied the relationship between the progressive tissue lumping in the direction from...
Source: The AAPS Journal - August 24, 2022 Category: Drugs & Pharmacology Source Type: research
Simulation of Intraluminal Performance of Lipophilic Weak Bases in Fasted Healthy Adults Using DDDPlusTM
AbstractThe majority of drug candidates exhibit weakly basic characteristics with high lipophilicity. The risk of intraluminal compound precipitation has been studiedin vivo and extensivelyin vitro using advanced dissolution transfer setups mimicking drug transfer from the stomach to the small intestine. The present investigation aims to evaluate the usefulness of the recently introduced Artificial Stomach-Duodenumin silico tool in the DDDPlusTM platform (ASD-D+) to simulate intraluminal drug behavior. The weakly basic drugs ketoconazole and dipyridamole were used as model drugs within the ASD-D+ model at two dose levels. ...
Source: The AAPS Journal - August 16, 2022 Category: Drugs & Pharmacology Source Type: research
Correction: An Artificial Gut/Absorption Simulator: Description, Modeling, and Validation Using Caffeine
(Source: The AAPS Journal)
Source: The AAPS Journal - August 16, 2022 Category: Drugs & Pharmacology Source Type: research
An Artificial Gut/Absorption Simulator: Description, Modeling, and Validation Using Caffeine
AbstractThe purpose of this study was to develop and validate a simultaneous dissolution and absorption testing tool, the “artificial gut simulator” (AGS), for oral drug formulations. The AGS was constructed using hollow fibers and housed in a 3-mL UV spectrophotometric cuvette that provided a large surface area-to-volume ratio to simulate absorption at a physiological rate. A quasi-steady-state model describing ab sorption was developed and validated using a high aqueous solubility, BCS-I model compound, caffeine. This model was used to optimize the AGS operating parameters to simulate physiological gastric emptying a...
Source: The AAPS Journal - July 25, 2022 Category: Drugs & Pharmacology Source Type: research
Metabolism of Speciociliatine, an Overlooked Kratom Alkaloid for its Potential Pharmacological Effects
In this report, we have characterized the metabolism of speciociliatine in human and preclinical sp ecies (mouse, rat, dog, and cynomolgus monkey) liver microsomes and hepatocytes. Speciociliatine metabolized rapidly in monkey, rat, and mouse hepatocytes (in vitro half-life was 6.6 ± 0.2, 8.3 ± 1.1, 11.2 ± 0.7 min, respectively), while a slower metabolism was observed in human and dog hepatocytes (91.7 ± 12.8 and > 120 min, respectively). Speciociliatine underwent extensive metabolism, primarily through monooxidation andO-demethylation metabolic pathways in liver microsomes and hepatocytes acr...
Source: The AAPS Journal - July 19, 2022 Category: Drugs & Pharmacology Source Type: research
Current Approaches for Predicting Human PK for Small Molecule Development Candidates: Findings from the IQ Human PK Prediction Working Group Survey
AbstractAccurate prediction of human clearance (CL) and volume of distribution at steady state (Vd,ss) for small molecule drug candidates is an essential component of assessing likely efficacious dose and clinical safety margins. In 2021, the IQ Consortium Human PK Prediction Working Group undertook a survey of IQ member companies to understand the current PK prediction methods being used to estimate these parameters across the pharmaceutical industry. The survey revealed a heterogeneity in approaches being used across the industry (e.g., the use of allometric approaches, differing incorporation of binding terms, and incon...
Source: The AAPS Journal - July 19, 2022 Category: Drugs & Pharmacology Source Type: research
Process Analytical Technology (PAT) Implementation for Membrane Operations in Continuous Manufacturing of mAbs: Model-Based Control of Single-Pass Tangential Flow Ultrafiltration
AbstractControl of single pass tangential flow ultrafiltration (SPTFF) is crucial for continuous manufacturing of monoclonal antibodies (mAbs). Integrating SPTFF technology into continuous manufacturing trains requires successful resolution of several challenges that arise due to the complexity of mass transfer interactions across multi-membrane configurations, the significant effect of feed material attributes and process variability on flux, and the need for advanced scheduling. In this paper, we propose a real-time, automated monitoring and control strategy for SPTFF in continuous processing of mAbs. The approach levera...
Source: The AAPS Journal - July 13, 2022 Category: Drugs & Pharmacology Source Type: research
Correction: International Regulatory Collaboration on the Analysis of Nitrosamines in Metformin-Containing Medicines
(Source: The AAPS Journal)
Source: The AAPS Journal - July 13, 2022 Category: Drugs & Pharmacology Source Type: research
Comparison of Titer and Signal to Noise (S/N) for Determination of Anti-drug Antibody Magnitude Using Clinical Data from an Industry Consortium
AbstractDuring biotherapeutic drug development, immunogenicity is evaluated by measuring anti-drug antibodies (ADAs). The presence and magnitude of ADA responses is assessed using a multi-tier workflow where samples are screened, confirmed, and titered. Recent reports suggest that the assay signal to noise ratio (S/N) obtained during the screening tier correlates well with titer. To determine whetherS/N could more broadly replace titer, anonymized ADA data from a consortium of sponsors was collected and analyzed. Datasets from clinical programs with therapeutics of varying immunogenicity risk levels (low to high), common A...
Source: The AAPS Journal - July 12, 2022 Category: Drugs & Pharmacology Source Type: research
Comparison Between Pure Component Modeling Approaches for Monitoring Pharmaceutical Powder Blends with Near-Infrared Spectroscopy in Continuous Manufacturing Schemes
AbstractNear-infrared (NIR) spectroscopy has become an important process analytical technology (PAT) for monitoring and implementing control in continuous manufacturing (CM) schemes. However, NIR requires complex multivariate models to properly extract the relevant information and the traditional model of choice, partial least squares, can be unfavorable on account of its high material and time investments for generating calibrations. To account for this, pure component-based approaches have been gaining attention due to their higher flexibility and ease of development. In the present study, the application of two pure com...
Source: The AAPS Journal - July 12, 2022 Category: Drugs & Pharmacology Source Type: research
A Simulation Study of the Comparative Performance of Partial Area under the Curve (pAUC) and Partial Area under the Effect Curve (pAUEC) Metrics in Crossover Versus Replicated Crossover Bioequivalence Studies for Concerta and Ritalin LA
AbstractConcerta and Ritalin LA are methylphenidate (MPH) drugs with different release mechanisms. Generic bioequivalence (BE) to these conventionally uses pAUC (partial area under the curve) as metrics in addition toCmax (maximum concentration), AUC0-t (area from time 0 to timet), and AUC0-infinity. The recommended BE design was a standard two-formulation, two-sequence, and two-period crossover; however, the currently recommended design is a replicated crossover to better define subject-by-formulation interaction variance. The current purpose was to compare via simulation, using literature MPH models, the performance of t...
Source: The AAPS Journal - July 8, 2022 Category: Drugs & Pharmacology Source Type: research
Model-Informed Approach Supporting Approval of Adalimumab (HUMIRA) in Pediatric Patients with Ulcerative Colitis from a Regulatory Perspective
This article provides a case example of successful model-informed drug development (MIDD), where modeling and simulation were utilized in combination with observed data from a clinical trial of limited size and scope to ultimately support the adalimumab approval in p ediatric patients with UC. (Source: The AAPS Journal)
Source: The AAPS Journal - July 6, 2022 Category: Drugs & Pharmacology Source Type: research
Pre-existing Reactivity to an IgG4 Fc-Epitope: Characterization and Mitigation of Interference in a Bridging Anti-drug Antibody Assay
AbstractTwenty percent of baseline patient samples exhibited a pre-existing response in a bridging anti-drug antibody (ADA) assay for a human IgG4 monoclonal antibody (mAb) therapeutic. In some cases, assay signals were more than 100-fold higher than background, potentially confounding detection of true treatment-emergent ADA responses. The pre-existing reactivity was mapped by competitive inhibition experiments using recombinant proteins or chimeric human mAbs with IgG4 heavy chain regions swapped for IgG1 sequences. These experiments demonstrated that the majority of the samples had reactivity to an epitope containing le...
Source: The AAPS Journal - July 1, 2022 Category: Drugs & Pharmacology Source Type: research
Pharmacokinetics of Gentamicin Components C1, C1a, and C2/C2a/C2b and Subsequent Decline in Glomerular Filtration Rate in Neonates
AbstractGentamicin is a commonly used antibiotic in neonates. Its components C1, C1a, C2, C2a, and C2b may have different nephrotoxic potential. We aimed to describe pharmacokinetics and nephrotoxic potential of gentamicin components in a joint model in neonates. Neonates with gestational age ≥ 32 weeks treated with gentamicin blood samples were collected at a steady state. Pharmacokinetics of C1, C1a, and C2/C2a/C2b were modelled in NONMEM and included competitive uptake into kidney proximal tubular cells and decrease in glomerular filtration rate. The nephrotoxic potential of t otal gentamicin, C1, C1a, and C2/C2...
Source: The AAPS Journal - June 27, 2022 Category: Drugs & Pharmacology Source Type: research
