Generic Drug Product Development in Japan: Regulatory Updates During 2014 –2019 and the Future
This report introduces the activities of the PMDA from fiscal years 2014 –2019. The number of approvals of new generic drug products and partial changes was trending downward. Alternatively, the PMDA conducted six types of consultation meetings to advise on development and application; the number of consultation meetings was increasing. Moreover, during this period, th e Ministry of Health, Labour and Welfare issued two basic principles for ophthalmic dosage forms and dry powder inhaler drug products and revised the guidelines for bioequivalence. Finally, the future of generic drug product development and considerati...
Source: European Journal of Drug Metabolism and Pharmacokinetics - September 29, 2021 Category: Drugs & Pharmacology Source Type: research

Correction to: Identifying Safety Thresholds for Immunosuppressive Drugs: Applying Insights from Primary Antibody Deficiencies to Mitigate Adverse Events in Secondary Antibody Deficiencies Using Mathematical Modeling of Preclinical and Early Clinical Data
(Source: European Journal of Drug Metabolism and Pharmacokinetics)
Source: European Journal of Drug Metabolism and Pharmacokinetics - September 28, 2021 Category: Drugs & Pharmacology Source Type: research

Severe 5-Fluorouracil-Associated Gastrointestinal Toxicity Unexplained by Dihydropyrimidine Dehydrogenase Deficiency and Renal Impairment: Should We Be Investigating Other Elimination Pathways to Assess the Risk of 5-Fluorouracil Toxicity?
(Source: European Journal of Drug Metabolism and Pharmacokinetics)
Source: European Journal of Drug Metabolism and Pharmacokinetics - September 27, 2021 Category: Drugs & Pharmacology Source Type: research

Pharmacokinetic Properties of S-oxiracetam After Single and Multiple Intravenous Infusions in Healthy Volunteers
ConclusionsS-ORT was well tolerated, and no serious adverse events occurred in 2.0, 4.0 and 8.0 g in single- and 4.0 g in multiple-dose studies. S-ORT showed dose linearity with increasing doses and no drug accumulation after 7 days of continuous administration was observed. (Source: European Journal of Drug Metabolism and Pharmacokinetics)
Source: European Journal of Drug Metabolism and Pharmacokinetics - September 21, 2021 Category: Drugs & Pharmacology Source Type: research

Physiologically-Based Pharmacokinetic Modelling of Entrectinib Parent and Active Metabolite to Support Regulatory Decision-Making
ConclusionsThe model simulations were used to derive dosing recommendations for co-administering entrectinib with CYP3A4 inhibitors or inducers. PBPK modeling has been used in lieu of clinical studies to enable regulatory decision-making. (Source: European Journal of Drug Metabolism and Pharmacokinetics)
Source: European Journal of Drug Metabolism and Pharmacokinetics - September 8, 2021 Category: Drugs & Pharmacology Source Type: research

Oral Antibiotics in Patients with Short Bowel Syndrome: Do or Don ’t?
(Source: European Journal of Drug Metabolism and Pharmacokinetics)
Source: European Journal of Drug Metabolism and Pharmacokinetics - September 7, 2021 Category: Drugs & Pharmacology Source Type: research

Advances in Thiopurine Drug Delivery: The Current State-of-the-Art
AbstractThiopurines (mercaptopurine, azathioprine and thioguanine) are well-established maintenance treatments for a wide range of diseases such as leukemia, inflammatory bowel disease (IBD), systemic lupus erythematosus (SLE) and other inflammatory and autoimmune diseases in general. Worldwide, millions of patients are treated with thiopurines. The use of thiopurines has been limited because of off-target effects such as myelotoxicity and hepatotoxicity. Therefore, seeking methods to enhance target-based thiopurine-based treatment is relevant, combined with pharmacogenetic testing. Controlled-release formulations for thio...
Source: European Journal of Drug Metabolism and Pharmacokinetics - September 6, 2021 Category: Drugs & Pharmacology Source Type: research

A Systematic Review of Multiple Linear Regression-Based Limited Sampling Strategies for Mycophenolic Acid Area Under the Concentration –Time Curve Estimation
ConclusionsThe review includes updated MPA LSSs, e.g., for different MPA formulations (suspension, dispersible tablets), generic form, and intravenous administration for adult and pediatric patients, and emphasizes the need of individual therapeutic approaches according to MMF indication. Five MLR-based MPA LSSs might be implemented into clinical practice after evaluation in independent groups of patients. Further studies are required, e.g., to establish fMPA LSS in pediatric patients. (Source: European Journal of Drug Metabolism and Pharmacokinetics)
Source: European Journal of Drug Metabolism and Pharmacokinetics - September 4, 2021 Category: Drugs & Pharmacology Source Type: research

Pharmacokinetics of Synthetic Cathinones Found in Bath Salts in Mouse Brain and Plasma Using High-Pressure Liquid Chromatography –Tandem Mass Spectrometry
ConclusionsThe pharmacokinetics of methylone, mepedrone, and MDPV are altered when the drugs are used in combination. These data provide insight into the consequences of co-exposure to synthetic cathinones in popular bath salt products. (Source: European Journal of Drug Metabolism and Pharmacokinetics)
Source: European Journal of Drug Metabolism and Pharmacokinetics - August 24, 2021 Category: Drugs & Pharmacology Source Type: research

Correction to: Bioavailability of a Capsaicin Lipid Multi ‑particulate Formulation in Rats
(Source: European Journal of Drug Metabolism and Pharmacokinetics)
Source: European Journal of Drug Metabolism and Pharmacokinetics - August 22, 2021 Category: Drugs & Pharmacology Source Type: research

Pharmacokinetics, Tolerability, and Safety of Single and Multiple Omecamtiv Mecarbil Doses in Healthy Japanese and Caucasian Subjects
ConclusionsOM showed consistent and predictable pharmacokinetics after multiple dosing in Japanese subjects. (Source: European Journal of Drug Metabolism and Pharmacokinetics)
Source: European Journal of Drug Metabolism and Pharmacokinetics - August 20, 2021 Category: Drugs & Pharmacology Source Type: research

Population Pharmacokinetics and Pharmacodynamics of Meropenem in Critically Ill Patients: How to Achieve Best Dosage Regimen According to the Clinical Situation
ConclusionsIdentified covariates in the model are easily accessible information in patient health records. The model highlighted the importance of considering the patient ’s overall condition (renal function and dialysis) and the pathogen’s characteristics (MIC target) during the establishment of a patient’s dosing regimen. (Source: European Journal of Drug Metabolism and Pharmacokinetics)
Source: European Journal of Drug Metabolism and Pharmacokinetics - August 17, 2021 Category: Drugs & Pharmacology Source Type: research

Effects of Repeated Oral Administration of Esaxerenone on the Pharmacokinetics of Midazolam in Healthy Japanese Males
ConclusionsEsaxerenone 5  mg/day had no clinically significant effect on midazolam pharmacokinetics and was not associated with any safety issues. Esaxerenone can be concomitantly administered with drugs of CYP3A substrates without dose adjustments.Clinical trial registrationJapiCTI-152832. (Source: European Journal of Drug Metabolism and Pharmacokinetics)
Source: European Journal of Drug Metabolism and Pharmacokinetics - August 12, 2021 Category: Drugs & Pharmacology Source Type: research

Gentamicin Dosing in Neonates with Normal Renal Function: Trough and Peak Levels
The objective of this study was to determine the extent of high trough (≥ 2 mg/l) and therapeutic peak serum gentamicin concentrations (5–12 mg/l) using our current gentamicin regimen and to adjust the dosing regimen accordingly and reassess.MethodsThis was a prospective cohort study of neonates, with normal renal function, who were prescribed gentamicin. Group 1: March 2014 –July 2017—gentamicin intravenous (IV) 2.5 mg/kg given every 36 h if
Source: European Journal of Drug Metabolism and Pharmacokinetics - August 9, 2021 Category: Drugs & Pharmacology Source Type: research

Comparison of the Pharmacokinetic Profiles of Trientine Tetrahydrochloride and Trientine Dihydrochloride in Healthy Subjects
ConclusionsCompared with an identical dose of a TETA 2HCl formulation, the TETA 4HCl formulation provided more rapid absorption of trientine and greater systemic exposure in healthy subjects.Clinical Trials Number EudraCT # 2015-002199-25. (Source: European Journal of Drug Metabolism and Pharmacokinetics)
Source: European Journal of Drug Metabolism and Pharmacokinetics - August 6, 2021 Category: Drugs & Pharmacology Source Type: research

Pharmacokinetic Modeling and Predictive Performance: Practical Considerations for Therapeutic Monoclonal Antibodies
AbstractPopulation pharmacokinetic (PopPK) model parameter estimation and predictive performance depend on the data adequacy for model building. PopPK models of therapeutic monoclonal antibodies (mAbs) may not be well supported by commonly used sparse sampling in late-stage development because of the slow absorption (days) and long half-life (weeks)  of mAbs, affecting accuracy of predicted exposure metrics which are often used to support drug development. A case study was presented for a representative mAb to compare the predictive performance of two established PopPK models from their respective data. Differences in...
Source: European Journal of Drug Metabolism and Pharmacokinetics - July 31, 2021 Category: Drugs & Pharmacology Source Type: research

Identifying Safety Thresholds for Immunosuppressive Drugs: Applying Insights from Primary Antibody Deficiencies to Mitigate Adverse Events in Secondary Antibody Deficiencies Using Mathematical Modeling of Preclinical and Early Clinical Data
AbstractImmunosuppressive drugs can alleviate debilitating symptoms of autoimmune diseases, but, by the same token, excessive immune suppression can result in an increased risk of infection. Despite the dangers of a compromised immune system, clear definitions of what constitutes excessive suppression remain elusive. Here we review the most common infections associated with primary antibody deficiencies (PADs), such as agammaglobulinemia, common variable immunodeficiency (CVID), and IgA deficiency, as well as infections that are associated with drug-induced or secondary antibody immunodeficiencies (SADs). We identify a num...
Source: European Journal of Drug Metabolism and Pharmacokinetics - July 30, 2021 Category: Drugs & Pharmacology Source Type: research

Quantification and Explanation of the Variability of First-Dose Amikacin Concentrations in Critically Ill Patients Admitted to the Emergency Department: A Population Pharmacokinetic Analysis
ConclusionThe IIV of amikacin pharmacokinetics in ED patients is large. Higher doses may be considered in patients with low serum sodium levels, low total protein levels, or a high fluid balance.Trial RegistrationClinicalTrials.gov ID: NCT02365272. (Source: European Journal of Drug Metabolism and Pharmacokinetics)
Source: European Journal of Drug Metabolism and Pharmacokinetics - July 23, 2021 Category: Drugs & Pharmacology Source Type: research

Bioavailability of a Capsaicin Lipid Multi-particulate Formulation in Rats
The objective of this study was to investigate the serum bioavailability of capsaicin supplementation with or without a lipid multi-particulate (LMP) formulation.MethodsThirty-five rats were divided into five groups and administered capsaicin at either 0.2 or 1 mg/kg with or without the LMP formulation. Capsaicin bioavailability was assessed based on the area under the concentation –time curve (AUC), the time to peak concentration (Tmax), and the peak serum concentration (Cmax).ResultsFor each formulation, the capsaicin  Cmax was reached at 90 min and decreased thereafter. Serum capsaicin concentrations were gre...
Source: European Journal of Drug Metabolism and Pharmacokinetics - July 21, 2021 Category: Drugs & Pharmacology Source Type: research

The Challenging Pharmacokinetics of Mitotane: An Old Drug in Need of New Packaging
This article aims to give a concise update of the clinical challenges associated with the administration of high-dose mitotane oral therapy which encompass the issues of poor bioavailability, difficult-to-predict pharmacokinetics and associated adverse events. Moreover, we present recent efforts to improve mitotane formulations. Their success has been limited, and we therefore propose an injectable mitotane formulation instead of oral administration, which could bypass many of the main issues associated with high-dose oral mitotane therapy. A parenteral administration of mitotane could not only help to alleviate the advers...
Source: European Journal of Drug Metabolism and Pharmacokinetics - July 21, 2021 Category: Drugs & Pharmacology Source Type: research

Bioavailability of a Capsaicin Lipid Multi-particulate Formulation in Rats
The objective of this study was to investigate the serum bioavailability of capsaicin supplementation with or without a lipid multi-particulate (LMP) formulation.MethodsThirty-five rats were divided into five groups and administered capsaicin at either 0.2 or 1 mg/kg with or without the LMP formulation. Capsaicin bioavailability was assessed based on the area under the concentation –time curve (AUC), the time to peak concentration (Tmax), and the peak serum concentration (Cmax).ResultsFor each formulation, the capsaicin  Cmax was reached at 90 min and decreased thereafter. Serum capsaicin concentrations were gre...
Source: European Journal of Drug Metabolism and Pharmacokinetics - July 21, 2021 Category: Drugs & Pharmacology Source Type: research

The Challenging Pharmacokinetics of Mitotane: An Old Drug in Need of New Packaging
This article aims to give a concise update of the clinical challenges associated with the administration of high-dose mitotane oral therapy which encompass the issues of poor bioavailability, difficult-to-predict pharmacokinetics and associated adverse events. Moreover, we present recent efforts to improve mitotane formulations. Their success has been limited, and we therefore propose an injectable mitotane formulation instead of oral administration, which could bypass many of the main issues associated with high-dose oral mitotane therapy. A parenteral administration of mitotane could not only help to alleviate the advers...
Source: European Journal of Drug Metabolism and Pharmacokinetics - July 21, 2021 Category: Drugs & Pharmacology Source Type: research

Serum and Synovial Vancomycin Concentrations in Patients with Prosthetic Joint Infection after Intra-articular Infusion
ConclusionsThe rational use of IA vancomycin infusion may help to achieve effective therapeutic concentrations of vancomycin in the serum and synovial fluid of patients with PJI. (Source: European Journal of Drug Metabolism and Pharmacokinetics)
Source: European Journal of Drug Metabolism and Pharmacokinetics - July 18, 2021 Category: Drugs & Pharmacology Source Type: research

Differential Inhibition of Equilibrative Nucleoside Transporter 1 (ENT1) Activity by Tyrosine Kinase Inhibitors
ConclusionOur data unambiguously add ENT1 to the list of drug transporters inhibited by TKIs, especially by lorlatinib. This point likely merits attention in terms of possible drug –drug interactions, notably for nucleoside analogues, whose ENT1-mediated uptake into their target cells may be hampered by co-administrated TKIs such as lorlatinib. (Source: European Journal of Drug Metabolism and Pharmacokinetics)
Source: European Journal of Drug Metabolism and Pharmacokinetics - July 18, 2021 Category: Drugs & Pharmacology Source Type: research

Serum and Synovial Vancomycin Concentrations in Patients with Prosthetic Joint Infection after Intra-articular Infusion
ConclusionsThe rational use of IA vancomycin infusion may help to achieve effective therapeutic concentrations of vancomycin in the serum and synovial fluid of patients with PJI. (Source: European Journal of Drug Metabolism and Pharmacokinetics)
Source: European Journal of Drug Metabolism and Pharmacokinetics - July 18, 2021 Category: Drugs & Pharmacology Source Type: research

Prediction of Non-Linear Pharmacokinetics of Monoclonal Antibodies in Human from Nonclinical Data: Are We There Yet?
(Source: European Journal of Drug Metabolism and Pharmacokinetics)
Source: European Journal of Drug Metabolism and Pharmacokinetics - July 17, 2021 Category: Drugs & Pharmacology Source Type: research

Novel Synthetic Analogues of 19(S/R)-Hydroxyeicosatetraenoic Acid Exhibit Noncompetitive Inhibitory Effect on the Activity of Cytochrome P450 1A1 and 1B1
ConclusionsTherefore, the synthetic analogues of 19-HETE could be considered as a novel therapeutic approach in the treatment of cancer and CVD. (Source: European Journal of Drug Metabolism and Pharmacokinetics)
Source: European Journal of Drug Metabolism and Pharmacokinetics - July 7, 2021 Category: Drugs & Pharmacology Source Type: research

Daptomycin Pharmacokinetics and Pharmacodynamics in Patients on Methadone Substitution Therapy
The objective of this study was to evaluate the pharmacokinetics and pharmacodynamics of daptomycin administered at a daily dosage of 12 mg/kg forStaphylococcus aureus infective endocarditis (IE) in patients concomitantly treated with methadone, and to compare the results with those published in the literature for healthy controls treated with the same daily dose.MethodsAntibiotic treatment included daptomycin (12 mg/kg daily) in combination with an antistaphylococcal β-lactam (cefazolin 2 g three times a day). The minimum inhibitory concentration (MIC) ofStaphylococcus aureus isolated through blood cultures was used ...
Source: European Journal of Drug Metabolism and Pharmacokinetics - July 6, 2021 Category: Drugs & Pharmacology Source Type: research