A Meta-Analysis of the Safety and Immunogenicity of Pharmacokinetic Similarity Studies and Comparative Clinical Studies.

A biosimilar clinical development program generally includes a pharmacokinetic similarity study and a comparative clinical study. Since both types of studies assess safety and immunogenicity, it is important to evaluate the role of each in determining whether there are any meaningful differences between the proposed biosimilar products and the reference products. We conducted a systematic review and meta-analysis of the safety and immunogenicity data from pharmacokinetic similarity studies and comparative clinical studies, using a database of approved monoclonal antibody and fusion protein biosimilars.

Evaluation of Truncated AUC as an Alternative Measure to Assess Pharmacokinetic Comparability in Bridging Biologic-Device Using Prefilled Syringes and Autoinjectors.

Pharmacokinetic (PK) comparisons between therapeutic biologics have largely been based on the total area under the concentration-time curve (AUC) and the maximum concentration (C ). For biologics with a long half-life, a PK comparability study may be long in duration and costly to conduct. The goal of this study was to evaluate whether a truncated AUC (tAUC) can be used to assess PK comparability when bridging prefilled syringe (PFS) and autoinjector (AI) treatment options for biologics with a long half-life.

Therapeutic Development in Polyarticular Course Juvenile Idiopathic Arthritis: Extrapolation, Dose Selection, and Clinical Trial Design.

Objective: Stakeholders met to address persistent challenges facing the development of therapeutics for polyarticular juvenile idiopathic arthritis (pJIA), which result in fewer approved therapies for children with pJIA than adults with rheumatoid arthritis (RA) and long lag times from adult RA approval to pediatric labeling. Ensuring that new medications are authorized in a timely manner to meet the needs of JIA patients worldwide is critically important to multiple stakeholders.

Methods: The Food and Drug Administration in collaboration with the University of Maryland Center for Regulatory Science and Innovation held a public workshop entitled "Accelerating Drug Development for pJIA" on October 2, 2019, to address challenges surrounding access to new medications for children and adolescents with pJIA.

Clinical pharmacology considerations for the approval of belimumab for the treatment of adult patients with active lupus nephritis: A regulatory perspective.

On 16 December 2020, FDA approved Benlysta® (belimumab) for both the intravenous (IV) and subcutaneous (SC) administration routes for the treatment of adult patients with active lupus nephritis (LN) who are receiving standard therapy. This approval represents the first FDA approved treatment of patients with active LN.The approved IV dosing regimen (10 mg/kg dose Q2W for three doses, then 10 mg/kg Q4W thereafter) was based on a randomized double-blind placebo controlled clinical trial in adult patients with LN.

Concentration-Response Model of Immediate Release Oxycodone Drug Liking by Different Routes of Abuse.

Objective: To understand the correlation between oxycodone concentration and drug liking response for immediate-release formulations as they relate to different doses and different routes of administration following manipulation involved in opioid misuse and nontherapeutic use.

Methods: Concentration-response and noncompartmental analyses of drug liking and plasma oxycodone data from Category 3 human abuse potential studies (n = 15-29 per study) were conducted, using Phoenix 6.0 software.

Association of partial systemic exposure and abuse potential for opioid analgesics with abuse deterrence labeling claims supporting product-specific guidance.

Background: Over the past decade, U.S. FDA has approved 10 opioid analgesics in abuse-deterrent formulations (ADFs).

Impact of Switching on Pharmacokinetics of Therapeutic Biologics and Interchangeability Assessment-A Simulation Study.

The risk in terms of safety or diminished efficacy of switching between an originator biological product and a proposed interchangeable product is an important consideration for interchangeability evaluation in the regulatory framework. This simulation study evaluated the impact of several switching study design scenarios on the pharmacokinetic (PK) assessment between a virtual originator biological product and a virtual proposed interchangeable product. Our results show that (1) at least 3 switches are needed to optimize the detection of potential PK differences, (2) the initial incidence of antidrug antibodies after treatment with the reference product in the lead-in period is a significant covariate affecting the PK results, and (3) the area under the concentration-time curve is more sensitive than peak concentration in assessing the impact of switching on PK similarity.

Impact of Sex on Clinical Response in Rheumatoid Arthritis Patients Treated With Biologics at Approved Dosing Regimens.

The prevalence of rheumatoid arthritis (RA) is higher in females than in males. With the development of new treatment options and strategies such as biologics, we found it worthwhile to identify whether males and females warrant different treatment regimens to ensure the best clinical response. Our meta-analysis included 11 clinical trials of RA patients in support of the Food and Drug Administration's approval of 6 biological products.

Immunomodulatory Therapeutic Proteins in COVID-19: Current Clinical Development and Clinical Pharmacology Considerations.

The coronavirus disease 2019 (COVID-19) pandemic caused by infection with SARS-CoV-2 has led to more than 600 000 deaths worldwide. Patients with severe disease often experience acute respiratory distress characterized by upregulation of multiple cytokines. Immunomodulatory biological therapies are being evaluated in clinical trials for the management of the systemic inflammatory response and pulmonary complications in patients with advanced stages of COVID-19.

Clinical Pharmacology Considerations for Developing Small-Molecule Treatments for COVID-19.

Numerous drugs are being investigated for the treatment of COVID-19, including antivirals and therapies targeting complications related to COVID-19. The clinical presentation of COVID-19 varies from mild fever, cough, and dyspnea in the early stages of disease to severe complications such as acute respiratory distress syndrome, systemic hyperinflammation, and sepsis. A thorough understanding of the disease pathogenesis and the disease complications is essential to developing effective therapies to treat this potentially life-threatening disease.

A Comprehensive Updated Review on SARS-CoV-2 and COVID-19.

This literature review aims to provide a comprehensive current summary of the pathogenesis, clinical features, disease course, host immune responses, and current investigational antiviral and immunomodulatory pharmacotherapies to facilitate the development of future therapies and measures for prevention and control.

Effects of Food on Bioavailability of Analgesics; Resulting Dosage and Administration Recommendations.

Objectives: To evaluate currently approved analgesics, that is, opioids, nonsteroidal anti-inflammatory drugs (NSAIDs), anticonvulsants, and serotonin and norepinephrine reuptake inhibitors (SNRIs) used as analgesics, for 1) differences in pharmacokinetic parameters under fed vs fasting conditions and 2) factors involved in dosage recommendations in relation to food.

Design: Systematic review.

Results: Food effect on the rate, extent of absorption, or shape of concentration-time profile can alter the onset of action, duration of action, or tolerability of a medication.

Drug Interaction Between Febuxostat and Thiopurine Antimetabolites: A Review of the FDA Adverse Event Reporting System and Medical Literature.

Background: There is a known drug interaction (DI) between xanthine oxidase (XO) inhibitors and the thiopurine immunosuppressants, azathioprine (AZA) and mercaptopurine (6-MP). Xanthine oxidase inhibition increases concentrations of AZA and 6-MP active metabolites, possibly resulting in myelosuppression. When allopurinol is used with AZA or 6-MP, dose reduction of AZA or 6-MP is recommended.

Update on Therapeutic Protein-Drug Interaction: Information in Labeling.

This review evaluated the significance of therapeutic protein (TP)-drug interactions and the current practices for assessing the interaction potential. We reviewed US FDA labels of approved TPs with drug-drug interaction (DDI) assessment. TP-drug interactions have been evaluated from in vitro studies, animal studies, and/or clinical settings.

Key Physicochemical Characteristics Influencing ADME Properties of Therapeutic Proteins.

Therapeutic proteins are a rapidly growing class of drugs in clinical settings. The pharmacokinetics (PK) of therapeutic proteins relies on their absorption, distribution, metabolism, and excretion (ADME) properties. Moreover, the ADME properties of therapeutic proteins are impacted by their physicochemical characteristics.

A Novel Pharmacokinetic Bridging Strategy to Support a Change in the Route of Administration for Biologics.

Determination of appropriate pharmacokinetic end point to bridge different dosing regimens is often a challenge when developing a new route of administration. Trough concentrations (C) are often considered the most relevant PK end point to predict efficacy (ACR20/DAS28) in the treatment of rheumatoid arthritis for biologics. However, no systematic research has been conducted to evaluate this approach.

A Model-Based Approach to Quantify the Time-Course of Anti-Drug Antibodies for Therapeutic Proteins.

A mathematical antidrug antibody (ADA) model was developed to quantitatively assess immunogenicity for therapeutic proteins. The ADA model was built with antibody titer data in subjects from 10 clinical trials. The time course of the antibody titers was quantitatively characterized with a two-component semimechanistic model describing the double peaks of ADA titers.

Use of a Systems Pharmacology Model Based Approach Toward Dose Optimization of Parathyroid Hormone Therapy in Hypoparathyroidism.

We present an application of a quantitative systems pharmacology (QSP) model to support a regulatory decision, specifically in assessing the adequacy of the proposed dosing regimen. On January 23, 2015, the US Food and Drug Administration (FDA) approved Natpara (human parathyroid hormone (PTH)) to control hypocalcemia in patients with hypoparathyroidism. Clinical trial results indicated that although once-daily PTH reduced calcium and vitamin D dose requirement while maintaining the normocalcemia, the regimen was not adequate to control hypercalciuria.

Methadone Metabolism and Drug-Drug Interactions: In Vitro and In Vivo Literature Review.

Methadone is utilized for the treatment of individuals with opiate dependence. Methadone undergoes N-demethylation by multiple cytochrome P450 (CYP) enzymes including CYP3A4, CYP2B6, CYP2C19, CYP2D6, CYP2C9, and CYP2C8. In vivo, polymorphism effects on methadone systemic exposure have been noted for CYP2B6, CYP3A4, and CYP2D6.

Exposure-Response Modeling and Power Analysis of Components of ACR Response Criteria in Rheumatoid Arthritis (Part 2: Continuous Model).

Population pharmacokinetic/pharmacodynamic (PK/PD) models were developed to quantitate the exposure-response relationships using continuous longitudinal data on American College of Rheumatology (ACR) subcomponents, that is, tender-joint count (TJC), swollen-joint count (SJC), C-reactive protein, patient's assessment of pain, patient's global assessment of disease activity, physician's global assessment of disease activity, and patient's assessment of physical function for 5 biologics approved for use in rheumatoid arthritis. The models were then used to simulate the time courses of clinical outcomes following different treatment regimens. The relative sensitivity of the 7 subcomponents was assessed using Monte Carlo simulation-based power analysis.

Exposure-Response Modeling and Power Analysis of Components of ACR Response Criteria in Rheumatoid Arthritis (Part 1: Binary Model).

American College of Rheumatology (ACR) response criteria is used to assess improvement in tender and swollen joint counts and in 3 of the 5 core measures (acute-phase reactant, physician global assessment, patient global assessment, pain, and physical function). From the clinical trial data on 5 approved biological products for the treatment of rheumatoid arthritis, population pharmacokinetic/pharmacodynamic models were developed to quantitatively describe the relationship between exposure and response rates of 3 individual components of ACR response criteria. The models were then used to simulate the clinical outcomes at various time points following different treatment regimens.

Kidney function changes with aging in adults: comparison between cross-sectional and longitudinal data analyses in renal function assessment.

The study evaluated whether the renal function decline rate per year with age in adults varies based on two primary statistical analyses: cross-section (CS), using one observation per subject, and longitudinal (LT), using multiple observations per subject over time. A total of 16628 records (3946 subjects; age range 30-92 years) of creatinine clearance and relevant demographic data were used. On average, four samples per subject were collected for up to 2364 days (mean: 793 days).

Canagliflozin use in patients with renal impairment-Utility of quantitative clinical pharmacology analyses in dose optimization.

Canagliflozin (INVOKANA™) is approved as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus (T2DM). Canagliflozin inhibits renal sodium-glucose co-transporter 2 (SGLT2), thereby, reducing reabsorption of filtered glucose and increasing urinary glucose excretion. Given the mechanism of action of SGLT2 inhibitors, we assessed the interplay between renal function, efficacy (HbA1c reduction), and safety (renal adverse reactions).