Clinical Pharmacology of RNA Interference-Based Therapeutics: A Summary Based on Food and Drug Administration-Approved Small Interfering RNAs.

RNA-based oligonucleotide therapeutics are revolutionizing drug development for disease treatment. This class of therapeutics differs from small molecules and protein therapeutics in various ways, including both its mechanism of action and clinical pharmacology characteristics. These unique characteristics, along with evolving oligonucleotide-associated conjugates allowing specific tissue targeting, have fueled interest in the evaluation of RNA-based oligonucleotide therapeutics in a rapidly increasing number of therapeutic areas.

Cefiderocol Dosing for Patients Receiving Continuous Renal Replacement Therapy.

In this report, we describe our scientific approach for including effluent flow rate (Q )-based dosing recommendations of cefiderocol for patients receiving continuous renal replacement therapy (CRRT) in the product labeling. The total clearance (CL) of cefiderocol in patients receiving CRRT was estimated as the sum of patients' nonrenal clearance (CL ) and extracorporeal clearance by CRRT (CL ), based on the following rationale: (a) The renal clearance (CL ) of cefiderocol is assumed to be negligible in patients receiving CRRT, (b) CL represents the CRRT patients' own remaining systemic clearance and is estimated from the observed clearance in participants with creatinine clearance (CLcr) < 15 mL/minute without undergoing hemodialysis, and (c) CL was estimated by the product of unbound (free) fraction of plasma drug concentration (f ) and Q because the free fraction of low-molecular-weight compounds like cefiderocol (752 Da) can be completely filtered by CRRT, regardless of CRRT modality. Hence, cefiderocol CL in CRRT patients was calculated by the equation of CL = CL  + f  × Q .

Using Endogenous Biomarkers to Derisk Assessment of Transporter-Mediated Drug-Drug Interactions: A Scientific Perspective.

Comprehensive characterization of transporter mediated drug-drug interactions (DDIs) is important to formulate clinical management strategies and ensure the safe and effective use of concomitantly administered drugs. The potential of a drug to inhibit transporters is predicted by comparing the ratio of the relevant concentration (depending on the transporter) and the half maximum inhibitory concentration to a predefined "cutoff" value. If the ratio is greater than the cutoff value, modeling approaches such as physiologically based pharmacokinetic modeling or a clinical DDI trial may be recommended.

Application of Population Pharmacokinetic Modeling, Exposure-Response Analysis, and Classification and Regression Tree Analysis to Support Dosage Regimen and Therapeutic Drug Monitoring of Plazomicin in Complicated Urinary Tract Infection Patients with Renal Impairment.

In 2018, the FDA approved plazomicin for the treatment of complicated urinary tract infections (cUTI) including pyelonephritis in adult patients with limited or no alternative treatment options. The objective of this article is to provide the scientific rationales behind the recommended dosage regimen and therapeutic drug monitoring (TDM) of plazomicin in cUTI patients with renal impairment. A previous population pharmacokinetic (PK) model was used to evaluate the dosage regimen in cUTI patients with different degrees of renal impairment.

Whole Body PBPK Modeling of Remdesivir and Its Metabolites to Aid in Estimating Active Metabolite Exposure in the Lung and Liver in Patients With Organ Dysfunction.

Remdesivir (RDV) is the first drug approved by the US Food and Drug Administration (FDA) for the treatment of coronavirus disease 2019 (COVID-19) in certain patients requiring hospitalization. As a nucleoside analogue prodrug, RDV undergoes intracellular multistep activation to form its pharmacologically active species, GS-443902, which is not detectable in the plasma. A question arises that whether the observed plasma exposure of RDV and its metabolites would correlate with or be informative about the exposure of GS-443902 in tissues.

Variations in pharmacokinetic-pharmacodynamic target values across MICs and their potential impact on determination of susceptibility test interpretive criteria.

Background: An antibacterial drug's susceptibility test interpretive criteria (STIC) are determined by integrating clinical, microbiological and pharmacokinetic-pharmacodynamic (PK-PD) data. PTA analysis plays a pivotal or supportive role in STIC determination and is heavily dependent on the PK-PD target values determined from animal PK-PD studies. Therefore, variations in PK-PD target values may impact STIC determination.

Anti-SARS-CoV-2 Repurposing Drug Database: Clinical Pharmacology Considerations.

A critical step to evaluate the potential in vivo antiviral activity of a drug is to connect the in vivo exposure to its in vitro antiviral activity. The Anti-SARS-CoV-2 Repurposing Drug Database is a database that includes both in vitro anti-SARS-CoV-2 activity and in vivo pharmacokinetic data to facilitate the extrapolation from in vitro antiviral activity to potential in vivo antiviral activity for a large set of drugs/compounds. In addition to serving as a data source for in vitro anti-SARS-CoV-2 activity and in vivo pharmacokinetic information, the database is also a calculation tool that can be used to compare the in vitro antiviral activity with in vivo drug exposure to identify potential anti-SARS-CoV-2 drugs.

Effect of Body Weight and Age on the Pharmacokinetics of Dihydroartemisinin: Food and Drug Administration Basis for Dose Determination of Artesunate for Injection in Pediatric Patients With Severe Malaria.

For treatment of severe malaria, the World Health Organization recommends 3 mg/kg intravenous artesunate in pediatric patients weighing less than 20 kg. Here we describe the Food and Drug Administration's rationale for selecting 2.4 mg/kg in pediatric patients weighing less than 20 kg based on literature review and independent analyses.

Evaluating Patients With Impaired Renal Function During Drug Development: Highlights From the 2019 US FDA Pharmaceutical Science and Clinical Pharmacology Advisory Committee Meeting.

Patients with multiple chronic conditions, including more advanced chronic kidney disease (CKD), are often excluded from clinical trials, creating challenges in deriving appropriate dosing information and labeling. This article summarizes the May 7, 2019, US Food and Drug Administration Pharmaceutical Science and Clinical Pharmacology Advisory Committee Meeting, which solicited expert opinions on how to enroll patients with more advanced CKD into clinical trials as well as the assumptions behind and different approaches of exposure-matching.

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.

Evaluation of Hemodialysis Effect on Pharmacokinetics of Meropenem/Vaborbactam in End-Stage Renal Disease Patients Using Modeling and Simulation.

The objectives of this study were to evaluate the effect of hemodialysis (HD) on the pharmacokinetics (PK) of meropenem/vaborbactam, an approved beta-lactam/beta-lactamase inhibitor combination, and provide the rationale for the recommended timing of meropenem/vaborbactam administration relative to HD in end-stage renal disease (ESRD) patients. Population PK models were developed separately for meropenem and vaborbactam in subjects with normal renal function and different degrees of renal impairment, including those receiving HD. Simulations were performed to evaluate the exposure of meropenem and vaborbactam in ESRD patients who received a fixed dose of 0.

Breaking Down Barriers to Effective Patient Care.

The theme for the 2018 ASCPT Annual Meeting is "Breaking Down Barriers to Effective Patient Care." This theme refers to the essential contributions of clinical pharmacology to the development of today's discovery into tomorrow's medicine. The various subdisciplines within clinical pharmacology serve to move molecules through the various stages of drug development and also refine or expand use of the drug postapproval.

In Vitro-In Vivo Extrapolation of Metabolism- and Transporter-Mediated Drug-Drug Interactions-Overview of Basic Prediction Methods.

Evaluation of drug-drug interaction (DDI) risk is vital to establish benefit-risk profiles of investigational new drugs during drug development. In vitro experiments are routinely conducted as an important first step to assess metabolism- and transporter-mediated DDI potential of investigational new drugs. Results from these experiments are interpreted, often with the aid of in vitro-in vivo extrapolation methods, to determine whether and how DDI should be evaluated clinically to provide the basis for proper DDI management strategies, including dosing recommendations, alternative therapies, or contraindications under various DDI scenarios and in different patient population.

Clinical Drug-Drug Interaction Evaluations to Inform Drug Use and Enable Drug Access.

Clinical drug-drug interactions (DDIs) can occur when multiple drugs are taken by the same patient. Significant DDIs can result in clinical toxicity or treatment failure. Therefore, DDI assessment is an integral part of drug development and the benefit-risk assessment of new therapies.

Developing and Using Therapeutics for Emerging Infections.

This issue of Clinical Pharmacology & Therapeutics focuses on emerging infections. The outbreaks of the vaccine-preventable diseases (e.g.

Predicting the effect of cytochrome P450 inhibitors on substrate drugs: analysis of physiologically based pharmacokinetic modeling submissions to the US Food and Drug Administration.

Background And Objective: The US Food and Drug Administration (FDA) has seen a recent increase in the application of physiologically based pharmacokinetic (PBPK) modeling towards assessing the potential of drug-drug interactions (DDI) in clinically relevant scenarios. To continue our assessment of such approaches, we evaluated the predictive performance of PBPK modeling in predicting cytochrome P450 (CYP)-mediated DDI.

Methods: This evaluation was based on 15 substrate PBPK models submitted by nine sponsors between 2009 and 2013.

Does an increase in serum creatinine always reflect renal injury? The case of Stribild®.

Single tablet, once-daily HIV treatment regimens offer patient convenience, the potential for increased adherence, and fewer patient-related dosing errors . Stribild® (manufactured and marketed by Gilead Sciences; referred to as "applicant" in this report), a 4-drug fixed-dose combination (FDC) tablet, is approved for the treatment of HIV-1 infection in treatment-naïve adult patients. Stribild® contains elvitegravir (an integrase strand transfer inhibitor), cobicistat (an inhibitor of cytochrome P450 enzymes), and the nucleoside/nucleotide reverse transcriptase inhibitors emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF).

Evaluation of exposure change of nonrenally eliminated drugs in patients with chronic kidney disease using physiologically based pharmacokinetic modeling and simulation.

Chronic kidney disease, or renal impairment (RI) can increase plasma levels for drugs that are primarily renally cleared and for some drugs whose renal elimination is not a major pathway. We constructed physiologically based pharmacokinetic (PBPK) models for 3 nonrenally eliminated drugs (sildenafil, repaglinide, and telithromycin). These models integrate drug-dependent parameters derived from in vitro, in silico, and in vivo data, and system-dependent parameters that are independent of the test drugs.

Drug interactions evaluation: an integrated part of risk assessment of therapeutics.

Pharmacokinetic drug interactions can lead to serious adverse events or decreased drug efficacy. The evaluation of a new molecular entity's (NME's) drug-drug interaction potential is an integral part of risk assessment during drug development and regulatory review. Alteration of activities of enzymes or transporters involved in the absorption, distribution, metabolism, or excretion of a new molecular entity by concomitant drugs may alter drug exposure, which can impact response (safety or efficacy).

A regulatory perspective on the role of drug interactions in antiretroviral drug development.

Purpose Of Review: To provide a regulatory perspective on the role of drug interaction information in the development of antiretroviral drugs. Additionally, this review highlights novel studies that provided important information for the safe and effective use of antiretroviral medications. The management of drug interactions in HIV therapy becomes more complex with the introduction of each new drug because many antiretroviral drugs are involved in multiple metabolic and transporter-based interactions.

Quantitative evaluation of pharmacokinetic inhibition of CYP3A substrates by ketoconazole: a simulation study.

The US Food and Drug Administration draft drug interaction guidance recommends that 400 mg ketoconazole (KTZ) be administered once daily for several days (QD400) for maximal CYP3A inhibition. Some investigators suggest that a single dose of 400 mg (SD400) KTZ is sufficient given its short half-life (t(1/2) approximately 3-5 hr). To determine the impact of KTZ regimens on CYP3A inhibition, we simulated AUC fold-change (AUCR) in the presence of SD400, QD400, or 200 mg twice-daily (BID200) KTZ for theoretical CYP3A substrates.

New era in drug interaction evaluation: US Food and Drug Administration update on CYP enzymes, transporters, and the guidance process.

Predicting clinically significant drug interactions during drug development is a challenge for the pharmaceutical industry and regulatory agencies. Since the publication of the US Food and Drug Administration's (FDA's) first in vitro and in vivo drug interaction guidance documents in 1997 and 1999, researchers and clinicians have gained a better understanding of drug interactions. This knowledge has enabled the FDA and the industry to progress and begin to overcome these challenges.