Correction.
Authors: PMID: 33140410 [PubMed] (Source: The Journal of Clinical Pharmacology)
Source: The Journal of Clinical Pharmacology - November 4, 2020 Category: Drugs & Pharmacology Tags: J Clin Pharmacol Source Type: research

Prediction of Fracture Risk From Early-Stage Bone Markers in Patients With Osteoporosis Treated With Once-Yearly Administered Zoledronic Acid.
This study aimed to develop a mathematical model quantifying the long-term fracture risk after 2 annual doses of 5 mg of once-yearly administered zoledronic acid or placebo based on the short-term measurement of bone turnover markers or bone mineral density (BMD). The data used in this analysis were obtained from a randomized, placebo-controlled, double-blind, 2-year study of zoledronic acid that included 656 patients with primary osteoporosis. Two-year individual bone resorption marker (tartrate-resistant acid phosphatase 5b [TRACP-5b]) and lumbar spine (L2-L4) BMD profiles were simulated using baseline values and short-t...
Source: The Journal of Clinical Pharmacology - November 1, 2020 Category: Drugs & Pharmacology Authors: Kasai H, Mori Y, Ose A, Shiraki M, Tanigawara Y Tags: J Clin Pharmacol Source Type: research

The Effects of Continuous Albuterol Inhalation on the Serum Metabolome in Healthy Subjects: More than Just Lactic Acid.
This article is protected by copyright. All rights reserved. PMID: 33128239 [PubMed - as supplied by publisher] (Source: The Journal of Clinical Pharmacology)
Source: The Journal of Clinical Pharmacology - October 30, 2020 Category: Drugs & Pharmacology Authors: Nowadly CD, Liao SY, Rose JS Tags: J Clin Pharmacol Source Type: research

Demonstrating Feasibility of an Opportunistic Sampling Approach for Pharmacokinetic Studies of β-Lactam Antibiotics in Critically Ill Children.
The objective of this study was to demonstrate the feasibility of an opportunistic sampling approach that utilizes scavenged residual blood for future pharmacokinetic studies of cefepime, meropenem, and piperacillin. We aimed to show that opportunistic samples would cover the full concentration-versus-time profiles and to evaluate stability of the antibiotics in whole blood and plasma to optimize future use of the opportunistic sampling approach. A prospective observational study was conducted in a single-center pediatric intensive care unit, where pediatric patients administered at least 1 dose of cefepime, meropenem, or ...
Source: The Journal of Clinical Pharmacology - October 27, 2020 Category: Drugs & Pharmacology Authors: Tang Girdwood SC, Tang PH, Murphy ME, Chamberlain AR, Benken LA, Jones RL, Stoneman EM, Kaplan JM, Vinks AA Tags: J Clin Pharmacol Source Type: research

Parametric Approaches in Population Pharmacokinetics.
Abstract Population pharmacokinetic (popPK) approaches have spread widely throughout clinical pharmacology research, and every clinician should have some understanding of them. After a general introduction on the fundamentals and fields of application of these approaches, this review focuses on parametric popPK methods to provide the clinicians with the conceptual tools to interpret appropriately the results of parametric popPK analyses and to understand their clinical utility. The emphasis is put on the clinical questions that popPK methods are best suited to address. The basic principles of the methodology are i...
Source: The Journal of Clinical Pharmacology - October 26, 2020 Category: Drugs & Pharmacology Authors: Guidi M, Csajka C, Buclin T Tags: J Clin Pharmacol Source Type: research

Nonparametric Methods in Population Pharmacokinetics.
The objectives of this article are to present an overview of nonparametric methods used in population pharmacokinetic modeling and to explain their specific characteristics to inform scientists and clinicians about their potential value for data analysis, simulation, dosage design, and therapeutic drug monitoring (TDM). Nonparametric methods have several interesting characteristics for population PK analysis, including computation of exact likelihoods, the ability to accommodate parameter probability distributions of any shape (eg, non-Gaussian), and to detect subpopulations and outliers. Nonparametric population methods a...
Source: The Journal of Clinical Pharmacology - October 26, 2020 Category: Drugs & Pharmacology Authors: Goutelle S, Woillard JB, Neely M, Yamada W, Bourguignon L Tags: J Clin Pharmacol Source Type: research

Outcomes Associated with 4-Factor Prothrombin Complex Concentrate Administration to Reverse Oral Factor Xa Inhibitors in Bleeding Patients.
This article is protected by copyright. All rights reserved. PMID: 33094836 [PubMed - as supplied by publisher] (Source: The Journal of Clinical Pharmacology)
Source: The Journal of Clinical Pharmacology - October 23, 2020 Category: Drugs & Pharmacology Authors: Highsmith EA, Morton C, Varnado S, Donahue KR, Sulhan S, Lista A Tags: J Clin Pharmacol Source Type: research

Population Pharmacokinetics and Exposure-Response Analyses to Guide Dosing of Icatibant in Pediatric Patients With Hereditary Angioedema.
Abstract Elevated bradykinin levels are responsible for the development of clinical symptoms in patients with hereditary angioedema (HAE). Icatibant is a bradykinin type 2 receptor antagonist indicated for the acute treatment of HAE attacks. A population modeling and simulation approach was used to examine sources of variability impacting icatibant pharmacokinetics (PK) and provide guidance on icatibant dosing in pediatric patients with HAE. An exposure-response analysis was performed for the time to onset of symptom relief (TOSR). Data from 141 adults (133 healthy, 8 with HAE) who received subcutaneous icatibant ...
Source: The Journal of Clinical Pharmacology - October 22, 2020 Category: Drugs & Pharmacology Authors: Wang Y, Jomphe C, Marier JF, Martin P Tags: J Clin Pharmacol Source Type: research

Predicted Cardiac Hemodynamic Consequences of the Renal Actions of SGLT2i in the DAPA-HF Study Population: A Mathematical Modeling Analysis.
This study aimed to quantify the contribution of the known natriuretic/diuretic effects of SGLT2is to changes in cardiac hemodynamics, remodeling, and fluid homeostasis in the setting of HF-rEF. An integrated cardiorenal mathematical model was used to simulate inhibition of SGLT2 and its consequences on cardiac hemodynamics in a virtual population of HF-rEF patients generated by varying model parameters over physiologically plausible ranges and matching to baseline characteristics of individual DAPA-HF trial patients. Cardiovascular responses to placebo and SGLT2i over time were then simulated. The baseline characteristics...
Source: The Journal of Clinical Pharmacology - October 22, 2020 Category: Drugs & Pharmacology Authors: Yu H, Tang W, Greasley PJ, Penland RC, Boulton DW, Hallow KM Tags: J Clin Pharmacol Source Type: research

Pharmacokinetics of Voxelotor in Patients With Renal and Hepatic Impairment.
Abstract Two open-label studies assessed the safety, tolerability, and pharmacokinetics of Oxbryta (voxelotor) in subjects with hepatic or renal impairment. Eight subjects with severe renal impairment (estimated glomerular filtration rate
Source: The Journal of Clinical Pharmacology - October 20, 2020 Category: Drugs & Pharmacology Authors: Preston RA, Marbury T, Balaratnam G, Green M, Dixon S, Lehrer-Graiwer J, Washington C Tags: J Clin Pharmacol Source Type: research

Unusual Distribution Kinetics of Gadoxetate in Healthy Human Subjects Genotyped for OATP1B1: Application of Population Analysis and a Minimal Physiological-Based Pharmacokinetic Model.
Abstract Gadoxetate (Gd-EOB-DTPA) is a hepatobiliary-specific contrast agent for magnetic resonance imaging. Using a minimal physiological-based pharmacokinetic (PBPK) model, it has been shown for the first time, that the rapid initial decline of plasma concentration after intravenous injection is the result of an uptake into hepatocytes rather than of a distribution into the extravascular extracellular space. About 50% of the steady-state distribution volume is related to hepatic uptake. The hepatic extraction ratio and hepatic clearance estimated based on the liver model as a part of the PBPK model wer...
Source: The Journal of Clinical Pharmacology - October 20, 2020 Category: Drugs & Pharmacology Authors: Weiss M, Siegmund W Tags: J Clin Pharmacol Source Type: research

Target-Mediated Drug Disposition-A Class Effect of Soluble Epoxide Hydrolase Inhibitors.
Abstract Pharmacological target-mediated drug disposition (TMDD) represents a special source of nonlinear pharmacokinetics, and its occurrence in large-molecule compounds has been well recognized because numerous protein drugs have been reported to have TMDD due to specific binding to their pharmacological targets. Although TMDD can also happen in small-molecule compounds, it has been largely overlooked. In this mini-review, we summarize the occurrence of TMDD that we discovered recently in a series of small-molecule soluble epoxide hydrolase (sEH) inhibitors. Our journey started with an accidental discovery of ta...
Source: The Journal of Clinical Pharmacology - October 19, 2020 Category: Drugs & Pharmacology Authors: An G, Lee KSS, Yang J, Hammock BD Tags: J Clin Pharmacol Source Type: research

Hypophosphatemia Is Common After Intravenous Ferric Carboxymaltose Infusion Among Patients With Symptomatic Heart Failure With Reduced Ejection Fraction.
Abstract Administration of intravenous ferric carboxymaltose (FCM) for iron-deficient patients suffering heart failure with reduced ejection fraction (HFrEF) has been associated with transient hypophosphatemia. We sought to investigate and model the effect of intravenous FCM on phosphate levels in iron-deficient patients with HFrEF. In this single-center retrospective study, serum phosphate levels, recorded for clinical reasons, were collected out to 60 days following intravenous FCM. Hypophosphatemia was defined as a nadir serum phosphate level
Source: The Journal of Clinical Pharmacology - October 13, 2020 Category: Drugs & Pharmacology Authors: Dashwood A, Vale C, Laher S, Chui F, Hay K, Wong YW Tags: J Clin Pharmacol Source Type: research

Concomitant Use of Acetaminophen and Aspirin Increases Risk of Kidney Injury: Analysis of the Japanese Adverse Drug Event Report Database.
PMID: 33043465 [PubMed - as supplied by publisher] (Source: The Journal of Clinical Pharmacology)
Source: The Journal of Clinical Pharmacology - October 11, 2020 Category: Drugs & Pharmacology Authors: Mitsuboshi S, Niimura T, Zamami Y Tags: J Clin Pharmacol Source Type: research

Population Pharmacokinetic Analysis of Pexidartinib in Healthy Subjects and Patients With Tenosynovial Giant Cell Tumor or Other Solid Tumors.
Abstract Pexidartinib is a kinase inhibitor that induces tumor response and improvements in symptoms and functional outcomes in adult patients with symptomatic tenosynovial giant cell tumor (TGCT). A population pharmacokinetic (PK) model for pexidartinib and its metabolite, ZAAD, was developed, and effects of demographic and clinical factors on the PK of pexidartinib and ZAAD were estimated. The analysis included pooled data from 7 studies in healthy volunteers (N = 159) and 2 studies in patients with TGCT or other solid tumors (N = 216). A structural 2-compartment model with sequential zero- and first-o...
Source: The Journal of Clinical Pharmacology - October 11, 2020 Category: Drugs & Pharmacology Authors: Yin O, Wagner AJ, Kang J, Knebel W, Zahir H, van de Sande M, Tap WD, Gelderblom H, Healey JH, Shuster D, Stacchiotti S Tags: J Clin Pharmacol Source Type: research

Relationship of Edoxaban Plasma Concentration and Blood Coagulation in Healthy Volunteers Using Standard Laboratory Tests and Viscoelastic Analysis.
In conclusion, ROTEM CT correlates significantly with edoxaban plasma concentrations and can be used to estimate the effect of edoxaban. ROTEM should be considered as part of the assessment of coagulation, with the big advantage of being readily available on site. PMID: 33027547 [PubMed - as supplied by publisher] (Source: The Journal of Clinical Pharmacology)
Source: The Journal of Clinical Pharmacology - October 7, 2020 Category: Drugs & Pharmacology Authors: Havrdová M, Saari TI, Jalonen J, Peltoniemi M, Kurkela M, Vahlberg T, Tienhaara A, Backman JT, Olkkola KT, Schramko A Tags: J Clin Pharmacol Source Type: research

Hydroxyurea Pharmacokinetics in Pediatric Patients After Total Pancreatectomy With Islet Autotransplantation.
Abstract Total pancreatectomy with islet autotransplantation is a complex surgical approach for acute recurrent or chronic pancreatitis that frequently triggers extreme thrombocytosis (platelets ≥ 1000 × 109 /L). Thrombocytosis can be prothrombotic, so cytoreductive hydroxyurea is often initiated after this surgery; however, optimal dosing strategy and efficacy are unknown. This prospective pilot study characterized the pharmacokinetics of hydroxyurea after this procedure in children. It also compared them with previously published pediatric parameters in sickle cell anemia (SCA), the disease in which ped...
Source: The Journal of Clinical Pharmacology - October 7, 2020 Category: Drugs & Pharmacology Authors: Boucher AA, Dong M, Vinks AA, Marahatta A, Howard TA, Ware RE, Nathan JD, Abu-El-Haija M, Luchtman-Jones L Tags: J Clin Pharmacol Source Type: research

Pharmacokinetics of Hydrochlorothiazide in Children: A Potential Surrogate for Renal Secretion Maturation.
This study examined 83 plasma samples from 49 participants (69% male) taking enteral HCTZ. The median (range) postnatal age was 6.7 years (0.03-19.5 years), and 17 (34%) participants were obese or morbidly obese. The median (range) dose of HCTZ was 0.654 mg/kg (0.11-1.8 kg) and the median number of doses recorded per participant was 5 (1-8). HCTZ PK was well characterized by a 1-compartment PK model. Body weight and a maturation model based on postmenstrual age were significant covariates for apparent clearance, but the presence of obesity was not. Dosing simulations were performed with a standardized 1mg/kg. Simulated exp...
Source: The Journal of Clinical Pharmacology - October 7, 2020 Category: Drugs & Pharmacology Authors: Commander SJ, Wu H, Boakye-Agyeman F, Melloni C, Hornik CD, Zimmerman K, Al-Uzri A, Mendley SR, Harper B, Cohen-Wolkowiez M, Hornik CP, Best Pharmaceuticals for Children Act-Pediatric Trials Network Steering Committee Tags: J Clin Pharmacol Source Type: research

Population Pharmacokinetics and Dosing Optimization of Amoxicillin in Chinese Infants.
Abstract Amoxicillin is used to treat various bacterial infections (eg, pneumonia, sepsis, meningitis) in infants. Despite its frequent use, there is a lack of population pharmacokinetic studies in infants, resulting in a substantial variability in dosing regimens used in clinical practice. Therefore, the objective of this study was to evaluate the population pharmacokinetics of intravenous amoxicillin in infants and suggest an optimal dosage regimen. Blood samples were collected for the determination of amoxicillin concentrations using an opportunistic sampling strategy. The amoxicillin plasma concentrations were...
Source: The Journal of Clinical Pharmacology - September 28, 2020 Category: Drugs & Pharmacology Authors: Wu YE, Wang YK, Tang BH, Dong L, Li X, Zhang W, Li DF, Tian LY, van den Anker J, You DP, Zhao W Tags: J Clin Pharmacol Source Type: research

Physiologically Based Pharmacokinetic Modeling of Doravirine and Its Major Metabolite to Support Dose Adjustment With Rifabutin.
Abstract Doravirine, a novel nonnucleoside reverse transcriptase inhibitor for the treatment of human immunodeficiency virus 1 (HIV-1), is predominantly cleared by cytochrome P450 (CYP) 3A4 and metabolized to an oxidative metabolite (M9). Coadministration with rifabutin, a moderate CYP3A4 inducer, decreased doravirine exposure. Based on nonparametric superposition modeling, a doravirine dose adjustment from 100 mg once daily to 100 mg twice daily during rifabutin coadministration was proposed. However, M9 exposure may also be impacted by induction, in addition to the dose adjustment. As M9 concentrations have not ...
Source: The Journal of Clinical Pharmacology - September 27, 2020 Category: Drugs & Pharmacology Authors: Yee KL, Cabalu TD, Kuo Y, Fillgrove KL, Liu Y, Triantafyllou I, McClain S, Dreyer D, Wenning L, Stoch SA, Iwamoto M, Sanchez RI, Khalilieh SG Tags: J Clin Pharmacol Source Type: research

Tucatinib Inhibits Renal Transporters OCT2 and MATE Without Impacting Renal Function in Healthy Subjects.
Abstract Tucatinib is a potent tyrosine kinase inhibitor selective for human epidermal growth factor receptor 2 (HER2) approved by the US Food and Drug Administration for the treatment of HER2-positive metastatic breast cancer and in development for other HER2-positive solid tumors. Modest, reversible serum creatinine (SCr) elevations have been observed in tucatinib clinical trials. SCr is conveyed by the renal drug transporters organic cation transporter 2 (OCT2) and multidrug and toxin extrusion protein 1 (MATE1) and 2-K (MATE2-K) and can increase in the presence of inhibitors of these transporters. In vitro, tu...
Source: The Journal of Clinical Pharmacology - September 27, 2020 Category: Drugs & Pharmacology Authors: Topletz-Erickson AR, Lee AJ, Mayor JG, Rustia EL, Abdulrasool LI, Wise AL, Dailey B, DeChenne S, Walker LN, Alley SC, Endres CJ Tags: J Clin Pharmacol Source Type: research

Absolute Bioavailability of Microdosed Midazolam After Buccal Administration Is Dependent on Buccal Exposure Time.
In conclusion, midazolam bioavailability is highly dependent on buccal exposure time, and even a few seconds of buccal exposure will increase bioavailability due to buccal absorption. This needs to be taken into account for any buccal administration of midazolam. PMID: 32976642 [PubMed - as supplied by publisher] (Source: The Journal of Clinical Pharmacology)
Source: The Journal of Clinical Pharmacology - September 24, 2020 Category: Drugs & Pharmacology Authors: Grass J, Rose P, Burhenne J, Blank A, Haefeli WE, Mikus G Tags: J Clin Pharmacol Source Type: research

Nifedipine Does Not Alter the Pharmacokinetics of Venlafaxine Enantiomers in Healthy Subjects Phenotyped for CYP2D6, CYP2C19, and CYP3A.
Abstract Venlafaxine (VEN) is a P-glycoprotein (P-gp) substrate, and nifedipine has been described by in vitro and experimental studies as a P-gp inhibitor. The present study aimed to investigate whether nifedipine alters the kinetic disposition of VEN enantiomers and their metabolites in healthy subjects. A crossover study was conducted in 10 healthy subjects phenotyped as extensive metabolizers for cytochrome P450 (CYP) 2D6, CYP2C19, and CYP3A. In phase 1, the subjects received a single oral dose of 150 mg racemic VEN, and in phase 2, a single oral dose of 40 mg nifedipine was administered with the VEN treatment...
Source: The Journal of Clinical Pharmacology - September 23, 2020 Category: Drugs & Pharmacology Authors: Tozatto E, Benzi JRL, Rocha A, Coelho EB, Lanchote VL Tags: J Clin Pharmacol Source Type: research

Evaluation of the Relationship of Glasdegib Exposure and Safety End Points in Patients With Refractory Solid Tumors and Hematologic Malignancies.
Abstract Glasdegib is approved for treating acute myeloid leukemia in elderly patients at 100 mg once daily in combination with low-dose cytarabine. Exposure-efficacy analysis showed that the survival benefit of glasdegib was not glasdegib exposure-dependent. The relationship between glasdegib exposure and adverse event (AE) cluster terms of clinical concern was explored in this analysis. The incidence and severity of dysgeusia, muscle spasms, renal toxicity, and QT interval prolonged was modeled using ordinal logistic regression. AEs were graded using the National Cancer Institute Common Terminology Criteria...
Source: The Journal of Clinical Pharmacology - September 23, 2020 Category: Drugs & Pharmacology Authors: Ruiz-Garcia A, Shaik N, Lin S, Jamieson C, Heuser M, Chan G Tags: J Clin Pharmacol Source Type: research

Therapeutic Protein Drug Interaction Potential in Subjects With Psoriasis: An Assessment Based on Population Pharmacokinetic Analyses of Sensitive Cytochrome P450 Probe Substrates.
Abstract Elevated cytokine levels in inflammatory diseases are associated with downregulation of certain cytochrome P450 (CYP) enzymes. Upon treatment with some cytokine-targeting therapeutic proteins, the CYP enzymes levels may be restored resulting in therapeutic protein-mediated drug interactions (TP-DI). These analyses characterized the worst-case scenario for CYP1A2, 2C9, and 3A-based TP-DI potential in patients with psoriasis by comparing the pharmacokinetics of probe substrates between healthy volunteers and subjects with moderate to severe psoriasis. Data for the CYP probe substrates midazolam (CYP3A), caf...
Source: The Journal of Clinical Pharmacology - September 21, 2020 Category: Drugs & Pharmacology Authors: Sathe AG, Othman AA, Mohamed MF Tags: J Clin Pharmacol Source Type: research

Pilot Study of Peak Plasma Concentration After High-Dose Oral Montelukast in Children With Acute Asthma Exacerbations.
Abstract Acute asthma exacerbations are primarily due to airway inflammation and remain one of the most frequent reasons for childhood hospitalizations. Although systemic corticosteroids remain the mainstay of therapy because of their anti-inflammatory properties, not all inflammatory pathways are responsive to systemic corticosteroids, necessitating hospital admission for further management. Cysteinyl leukotrienes (LTs) are proinflammatory mediators that play an important role in systemic corticosteroids non-responsiveness. Montelukast is a potent LT-receptor antagonist, and an intravenous preparation caused rapi...
Source: The Journal of Clinical Pharmacology - September 21, 2020 Category: Drugs & Pharmacology Authors: Arnold DH, Van Driest SL, Reiss TF, King JC, Akers WS Tags: J Clin Pharmacol Source Type: research

Effect of Pregnancy and Concomitant Antiretrovirals on the Pharmacokinetics of Tenofovir in Women With HIV Receiving Temofovir Disoproxil Fumarate-Based Antiretroviral Therapy Versus Women With HBV Receiving Temofovir Disoproxil Fumarate Monotherapy.
Abstract Tenofovir disoproxil fumarate (TDF) is recommended as part of antiretroviral therapy (ART) for pregnant women with HIV and as monotherapy for pregnant women with hepatitis B virus (HBV) monoinfection at high risk of transmitting infection to their infants. Tenofovir (TFV) plasma exposures are reduced during pregnancy; however, concomitant antiretrovirals and the viral infection itself can also influence TFV pharmacokinetics. Our aim was to compare TFV pharmacokinetics in pregnant women receiving TDF-based ART, with or without a ritonavir-boosted protease inhibitor (r/PI), to pregnant women with HBV receiv...
Source: The Journal of Clinical Pharmacology - September 21, 2020 Category: Drugs & Pharmacology Authors: Bukkems VE, Smolders EJ, Jourdain G, Burger DM, Colbers AP, Cressey TR, PANNA Network and iTAP Study Group Tags: J Clin Pharmacol Source Type: research

Population Pharmacokinetics of Phenobarbital in Neonates and Infants on Extracorporeal Membrane Oxygenation and the Influence of Concomitant Renal Replacement Therapy.
The objective of this study was to describe the pharmacokinetics (PK) of intravenous phenobarbital in neonates and infants on extracorporeal membrane oxygenation (ECMO) and to provide dosing recommendations in this population. We performed a retrospective single-center PK study of phenobarbital in neonates and infants on ECMO between January 1, 2014, and December 31, 2018. We developed a population PK model using nonlinear mixed-effects modeling, performed simulations using the final PK parameters, and determined optimal dosing based on attainment of peak and trough concentrations between 20 and 40 mg/L. We included 3...
Source: The Journal of Clinical Pharmacology - September 21, 2020 Category: Drugs & Pharmacology Authors: Thibault C, Massey SL, Abend NS, Naim MY, Zoraian A, Zuppa AF Tags: J Clin Pharmacol Source Type: research

Modeling the Efficacy of Natalizumab in Multiple Sclerosis Patients Who Switch From Every-4-Week Dosing to Extended-Interval Dosing.
Abstract Natalizumab is approved for multiple sclerosis treatment at a dose of 300 mg every 4 weeks. Extended-interval dosing of natalizumab has been proposed as a strategy to mitigate the risk of progressive multifocal leukoencephalopathy, but the efficacy of extended-interval dosing is not established. Previous models suggesting lower efficacy when initiating natalizumab treatment with extended-interval dosing rather than every-4-week dosing are inconsistent with reports from clinical observations and real-world studies conducted in patient populations switching to extended-interval dosing after a period of rece...
Source: The Journal of Clinical Pharmacology - September 18, 2020 Category: Drugs & Pharmacology Authors: Chang I, Muralidharan KK, Campbell N, Ho PR Tags: J Clin Pharmacol Source Type: research

Population Pharmacokinetic Analysis for Plasma and Epithelial Lining Fluid Ceftolozane/Tazobactam Concentrations in Patients With Ventilated Nosocomial Pneumonia.
Abstract Ceftolozane/tazobactam (C/T) is a combination of a novel cephalosporin with tazobactam, recently approved for the treatment of hospital-acquired and ventilator-associated pneumonia. The plasma pharmacokinetics (PK) of a 3-g dose of C/T (2 g ceftolozane and 1 g tazobactam) administered via a 1-hour infusion every 8 hours in adult patients with nosocomial pneumonia (NP) were evaluated in a phase 3 study (ASPECT-NP; NCT02070757). The present work describes the development of population PK models for ceftolozane and tazobactam in plasma and pulmonary epithelial lining fluid (ELF). The concentration-time profi...
Source: The Journal of Clinical Pharmacology - September 17, 2020 Category: Drugs & Pharmacology Authors: Zhang Z, Patel YT, Fiedler-Kelly J, Feng HP, Bruno CJ, Gao W Tags: J Clin Pharmacol Source Type: research

Population Pharmacokinetics and Bayesian Estimation of the Area Under the Concentration-Time Curve for Ganciclovir in Adult Chinese Renal Allograft Recipients After Valganciclovir Administration.
The objective of this study was to establish a population pharmacokinetic model (PPK) of GCV to investigate the PK characteristics of GCV after administration of VGCV in adult Chinese renal allograft recipients. Seventy Chinese renal allograft recipients were given 450 mg (n = 41) or 900 mg (n = 29) VGCV daily. Blood samples were drawn 0-24 hours after 5 days' therapy, and GCV plasma levels were determined. The PPK model was constructed using nonlinear mixed-effects modeling, and the Bayesian estimation of AUC0-24h was constructed for an individual patient based on limited plasma samples. The PK of GCV was best described b...
Source: The Journal of Clinical Pharmacology - September 13, 2020 Category: Drugs & Pharmacology Authors: Chen B, Hu SS, Rui WB, An HM, Zhai XH, Wang XH, Lu JQ, Shao K, Zhou PJ Tags: J Clin Pharmacol Source Type: research

Evaluation of Potential Drug-Drug Interaction Risk of Pexidartinib With Substrates of Cytochrome P450 and P-Glycoprotein.
Abstract Pexidartinib is approved for treatment of adults with symptomatic tenosynovial giant cell tumor. In vitro data showed pexidartinib's potential to inhibit and induce cytochrome P450 (CYP) 3A, inhibit CYP2C9, CYP2C19 and P-glycoprotein (P-gp). Herein, 2 open-label, single-sequence, crossover studies evaluated the drug-drug interaction potential of pexidartinib on CYP enzymes (CYP2C9, CYP2C19, and CYP3A) and P-gp. Thirty-two subjects received single oral doses of midazolam (CYP3A substrate) and tolbutamide (CYP2C9 substrate) alone and after single and multiple oral doses of pexidartinib. Twenty subjects rece...
Source: The Journal of Clinical Pharmacology - September 11, 2020 Category: Drugs & Pharmacology Authors: Zahir H, Kobayashi F, Zamora C, Gajee R, Gordon MS, Babiker HM, Wang Q, Greenberg J, Wagner AJ Tags: J Clin Pharmacol Source Type: research

Increased Induction Infliximab Clearance Predicts Early Antidrug Antibody Detection.
Abstract Treatment of patients with biologics such as infliximab may trigger development of antidrug antibodies, which are associated with faster drug clearance, reduced treatment efficacy, and increased risk of infusion-related reactions. The aim of this study was to identify predictors of baseline infliximab clearance and early antidrug antibody formation. Pharmacokinetic and pharmacokinetic/pharmacodynamic models for infliximab were developed using 21 178 observations from 859 patients from the PLANETRA (ClinicalTrials.gov identifier: NCT01217086) and PLANETAS (NCT01220518) studies in rheumatoid arthritis ...
Source: The Journal of Clinical Pharmacology - September 8, 2020 Category: Drugs & Pharmacology Authors: Eser A, Reinisch W, Schreiber S, Ahmad T, Boulos S, Mould DR Tags: J Clin Pharmacol Source Type: research

Development and Verification of a Body Weight-Directed Disease Trial Model for Glucose Homeostasis.
Abstract Weight loss has been associated with improvement in insulin sensitivity. It is consequently a cornerstone in the management of type 2 diabetes mellitus (T2DM). However, the strictly quantitative relationship between weight loss, insulin sensitivity, and clinically relevant glucose homeostasis biomarkers as well as changes therein as T2DM progresses is not yet fully understood. Therefore, the objective of our research was to establish a body weight-directed disease trial model for glucose homeostasis. To that end, we conducted a model-based meta-analysis using time course data of body weight loss (followin...
Source: The Journal of Clinical Pharmacology - September 6, 2020 Category: Drugs & Pharmacology Authors: Farhan N, Gebert I, Xing Y, Wieser K, Lingineni K, Ma X, Chien JY, Garhyan P, Schmidt S Tags: J Clin Pharmacol Source Type: research

Empiric therapeutic anticoagulation and mortality in critically ill patients with respiratory failure from SARS-CoV-2: A retrospective cohort study.
This article is protected by copyright. All rights reserved. PMID: 32885463 [PubMed - as supplied by publisher] (Source: The Journal of Clinical Pharmacology)
Source: The Journal of Clinical Pharmacology - September 2, 2020 Category: Drugs & Pharmacology Authors: Ferguson J, Volk S, Vondracek T, Flanigan J, Chernaik A Tags: J Clin Pharmacol Source Type: research

Does "Birth" as an Event Impact Maturation Trajectory of Renal Clearance via Glomerular Filtration? Reexamining Data in Preterm and Full-Term Neonates by Avoiding the Creatinine Bias.
Does "Birth" as an Event Impact Maturation Trajectory of Renal Clearance via Glomerular Filtration? Reexamining Data in Preterm and Full-Term Neonates by Avoiding the Creatinine Bias. J Clin Pharmacol. 2020 Sep 03;: Authors: Salem F, Johnson TN, Hodgkinson ABJ, Ogungbenro K, Rostami-Hodjegan A Abstract Glomerular filtration rate (GFR) is an important measure of renal function. Various models for its maturation have recently been compared; however, these have used markers, which are subject to different renal elimination processes. Inulin clearance data (a purer probe of GFR) collected from t...
Source: The Journal of Clinical Pharmacology - September 2, 2020 Category: Drugs & Pharmacology Authors: Salem F, Johnson TN, Hodgkinson ABJ, Ogungbenro K, Rostami-Hodjegan A Tags: J Clin Pharmacol Source Type: research

CD33-Targeted Therapies: Beating the Disease or Beaten to Death?
Abstract CD33 is a transmembrane protein that is found on cells of myeloid lineage. It is also intensely expressed on acute myeloid leukemia (AML) progenitor cells but not on normal stem cells. It internalizes on binding and dimerization, making it a specific and ideal target for AML therapeutics and drug delivery. Several targeted therapies have been tested and many are still currently in development. Gemtuzumab ozogamicin was the first and only CD33-directed antibody-drug conjugate to be US Food and Drug Administration approved for AML. Other targeted agents have not achieved such success. Promising new strategi...
Source: The Journal of Clinical Pharmacology - August 31, 2020 Category: Drugs & Pharmacology Authors: Maakaron JE, Rogosheske J, Long M, Bachanova V, Mims AS Tags: J Clin Pharmacol Source Type: research

An In Vitro and In Vivo Evaluation of the Effect of Relacorilant on the Activity of Cytochrome P450 Drug Metabolizing Enzymes.
Abstract Relacorilant is a selective modulator of the glucocorticoid receptor in development for the treatment of several serious diseases. The widely used cocktail method was employed to assess relacorilant's effect on various cytochrome P450 (CYP) drug metabolizing enzymes in vitro and in vivo. Inhibition of CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2B6, CYP2C8, CYP3A4, and CYP3A5 as well as induction of CYP1A2, CYP2B6, and CYP3A4 were assessed in vitro (relacorilant concentrations up to 10 µM). A clinical study in healthy subjects (n = 27) evaluated the inhibition of CYP3A4, CYP2C8, and CYP2C9 in vivo by a...
Source: The Journal of Clinical Pharmacology - August 30, 2020 Category: Drugs & Pharmacology Authors: Custodio JM, Donaldson KM, Hunt HJ Tags: J Clin Pharmacol Source Type: research

Slow Accumulation and Elimination of Diazepam and Its Active Metabolite With Extended Treatment in the Elderly.
Abstract Age-related changes in disposition of diazepam and its principal active metabolite, desmethyldiazepam (DMDZ), during and after extended dosage with diazepam were studied in healthy volunteers. Eight elderly subjects (ages 61-78 years) and 7 young subjects (21-33 years) received 2.5 mg of diazepam twice daily for 15 days. Predose (trough) concentrations of diazepam and DMDZ were measured during the 15 days of dosing, and in the postdosage washout period. Kinetic properties were determined by nonlinear regression using a sequential drug-to-metabolite pharmacokinetic model. Steady-state plasma concentrations...
Source: The Journal of Clinical Pharmacology - August 26, 2020 Category: Drugs & Pharmacology Authors: Greenblatt DJ, Harmatz JS, Zhang Q, Chen Y, Shader RI Tags: J Clin Pharmacol Source Type: research

Evaluation and Development of Vancomycin Dosing Schemes to Meet New AUC/MIC Targets in Intermittent Hemodialysis Using Monte Carlo Simulation Techniques.
Abstract Published vancomycin dosing recommendations for patients receiving maintenance hemodialysis were not designed to meet newly recommended 24-hour area under the curve/minimum inhibitory concentration (AUC24h /MIC) pharmacokinetic/pharmacodynamic targets. The aims of this study were to predict pharmacokinetic/pharmacodynamic target attainment rates with a commonly used vancomycin regimen and to design a new dosing scheme incorporating therapeutic drug monitoring (TDM) to maximize target attainment in patients receiving vancomycin and hemodialysis with high- or low-flux hemodialyzers. Vancomycin pharmacokinet...
Source: The Journal of Clinical Pharmacology - August 25, 2020 Category: Drugs & Pharmacology Authors: Lewis SJ, Mueller BA Tags: J Clin Pharmacol Source Type: research

Neonatal and Childhood Outcomes in Offspring of Pregnant Women Using Antidepressant Medications: A Critical Review of Current Meta-Analyses.
This article reviewed the results of 21 recent meta-analyses examining the relationship between maternal use of antidepressants during pregnancy and negative outcomes in newborns and children. PubMed was searched for meta-analyses published in English between January 1, 2011, and November 30, 2019, by using combinations of the keywords pregnancy, antidepressants, review, meta-analysis, selective serotonin reuptake inhibitors, selective serotonin-norepinephrine reuptake inhibitors, tricyclic antidepressants, neonatal outcomes, autism spectrum disorders, attention deficit hyperactivity disorder (ADHD), preterm birth, low bir...
Source: The Journal of Clinical Pharmacology - August 23, 2020 Category: Drugs & Pharmacology Authors: Uguz F Tags: J Clin Pharmacol Source Type: research

SGLT2 Inhibitors and Bladder Cancer: Analysis of Cases Reported in the European Pharmacovigilance Database.
The objective of this study was to analyze whether a disproportionate number of cases of bladder cancer are reported for SGLT2is in EudraVigilance. A case/noncase study was conducted to assess the association between bladder cancer and SGLT2is, calculating reporting odds ratios (RORs) from November 11, 2012 (approval date for the first SGLT2i, dapagliflozin) to May 19, 2020. First, cases involving SGLT2is were compared with those involving all other drugs; and similar analysis was performed for each SGLT2i. Second, to reduce the risk of confounding by indication, the RORs for SGLT2is compared with other antidiabetics were ...
Source: The Journal of Clinical Pharmacology - August 20, 2020 Category: Drugs & Pharmacology Authors: García M, Arteche-Martinez U, Lertxundi U, Aguirre C Tags: J Clin Pharmacol Source Type: research

Population Pharmacokinetic Analysis of Dalteparin in Pediatric Patients With Venous Thromboembolism.
This article describes the population pharmacokinetics (PK) of dalteparin in pediatric patients with venous thromboembolism (VTE). A prospective multicenter open-label study was conducted in children who required anticoagulation for the treatment of VTE. The study population included children with and without cancer. The goal was to describe the pharmacokinetics of dalteparin using anti-Xa as a surrogate marker and to determine the dose required to achieve therapeutic anti-Xa levels (0.5-1.0 IU/mL). The anti-Xa data were supplemented with 2 published studies and analyzed using population pharmacokinetic approaches. The pha...
Source: The Journal of Clinical Pharmacology - August 20, 2020 Category: Drugs & Pharmacology Authors: Damle B, Jen F, Sherman N, Jani D, Sweeney K Tags: J Clin Pharmacol Source Type: research

Justification for a Fixed Dose of Eflapegrastim, a Long-Acting G-CSF, in Patients Receiving Docetaxel-Cyclophosphamide Chemotherapy.
Abstract Eflapegrastim (Rolontis) is a long-acting granulocyte colony-stimulating factor (G-CSF) produced by conjugating a human G-CSF analogue and a human immunoglobulin G4 Fc fragment, linked via a polyethylene glycol linker. Weight-based doses of 45 to 270 μg/kg eflapegrastim (12.3-73.6 μg/kg as G-CSF) were evaluated in a phase 2 study in patients. Based on these results, a fixed dose of 13.2 mg eflapegrastim (3.6 mg G-CSF) was compared with pegfilgrastim (6 mg G-CSF) in 2 phase 3 studies and in a pharmacokinetic single-arm multicenter study. Absolute neutrophil count (ANC) data from t...
Source: The Journal of Clinical Pharmacology - August 20, 2020 Category: Drugs & Pharmacology Authors: Barrett JA, Greene D, Lakshmikanthan S, Kolli P, Chawla S, Lebel F Tags: J Clin Pharmacol Source Type: research

An Adaptive Physiologically Based Pharmacokinetic-Driven Design to Investigate the Effect of Itraconazole and Rifampicin on the Pharmacokinetics of Molibresib (GSK525762) in Healthy Female Volunteers.
Abstract Molibresib (GSK525762), an orally bioavailable small molecule with 2 major equipotent active metabolites, is being developed for the treatment of cancers. Molibresib is a substrate of cytochrome P450 (CYP) 3A4 and P-glycoprotein (P-gp). To enable administering safe doses of molibresib to healthy volunteers, this 2-part randomized, open-label, crossover drug-drug interaction trial was conducted as an adaptive design study using physiologically based pharmacokinetic (PBPK) modeling and simulation to predict the lowest doses of molibresib that could be safely administered alone (10 mg) or with itraconaz...
Source: The Journal of Clinical Pharmacology - August 19, 2020 Category: Drugs & Pharmacology Authors: Riddell K, Patel A, Collins G, Zhou Y, Schramek D, Kremer BE, Ferron-Brady G Tags: J Clin Pharmacol Source Type: research

Pharmacokinetic Enhancement of HIV Antiretroviral Therapy During Pregnancy.
The objectives of this article are to review pharmacokinetic enhancement of ARVs with ritonavir and cobicistat during pregnancy and postpartum, describe clinical implications, and provide recommendations for future research. PMID: 32798276 [PubMed - as supplied by publisher] (Source: The Journal of Clinical Pharmacology)
Source: The Journal of Clinical Pharmacology - August 13, 2020 Category: Drugs & Pharmacology Authors: Salama E, Eke AC, Best BM, Mirochnick M, Momper JD Tags: J Clin Pharmacol Source Type: research

Nonrelevant Pharmacokinetic Drug-Drug Interaction Between Furosemide and Pindolol Enantiomers in Hypertensive Parturient Women.
te VL PMID: 32789919 [PubMed - as supplied by publisher] (Source: The Journal of Clinical Pharmacology)
Source: The Journal of Clinical Pharmacology - August 11, 2020 Category: Drugs & Pharmacology Authors: Gonçalves PVB, Moreira FL, Benzi JRL, Cavalli RC, Duarte G, Lanchote VL Tags: J Clin Pharmacol Source Type: research

Immunomodulatory Therapeutic Proteins in COVID-19: Current Clinical Development and Clinical Pharmacology Considerations.
This article is protected by copyright. All rights reserved. PMID: 32779201 [PubMed - as supplied by publisher] (Source: The Journal of Clinical Pharmacology)
Source: The Journal of Clinical Pharmacology - August 9, 2020 Category: Drugs & Pharmacology Authors: Ji P, Chen J, Golding A, Nikolov NP, Saluja B, Ren YR, Sahajwalla C Tags: J Clin Pharmacol Source Type: research

Enhancing Pediatric Adverse Drug Reaction Documentation in the Electronic Medical Record.
Abstract Adverse drug reactions (ADRs) often go unreported or are inaccurately documented in the electronic medical recorded (EMR), even when they are severe and life-threatening. Incomplete reporting can lead to future prescribing challenges and ADR reoccurrence. The aim of this study was to evaluate the documentation of ADRs within the EMR and determine specific factors associated with appropriate and timely ADR documentation. Retrospective data were collected from a pediatric hospital system ADR reports from October 2010 to November 2018. Data included implicated medication, type, and severity of reaction, trea...
Source: The Journal of Clinical Pharmacology - August 8, 2020 Category: Drugs & Pharmacology Authors: Tillman EM, Suppes SL, Feldman K, Goldman JL Tags: J Clin Pharmacol Source Type: research

Optimal Designs for Model-Based Assessment of Insulin Sensitivity and Glucose Effectiveness.
Abstract The integrated minimal model allows assessment of clinical diagnosis indices, for example, insulin sensitivity (SI ) and glucose effectiveness (SG ), from data of the insulin-modified intravenous glucose tolerance test (IVGTT), which is laborious with an intense sampling schedule, up to 32 samples. The aim of this study was to propose a more informative, although less laborious, IVGTT design to be used for model-based assessment of SI and SG . The IVGTT design was optimized simultaneously for all design variables: glucose and insulin infusion doses, time of glucose dose and start of insulin infusion, insu...
Source: The Journal of Clinical Pharmacology - July 28, 2020 Category: Drugs & Pharmacology Authors: Ibrahim MMA, Redestad E, Kjellsson MC Tags: J Clin Pharmacol Source Type: research