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 29, 2020 Category: Drugs & Pharmacology Authors: Ibrahim MMA, Redestad E, Kjellsson MC Tags: J Clin Pharmacol Source Type: research

Pharmacokinetics and Pharmacodynamics of Subcutaneous Sarilumab and Intravenous Tocilizumab Following Single-Dose Administration in Patients With Active Rheumatoid Arthritis on Stable Methotrexate.
In conclusion, despite differences in PK, the onset of the decrease in CRP (efficacy) and ANC (safety) after a single dose were similar for subcutaneous sarilumab and intravenous tocilizumab. PD effects and safety were consistent with previous studies. PMID: 32726514 [PubMed - as supplied by publisher] (Source: The Journal of Clinical Pharmacology)
Source: The Journal of Clinical Pharmacology - July 29, 2020 Category: Drugs & Pharmacology Authors: Paccaly AJ, Kovalenko P, Parrino J, Boyapati A, Xu C, van Hoogstraten H, Ishii T, Davis JD, DiCioccio AT Tags: J Clin Pharmacol Source Type: research

Population Pharmacokinetics and Exposure-Response Relationship of Luspatercept, an Erythroid Maturation Agent, in Anemic Patients With β-Thalassemia.
Population Pharmacokinetics and Exposure-Response Relationship of Luspatercept, an Erythroid Maturation Agent, in Anemic Patients With β-Thalassemia. J Clin Pharmacol. 2020 Jul 21;: Authors: Chen N, Kassir N, Laadem A, Giuseppi AC, Shetty J, Maxwell SE, Sriraman P, Ritland S, Linde PG, Budda B, Reynolds JG, Zhou S, Palmisano M Abstract β-Thalassemia is an inherited blood disorder resulting from defects in hemoglobin production, leading to premature death of red blood cells (RBCs) or their precursors. Patients with transfusion-dependent β-thalassemia often need lifelong regular RBC trans...
Source: The Journal of Clinical Pharmacology - July 21, 2020 Category: Drugs & Pharmacology Authors: Chen N, Kassir N, Laadem A, Giuseppi AC, Shetty J, Maxwell SE, Sriraman P, Ritland S, Linde PG, Budda B, Reynolds JG, Zhou S, Palmisano M Tags: J Clin Pharmacol Source Type: research

Discordance Between Child-Pugh and National Cancer Institute Classifications for Hepatic Dysfunction: Implications on Dosing Recommendations for Oncology Compounds.
Abstract Guidance from the U.S. Food and Drug Administration (FDA) and the European Medicines Agency recommends using Child-Pugh classification for pharmacokinetic evaluation in noncancer subjects with hepatic impairment (HI). Therefore, dosing recommendations for oncology compounds for patients with HI are commonly based on Child-Pugh classification. In oncology clinical practice, National Cancer Institute classification (NCIc), is commonly used for evaluating hepatic function and dosing decisions for oncology patients. This work evaluated the discordance between the 2 systems and the impact on dosing recommendat...
Source: The Journal of Clinical Pharmacology - July 20, 2020 Category: Drugs & Pharmacology Authors: Elmeliegy M, Yang DZ, Salama E, Parivar K, Wang DD Tags: J Clin Pharmacol Source Type: research

Computer Algorithm-Based Hydroxyurea Dosing Facilitates Titration to Maximum Tolerated Dose in Sickle Cell Anemia.
Abstract Adults with sickle cell disease (SCD) experience acute and chronic complications and die prematurely. When taken at maximum tolerated dose (MTD), hydroxyurea prolongs survival; however, it has not consistently reversed organ dysfunction. Patients also frequently do not take hydroxyurea, at least in part because of physician discomfort with prescribing hydroxyurea. We sought to develop a computer program that could easily titrate hydroxyurea to MTD. This was a single-arm, open-label pilot study. Fifteen patients with homozygous SCD were enrolled in the protocol, and 10 patients were followed at baseline an...
Source: The Journal of Clinical Pharmacology - July 16, 2020 Category: Drugs & Pharmacology Authors: Oldham M, Conrey A, Pittman C, Fisher C, Hargrett S, West K, Jackson M, Martin S, Hsieh MM, Jeffries N, Kaplarevic M, Johnson D, Olkhanud P, Fitzhugh CD Tags: J Clin Pharmacol Source Type: research

Correction.
Authors: PMID: 32671838 [PubMed - as supplied by publisher] (Source: The Journal of Clinical Pharmacology)
Source: The Journal of Clinical Pharmacology - July 15, 2020 Category: Drugs & Pharmacology Tags: J Clin Pharmacol Source Type: research

Population Pharmacokinetics and Exposure-Response Analyses for the Most Frequent Adverse Events Following Treatment With Lemborexant, an Orexin Receptor Antagonist, in Subjects With Insomnia Disorder.
This article describes the population pharmacokinetics (PK) of lemborexant and the relationship of its daily steady-state exposure (Cav,ss ) to the probability of most frequent treatment-emergent adverse events (TEAEs). The 12 230-observation, 1892-subject PK data set included data from 12 clinical studies with predominantly female subjects (66%) ranging in age from 18 to 88 years and from 37 to 168 kg in body weight. The 1664-subject exposure-response data set included data from 3 late-stage studies. Lemborexant pharmacokinetics were described by a 3-compartment model with combined first- and zero-order absorption wi...
Source: The Journal of Clinical Pharmacology - July 14, 2020 Category: Drugs & Pharmacology Authors: Lalovic B, Majid O, Aluri J, Landry I, Moline M, Hussein Z Tags: J Clin Pharmacol Source Type: research

Overview on the Amendments of Provisions for Drug Registration in China.
This article describes the history of the drug registration management system in China, explains the background of the revision of the Provisions for Drug Registration in 2020, and introduces the main modifications of the Provisions for Drug Registration in 2020 in the aspects of registration classification, application for clinical trial on drug, application for drug marketing authorization, accelerated procedure for drug registration, working timeline, and supervision and administration. This article is intended to give a brief overview for those who wish to submit a drug registration application in China or for those wh...
Source: The Journal of Clinical Pharmacology - July 12, 2020 Category: Drugs & Pharmacology Authors: Dai W, Zhong M, Lin W, Su L Tags: J Clin Pharmacol Source Type: research

Model-Based Determination of Elotuzumab Pharmacokinetics in Japanese Patients With Multiple Myeloma Incorporating Time-Varying M Protein.
In conclusion, the current analysis demonstrates that Japanese ethnicity, prior line of therapy, time-varying M protein, and change in elotuzumab dosing regimen in cycle 19 have no clinically meaningful impact on elotuzumab pharmacokinetics and exposure in Japanese patients with multiple myeloma. PMID: 32656777 [PubMed - as supplied by publisher] (Source: The Journal of Clinical Pharmacology)
Source: The Journal of Clinical Pharmacology - July 12, 2020 Category: Drugs & Pharmacology Authors: Ide T, Roy A, Imai Y, Vezina HE Tags: J Clin Pharmacol Source Type: research

Estimation of Attainment of Steady-State Conditions for Compounds With a Long Half-Life.
Abstract Half-life is a standard result reported with analysis of pharmacokinetic data. Different definitions such as noncompartmental half-life, terminal half-life, effective half-life, and context-sensitive half-life can yield substantially different estimates of the quantity "half-life." Time to attainment of steady-state conditions is generally derived from (terminal) half-life and therefore sensitive toward the definition of half-life. Thus, estimates of the time to attain steady state must be provided with a precise definition of steady state and the method used for estimation, particularly for dru...
Source: The Journal of Clinical Pharmacology - July 12, 2020 Category: Drugs & Pharmacology Authors: Krause A, Lott D, Dingemanse J Tags: J Clin Pharmacol Source Type: research

A Phase 2, Double-Blind, Placebo-Controlled Trial to Investigate Potential Drug-Drug Interactions Between Cannabidiol and Clobazam.
Abstract We investigated the effects of cannabidiol (CBD; 21-day maintenance dose) on the pharmacokinetics (PK) of clobazam (CLB) and monitored the safety of CBD (or placebo) plus CLB in 20 patients with uncontrolled epilepsy on stable doses of CLB. Blood samples collected until 24 hours postdose were evaluated by liquid chromatography tandem mass spectrometry. PK parameters of CLB and major metabolite N-desmethylclobazam (N-CLB), valproic acid, stiripentol, levetiracetam, topiramate, plant-derived highly purified CBD (Epidiolex in the United States; 100 mg/mL oral solution) and its major metabolites were der...
Source: The Journal of Clinical Pharmacology - July 11, 2020 Category: Drugs & Pharmacology Authors: VanLandingham KE, Crockett J, Taylor L, Morrison G Tags: J Clin Pharmacol Source Type: research

A Survey on Knowledge Gaps in Assessment and Management of Severe Drug Hypersensitivity Reactions: Multicenter Cross-Sectional Study of Australian Health Care Providers.
Abstract Severe drug hypersensitivity reactions (DHRs) are often encountered by health care professionals (HCPs). We evaluated knowledge of doctors and pharmacists in the assessment and management of severe DHRs using a structured questionnaire. A cross-sectional study was conducted in 4 metropolitan hospital networks in Melbourne, Australia. A 13-question, scenario-based multiple-choice questionnaire to assess specific knowledge domains in drug hypersensitivity syndrome recognition, causality attribution, cross-reactivity patterns, appropriate diagnostic tests, and therapy was administered to HCPs of various voca...
Source: The Journal of Clinical Pharmacology - July 10, 2020 Category: Drugs & Pharmacology Authors: Mazzoni D, Tee HW, de Menezes SL, Graudins LV, Johnson DF, Newnham ED, Kelley PG, Zubrinich CM, Goh MSY, Trubiano JA, Aung AK Tags: J Clin Pharmacol Source Type: research

Direct Oral to Parenteral Anticoagulants: Strategies for Inpatient Transition.
Abstract The primary objective of this study was to describe the impact on bleeding rates of 2 different strategies for transitioning from a direct oral anticoagulant (DOAC) to a parenteral anticoagulant: a delayed, clinically driven strategy versus the standard per-package-insert strategy. This was a single-center descriptive cohort study conducted at a large academic medical center. Included patients were 18 years or older, admitted as an inpatient, and had received at least 1 dose of a DOAC prior to initiation of therapeutic parenteral anticoagulation. The primary end point was the incidence of major bleeds on ...
Source: The Journal of Clinical Pharmacology - July 8, 2020 Category: Drugs & Pharmacology Authors: Lopez CN, Succar L, Varnado S, Donahue KR Tags: J Clin Pharmacol Source Type: research

Comparison of the Effects of Low-Molecular-Weight Heparin and Fondaparinux on Liver Function in Patients With Pulmonary Embolism.
This study assessed the effects of LMWH and fondaparinux on liver function in patients with pulmonary embolism based on a retrospective cohort. As a result, a total of 463 patients with pulmonary embolism and treated with LMWH (enoxaparin sodium or nadroparin calcium) or fondaparinux sodium were included. Liver dysfunction was identified in 79 patients (17.1%), of whom 97.5% had grade 1 drug-induced liver injury (DILI) and 2.5% had grade 2 DILI. The results showed that liver dysfunction usually occurred in the first week after anticoagulant administration, and the liver tests of all patients with liver dysfunction graduall...
Source: The Journal of Clinical Pharmacology - July 8, 2020 Category: Drugs & Pharmacology Authors: Yang X, Li N, Guo T, Guan X, Tan J, Gao X, Wu Y, Jia L, Gu M, Hua L, Liu H Tags: J Clin Pharmacol Source Type: research

Pharmacokinetics of the Monoclonal Antibody MHAA4549A Administered in Combination With Oseltamivir in Patients Hospitalized With Severe Influenza A Infection.
We report MHAA4549A serum, nasopharyngeal, and tracheal aspirate pharmacokinetics from a phase 2b study in hospitalized patients with severe influenza A. Patients were randomized 1:1:1 into 3 groups receiving single intravenous doses of 3600 mg (n = 55) or 8400 mg (n = 47) MHAA4549A or placebo (n = 56). Patients also received oral oseltamivir twice daily for ≥5 days. Serum, nasopharyngeal, and tracheal aspirate pharmacokinetic samples were collected on days 1-60 from MHAA4549A-treated groups. Day 5 plasma samples from all groups were collected for assessing the pharmacokinetics of oseltamivir and its active metabolite, ...
Source: The Journal of Clinical Pharmacology - July 4, 2020 Category: Drugs & Pharmacology Authors: Deng R, She G, Maia M, Lim JJ, Peck MC, McBride JM, Kulkarni P, Horn P, Castro A, Newton E, Tavel JA, Hanley WD Tags: J Clin Pharmacol Source Type: research

Overmedication in COVID-19 context: a report from Peru.
PMID: 32609883 [PubMed - as supplied by publisher] (Source: The Journal of Clinical Pharmacology)
Source: The Journal of Clinical Pharmacology - July 1, 2020 Category: Drugs & Pharmacology Authors: Martinez-Rivera RN, Taype-Rondan A Tags: J Clin Pharmacol Source Type: research

Oral Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitor Roxadustat (FG-4592) for Treatment of Anemia in Chronic Kidney Disease: A Placebo-Controlled Study of Pharmacokinetic and Pharmacodynamic Profiles in Hemodialysis Patients.
Abstract Roxadustat (FG-4592), an oral hypoxia-inducible factor prolyl hydroxylase inhibitor that stimulates erythropoiesis, was evaluated in a phase 1b study in patients with end-stage renal disease with anemia on hemodialysis. Seventeen patients, on epoetin-alfa maintenance therapy with stable hemoglobin levels ≥10 g/dL, had epoetin-alfa discontinued on day 3 and were enrolled in this double-blind placebo-controlled study. Two cohorts were randomized 3:1 (roxadustat: placebo). Patients received single doses of roxadustat (1 or 2 mg/kg) or placebo 1 hour after hemodialysis on day 1 and 2 hours before...
Source: The Journal of Clinical Pharmacology - June 30, 2020 Category: Drugs & Pharmacology Authors: Provenzano R, Tumlin J, Zabaneh R, Chou J, Hemmerich S, Neff TB, Yu KP Tags: J Clin Pharmacol Source Type: research

Clinical Experiences of Intravenous Hydralazine and Labetalol for Acute Treatment of Severe Hypertension in Pregnant Thai Women.
Abstract Response to acute treatment of severe hypertension during pregnancy in Asian women was not known. Labor and delivery checklists of Thai women treated with intravenous hydralazine or labetalol for systolic blood pressure (SBP) ≥ 160 or diastolic blood pressure (DBP) ≥ 110 mm Hg from January 2011 to December 2013 were reviewed as parts of an audit. Primary outcome was prompt achievement of SBP 140-150 and DBP 90-100 mm Hg after the first bolus. Secondary outcomes were medication-related undesired effects. The mean ± standard deviation age and prevalence of chronic hypertension in hydr...
Source: The Journal of Clinical Pharmacology - June 29, 2020 Category: Drugs & Pharmacology Authors: Chera-Aree P, Tengtrakulcharoen P, Leetheeragul J, Sampaojarean U, Surasereewong S, Wataganara T Tags: J Clin Pharmacol Source Type: research

Population Pharmacokinetic Analysis of Quizartinib in Healthy Volunteers and Patients With Relapsed/Refractory Acute Myeloid Leukemia.
n O Abstract Quizartinib is an FMS-like tyrosine kinase 3 (FLT3) inhibitor that has shown robust clinical activity in patients with FLT3-internal tandem duplication-mutated relapsed/refractory acute myeloid leukemia (AML). This analysis evaluated the population pharmacokinetics (PK) of quizartinib and its active metabolite, AC886, in a pooled analysis of data from 649 healthy volunteers or patients with AML from 8 clinical trials including the phase 3 QuANTUM-R study. Quizartinib was given as a single dose or multiple once-daily doses of 20, 30, 60, or 90 mg. Nonlinear mixed-effects modeling was performed using ob...
Source: The Journal of Clinical Pharmacology - June 29, 2020 Category: Drugs & Pharmacology Authors: Kang D, Ludwig E, Jaworowicz D, Huang H, Fiedler-Kelly J, Cortes J, Ganguly S, Khaled S, Krämer A, Levis M, Martinelli G, Perl A, Russell N, Abutarif M, Choi Y, Mendell J, Yin O Tags: J Clin Pharmacol Source Type: research

Population Pharmacokinetics of Brentuximab Vedotin in Adult and Pediatric Patients With Relapsed/Refractory Hematologic Malignancies: Model-Informed Hypothesis Generation for Pediatric Dosing Regimens.
Abstract Prior pharmacokinetic (PK) analyses of the antibody-drug conjugate (ADC) brentuximab vedotin (1.8 mg/kg every 3 weeks) in pediatric patients with relapsed/refractory hematologic malignancies found that patients aged
Source: The Journal of Clinical Pharmacology - June 28, 2020 Category: Drugs & Pharmacology Authors: Suri A, Mould DR, Song G, Kinley J, Venkatakrishnan K Tags: J Clin Pharmacol Source Type: research

Application of Physiologically Based Pharmacokinetic Modeling to Predict Drug Exposure and Support Dosing Recommendations for Potential Drug-Drug Interactions or in Special Populations: An Example Using Tofacitinib.
This study aimed to predict the impact of drug-drug interactions and renal or hepatic impairment on tofacitinib pharmacokinetics using a physiologically based pharmacokinetic (PBPK) model. The model was developed using Simcyp based on the physicochemical properties and in vitro and in vivo pharmacokinetics data for tofacitinib. The model was verified by comparing the predicted pharmacokinetic profiles with those observed in available clinical studies after single or multiple doses of tofacitinib, as well as with tofacitinib as a victim of drug-drug interactions (because of inhibition of cytochrome P450 [CYP450] 3A4, CYP450...
Source: The Journal of Clinical Pharmacology - June 27, 2020 Category: Drugs & Pharmacology Authors: Tse S, Dowty ME, Menon S, Gupta P, Krishnaswami S Tags: J Clin Pharmacol Source Type: research

Clinical pharmacology considerations for developing small molecule treatments for COVID-19.
This article is protected by copyright. All rights reserved. PMID: 32579707 [PubMed - as supplied by publisher] (Source: The Journal of Clinical Pharmacology)
Source: The Journal of Clinical Pharmacology - June 24, 2020 Category: Drugs & Pharmacology Authors: Brunsdon P, Saluja B, Sahajwalla C Tags: J Clin Pharmacol Source Type: research

Prenatal Exposure to Antibiotics and Development of Epilepsy in Children.
Abstract We aimed to confirm or reject previous reports on the association of prenatal antibiotic exposure and development of epilepsy in offspring by accounting for known and unidentified confounding factors. In a retrospective cohort investigation, we enrolled children aged 3-18 years born between 1998 and 2012 at a single regional hospital and their mothers. A computerized medication database was linked with hospital records. The exposed group included children whose mothers purchased 1 or more antibiotic medications for use during pregnancy. Epilepsy was defined by epilepsy diagnosis and/or by chronic dispensi...
Source: The Journal of Clinical Pharmacology - June 23, 2020 Category: Drugs & Pharmacology Authors: Sassonker-Joseph N, Gorodischer R, Atar-Vardi M, Noyman I, Novack L Tags: J Clin Pharmacol Source Type: research

Model-Aided Adults-to-Children Pharmacokinetic Extrapolation and Empirical Body Size-Based Dosing Exploration for Therapeutic Monoclonal Antibodies-Is Allometry a Reasonable Choice?
Abstract The importance of pharmacokinetic (PK) evaluation in pediatric drug development is well recognized, and a pediatric PK study is generally recommended before pivotal trials to ensure the "right" dose in these studies. The PK of therapeutic monoclonal antibodies (mAbs) is primarily affected by body weight, where adults-to-children extrapolation may conform to allometry. Therefore, PK behavior of mAbs in pediatrics, particularly for those with linear PK, is expected to be predictable based on data in adults. To test this hypothesis, we reviewed published population PK reports of marketed mAbs and a...
Source: The Journal of Clinical Pharmacology - June 23, 2020 Category: Drugs & Pharmacology Authors: Xu Y, Langevin BA, Zhou H, Xu Z Tags: J Clin Pharmacol Source Type: research

The Effect of GS-548351 on the Pharmacokinetics of Midazolam Following Multiple Doses of ANS-6637 in Healthy Adults.
Abstract ANS-6637, a pro-drug of GS-548351, is a selective, reversible inhibitor of aldehyde dehydrogenase isoform 2 under development as an anticraving agent for the treatment of substance use disorders. In vitro testing indicates that GS-548351 is an inhibitor and inducer of cytochrome P450 family 3, subfamily A (CYP3A). In this phase 1 single-center, open-label, fixed-sequence drug-drug interaction study we assessed the impact of steady-state GS-548351 on single-dose pharmacokinetics of midazolam, an index substrate for CYP3A. Twelve healthy volunteers received 600 mg of ANS-6637 by mouth daily from study days ...
Source: The Journal of Clinical Pharmacology - June 23, 2020 Category: Drugs & Pharmacology Authors: Bunn HT, Rosenthal E, Mathur P, McLaughlin M, Proschan M, Vijan A, Aepfelbacher J, Kottilil S, Masur H, Kattakuzhy S, George JM Tags: J Clin Pharmacol Source Type: research

Extrapulmonary Surfactant Therapy: Review of Available Data and Research/Development Issues.
Abstract Since the discovery of surfactant, a large amount of knowledge has been accumulated about its biology and pharmacology. Surfactant is the cornerstone of neonatal respiratory critical care, but its proteins and phospholipids are produced in various tissues and organs, with possible roles only partially similar to that played in the alveoli. As surfactant research is focused mainly on its respiratory applications, knowledge about the possible role of surfactant in extrapulmonary disorders has never been summarized. Here we aim to comprehensively review the data about surfactant biology and pharmacology in o...
Source: The Journal of Clinical Pharmacology - June 23, 2020 Category: Drugs & Pharmacology Authors: Foligno S, Loi B, Pezza L, Piastra M, Autilio C, De Luca D Tags: J Clin Pharmacol Source Type: research

A Pilot Study of the Maternal-Fetal Pharmacokinetics of Furosemide in Plasma, Urine, and Amniotic Fluid of Hypertensive Parturient Women Under Cesarean Section.
This study evaluated the maternal-fetal pharmacokinetics and distribution to amniotic fluid of furosemide in hypertensive parturient women under cesarean section. Twelve hypertensive parturient women under methyldopa (250 mg/8 h) and/or pindolol (10 mg/12 h) treatment received a 40-mg single oral dose of furosemide 1 to 10 hours before delivery by cesarean section. Blood and urine samples were collected for 12 hours after furosemide administration. At delivery, samples were obtained from maternal and umbilical cord blood (n = 8) to assess the transplacental transfer. Amniotic fluid (n = 4) was collected at the time of deli...
Source: The Journal of Clinical Pharmacology - June 20, 2020 Category: Drugs & Pharmacology Authors: Gonçalves PVB, Moreira FL, Benzi JRL, Duarte G, Lanchote VL Tags: J Clin Pharmacol Source Type: research

A Comprehensive Review on Tocilizumab in COVID-19 Acute Respiratory Distress Syndrome.
This article is protected by copyright. All rights reserved. PMID: 32557541 [PubMed - as supplied by publisher] (Source: The Journal of Clinical Pharmacology)
Source: The Journal of Clinical Pharmacology - June 18, 2020 Category: Drugs & Pharmacology Authors: Khiali S, Khani E, Entezari-Maleki T Tags: J Clin Pharmacol Source Type: research

Pharmacokinetics and Pharmacodynamics of Garetosmab (Anti-Activin A): Results From a First-in-Human Phase 1 Study.
We describe outcomes from the first-in-human study of garetosmab (a fully human monoclonal antibody that inhibits activin A) under development for the treatment of fibrodysplasia ossificans progressiva (FOP). In a double-blind, placebo-controlled phase 1 study, 40 healthy women of nonchildbearing potential were randomized to receive a single dose of intravenous garetosmab 0.3, 1, 3, or 10 mg/kg; subcutaneous garetosmab 300 mg; or placebo. Serum concentrations of functional garetosmab (with ≥1 arm free to bind to target), total activin A, and antidrug antibodies were measured predose and up to 113 days post-first dose. G...
Source: The Journal of Clinical Pharmacology - June 18, 2020 Category: Drugs & Pharmacology Authors: Vanhoutte F, Liang S, Ruddy M, Zhao A, Drewery T, Wang Y, DelGizzi R, Forleo-Neto E, Rajadhyaksha M, Herman G, Davis JD Tags: J Clin Pharmacol Source Type: research

Population Pharmacokinetic Modeling of Cyclosporine Among Malaysian Renal Transplant Patients: An Evaluation of Methods to Handle Missing Doses in Conventional Drug-Monitoring Data.
This study aimed to develop a population pharmacokinetic model of cyclosporine in Malaysian renal transplant recipients as well as to evaluate the performances of different methodsfor handling missing doses. A total of 2804 concentrationts predose and 2 hours after doses were collected retrospectively from 113 renal transplant patients on cyclosporine in Penang General Hospital. Model structure and pharmacokinetic parameters were estimated using nonlinear mixed-effects modeling software. Missing doses were handled using different methods to evaluate their performance. Covariate analysis was performed using stepwise forward addition (P
Source: The Journal of Clinical Pharmacology - June 17, 2020 Category: Drugs & Pharmacology Authors: Albitar O, Ballouze R, Harun SN, Mohamed Noor DA, Sheikh Ghadzi SM Tags: J Clin Pharmacol Source Type: research

DosePredict: A Shiny Application for Generalized Pharmacokinetics-Based Dose Predictions.
Abstract In drug development, dose prediction is a routinely conducted quantitative data analysis. It involves combining available relevant preclinical and/or clinical data to conduct modeling and simulation analyses where various dose prediction scenarios are usually considered. As further data emerges during drug development, dose prediction may undergo several rounds of refinement. In this article, I present DosePredict, a Shiny-based graphical user interface software that can be used for the conduct of dose predictions. DosePredict is built based on pharmacokinetic (PK) models, including 1-, 2-, and 3-compartm...
Source: The Journal of Clinical Pharmacology - June 15, 2020 Category: Drugs & Pharmacology Authors: Okour M Tags: J Clin Pharmacol Source Type: research

Dosing Recommendations for Pediatric Patients With Renal Impairment.
The objective of this study was to examine the clinical evidence behind current renal impairment dosage recommendations for pediatric patients in a standard pediatric dosing handbook. The sources of recommendations and comparisons included the pediatric dosing handbook (Lexicomp), the U.S. Food and Drug Administration-approved manufacturer's labels, and published studies in the literature. One hundred twenty-six drugs in Lexicomp had pediatric renal dosing recommendations. Only 14% (18 of 126) of Lexicomp pediatric renal dosing recommendations referenced a pediatric clinical study, and 15% of manufacturer's labels (19 of 1...
Source: The Journal of Clinical Pharmacology - June 15, 2020 Category: Drugs & Pharmacology Authors: Al-Khouja A, Park K, Anderson DJC, Young C, Wang J, Huang SM, Khurana M, Burckart GJ Tags: J Clin Pharmacol Source Type: research

Critical Need for Implementation of Clinical Pharmacology Principles in Developing Drugs for the Treatment or Prevention of COVID-19.
PMID: 32535939 [PubMed - as supplied by publisher] (Source: The Journal of Clinical Pharmacology)
Source: The Journal of Clinical Pharmacology - June 14, 2020 Category: Drugs & Pharmacology Authors: Pastino G Tags: J Clin Pharmacol Source Type: research

A Correlation of a Medication-Focused Risk Score to Medication Errors at Discharge.
This study was split into 2 phases aimed to internally validate the risk score. Phase I of the study compared the predictability of 30-day unplanned readmissions between the UCSD-Rx risk score and a well-validated risk tool, the LACE+ index. To further specify our risk score for pharmacist use, phase II of the study analyzed the predictability of the risk score to medication errors at discharge. Phase I demonstrated similar classification performance of 30-day unplanned readmissions between the UCSD-Rx risk score (C-statistic, 0.66; 95% confidence interval [CI], 0.64-0.68; P
Source: The Journal of Clinical Pharmacology - June 13, 2020 Category: Drugs & Pharmacology Authors: Fung L, Huynh T, Brush T, Medders K, El-Kareh R, Daniels CE Tags: J Clin Pharmacol Source Type: research

Why your Patients' Believing Hydroxychloroquine and Chloroquine are 90% Effective for COVID-19 is 100% Dangerous.
PMID: 32530493 [PubMed - as supplied by publisher] (Source: The Journal of Clinical Pharmacology)
Source: The Journal of Clinical Pharmacology - June 12, 2020 Category: Drugs & Pharmacology Authors: White CM, Hernandez AV Tags: J Clin Pharmacol Source Type: research

Rivaroxaban as an Alternative Agent for Heparin-Induced Thrombocytopenia.
Abstract Heparin-induced thrombocytopenia (HIT) is a high-risk adverse drug reaction because of its associated risk of life- and limb-threatening thrombosis. Rivaroxaban may be considered as an ideal nonheparin anticoagulant alternative for the management of HIT. In this preliminary retrospective study, the efficacy and safety of rivaroxaban to control the clinically suspected HIT (4Ts score 4 points or greater) were evaluated. Patients with chronic kidney disease, hepatic impairment, mechanical heart valves, and active bleeding were excluded. Forty-two eligible patients who received rivaroxaban for clinically sus...
Source: The Journal of Clinical Pharmacology - June 10, 2020 Category: Drugs & Pharmacology Authors: Farasatinasab M, Zarei B, Moghtadaei M, Nasiripour S, Ansarinejad N, Zarei M Tags: J Clin Pharmacol Source Type: research

The Association Between Concurrence of Infection and the Onset of Severe Eruption or Liver Injury in Patients Using Antipyretic Analgesics: A Matched, Nested Case-Control Study.
Abstract Stevens-Johnson syndrome (SJS) and toxic epidermal necrosis (TEN) or drug-induced liver injury (DILI) are severe drug-induced reactions, known as idiosyncratic drug reactions. It is believed that immune response can lead to these severe adverse drug reactions. Our previous analysis of the Japanese Spontaneous Drug Reaction database suggested that the onset of SJS/TEN and DILI was strongly associated with infection. Hence, we conducted a matched, nested case-control study to elucidate the association between concurrent infection and the onset of SJS/TEN or liver injury in patients prescribed antipyretic an...
Source: The Journal of Clinical Pharmacology - June 10, 2020 Category: Drugs & Pharmacology Authors: Imatoh T, Sai K, Saito Y Tags: J Clin Pharmacol Source Type: research

An Open-Label Study to Assess the Effect of Itraconazole and Rifampin on Parsaclisib Pharmacokinetics When Administered Orally in Healthy Participants.
This study assessed the pharmacokinetics (PK) and safety of parsaclisib alone or combined with itraconazole (potent CYP3A inhibitor) or rifampin (potent CYP3A4 inducer) in healthy participants. In this open-label, fixed-sequence study, cohort 1 received oral parsaclisib 10 mg once daily on days 1 and 8 and oral itraconazole 200 mg once daily on days 4-11; cohort 2 received oral parsaclisib 20 mg once daily on days 1 and 11 and oral rifampin 600 mg once daily on days 4-12. Parsaclisib plasma concentration was tested and PK parameters calculated by noncompartmental analysis. Geometric mean ratios (GMRs) a...
Source: The Journal of Clinical Pharmacology - June 9, 2020 Category: Drugs & Pharmacology Authors: Li J, Rockich K, Yuska B, Zhou G, Epstein N, Punwani N, Chen X, Yeleswaram S Tags: J Clin Pharmacol Source Type: research

Colchicine and COVID-19.
PMID: 32511763 [PubMed - as supplied by publisher] (Source: The Journal of Clinical Pharmacology)
Source: The Journal of Clinical Pharmacology - June 8, 2020 Category: Drugs & Pharmacology Authors: Corral P, Corral G, Diaz R Tags: J Clin Pharmacol Source Type: research

Population Pharmacokinetic Model of Dexmedetomidine in a Heterogeneous Group of Patients.
This study aimed to propose a population pharmacokinetic (PK) model of dexmedetomidine in a heterogeneous group of intensive care unit patients, incorporating 29 covariates potentially linked with dexmedetomidine PK. Data were collected from 70 patients aged between 0.25 and 88 years and treated with dexmedetomidine infusion for various durations at 1 of 4 medical centers. Statistical analysis was performed using a nonlinear mixed-effect model. Categorical and continuous covariates including demographic data, hemodynamic parameters, biochemical markers, and 11 single-nucleotide polymorphisms were tested. A 2-compartment mo...
Source: The Journal of Clinical Pharmacology - June 5, 2020 Category: Drugs & Pharmacology Authors: Ber J, Wiczling P, Hołysz M, Klupczyńska A, Bartkowska-Śniatkowska A, Bieda K, Smuszkiewicz P, Nowicka M, Żurański Ł, Sobczyński P, Matysiak J, Grześkowiak E, Bienert A Tags: J Clin Pharmacol Source Type: research

Model-Based Evaluation of Linear Limited and Bayesian Sparse Sampling for Therapeutic Monitoring of Recombinant Coagulation Factor IX.
The objective of this study was to develop and evaluate 2 sparse sampling methods for the estimation of AUC of recombinant factor IX (BeneFIX) as proof of concept for dose individualization. A population pharmacokinetic model was used to generate the plasma factor IX activity-versus-time data. The linear limited sampling model (LLSM) was developed based on the correlation of factor IX activity versus AUC0-72 hours following screening of several blood sampling times in adolescent and adult subjects (n = 90 subjects). Factor IX trough concentrations were predicted from a relationship established from AUC versu...
Source: The Journal of Clinical Pharmacology - June 5, 2020 Category: Drugs & Pharmacology Authors: Tegenge MA, Mahmood I Tags: J Clin Pharmacol Source Type: research

Population Pharmacokinetic/Pharmacodynamic Modeling of Glenzocimab (ACT017) a Glycoprotein VI Inhibitor of Collagen-Induced Platelet Aggregation.
Abstract Glenzocimab (ACT017) is a humanized monoclonal antigen-binding fragment (Fab) directed against the human platelet glycoprotein VI, a key receptor for collagen and fibrin that plays a major role in thrombus growth and stability. Glenzocimab is being developed as an antiplatelet agent to treat the acute phase of ischemic stroke. During a phase I study in healthy volunteers, the population pharmacokinetics (PK) and pharmacodynamics (PD) of glenzocimab were modeled using Monolix software. The PK/PD model thus described glenzocimab plasma concentrations and its effects on ex vivo collagen-induced platelet aggr...
Source: The Journal of Clinical Pharmacology - June 4, 2020 Category: Drugs & Pharmacology Authors: Renaud L, Lebozec K, Voors-Pette C, Dogterom P, Billiald P, Jandrot Perrus M, Pletan Y, Machacek M Tags: J Clin Pharmacol Source Type: research

Randomized Crossover Trial to Compare Abuse Liability of Intravenous Remimazolam Versus Intravenous Midazolam and Placebo in Recreational Central Nervous System Depressant Users.
Abstract Remimazolam (RMZ) is a new and ultra-fast-acting, short-duration intravenous benzodiazepine, a drug class associated with abuse potential. This trial was designed to compare the abuse potential of remimazolam with placebo and midazolam (MDZ), a well-characterized member of the same pharmacological class in healthy, recreational drug users 18-55 years-of-age, who demonstrated good drug tolerance and were able to discriminate between midazolam and placebo. At equipotent intravenous doses selected to produce effects ranging from mild/moderate to relatively strong sedation without loss of consciousness (RMZ: ...
Source: The Journal of Clinical Pharmacology - June 3, 2020 Category: Drugs & Pharmacology Authors: Schippers F, Pesic M, Saunders R, Borkett K, Searle S, Webster L, Stoehr T Tags: J Clin Pharmacol Source Type: research

Population Pharmacokinetics and Pharmacodynamics of Norvancomycin in Children With Malignant Hematological Disease.
This study developed a population PK model of children aged 0-15 years; 112 opportunistic samples in total from 90 children were analyzed. The stability and prediction of the final model were evaluated by goodness-of-fit plots, nonparametric bootstrap, visual predictive check, and normalized prediction distribution errors. The PKs of NVCM in children was described by a 2-compartment model with first-order elimination along with body weight and estimated glomerular filtration rate as significant covariates on clearance. The population typical values of the PK parameters were as follows: clearance 0.12 L/kg/h, central compar...
Source: The Journal of Clinical Pharmacology - June 2, 2020 Category: Drugs & Pharmacology Authors: Wang J, Li SC, Ye Q, Gao LL, Nie YM, Xu H, Wu M, Cao P, Wang Y Tags: J Clin Pharmacol Source Type: research

Effect of 3 Single Doses of Trazodone on QTc Interval in Healthy Subjects.
This study evaluated the effect of 3 doses of a trazodone hydrochloride 6% oral drops solution on the QT interval of healthy volunteers. Subjects were randomly assigned to receive a single dose of trazodone 20 mg, 60 mg, and 140 mg, moxifloxacin 400 mg, and trazodone-matched placebo in 5 periods separated by 7-day washouts, according to a double-blind, crossover study design. Subjects were monitored continuously, and triplicate ECGs were extracted from baseline (predose) until 24 hours postdose. Blood samples for trazodone and moxifloxacin analyses were collected at the same time points. The concentrati...
Source: The Journal of Clinical Pharmacology - June 2, 2020 Category: Drugs & Pharmacology Authors: Tellone V, Rosignoli MT, Picollo R, Dragone P, Del Vecchio A, Comandini A, Radicioni M, Leuratti C, Calisti F Tags: J Clin Pharmacol Source Type: research

Suspected Adverse Drug Reactions From Corticosteroids: Analysis of Reported Notifications to the Portuguese Pharmacovigilance System.
os JL Abstract We performed a retrospective, observational, and descriptive study on the reports of adverse reactions resulting from the use of corticosteroids, based on data from the Portuguese Pharmacovigilance System recorded between January 2009 and December 2018. A total of 569 reports with at least 1 suspected corticosteroid were included in the study, of which 59.1% belonged to individuals aged between 19 and 64 years. There was no significant predominance of sex, with 55% female patients. The notification trend has increased over the years, with the highest number of cases in 2018, 29.5%. Among the 3 group...
Source: The Journal of Clinical Pharmacology - June 2, 2020 Category: Drugs & Pharmacology Authors: Gonçalves C, Monteiro C, Santos JL Tags: J Clin Pharmacol Source Type: research

Macroprolactinemia Attenuates the Impact of Levothyroxine on Hypothalamic-Pituitary-Thyroid Axis Activity and Thyroid Autoimmunity in Women With Autoimmune Hypothyroidism.
Abstract Because of contradictory results, clinical significance of elevated levels of macroprolactin (macroprolactinemia) remains unclear. The aim of this study was to investigate whether macroprolactinemia determines levothyroxine action on hypothalamic-pituitary-thyroid axis activity and thyroid antibody titers in women with autoimmune hypothyroidism. The study population included 2 age-, body mass index-, hormone-, and thyroid antibody-matched groups of premenopausal women with untreated autoimmune subclinical hypothyroidism: 15 subjects with coexisting macroprolactinemia and 29 individuals with prolactin leve...
Source: The Journal of Clinical Pharmacology - June 2, 2020 Category: Drugs & Pharmacology Authors: Krysiak R, Kowalcze K, Okopień B Tags: J Clin Pharmacol Source Type: research

Population Pharmacokinetics of Vemurafenib in Children With Recurrent/Refractory BRAF Gene V600E-Mutant Astrocytomas.
Abstract Vemurafenib (Zelboraf) is an orally available BRAFV600E inhibitor approved for the treatment of unresectable or metastatic BRAFV600E -mutant melanoma. The primary objective of this work was to characterize the pharmacokinetics (PK) of vemurafenib in pediatric patients with recurrent/refractory astrocytomas harboring the BRAFV600E mutation. The study was also designed to evaluate the feasibility of replacing whole vemurafenib tablets with crushed tablets in young children unable to swallow tablets. Twenty-five pediatric patients (median age, 8.8 years; range, 3.3-19.2) with recurrent/refractory BRAFV600E -...
Source: The Journal of Clinical Pharmacology - May 31, 2020 Category: Drugs & Pharmacology Authors: Wang H, Long-Boyle J, Winger BA, Nicolaides T, Mueller S, Prados M, Ivaturi V Tags: J Clin Pharmacol Source Type: research

Evaluation of potential therapeutic options for COVID-19.
PMID: 32469418 [PubMed - as supplied by publisher] (Source: The Journal of Clinical Pharmacology)
Source: The Journal of Clinical Pharmacology - May 29, 2020 Category: Drugs & Pharmacology Authors: Austin D, Okour M Tags: J Clin Pharmacol Source Type: research

A Comprehensive Updated Review on SARS-CoV-2 and COVID-19.
This article is protected by copyright. All rights reserved. PMID: 32469437 [PubMed - as supplied by publisher] (Source: The Journal of Clinical Pharmacology)
Source: The Journal of Clinical Pharmacology - May 29, 2020 Category: Drugs & Pharmacology Authors: Ren YR, Golding A, Sorbello A, Ji P, Chen J, Bhawana S, Witzmann K, Arya V, Reynolds KS, Choi SY, Nikolov N, Sahajwalla C Tags: J Clin Pharmacol Source Type: research