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Journal of Clinical Pharmacology

Benjamin Philosophe, Nicolae Leca, Patricia M West-Thielke, Timothy Horwedel, Christine Culkin-Gemmell, Kristin Kistler, Daniel R Stevens
The majority of United States kidney transplant patients are treated with tacrolimus, a drug effective in preventing graft rejection, but with a narrow therapeutic range, necessitating close monitoring to avoid increased risks of transplant rejection or toxicity if the tacrolimus concentration is too low or too high, respectively. The trough drug concentration tests are time sensitive; patients treated on a twice-daily basis have blood draws exactly 12 hours after their previous dose. The schedule's rigidity causes problems for both patients and health care providers...
February 20, 2018: Journal of Clinical Pharmacology
Hannah Hoseyni, Yan Xu, Honghui Zhou
Therapeutic drug monitoring (TDM), or the measurement of drug concentrations in blood and antidrug antibodies, for biologic therapies used to treat inflammatory bowel disease (IBD) is an area of growing interest within the IBD community. When there is a definable relationship between drug concentration and clinical effect, blood concentration of biologics (and antidrug antibodies assessment) could be used to predict patient response and to titrate the biologics to maximize therapeutic benefit. This dose individualization has been proven to be more efficacious and cost-effective than empiric dose adjustment and can better guide therapeutic decisions regarding therapy withdrawal or switch...
February 20, 2018: Journal of Clinical Pharmacology
Georg Ferber, Yaning Sun, Borje Darpo, Christine Garnett, Jiang Liu
The operating characteristics of dose-escalating studies in terms of false-negative predictions of the QT effect and the power to exclude clinically relevant QT effects are not quantitatively established. One thousand single-ascending-dose (SAD) studies with 7 dose groups with 6/2 subjects on active drug/placebo were generated through simulation for each of 32 scenarios with (1) 8 different QT effects of the study drug and (2) achieved plasma concentration 2- or 4-fold above therapeutic levels. For each subject, drug-free QT data from a thorough QT study were subsampled to capture the circadian profile, on which a drug effect was added...
February 8, 2018: Journal of Clinical Pharmacology
Yan Xin, Winnie Weng, Bernard P Murray, Eugene J Eisenberg, Jason W Chien, John Ling, Jeffrey A Silverman
Respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infections in young children. Presatovir (previously GS-5806) is a novel, orally administered RSV fusion inhibitor with a favorable safety profile and proven antiviral efficacy in preclinical and clinical studies. In vitro, presatovir is a substrate of the efflux transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) and hepatic uptake transporters organic anion transporting polypeptide (OATP) 1B1 and OATP1B3 and is slowly metabolized by cytochrome P450 (CYP) 3A4 and CYP3A5...
February 7, 2018: Journal of Clinical Pharmacology
Michael J Fossler, Brian M Sadler, Colm Farrell, David A Burt, Maria Pitsiu, Franck Skobieranda, David G Soergel
Conventional opioids bind to μ-opioid receptors and activate 2 downstream signaling pathways: G-protein coupling, linked to analgesia, and β-arrestin recruitment, linked to opioid-related adverse effects and limiting efficacy. Oliceridine (TRV130) is a novel G protein-biased ligand at the μ-opioid receptor that differentially activates G-protein coupling while mitigating β-arrestin recruitment. Using data derived from both phase 1 studies in healthy volunteers as well as data from a phase 2 study examining the efficacy of oliceridine for the treatment of postbunionectomy pain, we have developed a population pharmacokinetic/pharmacodynamic model linking the pharmacokinetics of oliceridine to its effect on pain, as measured by the Numeric Pain Rating Scale score...
February 7, 2018: Journal of Clinical Pharmacology
Michael J Fossler, Brian M Sadler, Colm Farrell, David A Burt, Maria Pitsiu, Franck Skobieranda, David G Soergel
Oliceridine is a novel G protein-biased ligand at the μ-opioid receptor that differentially activates G protein coupling while mitigating β-arrestin recruitment. Unlike morphine, oliceridine has no known active metabolites; therefore, analgesic efficacy is predictably linked to its concentration in the plasma. Oliceridine is primarily hepatically metabolized by CYP3A4 and CYP2D6. Using a pharmacokinetic/pharmacodynamic model relating oliceridine plasma concentrations to its effect on pain intensity as measured by numeric pain-rating scale (NPRS) scores, we have simulated potential dosing regimens using both fixed-dose regimens and as-needed (prn) dosing regimens in which various doses of oliceridine were administered if NPRS scores indicated moderate to severe pain (≥4 on a 0-10 scale)...
February 2, 2018: Journal of Clinical Pharmacology
Alexander Eser, Christian Primas, Sieglinde Reinisch, Harald Vogelsang, Gottfried Novacek, Diane R Mould, Walter Reinisch
Despite a robust exposure-response relationship of infliximab in inflammatory bowel disease (IBD), attempts to adjust dosing to individually predicted serum concentrations of infliximab (SICs) are lacking. Compared with labor-intensive conventional software for pharmacokinetic (PK) modeling (eg, NONMEM) dashboards are easy-to-use programs incorporating complex Bayesian statistics to determine individual pharmacokinetics. We evaluated various infliximab detection assays and the number of samples needed to precisely forecast individual SICs using a Bayesian dashboard...
January 30, 2018: Journal of Clinical Pharmacology
Roberto Gomeni, Françoise Bressolle-Gomeni, Maurizio Fava
The conventional statistical methodologies for evaluating treatment effect are based on hypothesis testing (P-value). Alternative measurements of treatment effect have been proposed for anti-infective treatments using the probability of target attainment. A general framework is proposed to extend this methodology to other therapeutic areas. A disease trial model is used for estimating the probability of reaching a treatment effect associated with relevant clinical benefits, in complement to the evaluation of the probability of rejecting the null hypothesis...
January 25, 2018: Journal of Clinical Pharmacology
Amit Khatri, Ahmed A Othman
ABT-122 is an IgG1 dual-variable domain immunoglobulin that specifically blocks TNF-α and IL-17A. This work characterized ABT-122 pharmacokinetics using nonlinear mixed-effects modeling and ABT-122 serum concentrations from 72 healthy subjects, 196 subjects with rheumatoid arthritis (RA), and 144 subjects with psoriatic arthritis (PsA) enrolled in 4 phase 1 and 2 phase 2 studies (0.1-10 mg/kg intravenously and 0.3-3 mg/kg subcutaneous single doses and 0.3-3.0 mg/kg subcutaneous and 60-240 mg subcutaneous doses weekly or every other week)...
January 24, 2018: Journal of Clinical Pharmacology
Domenico Chirchiglia, Saverio Paventi, Paolo Seminara, Erika Cione, Luca Gallelli
Palmitoyl ethanol amide (PEA) is an endogenous substance that plays a role in neuropathic pain. In this article, we evaluated both the safety and the efficacy of ultramicronized PEA (um-PEA) in the treatment of low back pain related to nonsurgical lumbar radiculopathy. In this prospective single-blind study, patients with low back pain related to nonsurgical lumbar radiculopathy received the fixed combination acetaminophen/codeine (500 mg + 30 mg/d) for 7 days, and then it was stopped and changed to um-PEA (1200 mg/d) for 30 days...
January 24, 2018: Journal of Clinical Pharmacology
Yong-An Wang, Yu-Chen Yang, Fu-Quan Long, Chang Sun
No abstract text is available yet for this article.
January 22, 2018: Journal of Clinical Pharmacology
Janelle D Vaughns, Laurie S Conklin, Ying Long, Panli Zheng, Fahim Faruque, Dionna J Green, John N van den Anker, Gilbert J Burckart
There is a lack of dosing guidelines for use in obese children. Moreover, the impact of obesity on drug safety and clinical outcomes is poorly defined. The paucity of information needed for the safe and effective use of drugs in obese patients remains a problem, even after drug approval. To assess the current incorporation of obesity as a covariate in pediatric drug development, the pediatric medical and clinical pharmacology reviews under the Food and Drug Administration (FDA) Amendments Act of 2007 and the FDA Safety and Innovation Act (FDASIA) of 2012 were reviewed for obesity studies...
January 19, 2018: Journal of Clinical Pharmacology
Zhenling Yao, Chuanpu Hu, Yaowei Zhu, Zhenhua Xu, Bruce Randazzo, Yasmine Wasfi, Yang Chen, Amarnath Sharma, Honghui Zhou
Psoriasis is a common inflammatory skin disorder that requires chronic treatment and is associated with multiple comorbidities. Guselkumab, a human immunoglobulin-G1-lambda monoclonal antibody, binds to interleukin-23 with high specificity and affinity and is effective in treating moderate to severe plaque psoriasis. As part of the guselkumab psoriasis clinical trial program, using a confirmatory approach, a population pharmacokinetics (PopPK) model was established using 13 014 PK samples from 1454 guselkumab-treated patients across 3 phase 2/3 trials...
January 17, 2018: Journal of Clinical Pharmacology
Hwa-Ping Feng, Luzelena Caro, Christine M Fandozzi, Zifang Guo, Jennifer Talaty, Dennis Wolford, Deborah Panebianco, Marian Iwamoto, Joan R Butterton, Wendy W Yeh
Elbasvir (EBR)/grazoprevir (GZR) may be coadministered with immunosuppressant drugs in posttransplant people who are infected with hepatitis C virus. The aim of the present study was to assess the safety and pharmacokinetic interactions between EBR and GZR and single doses of cyclosporine, tacrolimus, mycophenolate mofetil (MMF), and prednisone. This was a 4-part, open-label study in 58 healthy volunteers. Participants received single doses of cyclosporine 400 mg, tacrolimus 2 mg, MMF 1 g, or prednisone 40 mg alone or in the presence of once-daily EBR 50 mg/GZR 200 mg...
January 12, 2018: Journal of Clinical Pharmacology
Steven E Christensen, Stephen A Cooper, Randall J Mack, Stewart W McCallum, Wei Du, Alex Freyer
This randomized, controlled phase 2 study was conducted to evaluate the analgesic efficacy, safety, and tolerability of single intravenous (IV) doses of 15 mg, 30 mg, and 60 mg meloxicam compared with oral ibuprofen 400 mg and placebo after dental impaction surgery. The primary efficacy end point was the sum of time-weighted pain intensity differences for 0-24 hours postdose. Among 230 evaluable subjects, meloxicam IV 60 mg produced the greatest reduction in pain, followed by the 30-mg and 15-mg doses. Statistically significant differences in summed pain intensity differences over 24 hours were demonstrated for each active-treatment group vs placebo (favoring active treatment) and for meloxicam IV 30 mg and 60 mg vs ibuprofen 400 mg (favoring meloxicam IV)...
January 12, 2018: Journal of Clinical Pharmacology
Malek Okour, Pamala A Jacobson, Mariam A Ahmed, Ajay K Israni, Richard C Brundage
Mycophenolic acid (MPA) is an approved immunosuppressive agent widely prescribed to prevent rejection after kidney transplantation. Wide between-subject variability (BSV) in MPA exposure exists which in part may be due to variability in enterohepatic recirculation (EHC). Several modeling strategies were developed to evaluate EHC as part of MPA pharmacokinetics, however mechanistic representation of EHC is limited. These models have not provided a satisfactory representation of the physiology of EHC in their modeling assumptions...
January 12, 2018: Journal of Clinical Pharmacology
Jing Wang, Xiaodong Wang, Zhi-Yi Zhang, Sujata Arora, Sharon Lu, Vikram Kansra
Rolapitant is a selective and long-acting neurokinin-1 receptor antagonist approved in an oral formulation in combination with other antiemetic agents for the prevention of delayed chemotherapy-induced nausea and vomiting in adults. This was a phase 1 open-label, parallel-group pharmacokinetic and safety study of a single oral dose of 180 mg of rolapitant and its major active metabolite, M19, in subjects with mild and moderate hepatic impairment compared with healthy matched controls. Pharmacokinetics were assessed by a mixed-model analysis of variance of log-transformed values for maximum observed plasma concentration (Cmax ), observed time at Cmax (tmax ), area under the plasma concentration-time curve (AUC) from time 0 to the time of the last quantifiable concentration (AUC0-t ), and AUC from time 0 to 120 hours (AUC0-120 ), with hepatic group as a fixed effect...
January 12, 2018: Journal of Clinical Pharmacology
Vijay V Upreti, April M Barbour
No abstract text is available yet for this article.
January 12, 2018: Journal of Clinical Pharmacology
Raid W Amin, Rodney P Guttmann, Quianna R Harris, Janesha W Thomas
Vancomycin is a key antibiotic used in the treatment of multiple conditions including infections associated with cystic fibrosis and methicillin-resistant Staphylococcus aureus. The present study sought to develop a model based on empirical evidence of optimal vancomycin dose as judged by clinical observations that could accelerate the achievement of desired trough level in children with cystic fibrosis. Transformations of dose and trough were used to arrive at regression models with excellent fit for dose based on weight or age for a target trough...
January 10, 2018: Journal of Clinical Pharmacology
Andrea Cortegiani, Alessandra Pavan, Fabio Azzeri, Giuseppe Accurso, Filippo Vitale, Cesare Gregoretti
The aim of this study was to determine the relationship, precision, and bias of a propofol target-controlled infusion (TCI) system during prolonged infusion in neurosurgical patients. We retrospectively included patients undergoing general anesthesia for elective neurosurgical removal of brain tumors and postoperative sedation in the intensive care unit over a period of 3 months. TCI of propofol (Diprifusor - Marsh model) and remifentanil were used for general anesthesia and sedation. We compared propofol blood concentration (Cmeas ) measured by liquid chromatography-mass spectroscopy with predicted concentrations (Cpred ) by the TCI system at 40 minutes (T0), 2 hours (T1), and 4 hours (T2) and every 8 hours after starting the drug infusion and at the time of emergence from sedation...
January 9, 2018: Journal of Clinical Pharmacology
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