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Clinical Pharmacology in Drug Development

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https://www.readbyqxmd.com/read/28301098/pharmacokinetics-of-a-novel-anagrelide-extended-release-formulation-in-healthy-subjects-food-intake-and-comparison-with-a-reference-product
#1
Petro E Petrides, Christian Schoergenhofer, Rudolf Widmann, Bernd Jilma, Christoph S Klade
Anagrelide is an established therapy for essential thrombocythemia. Common adverse effects have been linked to peak plasma concentrations of anagrelide and its 3OH metabolite. Our study was performed to investigate the pharmacokinetics (PK) of a novel anagrelide extended-release (AER) formulation and its active metabolites. Thirty healthy volunteers were randomized to receive either 2 mg AER (under fasting and fed conditions) or 2 mg commercially available reference product (CARP) in an open-label, 3-way crossover trial with washout periods of 6 days...
March 16, 2017: Clinical Pharmacology in Drug Development
https://www.readbyqxmd.com/read/28301096/effects-of-tenapanor-on-cytochrome-p450-mediated-drug-drug-interactions
#2
Susanne Johansson, David P Rosenbaum, Marie Ahlqvist, Helen Rollison, Mikael Knutsson, Bergur Stefansson, Marie Elebring
Tenapanor (RDX5791, AZD1722) is an inhibitor of sodium/hydrogen exchanger isoform 3 in development for the treatment of constipation-predominant irritable bowel syndrome and the treatment of hyperphosphatemia in patients with chronic kidney disease on dialysis. We aimed to investigate whether tenapanor inhibits or induces cytochrome P450s (CYPs). In vitro experiments assessing the potential of tenapanor to affect various CYPs indicated that it could inhibit CYP3A4/5 (IC50 0.4-0.7 μM). An open-label, phase 1 clinical study (NCT02140268) evaluated the pharmacokinetics of the CYP3A4 substrate midazolam when administered with and without tenapanor...
March 16, 2017: Clinical Pharmacology in Drug Development
https://www.readbyqxmd.com/read/28301092/pharmacokinetics-and-safety-of-dw1029m-a-botanical-drug-for-the-treatment-of-diabetic-nephropathy-following-single-doses-in-healthy-subjects
#3
Yunjeong Kim, Ji-Young Jeon, Eun-Young Kim, Cheol-Hee Lim, Hwan Bong Jang, Min-Gul Kim
DW1029M is a botanical extract of Morus albalinne root bark and Puerariae radix that is used for the treatment of diabetic nephropathy. This study evaluated the safety and pharmacokinetics of DW1029M following its administration in healthy Korean subjects. We conducted a randomized, open-label, single-dose, crossover phase 1 clinical study. During each period, subjects received 300, 600, or 1200 mg oral doses of DW1029M. Plasma concentrations of puerarin, daidzin, and daidzein were analyzed using a liquid chromatography-tandem mass spectrometry...
March 16, 2017: Clinical Pharmacology in Drug Development
https://www.readbyqxmd.com/read/28301084/the-effect-of-verapamil-a-p-glycoprotein-inhibitor-on-the-pharmacokinetics-of-peficitinib-an-orally-administered-once-daily-jak-inhibitor
#4
Tong Zhu, Corrie Howieson, Tomasz Wojtkowski, Jay P Garg, David Han, Ogert Fisniku, James Keirns
Peficitinib is an orally administered, once-daily Janus kinase inhibitor currently in development for the treatment of rheumatoid arthritis. It has been shown to be a P-glycoprotein (P-gp) substrate in vitro. The effects of verapamil, an inhibitor of the efflux pump P-gp, on the pharmacokinetic profile of peficitinib were assessed in this open-label, single-center, single-sequence, crossover drug-interaction study. Twenty-four healthy volunteers received a single 150-mg dose of peficitinib on days 1 and 12 of a 14-day treatment period and received verapamil 80 mg 3 times daily on days 5-14...
March 16, 2017: Clinical Pharmacology in Drug Development
https://www.readbyqxmd.com/read/28176487/lornoxicam-immediate-release-tablets-formulation-and-bioequivalence-study-in-healthy-mediterranean-volunteers-using-a-validated-lc-ms-ms-method
#5
Abdel Naser Zaid, Ayman Mousa, Nidal Jaradat, Rana Bustami
This study aimed to demonstrate interchangeability between 2 lornoxicam tablet formulations under fasting conditions among Mediterranean Arabs by using a newly validated high-pressure liquid chromatography-tandem mass spectrometry method. A single-oral solid dosage form (8 mg/tablet), randomized, open-label, 2-way crossover study was conducted on 30 healthy male volunteers. Blood samples were collected prior to dosing and over a 24-hour period, and the washout period was 9 days. Statistical comparison of the main pharmacokinetic parameters showed no significant difference between generic and branded products...
February 8, 2017: Clinical Pharmacology in Drug Development
https://www.readbyqxmd.com/read/28176470/effect-of-sustained-elevated-gastric-ph-levels-on-gefitinib-exposure
#6
Weifeng Tang, Helen Tomkinson, Eric Masson
This open-label, randomized, phase 1 crossover study investigated the effect of elevated gastric pH level (>5) on the relative bioavailability and pharmacokinetic profile of the epidermal growth factor receptor tyrosine kinase inhibitor gefitinib. Healthy male volunteers (n = 26) were randomized to gefitinib 250 mg (fasted), either alone on day 1 (unmodified gastric pH) or 1 hour following the second of 2 oral doses of the H2 -receptor antagonist ranitidine 450 mg (elevated gastric pH). After a 3-week washout period, volunteers crossed to the other treatment...
February 8, 2017: Clinical Pharmacology in Drug Development
https://www.readbyqxmd.com/read/28168828/relative-bioavailability-of-a-dolutegravir-dispersible-tablet-and-the-effects-of-low-and-high-mineral-content-water-on-the-tablet-in-healthy-adults
#7
Ann M Buchanan, Michael Holton, Ian Conn, Mark Davies, Mike Choukour, Brian R Wynne
Dolutegravir (DTG) is approved in the United States to treat HIV-1-infected patients weighing ≥30 kg. A dispersible DTG tablet formulation was recently developed for pediatric patients. This study compares the pharmacokinetics (PK) of the dispersible tablet with that of a previously evaluated granule formulation. In this randomized, open-label, crossover study, 15 healthy adults received single oral doses of DTG 20 mg every 7 days across 5 treatment arms: granules consumed immediately after mixture with purified water, dispersible DTG consumed immediately after reconstitution in low-mineral-content (LMC) or high-mineral-content (HMC) water, and dispersible DTG consumed 30 minutes after dispersal in LMC or HMC water...
February 7, 2017: Clinical Pharmacology in Drug Development
https://www.readbyqxmd.com/read/28127948/bioequivalence-studies-of-a-reformulated-dutasteride-and-tamsulosin-hydrochloride-combination-capsule-and-a-commercially-available-formulation
#8
Renee Kurczewski, Chet Bowen, David Collins, John Zhu, Gulyeter Serbest, Michael Manyak
A dutasteride 0.5 mg and tamsulosin hydrochloride 0.4 mg combination (DTC) capsule (Duodart(®) ) was reformulated to reduce the capsule size and enhance product stability. Bioequivalence of the reformulated DTC capsule with the commercial formulation was evaluated in 2 single-dose, open-label, randomized, 2-way crossover studies in healthy adult male volunteers. Subjects in a fasted or fed state received a single oral dose of either the reformulated DTC or the commercial formulation followed by a 28-day washout period between treatments...
January 27, 2017: Clinical Pharmacology in Drug Development
https://www.readbyqxmd.com/read/28127938/an-open-label-randomized-bioavailability-study-of-alternative-methods-of-oral-administration-of-naloxegol-in-healthy-subjects
#9
Khanh Bui, Bruce Birmingham, Ulysses Diva, Bruce Berger
Naloxegol is a peripherally acting μ-opioid receptor antagonist approved as an orally administered tablet for the treatment of opioid-induced constipation. Patients with swallowing difficulties may benefit from alternative approaches to the oral administration of the whole-tablet formulation of naloxegol. This open-label, randomized, 4-period, 4-treatment, crossover, single-dose study (NCT02446171) evaluated the pharmacokinetic (PK) characteristics of crushed naloxegol 25-mg tablets (suspended in water) administered orally or by nasogastric tube and a naloxegol solution compared with the commercially available 25-mg tablet formulation in healthy volunteers...
January 27, 2017: Clinical Pharmacology in Drug Development
https://www.readbyqxmd.com/read/28111929/acid-inhibitory-effect-of-a-combination-of-omeprazole-and-sodium-bicarbonate-cdfr0209-compared-with-delayed-release-omeprazole-40%C3%A2-mg-alone-in-healthy-adult-male-subjects
#10
Kyu-Nam Kim, Sung-Won Yang, Hyunil Kim, Seong Shin Kwak, Young-Sang Kim, Doo-Yeoun Cho
CDFR0209, a combination of an immediate-release formulation of omeprazole 40 mg and sodium bicarbonate 1100 mg, has been developed to treat acid-related disorders. We compared the acid inhibitory effects of CDFR0209 and delayed-release omeprazole (omeprazole-DR, Losec 40 mg) after repeated dosing in Helicobacter pylori-negative healthy adult male subjects. In this 2-period crossover study, 30 subjects were randomized to CDFR0209 or omeprazole-DR daily for 7 days. An ambulatory continuous 24-hour intragastric pH recording was performed at baseline and on days 1 and 7 of each administration period...
January 23, 2017: Clinical Pharmacology in Drug Development
https://www.readbyqxmd.com/read/28074640/evaluation-of-pharmacokinetic-interactions-between-lesinurad-a-new-selective-urate-reabsorption-inhibitor-and-commonly-used-drugs-for-gout-treatment
#11
Zancong Shen, Kathy Tieu, David Wilson, Gail Bucci, Michael Gillen, Caroline Lee, Bradley Kerr
Lesinurad is a novel selective uric acid reabsorption inhibitor approved for treatment of hyperuricemia associated with gout in combination with xanthine oxidase inhibitors (XOIs). Open-label pharmacokinetic studies were performed in volunteers or subjects with hyperuricemia (serum uric acid ≥ 8 mg/dL) to investigate interactions of lesinurad (with and without concurrent XOIs) with colchicine and 2 nonsteroidal anti-inflammatory drugs: naproxen and indomethacin. Colchicine studies included consecutive 7-day treatment periods of (1) allopurinol 300 mg, allopurinol 300 mg plus lesinurad 400 or 600 mg, and continued lesinurad 400 or 600 mg; or (2) febuxostat 40 or 80 mg, febuxostat 40 or 80 mg plus lesinurad 400 mg, and continued febuxostat 40 or 80 mg plus lesinurad 600 mg...
January 11, 2017: Clinical Pharmacology in Drug Development
https://www.readbyqxmd.com/read/28067999/evaluation-of-pharmacokinetic-interactions-between-lesinurad-a-new-selective-urate-reabsorption-inhibitor-and-cyp-enzyme-substrates-sildenafil-amlodipine-tolbutamide-and-repaglinide
#12
Michael Gillen, Chun Yang, David Wilson, Shakti Valdez, Caroline Lee, Bradley Kerr, Zancong Shen
Lesinurad is a selective uric acid reabsorption inhibitor approved for the treatment of hyperuricemia associated with gout in combination with xanthine oxidase inhibitors. In vitro assays indicate that lesinurad is an inducer of CYPs in the order CYP3A > CYP2C8 > CYP2C9 > CYP2C19 > CYP2B6 and an inhibitor of CYP2C8 and CYP2C9. To investigate the drug interaction potential of lesinurad, clinical drug interaction studies were conducted. Open-label studies in volunteers investigated the effects of single-/multiple-dose lesinurad on the pharmacokinetics of sildenafil and amlodipine (CYP3A4 induction), tolbutamide (CYP2C9 inhibition/induction), and repaglinide (CYP2C8 inhibition/induction)...
January 9, 2017: Clinical Pharmacology in Drug Development
https://www.readbyqxmd.com/read/28052588/absolute-bioavailability-and-pharmacokinetic-comparability-of-sirukumab-following-subcutaneous-administration-by-a-prefilled-syringe-or-an-autoinjector
#13
Y Zhuang, D E de Vries, S J Marciniak, H Liu, H Zhou, H M Davis, F Leon, D Raible, Z Xu
This phase 1, randomized, open-label study assessed the absolute bioavailability and pharmacokinetic comparability of sirukumab, a human anti-interleukin-6 monoclonal antibody, following subcutaneous (SC) administration via Prefilled Syringe-UltraSafe Passive® Delivery System (PFS-U) or Prefilled Syringe-SmartJect® Autoinjector (PFS-AI; Janssen Research & Development, LLC, Spring House, Pennsylvania). A total of 144 healthy male subjects were randomized to 5 single-dose treatment groups: sirukumab 50 mg and 100 mg (each by PFS-U and PFS-AI) and sirukumab 100 mg intravenous (IV) infusion...
January 3, 2017: Clinical Pharmacology in Drug Development
https://www.readbyqxmd.com/read/28032482/population-pharmacokinetics-of-edoxaban-in-japanese-atrial-fibrillation-patients-with-severe-renal-impairment
#14
Takako Shimizu, Masaya Tachibana, Tetsuya Kimura, Tomohiko Kumakura, Kazutaka Yoshihara
This is a population pharmacokinetic (PopPK) analysis to predict PK of edoxaban, a direct-acting oral anticoagulant, in nonvalvular atrial fibrillation (NVAF) patients with severe renal impairment (SRI; creatinine clearance [CLcr ] <30 mL/min). Data from a phase 3 study recently conducted in Japanese NVAF patients (n = 90), including patients with SRI, were used to update the ENGAGE PopPK model that had been developed based on pooled data from the phase 3 ENGAGE AF-TIMI 48 study and 13 phase 1 PK studies, which included few patients with SRI...
December 29, 2016: Clinical Pharmacology in Drug Development
https://www.readbyqxmd.com/read/28032481/safety-tolerability-and-antihypertensive-effect-of-ser100-an-opiate-receptor-like-1-orl-1-partial-agonist-in-patients-with-isolated-systolic-hypertension
#15
Ilkka Kantola, Mika Scheinin, Trygve Gulbrandsen, Nils Meland, Knut T Smerud
The purpose of the present trial was to evaluate safety, tolerability, and effect on systolic blood pressure (SBP) of SER100 in a small group of patients with isolated systolic hypertension (ISH) in treatment with at least 1 antihypertensive drug. Eligible patients were randomized to either SER100 (10 mg) or placebo in a crossover design, and 2 doses were given subcutaneously (SC), 8 hours apart, on 2 consecutive days. On all treatment days patients were monitored with an ambulatory blood pressure measurement device for 12 daytime hours...
December 29, 2016: Clinical Pharmacology in Drug Development
https://www.readbyqxmd.com/read/28263467/mechanisms-and-consequences-of-drug-drug-interactions
#16
David J Greenblatt
Medications used to treat human immunodeficiency virus (HIV) and hepatitis C virus (HCV) infections present a special challenge with respect to the management of potential and actual drug-drug interactions (DDIs). The HIV and HCV treatments may interact with each other, and also interact with drugs of abuse and/or with medications used to treat substance abuse. Possible mechanisms of these DDIs generally include induction or inhibition of activity/expression of human cytochromes P450, glucuronosyl transferases, or energy-dependent transport proteins...
March 2017: Clinical Pharmacology in Drug Development
https://www.readbyqxmd.com/read/28263466/cure-strategies-for-hepatitis-b-virus-the-promise-of-immunotherapy
#17
Norah J Shire
Chronic hepatitits B virus remains a public health challenge, infecting more than 240 million people globally and causing 600,000 deaths per year from end-stage liver disease and/or hepatocellular carcinoma. Current antiviral therapeutic agents are highly effective at blocking viral replication, but discontinuation of therapy prior to loss of hepatitis B surface antigen generally leads to relapse. New modalities that target host factors of viral persistence such as immune response pathway inhibition hold promise...
March 2017: Clinical Pharmacology in Drug Development
https://www.readbyqxmd.com/read/28263465/pharmacokinetic-considerations-for-combining-antiretroviral-therapy-direct-acting-antiviral-agents-for-hepatitis-c-virus-and-addiction-treatment-medications
#18
LETTER
Cindy J Bednasz, Charles S Venuto, Qing Ma, Gene D Morse
There are many factors that can affect the pharmacokinetics (PK) of drugs. Pathophysiological changes from disease states can alter the mechanisms that control the PK of antiretrovirals (ARVs), direct-acting antivirals (DAAs), and addiction treatment medications. Drug-drug interaction pathways of certain ARVs and DAAs can be very complex, with agents being substrates, inhibitors, or inducers of multiple metabolic and transporter pathways. Buprenorphine and methadone may be used in HIV- and hepatitis C virus (HCV)-infected patients and may also be affected by drug interactions...
March 2017: Clinical Pharmacology in Drug Development
https://www.readbyqxmd.com/read/28263464/assessment-of-hepatic-impairment-and-implications-for-pharmacokinetics-of-substance-use-treatment
#19
Andrew H Talal, Charles S Venuto, Islam Younis
Although the liver is the primary site of metabolism and biliary excretion for many medications, data are limited on the liver's pharmacokinetic abilities in cirrhosis. Cirrhosis develops through collagen deposition, eventually culminating in end-stage liver disease that compromises hepatic drug metabolism. Consequently, the US Food and Drug Administration (FDA) recommends evaluating the pharmacokinetics of medications in subjects with hepatic impairment if hepatic metabolism constitutes more than 20% of their elimination or if they have a narrow therapeutic range...
March 2017: Clinical Pharmacology in Drug Development
https://www.readbyqxmd.com/read/28263463/drug-and-drug-abuse-associated-hyperbilirubinemia-experience-with-atazanavir
#20
Jayanta Roy-Chowdhury, Namita Roy-Chowdhury, Irving Listowsky, Allan W Wolkoff
Hyperbilirubinemia is a common finding in individuals with a history of substance abuse. Although this may indicate a serious disorder of liver function, this is not always the case. An understanding of bilirubin formation, metabolism, and transport can provide a helpful approach to dealing with these patients. This is typified by studies of patients treated with the antiretroviral drug atazanavir. Atazanavir has been associated with hyperbilirubinemia in as many as one-third of individuals for whom it has been prescribed, evoking concerns of hepatotoxicity...
March 2017: Clinical Pharmacology in Drug Development
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