scholarly journals Evaluation of the Effects of Repeat‐Dose Dabrafenib on the Single‐Dose Pharmacokinetics of Rosuvastatin (OATP1B1/1B3 Substrate) and Midazolam (CYP3A4 Substrate)

2021 ◽  
Author(s):  
Noelia Nebot ◽  
Christina S. Won ◽  
Victor Moreno ◽  
Eva Muñoz‐Couselo ◽  
Dung‐Yang Lee ◽  
...  
Keyword(s):  
Single Dose ◽  
Repeat Dose ◽  
Cyp3a4 Substrate

scholarly journals Cardiac Conduction Safety during Coadministration of Artemether-Lumefantrine and Lopinavir/Ritonavir in HIV-Infected Ugandan Adults

2011 ◽  
Vol 2011 ◽  
pp. 1-4 ◽  
Author(s):  
Pauline Byakika-Kibwika ◽  
Mohammed Lamorde ◽  
Peter Lwabi ◽  
Wilson B. Nyakoojo ◽  
Violet Okaba-Kayom ◽  
...  
Keyword(s):  
Single Dose ◽  
Cardiac Conduction ◽  
Hiv Positive ◽  
Cyp3a4 Inhibitor ◽  
Open Label ◽  
Safety Study ◽  
Serious Adverse Events ◽  
Normal Limits ◽  
Hiv Positive Adults ◽  
Cyp3a4 Substrate

Background. We aimed to assess cardiac conduction safety of coadministration of the CYP3A4 inhibitor lopinavir/ritonavir (LPV/r) and the CYP3A4 substrate artemether-lumefantrine (AL) in HIV-positive Ugandans. Methods. Open-label safety study of HIV-positive adults administered single-dose AL (80/400 mg) alone or with LPV/r (400/100 mg). Cardiac function was monitored using continuous electrocardiograph (ECG). Results. Thirty-two patients were enrolled; 16 taking LPV/r -based ART and 16 ART naïve. All took single dose AL. No serious adverse events were observed. ECG parameters in milliseconds remained within normal limits. QTc measurements did not change significantly over 72 hours although were higher in LPV/r arm at 24 (424 versus 406; P=.02) and 72 hours (424 versus 408; P=.004) after AL intake. Conclusion. Coadministration of single dose of AL with LPV/r was safe; however, safety of six-dose AL regimen with LPV/r should be investigated.

XmAb™2513, an Fc Engineered Humanized Anti-CD30 Monoclonal Antibody, Has Potent In Vitro and In Vivo Activities, and Has the Potential for Treating Hematologic Malignancies.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2340-2340 ◽  
Author(s):  
Chris E. Lawrence ◽  
Phil W. Hammond ◽  
Jonathan Zalevsky ◽  
Holly Horton ◽  
Seung Chu ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Single Dose ◽  
Tumor Growth ◽  
Cynomolgus Monkey ◽  
Hematologic Malignancies ◽  
Repeat Dose ◽  
Dose Administration ◽  
Dose Study ◽  
Dependent Cell

Abstract XmAb2513 is a novel humanized monoclonal antibody (mAb) that binds to the human cell surface antigen CD30 and demonstrates anti-proliferative activity against CD30-positive (CD30+) cell lines. XmAb2513 also has an engineered Fc region to enhance cell killing activity via recruitment of effector cells through increased binding affinity to Fcγ receptors (FcγRs). Consequently, XmAb2513 exhibits superior antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cell-mediated phagocytosis (ADCP), when compared to a native IgG1 (unengineered) version of the antibody. To evaluate the potential clinical activity of XmAb2513 in CD30+ diseases such as Hodgkin Lymphoma (HL) and Anaplastic Large Cell Lymphoma (ALCL), XmAb2513 was tested in murine subcutaneous xenograft models of HL using the CD30+ L540 cell line. In the ICR-SCID mouse strain, intraperitoneal (ip) administration of XmAb2513 at 3 mg/kg every 4 days for 10 doses (q4d ×10), gave a statistically significant reduction in tumor growth and enhanced survival relative to the control. At doses of 10 and 30 mg/kg XmAb2513 (ip, q4d ×10) tumor growth was not only slowed, but elimination of established tumors was observed in 3/9 and 5/9 animals respectively. The treatment was well-tolerated. Preclinical studies were conducted to evaluate the safety and pharmacokinetics of XmAb2513 in large animals. In vitro studies demonstrated that the cynomolgus monkey was the appropriate species for study. Binding affinities of XmAb2513 to both human and cynomolgus monkey CD30 and FcγRs were evaluated by Biacore methods and were found to be similar. Additionally, fluorescein-XmAb2513 gave similar staining patterns in immunohistochemistry cross-reactivity studies with normal human and cynomolgus monkey tissue panels. As evidenced by in-life observations single (0, 1 and 100 mg/kg XmAb2513, intravenous [iv] infusion) and repeat dose (0, 10, 30 and 100 mg/kg XmAb2513, q5d ×6, iv infusion) treatment with XmAb2513 was well-tolerated. Serum cytokines showed no trend that was indicative of an XmAb2513-related effect following single dose administration. The pharmacokinetics of XmAb2513 was also determined after either single or repeat dose administration. In the repeat dose study (0, 3, 10 and 30 mg/kg XmAb2513, q5d ×6, iv infusion) exposure increased in a dose proportional manner, and terminal half-life (t1/2) ranged from 12–17 days. In the single dose study (0, 1 and 100 mg/kg XmAb2513, iv infusion) exposure was also proportional to dose. The exposure and t1/2 data support an every other week dosing interval in the clinic. These preclinical data provide a rationale for the clinical testing of XmAb2513 in patients with hematologic malignancies that express CD30, specifically HL and ALCL, and support the safety of repeat administration of XmAb2513 in humans.

Evaluating Associations Between Nonclinical Cardiovascular Functional Endpoints and Repeat-dose Cardiovascular Toxicity in the Beagle Dog: A Cross-company Initiative

2020 ◽  
Vol 176 (1) ◽  
pp. 224-235 ◽  
Author(s):  
Philip Milliken ◽  
Mike Aylott ◽  
Nick Edmunds ◽  
Steven Engle ◽  
Lorna Ewart ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Heart Rate ◽  
Single Dose ◽  
Cardiac Muscle ◽  
Trend Test ◽  
Muscle Pathology ◽  
Repeat Dose ◽  
Predictive Values ◽  
Functional Changes ◽  
Safety Pharmacology

Abstract Integrating nonclinical in vitro, in silico, and in vivo datasets holistically can improve hazard characterization and risk assessment. In pharmaceutical development, cardiovascular liabilities are a leading cause of compound attrition. Prior to clinical studies, functional cardiovascular data are generated in single-dose safety pharmacology telemetry studies, with structural pathology data obtained from repeat-dose toxicology studies with limited concurrent functional endpoints, eg, electrocardiogram via jacketed telemetry. Relationships between datasets remain largely undetermined. To address this gap, a cross-pharma collaboration collated functional and structural data from 135 compounds. Retrospective functional data were collected from good laboratory practice conscious dog safety pharmacology studies: effects defined as hemodynamic blood pressure or heart rate changes. Morphologic pathology findings (mainly degeneration, vacuolation, inflammation) from related toxicology studies in the dog (3–91 days repeat-dosing) were reviewed, harmonized, and location categorized: cardiac muscle (myocardium, epicardium, endocardium, unspecified), atrioventricular/aortic valves, blood vessels. The prevalence of cardiovascular histopathology changes was 11.1% of compounds, with 53% recording a functional blood pressure or heart rate change. Correlations were assessed using the Mantel-Haenszel Chi-square trend test, identifying statistically significant associations between cardiac muscle pathology and (1) decreased blood pressure, (2) increased heart rate, and between cardiovascular vessel pathology and increased heart rate. Negative predictive values were high, suggesting few compounds cause repeat-dose cardiovascular structural change in the absence of functional effects in single-dose safety pharmacology studies. Therefore, observed functional changes could prompt moving (sub)chronic toxicology studies forward, to identify cardiovascular liabilities earlier in development, and reduce late-stage attrition.

Safety, Tolerability, and Pharmacokinetics of Sumatriptan Suppositories Following Single and Multiple doses in Healthy Volunteers

Cephalalgia ◽  
1997 ◽  
Vol 17 (4) ◽  
pp. 532-540 ◽  
Author(s):  
RL Kunka ◽  
EK Hussey ◽  
S Shaw ◽  
P Warner ◽  
B Aubert ◽  
...  
Keyword(s):  
Single Dose ◽  
Adverse Events ◽  
Plasma Concentrations ◽  
Repeat Dose ◽  
Oral Tablet ◽  
Single Dose Study ◽  
Multiple Doses ◽  
Dose Study ◽  
To Receive ◽  
Male Subjects

A suppository formulation of file 5HT1 agonist sumatriptan could prove an important therapeutic option in migraine patients who dislike or poorly tolerate injectable therapy and where oral tablet administration is unsuitable because of severe migraine-related vomiting. Two independent double-blind, randomized clinical studies were conducted to evaluate the safety, tolerability and pharmacokinetics of sumatriptan suppositories following ascending single dose. (four different dose levels) and multiple doses. In the four-period, crossover, single-dose study, 24 healthy male subjects were randomized to receive a suppository containing 12.5, 25, 50, or 100 mg on separate occasions 3–14 days apart. The suppositories were generally well tolerated; transient asthenia, drowsiness, and headache were the most frequently reported adverse events, and these were not close-related. Peak plasma concentrations (Cmax) of sumatriptan were proportional to close from 25 to 100 mg; area under the plasma concentration-time curve (AUCx) values were proportional to dose except at the highest doses, when they were greater than those predicted from lower doses. For all doses, the tmax of sumatriptan occurred within 2.5h, and the t1/2 was approximately 2h. In the two-period, placebo-controlled, crossover, repeat-dose study, 12 healthy adult male subjects were randomized to receive either a 50-mg sumatriptan suppository or placebo suppository, administered rectally twice a day, for 11 doses (5 1/2 days). Adverse events were no more frequent with sumatriptan than with placebo, and stool guaiac, rectal examinations, and physical examinations remained normal. No significant differences were noted between Day 1 and Day 6 values in the AUC, Cmax, time of peak serum concentration (tmax), elimination half-life (t1/2), fraction of the dose excreted in the urine (fe), or renal clearance (Clr) of sumatriptan or its pharmacologically inactive indole acetic acid metabolite. Serum metabolite concentrations were two to threefold higher than corresponding sumatriptan concentrations. No clinically significant accumulation of sumatriptan or its metabolite occurred. Overall, these studies show that sumatriptan administration via a suppository formulation is well tolerated, allows rapid absorption of sumatriptan, results in sumatriptan Cmax values that are proportion I to dose from 25 to 100 mg, and is not associated with accumulation of sumatriptan or its nnetabolite.

Characterising the plasma-target occupancy relationship of the neurokinin antagonist GSK1144814 with PET

2014 ◽  
Vol 28 (3) ◽  
pp. 244-253 ◽  
Author(s):  
Khanum Ridler ◽  
Roger N Gunn ◽  
Graham E Searle ◽  
Julien Barletta ◽  
Jan Passchier ◽  
...  
Keyword(s):  
Single Dose ◽  
Plasma Concentration ◽  
Human Brain ◽  
Dose Range ◽  
Receptor Occupancy ◽  
Repeat Dose ◽  
Dose Selection ◽  
Dose Administration ◽  
Single Dose Administration

GSK1144814 is a potent, insurmountable antagonist at human NK1 and NK3 receptors. Understanding the relationship between plasma pharmacokinetics and receptor occupancy in the human brain, was crucial for dose selection in future clinical studies. GSK1144814 occupancy data were acquired in parallel with the first-time-in-human safety and tolerability study. [11C]GR-205171 a selective NK1 receptor PET ligand was used to estimate NK1 occupancy at several time-points following single dose administration of GSK1144814. The time-plasma concentration–occupancy relationship post-single dose administration was assessed, and used to predict the plasma concentration–occupancy relationship following repeat dose administration. Repeat dose predictions were tested in a subsequent cohort of subjects examined following approximately 7 and 14 days dosing with GSK1144814. GSK1144814 was shown to demonstrate a dose-dependent occupancy of the NK1 receptor with an estimated in vivo EC50 ~0.9 ng/mL in the human brain. A direct relationship was seen between the GSK1144814 plasma concentration and its occupancy of the brain NK1 receptor, indicating that in future clinical trials the occupancy of brain receptors can be accurately inferred from the measured plasma concentration. Our data provided support for the further progression of this compound and have optimised the likely therapeutic dose range.

scholarly journals In vitro and clinical investigations to determine the drug-drug interaction potential of entrectinib, a small molecule inhibitor of neurotrophic tyrosine receptor kinase (NTRK)

2021 ◽  
Author(s):  
Georgina Meneses-Lorente ◽  
Stephen Fowler ◽  
Elena Guerini ◽  
Karey Kowalski ◽  
Edna Chow-Maneval ◽  
...  
Keyword(s):  
Single Dose ◽  
Clinical Studies ◽  
Healthy Subjects ◽  
Phase 1 ◽  
Anaplastic Lymphoma ◽  
P Glycoprotein ◽  
Cyp3a4 Inducer ◽  
Cyp3a4 Substrate ◽  
Registration Number

AbstractBackground Entrectinib is a CNS-active, potent inhibitor of tyrosine receptor kinases A/B/C, ROS1 and anaplastic lymphoma kinase approved for use in patients with solid tumors. We describe the in vitro and clinical studies investigating potential entrectinib drug-drug interactions. Methods In vitro studies with human biomaterials assessed the enzymes involved in entrectinib metabolism, and whether entrectinib modulates the activity of the major cytochrome P450 (CYP) enzymes or drug transporter P-glycoprotein. Clinical studies investigated the effect of a strong CYP3A4 inhibitor (itraconazole) and inducer (rifampin) on single-dose entrectinib pharmacokinetics. The effect of entrectinib on sensitive probe substrates for CYP3A4 (midazolam) and P-glycoprotein (digoxin) were also investigated. Results Entrectinib is primarily metabolized by CYP3A4. In vitro, entrectinib is a CYP3A4/5 inhibitor (IC50 2 μM) and a weak CYP3A4 inducer. Entrectinib inhibited P-glycoprotein (IC50 1.33 μM) but is a poor substrate. In healthy subjects, itraconazole increased entrectinib Cmax and AUC by 73% and 504%, respectively, and rifampin decreased entrectinib Cmax and AUC by 56% and 77%, respectively. Single dose entrectinib did not affect midazolam AUC, although Cmax decreased by 34%. Multiple dose entrectinib increased midazolam AUC by 50% and decreased Cmax by 21%. Single dose entrectinib increased digoxin AUC and Cmax by 18% and 28%, respectively, but did not affect digoxin renal clearance. Conclusions Entrectinib is a CYP3A4 substrate and is sensitive to the effects of coadministered moderate/strong CYP3A4 inhibitors and strong inducers, and requires dose adjustment. Entrectinib is a weak inhibitor of CYP3A4 and P-glycoprotein and no dose adjustments are required with CYP3A4/P- glycoprotein substrates.Registration Number (Study 2) NCT03330990 (first posted online November 6, 2017) As studies 1 and 3 are phase 1 trials in healthy subjects, they are not required to be registered.

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