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.

scholarly journals Phase I Study Assessing the Pharmacokinetic Profile, Safety, and Tolerability of a Single Dose of Ceftazidime-Avibactam in Hospitalized Pediatric Patients

2016 ◽  
Vol 60 (10) ◽  
pp. 6252-6259 ◽  
Author(s):  
John S. Bradley ◽  
Jon Armstrong ◽  
Antonio Arrieta ◽  
Raafat Bishai ◽  
Shampa Das ◽  
...  
Keyword(s):  
Single Dose ◽  
Phase I ◽  
Pediatric Patients ◽  
Geometric Mean ◽  
Open Label ◽  
Serious Adverse Events ◽  
Time Curve ◽  
Age Cohorts ◽  
Concentration Time ◽  
Systemic Antibiotic Therapy

ABSTRACTThis study aimed to investigate the pharmacokinetics (PK), safety, and tolerability of a single dose of ceftazidime-avibactam in pediatric patients. A phase I, multicenter, open-label PK study was conducted in pediatric patients hospitalized with an infection and receiving systemic antibiotic therapy. Patients were enrolled into four age cohorts (cohort 1, ≥12 to <18 years; cohort 2, ≥6 to <12 years; cohort 3, ≥2 to <6 years; cohort 4, ≥3 months to <2 years). Patients received a single 2-h intravenous infusion of ceftazidime-avibactam (cohort 1, 2,000 to 500 mg; cohort 2, 2,000 to 500 mg [≥40 kg] or 50 to 12.5 mg/kg [<40 kg]; cohorts 3 and 4, 50 to 12.5 mg/kg). Blood samples were collected to describe individual PK characteristics for ceftazidime and avibactam. Population PK modeling was used to describe characteristics of ceftazidime and avibactam PK across all age groups. Safety and tolerability were assessed. Thirty-two patients received study drug. Mean plasma concentration-time curves, geometric mean maximum concentration (Cmax), and area under the concentration-time curve from time zero to infinity (AUC0–∞) were similar across all cohorts for both drugs. Six patients (18.8%) reported an adverse event, all mild or moderate in intensity. No deaths or serious adverse events occurred. The single-dose PK of ceftazidime and avibactam were comparable between each of the 4 age cohorts investigated and were broadly similar to those previously observed in adults. No new safety concerns were identified. (This study has been registered at ClinicalTrials.gov under registration no. NCT01893346.)

scholarly journals Single center, open label dose escalating trial evaluating once weekly oral ixazomib in ART-suppressed, HIV positive adults and effects on HIV reservoir size in vivo.

2021 ◽  
Vol 42 ◽  
pp. 101225
Author(s):  
Nathan W Cummins ◽  
Jason Baker ◽  
Rana Chakraborty ◽  
Patrick G Dean ◽  
Enrique Garcia-Rivera ◽  
...  
Keyword(s):  
Hiv Positive ◽  
Single Center ◽  
Open Label ◽  
Hiv Reservoir ◽  
Label Dose ◽  
Hiv Positive Adults ◽  
Dose Escalating

scholarly journals A Phase 3 Multicenter, Prospective, Open-Label Efficacy and Safety Study of Immune Globulin (Human) 10% Caprylate/Chromatography Purified in Patients with Myasthenia Gravis Exacerbations

2019 ◽  
Vol 81 (5-6) ◽  
pp. 223-230 ◽  
Author(s):  
Guntis Karelis ◽  
Rodica Balasa ◽  
Jan L. De Bleecker ◽  
Tima Stuchevskaya ◽  
Andres Villa ◽  
...  
Keyword(s):  
Myasthenia Gravis ◽  
Immune Globulin ◽  
Autoimmune Disorder ◽  
Efficacy And Safety ◽  
Open Label ◽  
Safety Study ◽  
Serious Adverse Events ◽  
Good Tolerability ◽  
Secondary Endpoints ◽  
Patients Experience

Background: Myasthenia gravis (MG) is an autoimmune disorder affecting neuromuscular transmission. Exacerbations may involve increasing bulbar weakness and/or sudden respiratory failure, both of which can be critically disabling. Management of MG exacerbations includes plasma exchange and intravenous immunoglobulin (IVIG); they are equally effective, but patients experience fewer side effects with IVIG. The objective of this study was to assess the efficacy and safety of immune globulin caprylate/chromatography purified (IGIV-C) in subjects with MG exacerbations. Methods: This prospective, open-label, non-controlled 28-day clinical trial was conducted in adults with MG Foundation of America class IVb or V status. Subjects received IGIV-C 2 g/kg over 2 consecutive days (1 g/kg/day) and were assessed for efficacy/safety on Days 7, 14, 21, and 28. The primary efficacy endpoint was the change from Baseline in quantitative MG (QMG) score to Day 14. Secondary endpoints of clinical response, Baseline to Day 14, included at least a 3-point decrease in QMG and MG Composite and a 2-point decrease in MG-activities of daily living (MG-ADL). Results: Forty-nine subjects enrolled. The change in QMG score at Day 14 was significant (p < 0.001) in the Evaluable (–6.4, n = 43) and Safety (–6.7, n = 49) populations. Among evaluable subjects, Day 14 response rates were 77, 86, and 88% for QMG, MG Composite, and MG-ADL, respectively. IGIV-C showed good tolerability with no serious adverse events. Conclusions: The results of this study show that IGIV-C was effective, safe, and well tolerated in the treatment of MG exacerbations.

A drug-drug interaction study between the strong CYP3A4 inhibitor ketoconazole (keto) and ixazomib citrate (MLN9708), an investigational, orally active proteasome inhibitor, in patients with advanced solid tumors or lymphoma.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2555-2555 ◽  
Author(s):  
Neeraj Gupta ◽  
Karthik Venkatakrishnan ◽  
Dennis A Noe ◽  
Michael J Hanley ◽  
Jiang Yu ◽  
...  
Keyword(s):  
Single Dose ◽  
Proteasome Inhibitor ◽  
Active Form ◽  
Fold Increase ◽  
Biologically Active ◽  
Cyp3a4 Inhibitor ◽  
Open Label ◽  
Fixed Sequence ◽  
Cyp3a4 Inhibitors ◽  
D 12

2555 Background: MLN9708 is an oral proteasome inhibitor currently being investigated in multiple myeloma and amyloidosis in phase 3 studies. MLN9708 immediately hydrolyzes to its biologically active form, MLN2238, in aqueous solutions or plasma. Metabolism by multiple cytochrome p450s (CYPs) including 3A4 and 1A2 (>25% contribution by each) was expected to be the primary clearance mechanism for MLN2238 based on human liver microsomal metabolism studies. This open-label, multicenter study (NCT01454076) characterizes the effect of CYP3A4 inhibition with keto on single-dose pharmacokinetics (PK) of MLN9708 in a fixed sequence design. Methods: Patients received MLN9708 2.5 mg on d 1 and 15, and keto 400 mg (PO) daily on d 12–25. On d 15, MLN9708 and keto were administered concomitantly. Serial blood samples were collected over 0–264 hr after MLN9708 doses on d 1 and 15 for PK characterization. Plasma PK parameters were estimated by non-compartmental methods. The effect of keto co-administration on MLN9708 AUC0–264hr and Cmaxwas evaluated by Analysis of Variance of log-transformed values. Results: 16 PK-evaluable patients (11 Caucasian, 3 African American, 2 Hispanic; 6M, 10F) with mean (range) age of 61 years (48–79) and body surface area of 1.8 m2 (1.5–2.3) were enrolled. Co-administration of MLN9708 and keto resulted in a 2-fold increase in MLN9708 AUC0–264hr but no change in Cmax(Table). No differences in adverse events were observed +/- the addition of keto, to a single dose of 2.5 mg MLN9708. Conclusions: The observed 2-fold increase in MLN9708 AUC0–264hrwith a strong CYP3A4 inhibitor suggests the contribution of CYP3A4 clearance to the total clearance of MLN9708 is significant. These results support the continued exclusion of strong CYP3A4 inhibitors in ongoing and planned clinical trials of MLN9708. Clinical trial information: NCT01454076. [Table: see text]

scholarly journals Efficacy and Safety of a Single Dose of Ivermectin, Diethylcarbamazine, and Albendazole for Treatment of Lymphatic Filariasis in Côte d’Ivoire: An Open-label Randomized Controlled Trial

2019 ◽  
Vol 71 (7) ◽  
pp. e68-e75 ◽  
Author(s):  
Catherine M Bjerum ◽  
Allassane F Ouattara ◽  
Méité Aboulaye ◽  
Olivier Kouadio ◽  
Vanga K Marius ◽  
...  
Keyword(s):  
Single Dose ◽  
Lymphatic Filariasis ◽  
Cote D'ivoire ◽  
Côte D’Ivoire ◽  
Controlled Trial ◽  
Wuchereria Bancrofti ◽  
Open Label ◽  
Serious Adverse Events ◽  
Cote D’Ivoire ◽  
Côte D'ivoire

Abstract Background Improved drug regimens are needed to accelerate elimination of lymphatic filariasis in Africa. This study determined whether a single co-administered dose of ivermectin plus diethylcarbamazine plus albendazole [IDA] is noninferior to standard 3 annual doses of ivermectin plus albendazole (IA) used in many LF-endemic areas of Africa. Methods Treatment-naive adults with Wuchereria bancrofti microfilaremia in Côte d’Ivoire were randomized to receive a single dose of IDA (n = 43) or 3 annual doses of IA (n = 52) in an open-label, single-blinded trial. The primary endpoint was the proportion of participants who were microfilaria (Mf) negative at 36 months. Secondary endpoints were Mf clearance at 6, 12, and 24 months; inactivation of adult worm nests; and safety. Results At 36 months posttreatment with IDA, 18/33 (55%; 95% CI, 38–72%) cleared Mf versus 33/42 (79%; 67–91%) with IA (P = .045). At 6 and 12 months IDA was superior to IA in clearing Mf (89% [77–99%] and 71% [56–85%]), respectively, versus 34% (20–48%) and 26% (14–42%) (P &lt; .001). IDA was equivalent to IA at 24 months (61% [45–77%] vs 54% [38–72%]; P = .53). IDA was superior to IA for inactivating adult worms at all time points. Both treatments were well tolerated, and there were no serious adverse events. Conclusions A single dose of IDA was superior to 2 doses of IA in reducing the overall Mf burden by 24 months. Reinfection may have contributed to the lack of sustained clearance of Mf with IDA. Clinical Trials Registration NCT02974049.

scholarly journals 1320. Pharmacokinetics of Isavuconazole Administered as Isavuconazonium Sulfate Intravenous Solution via Nasogastric Tube or Orally in Healthy Volunteers

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S671-S671
Author(s):  
Amit Desai ◽  
Melanie Helmick ◽  
Nakyo Heo ◽  
Selina Moy ◽  
Stephen Stanhope ◽  
...  
Keyword(s):  
Single Dose ◽  
Fungal Infections ◽  
Tube Feeding ◽  
Least Square ◽  
Multiple Time ◽  
Global Development ◽  
Open Label ◽  
Serious Adverse Events ◽  
Material Support ◽  
Routes Of Administration

Abstract Background Nasogastric (NG) tube feeding is most common in the intensive care unit and is also used for cancer patients who are unable to eat (e.g. patients with mucositis) or do not want to eat due to severe nausea1. For such critically ill patients with invasive fungal infections, administration of isavuconazonium sulfate (ISAVUSULF) via NG tube can be an alternate route of drug administration. Methods This was a randomized, open-label, 2-period, 2-sequence single dose crossover study in healthy male and female subjects. Each subject participated in 2 treatment periods separated by a washout of at least 30 days between investigational product administrations in each period. Subjects were administered a single dose of 372 mg ISAVUSULF intravenous (IV) solution via NG tube (test formulation) or 372 mg ISAVUSULF capsules for oral (PO) administration (i.e., PO capsules administered to subjects without NG tube) (reference formulation) under fasting conditions on day 1 of each period. Pharmacokinetic (PK) samples were collected predose on day 1 of each period and at multiple time points postdose through day 21. Standard safety and tolerability assessments were conducted in each period. Results Eighteen subjects were randomized in this study and 13 provided concentrations in both sequences that were PK evaluable. The analysis of variance estimate (Table 1) of the study population suggests that the isavuconazole IV NG tube administration geometric least-square (LS) mean values of the observed maximum concentration (Cmax), area under the plasma concentration-time curve (AUC) to the last measurable concentration (AUClast), AUC to time infinity (AUCinf), and AUC from start of dosing to 72 hours (AUC72) were 105.3%, 97.6%, 99.3% and 97.8%, respectively, of the corresponding oral administration values. The geometric LS mean ratio and 90% Confidence Intervals for the Cmax, AUClast, AUCinf, and AUC72 are completely contained within the prespecified limits of 80% to 125%. There were no deaths or serious adverse events that led to withdrawal of treatment during the conduct of the study. Table 1 Conclusion The study met its primary endpoint of bioequivalence between the two routes of administration in this population. Both routes of administration are well tolerated. Reference 1 Disclosures Amit Desai, PhD, Astellas Pharma Inc. (Employee, Other Financial or Material Support, This study was initiated and sponsored by Astellas Pharma Global Development Inc) Melanie Helmick, BA, Clinical Research, Astellas Pharma Inc. (Employee, Other Financial or Material Support, This study was initiated and sponsored by Astellas Pharma Global Development Inc) Nakyo Heo, PharmD, MS, Astellas Pharma Inc. (Employee, Other Financial or Material Support, This study was initiated and sponsored by Astellas Pharma Global Development Inc) Selina Moy, BS, Astellas Pharma Inc. (Employee, Other Financial or Material Support, This study was initiated and sponsored by Astellas Pharma Global Development Inc) Stephen Stanhope, PhD, Astellas Pharma Inc. (Employee, Other Financial or Material Support, This study was initiated and sponsored by Astellas Pharma Global Development Inc) Ronald Goldwater, MDCM, Astellas Pharma Inc. (Other Financial or Material Support, This study was initiated and sponsored by Astellas Pharma Global Development Inc. Parexel International received fees for research support from Astellas Pharma Global Development Inc.)Parexel International (Employee, Employee of Parexel International) Nancy Martin, MD, PharmD, Astellas Pharma Inc. (Employee, Other Financial or Material Support, This study was initiated and sponsored by Astellas Pharma Global Development Inc)

Effects of a potent CYP3A inhibitor on the pharmacokinetics and safety of enzastaurin

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 2572-2572
Author(s):  
L. Musib ◽  
C. Darstein ◽  
J. Suico ◽  
J. Baldwin ◽  
P. Welch
Keyword(s):  
Single Dose ◽  
Plasma Concentrations ◽  
Clinical Effects ◽  
Open Label ◽  
Post Dose ◽  
Serious Adverse Events ◽  
Fixed Sequence ◽  
Qt Intervals ◽  
Small Change

2572 Background: Enzastaurin (ENZ) targets the PKCβ and PI3K/AKT pathways to induce tumor cell apoptosis, reduce proliferation, and suppress tumor-induced angiogenesis. ENZ is metabolized by CYP3A in vitro. This study examined the potential clinical effects of a potent CYP3A4 inhibitor, ketoconazole (KETO), on the pharmacokinetics and safety of ENZ. Methods: In this open-label, fixed-sequence, three-period, crossover study (duration = 6 weeks), healthy subjects received an oral, 200- mg, single dose of ENZ (period 1); 400-mg daily doses of KETO for 4 days to assess QT (period 2); and 400-mg daily doses of KETO for 14 days, with a 200-mg single dose of ENZ given on day 4 (period 3). Plasma samples for PK analysis were collected predose and after ENZ administration in periods 1 and 3 at scheduled intervals. Results: Of the 16 women enrolled, 13 completed the study. Changes in PK parameters of ENZ and its metabolite, LY326020, in the presence of KETO are summarized in the table . No serious adverse events (AEs) occurred. A similar number of AEs possibly related to enzastaurin occurred in period 1 (6) and period 3 (7). Headache (n=4) and nausea (n=3) were more frequent in period 3, but were also the most common AEs related to KETO. Three patients had hepatic transaminase elevations, but no consistent pattern with dosing period or ENZ exposures was observed. At 4 hours post-dose, QT intervals were prolonged by a mean 5.88 (95% CI: 1.767–10.00) msec after four daily doses of KETO and by a mean 9.29 (95% CI: 5.165–13.41) msec when coadministered with ENZ. Conclusion: In the presence of KETO, plasma concentrations of ENZ and its metabolites increased significantly. ENZ alone did not increase QT intervals. Ketoconazole plus ENZ caused a slightly greater increase in QT intervals compared to KETO alone, but this very small change may not be clinically significant. ENZ was generally well tolerated, alone or with KETO. [Table: see text] No significant financial relationships to disclose.

scholarly journals Efficacy and Safety of Pyronaridine-Artesunate plus Single-Dose Primaquine for Treatment of UncomplicatedPlasmodium falciparumMalaria in Eastern Cambodia

2019 ◽  
Vol 63 (3) ◽  
Author(s):  
Rithea Leang ◽  
Melissa Mairet-Khedim ◽  
Huch Chea ◽  
Rekol Huy ◽  
Nimol Khim ◽  
...  
Keyword(s):  
Single Dose ◽  
Adverse Events ◽  
Multidrug Resistant ◽  
Open Label ◽  
Serious Adverse Events ◽  
Content Type ◽  
Copy Numbers ◽  
Kaplan Meier ◽  
Antimalarial Therapy ◽  
Clinical Trials Registry

ABSTRACTIn Cambodia, multidrug-resistantPlasmodium falciparumundermines the treatment of uncomplicated malaria, and new therapeutic options are needed. Pyronaridine-artesunate has not previously been evaluated in eastern Cambodia. We conducted a single-arm, open-label, prospective study between July and December 2017 at the Koh Gnek (Mondulkiri) and Veun Sai (Rattanakiri) health centers in eastern Cambodia. Eligible patients were aged ≥7 years (females, ages 12 to 18 years, were excluded), weighing ≥20 kg, with microscopically confirmedP. falciparummonoinfection and fever. Oral pyronaridine-artesunate was administered once daily for 3 days, dosed according to body weight, plus a single dose of primaquine on day 0. Sixty patients were recruited to Koh Gnek, and 61 patients were recruited to Veun Sai. The primary outcomes, i.e., the day 42 PCR-adjusted adequate clinical and parasitological responses (ACPRs), were 98.3% (95% confidence interval [CI], 88.4 to 99.8) in Koh Gnek and 96.7% (95% CI, 87.3 to 99.2) in Veun Sai (Kaplan-Meier). In a per-protocol analysis, the proportions of patients with day 42 PCR-adjusted ACPRs were 98.3% (57/58; 95% CI, 90.8 to 100.0) at Koh Gnek and 96.7% (58/60; 95% CI, 88.5 to 99.6) at Veun Sai. TheKelch13(C580Y) mutation was present in 70.0% (77/110) of isolates. The copy numbers were increased in 61.3% (73/119) of isolates forPfpm2and in 1.7% (2/119) forPfmdr1. There was no relationship between outcome and the 50% inhibitory concentration of pyronaridine. Adverse events were consistent with malaria, and there were no serious adverse events. Pyronaridine-artesunate has high efficacy in eastern Cambodia and could be used to increase the diversity of antimalarial therapy in the region. (This study is registered in the Australian New Zealand Clinical Trials Registry [ANZCTR] under no. ACTRN12618001300268.)

scholarly journals 1318. Pharmacokinetics and Safety of Cefepime-Taniborbactam (formerly Cefepime/VNRX-5133) in Subjects with Renal Impairment

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S670-S670
Author(s):  
Brooke Geibel ◽  
James A Dowell ◽  
Thomas C Marbury ◽  
William Smith ◽  
Paul C McGovern ◽  
...  
Keyword(s):  
Single Dose ◽  
Adverse Events ◽  
Renal Impairment ◽  
Clinical Laboratory ◽  
Severe Renal Impairment ◽  
Phase 1 ◽  
Vital Signs ◽  
Open Label ◽  
Independent Contractor ◽  
Serious Adverse Events

Abstract Background Taniborbactam is a novel, non-ß-lactam, ß-lactamase inhibitor with activity against serine (Class A, C, D) and metallo (Class B) ß-lactamases including epidemiologically important carbapenemases. Both cefepime and taniborbactam are predominantly renally excreted and are likely to require dose adjustment in patients with renal impairment and end-stage renal disease (ESRD). The current study was designed to evaluate the pharmacokinetics and safety in patients with renal impairment and ESRD. Methods This was a Phase 1, open-label study in subjects with normal renal function (eCLCR ≥ 90 mL/min) matched to subjects with mild, moderate, and severe renal impairment (eGFR 60-89, 30-59, and &lt; 30 mL/min/1.73m2, respectively), and patients with ESRD on hemodialysis. Subjects received a single dose of cefepime 2 g and taniborbactam 500 mg; subjects with ESRD received a single dose before HD and after a 9 day washout period, following HD. PK parameters including AUC0-inf and total body clearance (CL) were evaluated. Safety assessments included adverse events (AEs), vital signs, clinical laboratory evaluations, electrocardiograms, and physical examinations. Results Thirty-three subjects were enrolled; 67% male, 58% white and 39% black/African Americans. Median age and BMI were 55.0 years and 29.5 kg/m2, respectively. For both cefepime and taniborbactam, exposures increased, and CL decreased with increasing renal impairment (see Table). The hemodialysis extraction ratio was 49.7% and 47.4% for taniborbactam and cefepime respectively. No safety signals were observed and there were no serious adverse events. Table Conclusion Cefepime and taniborbactam CL is similarly reduced with varying degrees of renal impairment. Dialysis removes a high fraction of both drugs. Dose adjustments recommended for cefepime are appropriate for taniborbactam. Disclosures Brooke Geibel, BS, Venatorx Pharmaceuticals (Employee, Shareholder) James A. Dowell, PhD, Venatorx Pharmaceuticals (Independent Contractor) Thomas C. Marbury, MD, Venatorx Pharmaceuticals (Independent Contractor) William Smith, MD, Venatorx Pharmaceuticals (Independent Contractor) Paul C. McGovern, MD, Venatorx Pharmaceuticals (Employee) Cynthia Richards, MD, Venatorx Pharmaceuticals (Independent Contractor) Tim Henkel, MD, PhD, Venatorx Pharmaceuticals (Employee, Shareholder)

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