scholarly journals Impact of Rifabutin or Rifampin on Bedaquiline Safety, Tolerability, and Pharmacokinetics Assessed in a Randomized Clinical Trial with Healthy Adult Volunteers

2017 ◽  
Vol 62 (1) ◽  
Author(s):  
Amanda M. Healan ◽  
J. McLeod Griffiss ◽  
Howard M. Proskin ◽  
Mary Ann O'Riordan ◽  
Wesley A. Gray ◽  
...  

ABSTRACT Bedaquiline is a diarylquinoline that specifically inhibits mycobacterial ATP synthase. Bedaquiline has been used to effectively treat tuberculosis (TB) caused by drug-susceptible and drug-resistant Mycobacterium tuberculosis. Rifamycins are a cornerstone of combination drug regimens for the treatment of TB. This phase 1, open-label, randomized, controlled trial evaluated the effect of steady-state dosing of rifabutin or rifampin on the safety, tolerability, and pharmacokinetics of bedaquiline given as a single dose. Thirty-three healthy subjects were enrolled to receive a 400-mg single oral dose of bedaquiline at two time points, on study days 1 and 29. Subjects were randomly assigned to once daily oral doses of rifabutin (300 mg/day, n = 17) or rifampin (600 mg/day, n = 16) during period 2 from days 20 to 41. Serial blood sampling for bedaquiline measurement occurred on days 1 and 29 through 336 h after bedaquiline administration. The day 29 bedaquiline pharmacokinetic parameter estimates were compared to the corresponding day 1 estimates for each rifamycin group. Steady-state rifampin reduced bedaquiline AUC0–336 approximately 45%, from 47.69 h·μg/ml in period 1 to 26.33 h·μg/ml in period 2. Bedaquiline apparent clearance accelerated 24% in rifampin-treated subjects from 6.59 liters/h in period 1 to 8.19 liters/h in period 2. Steady-state rifabutin resulted in little quantitative impact on bedaquiline exposure but was associated with grade 3 and 4 adverse events before and after the day 29 bedaquiline dose. Dosage adjustments may therefore be necessary to ensure that bedaquiline plasma concentrations reach therapeutic levels safely when combining bedaquiline and rifamycins in TB treatment regimens. (This single-site, randomized, open-label, prospective study in healthy adult volunteers was registered at Clinicaltrials.gov under registration no. NCT01341184.)

2009 ◽  
Vol 53 (11) ◽  
pp. 4840-4844 ◽  
Author(s):  
C. J. L. la Porte ◽  
J. P. Sabo ◽  
L. Béïque ◽  
D. W. Cameron

ABSTRACT Previously it has been shown that tipranavir-ritonavir (TPV/r) does not affect efavirenz (EFV) plasma concentrations. This study investigates the effect of steady-state EFV on steady-state TPV/r pharmacokinetics. This was a single-center, open-label, multiple-dose study of healthy adult female and male volunteers. TPV/r 500/200 mg twice a day (BID) was given with food for 24 days. After dosing with TPV/r for 10 days, EFV 600 mg once a day was added to the regimen. Intensive pharmacokinetic (PK) sampling was done on days 10 and 24. Validated bioanalytical high-pressure liquid chromatography-tandem mass spectrometry methods were used to determine plasma tipranavir (TPV), ritonavir (RTV), and EFV concentrations. Thirty-four subjects were entered into the study, and 16 subjects completed it. The geometric mean ratios (90% confidence intervals) for TPV and RTV area under the curves, C maxs, and C mins comparing TPV/r alone and in combination with EFV were 0.97 (0.87 to 1.09), 0.92 (0.81 to 1.03), and 1.19 (0.93 to 1.54) for TPV and 1.03 (0.78 to 1.38), 0.92 (0.65 to 1.30), and 1.04 (0.72 to 1.48) for RTV. Frequently observed adverse events were diarrhea, headache, dizziness, abnormal dreams, and rash. EFV had no effect on the steady-state PK of TPV or RTV, with the exception of a 19% increase in the TPV C min, which is not clinically relevant. TPV/r can be safely coadministered with EFV and without the need for a dose adjustment.


2020 ◽  
Vol 64 (8) ◽  
Author(s):  
George R. Thompson ◽  
Phoebe Lewis ◽  
Stuart Mudge ◽  
Thomas F. Patterson ◽  
Bruce P. Burnett

ABSTRACT Super bioavailability (SUBA) itraconazole (S-ITZ), which releases drug in the duodenum, and conventional itraconazole (C-ITZ), which releases drug in the stomach, were compared in two pharmacokinetic (PK) studies: a 3-day loading dose study and a 15-day steady-state administration study. These were crossover oral bioequivalence studies performed under fed conditions in healthy adult volunteers. In the loading dose study, C-ITZ (two doses of 100 mg each) and S-ITZ (two doses of 65 mg each) were administered three times daily for 3 days and once on day 4 (n = 15). For the steady-state administration study, C-ITZ (two doses of 100 mg each) and S-ITZ (two doses of 65 mg each) were administered twice daily for 14 days and a last dose was administered 30 min after a meal on day 15 (n = 16). Blood samples collected throughout both studies were analyzed for ITZ and hydroxy-ITZ (OH-ITZ) levels. Least-squares geometric means were used to compare the maximum peak concentration of drug after administration at steady state prior to administration of the subsequent dose (Cmax_ss), the minimum drug level after administration prior to the subsequent dose (Ctrough), and the area under the curve over the dosing interval (AUCtau) of each formulation. The ratios of itraconazole (ITZ) and OH-ITZ for S-ITZ to C-ITZ were between 107% and 118% in both studies for Cmax_ss, Ctrough, and AUCtau, which were within the U.S. FDA-required bioequivalence range of 80% to 125%. At the end of the steady-state administration study, 13 of 16 volunteers obtained higher mean ITZ blood Ctrough levels of >1,000 ng/ml when they were administered S-ITZ (81%) than when they were administered C-ITZ (44%). The study drugs were well tolerated in both studies, with similar adverse events (AEs). All treatment-emergent AEs resolved after study completion. One volunteer receiving C-ITZ discontinued due to a treatment-unrelated AE in the steady-state administration study. No serious AEs were reported. Total, trough, and peak ITZ and OH-ITZ exposures were similar between the two formulations. Therefore, SUBA-ITZ, which has 35% less drug than C-ITZ, was bioequivalent to C-ITZ in healthy adult volunteers and exhibited a safety profile similar to that of C-ITZ.


2012 ◽  
Vol 8 (8) ◽  
pp. 1077-1081 ◽  
Author(s):  
Mysore Kalappa Sudarshan ◽  
Doddabele Hanumanthaiah Ashwath Narayana ◽  
Shampur Narayan Madhusudana ◽  
Ramesh Holla ◽  
Belludi Yajaman Ashwin ◽  
...  

2014 ◽  
Vol 34 (7) ◽  
pp. 475-482 ◽  
Author(s):  
Christine Y. Yu ◽  
Stuart E. Campbell ◽  
Craig A. Sponseller ◽  
David S. Small ◽  
Matthew M. Medlock ◽  
...  

2012 ◽  
Vol 56 (10) ◽  
pp. 5076-5081 ◽  
Author(s):  
Keith A. Rodvold ◽  
Mark H. Gotfried ◽  
J. Gordon Still ◽  
Kay Clark ◽  
Prabhavathi Fernandes

ABSTRACTThe steady-state concentrations of solithromycin in plasma were compared with concomitant concentrations in epithelial lining fluid (ELF) and alveolar macrophages (AM) obtained from intrapulmonary samples during bronchoscopy and bronchoalveolar lavage (BAL) in 30 healthy adult subjects. Subjects received oral solithromycin at 400 mg once daily for five consecutive days. Bronchoscopy and BAL were carried out once in each subject at either 3, 6, 9, 12, or 24 h after the last administered dose of solithromycin. Drug concentrations in plasma, ELF, and AM were assayed by a high-performance liquid chromatography-tandem mass spectrometry method. Solithromycin was concentrated extensively in ELF (range of mean [± standard deviation] concentrations, 1.02 ± 0.83 to 7.58 ± 6.69 mg/liter) and AM (25.9 ± 20.3 to 101.7 ± 52.6 mg/liter) in comparison with simultaneous plasma concentrations (0.086 ± 0.070 to 0.730 ± 0.692 mg/liter). The values for the area under the concentration-time curve from 0 to 24 h (AUC0–24values) based on mean and median ELF concentrations were 80.3 and 63.2 mg · h/liter, respectively. The ratio of ELF to plasma concentrations based on the mean and median AUC0–24values were 10.3 and 10.0, respectively. The AUC0–24values based on mean and median concentrations in AM were 1,498 and 1,282 mg · h/L, respectively. The ratio of AM to plasma concentrations based on the mean and median AUC0–24values were 193 and 202, respectively. Once-daily oral dosing of solithromycin at 400 mg produced steady-state concentrations that were significantly (P< 0.05) higher in ELF (2.4 to 28.6 times) and AM (44 to 515 times) than simultaneous plasma concentrations throughout the 24-h period after 5 days of solithromycin administration.


2001 ◽  
Vol 183 (10) ◽  
pp. 1485-1493 ◽  
Author(s):  
Thomas G. Evans ◽  
William Bonnez ◽  
Robert C. Rose ◽  
Scott Koenig ◽  
Lisa Demeter ◽  
...  

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 35-35
Author(s):  
Patricia A. Young ◽  
Fabio D Mataveli

Background:Non-Hodgkin lymphoma (NHL) is the most common, adult hematologic malignancy. Despite available treatment, relapse rates are high and novel therapies are warranted. IGN002 consists of an anti-CD20 monoclonal antibody (mAb) fused to interferon-alpha (IFNα) via a short peptide linker. The mAb portion of IGN002 is a chimeric IgG1 antibody with the same amino acid sequence as rituximab. The interferon amino acid sequence is human IFNα2b (hIFNα2b). In nonclinical pharmacology studies using CD20-positive human NHL cells, IGN002 demonstrates compelling anti-tumor effects. When compared to rituximab, IGN002 demonstrated enhanced complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC) effector functions against CD20-positive NHL cells. Moreover, compared to rituximab against normal human primary B-cells, IGN002 displayed higher maximal and more potent ADCC activity. Finally, in xenograft studies with immunodeficient mice using 3 different human NHL cell lines comparing IGN002 to rituximab, IGN002 demonstrated superior median and overall survival in all 3 NHL xenograft tumor lines. Study Design and Methods :This open-label, non-randomized, first-in-human, dose finding Phase 1 study comprises a Dose-Escalation Stage and an Expansion Stage (NCT02519270). In the Dose-Escalation Stage, ascending dose cohorts will be treated in 2 periods until the maximum tolerated dose (MTD) or recommended Phase 2 dose (RP2D) is identified. In Period 1, subjects will receive 2 doses of IGN002 administered weekly. Subjects with no anti-drug antibodies to IGN002 at Week 6 in Period 1 will proceed to Period 2 and receive up to 24 additional doses of IGN002 administered weekly in three 8-week cycles, with no treatment-free interval. In the Expansion Stage, subjects will receive up to 24 doses of IGN002 at the MTD or RP2D administered weekly in three 8-week cycles, with no treatment-free interval. Cohorts 1-5 at dose level 0.1, 0.3, 1, 3, and 10 ug/kg, respectively, have been completed without any dose limiting toxicity (DLT) and enrollment for Cohorts 6-8 is impending. Clinical Endpoints:The primary outcome measures are the evaluation of safety and tolerability of multiple doses of IGN002 administered weekly as an IV infusion to subjects with refractory NHL and the determination of MTD or RP2D of IGN002. The secondary outcome measures include characterizing the pharmacokinetic profile of ascending doses of IGN002, the incidence of anti-IGN002 antibody formation, and assessment of anti-tumor activity (e.g., response rate, duration) of IGN002 using the Lugano Classification criteria for NHL. Eligibility Criteria:This study is enrolling patients &gt; 18 years with an ECOG &lt;2 who have a documented history of immunohistochemistry-confirmed CD20-positive B-cell NHL, including diffuse large B-cell, mantle cell, marginal zone, lymphoplasmacytic, follicular, transformed follicular, or primary mediastinal B-cell lymphoma that is refractory to at least 1 documented regimen containing rituximab or a similar anti-CD20 therapy. Patients must also have measurable disease and adequate organ function. The exclusionary criteria encompass treatment with an approved or investigational chemotherapy or anti-CD20 drug within 28 days of Day 1, treatment with an approved or investigational biologic drug that does not target CD20 within 90 days of Day 1, or radiation therapy within 4 weeks of Day 1. Statistical Methods:The sample size was not predicated on formal statistical considerations. Descriptive statistics will be used to summarize continuous variables. Dichotomous endpoints will be summarized using frequencies, proportions, and exact binomial 95% CI. For subjects treated at the MTD or RP2D in Period 2 of the Dose-Escalation Stage and the Expansion Stage, time-to-event variables will be summarized using the Kaplan-Meier method. Target Accrual:In the Dose-Escalation Stage and Expansion Stage, approximately 9-18 (~3-6 subjects per cohort) and 14 subjects, respectively, will be accrued. Enrollment for Cohort 6 is expected to commence in September 2020. Disclosures Mataveli: Spectrum Pharmaceuticals:Current Employment, Current equity holder in publicly-traded company.


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