scholarly journals Pharmacokinetics of Different Dosing Strategies of Oral Posaconazole in Patients with Compromised Gastrointestinal Function and Who Are at High Risk for Invasive Fungal Infection

2012 ◽  
Vol 56 (5) ◽  
pp. 2652-2658 ◽  
Author(s):  
Oliver A. Cornely ◽  
David Helfgott ◽  
Amelia Langston ◽  
Werner Heinz ◽  
Jörg-Janne Vehreschild ◽  
...  
Keyword(s):  
Steady State ◽  
High Risk ◽  
Fungal Infections ◽  
Plasma Concentrations ◽  
Nutritional Supplement ◽  
Gastrointestinal Function ◽  
Open Label ◽  
Dosing Regimens ◽  
Dosing Strategies ◽  
Poor Absorption

ABSTRACTThe aim of this study was to assess different dosing strategies that may result in increased posaconazole bioavailability in patients with compromised gastrointestinal function and at high risk for invasive fungal infections. Patients undergoing chemotherapy and at risk for compromised gastrointestinal function received open-label posaconazole at 200 mg three times daily (TID) on days 1 to 8. Patients were randomized to one of three open-label dosing regimens of posaconazole on days 9 to 15: 200 mg TID, 400 mg twice daily (BID), or 400 mg TID. The plasma concentrations of interest on days 8 and 15 were 500 and 700 ng/ml, respectively; day 2 plasma concentrations of 250 and 350 ng/ml were chosen as levels that might result in steady-state concentrations of >500 and >700 ng/ml, respectively. A total of 75 patients enrolled; 52/75 (69%) completed the study, and 49/75 were included in the pharmacokinetic analyses. Mean plasma concentrations were 230, 346, and 637 ng/ml on days 2, 3, and 8, respectively. The day 15 values were 660, 930, and 671 ng/ml for 200 mg TID, 400 mg BID, and 400 mg TID, respectively. In 12 patients with a day 8 posaconazole concentration of <250 ng/ml, an overall benefit of the higher two doses was not apparent, suggesting that a subset of patients has low steady-state plasma concentrations. A change in dosing regimen on day 9 did not lead to higher exposures in these “poor absorbers” on day 15. Poor absorption may be enhanced with a high-fat meal, a nutritional supplement, or acidification.

scholarly journals Posaconazole Plasma Concentrations on Days Three to Five Predict Steady-State Levels

2016 ◽  
Vol 60 (9) ◽  
pp. 5595-5599 ◽  
Author(s):  
Jürgen Prattes ◽  
Wiebke Duettmann ◽  
Martin Hoenigl
Keyword(s):  
Steady State ◽  
Operating Characteristic ◽  
Hematological Malignancies ◽  
Fungal Infections ◽  
Plasma Concentrations ◽  
Area Under The Curve ◽  
Oral Solution ◽  
Curve Analysis ◽  
Roc Curve Analysis ◽  
Steady State Levels

ABSTRACTLow posaconazole plasma concentrations (PPCs) have been associated with breakthrough invasive fungal infections. We assessed the correlation between pre-steady-state PPCs (obtained between days 3 and 5) and PPCs obtained during steady state in 48 patients with underlying hematological malignancies receiving posaconazole oral-solution prophylaxis. Pre-steady-state PPCs correlated significantly with PPCs obtained at steady state (Spearmanr= 0.754;P< 0.001). Receiver operating characteristic (ROC) curve analysis of pre-steady-state PPCs revealed an area under the curve (AUC) of 0.884 (95% confidence interval [CI], 0.790 to 0.977) for predicting satisfactory PPCs at steady state.

scholarly journals Lack of Effect of Efavirenz on the Pharmacokinetics of Tipranavir-Ritonavir in Healthy Volunteers

2009 ◽  
Vol 53 (11) ◽  
pp. 4840-4844 ◽  
Author(s):  
C. J. L. la Porte ◽  
J. P. Sabo ◽  
L. Béïque ◽  
D. W. Cameron
Keyword(s):  
Steady State ◽  
Multiple Dose ◽  
Healthy Adult ◽  
Geometric Mean ◽  
Plasma Concentrations ◽  
Open Label ◽  
Multiple Dose Study ◽  
Chromatography Tandem Mass Spectrometry ◽  
Liquid Chromatography Tandem Mass ◽  
Dose Study

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.

scholarly journals Pharmacokinetics and Pharmacodynamics of Multiple-Dose Intravenous Nemonoxacin in Healthy Chinese Volunteers

2014 ◽  
Vol 59 (3) ◽  
pp. 1446-1454 ◽  
Author(s):  
Xiao-jie Wu ◽  
Jing Zhang ◽  
Bei-ning Guo ◽  
Ying-yuan Zhang ◽  
Ji-cheng Yu ◽  
...  
Keyword(s):  
Steady State ◽  
Infusion Rate ◽  
Multiple Dose ◽  
Open Label ◽  
Double Blind ◽  
Time Curve ◽  
Content Type ◽  
Second Stage ◽  
Dosing Regimens ◽  
Healthy Chinese

ABSTRACTThis study evaluated the safety and pharmacokinetic/pharmacodynamic profiles of nemonoxacin in healthy Chinese volunteers following multiple-dose intravenous infusion once daily for 10 consecutive days. The study was composed of two stages. In the open-label stage, 500 mg or 750 mg of nemonoxacin (n =12 each) was administered at an infusion rate of 5.56 mg/min. In the second stage, with a randomized double-blind placebo-controlled design, 500, 650, or 750 mg of nemonoxacin (n =16 in each cohort; 12 subjects received the drug and the other 4 subjects received the placebo) was given at an infusion rate of 4.17 mg/min. The results showed that, in the first stage, the maximal nemonoxacin concentrations (mean ± SD) at steady state (Cmax_ss) were 9.60 ± 1.84 and 11.04 ± 2.18 μg/ml in the 500-mg and 750-mg cohorts, respectively; the areas under the concentration-time curve at steady state (AUC0–24_ss) were 44.03 ± 8.62 and 65.82 ± 10.78 μg · h/ml in the 500-mg and 750-mg cohorts, respectively. In the second stage, the nemonoxacinCmax_ssvalues were 7.13 ± 1.47, 8.17 ± 1.76, and 9.96 ± 2.23 μg/ml in the 500-mg, 650-mg, and 750-mg cohorts, respectively; the AUC0–24_ssvalues were 40.46 ± 9.52, 54.17 ± 12.10, and 71.34 ± 17.79 μg · h/ml in the 500-mg, 650-mg, and 750-mg cohorts, respectively. No accumulation was found after the 10-day infusion with any regimen. The drug was well tolerated. A Monte Carlo simulation indicated that the cumulative fraction of response of any dosing regimen was nearly 100% againstStreptococcus pneumoniae. The probability of target attainment of nemonoxacin therapy was >98% when the MIC of nemonoxacin againstS. pneumoniaewas ≤1 mg/liter. It is suggested that all of the studied intravenous nemonoxacin dosing regimens should have favorable clinical and microbiological efficacies in future clinical studies. (This study has been registered atClinicalTrials.govunder registration no. NCT01944774.)

scholarly journals Exposure-Response Relationships for Isavuconazole in Patients with Invasive Aspergillosis and Other Filamentous Fungi

2017 ◽  
Vol 61 (12) ◽  
Author(s):  
Amit V. Desai ◽  
Laura L. Kovanda ◽  
William W. Hope ◽  
David Andes ◽  
Johan W. Mouton ◽  
...  
Keyword(s):  
Steady State ◽  
Invasive Aspergillosis ◽  
Filamentous Fungi ◽  
Aspartate Aminotransferase ◽  
Drug Exposure ◽  
Fungal Infections ◽  
Plasma Concentrations ◽  
Water Soluble ◽  
Therapeutic Drug ◽  
Exposure Response

ABSTRACT Isavuconazole, the active moiety of the water-soluble prodrug isavuconazonium sulfate, is a triazole antifungal agent for the treatment of invasive fungal infections. The purpose of this analysis was to characterize the isavuconazole exposure-response relationship for measures of efficacy and safety in patients with invasive aspergillosis and infections by other filamentous fungi from the SECURE clinical trial. Two hundred thirty-one patients who received the clinical dosing regimen and had exposure parameters were included in the analysis. The primary drug exposure parameters included were predicted trough steady-state plasma concentrations, predicted trough concentrations after 7 and 14 days of drug administration, and area under the curve estimated at steady state (AUCss). The exposure parameters were analyzed against efficacy endpoints that included all-cause mortality through day 42 in the intent-to-treat (ITT) and modified ITT populations, data review committee (DRC)-adjudicated overall response at end of treatment (EOT), and DRC-adjudicated clinical response at EOT. The safety endpoints analyzed were elevated or abnormal alanine aminotransferase, increased aspartate aminotransferase, and a combination of the two. The endpoints were analyzed using logistic regression models. No statistically significant relationship (P > 0.05) was found between isavuconazole exposure and either efficacy or safety endpoints. The lack of association between exposure and efficacy indicates that the isavuconazole exposures achieved by clinical dosing were appropriate for treating the infecting organisms in the SECURE study and that increases in alanine or aspartate aminotransferase were not related to increase in exposures. Without a clear relationship, there is no current clinical evidence for recommending routine therapeutic drug monitoring for isavuconazole.

Evaluation of Voriconazole and Posaconazole Dosing in Patients with Thermal Burn Injuries

2021 ◽  
Author(s):  
Kaitlin L Musick ◽  
Savannah L Jones ◽  
Ashlyn M Norris ◽  
Lauren J Hochstetler ◽  
Felicia N Williams ◽  
...  
Keyword(s):  
Fungal Infections ◽  
Patient Specific ◽  
Burn Patients ◽  
Therapeutic Level ◽  
Thermal Burn ◽  
Adequate Treatment ◽  
Treatment Regimens ◽  
Optimal Dosing ◽  
Dosing Regimens ◽  
Dosing Strategies

Abstract Fungal infections are a recognized cause of increased morbidity and mortality in thermal burn patients. Adequate treatment regimens remain a challenge due to unpredictable pharmacokinetic/pharmacodynamic changes caused by a hypermetabolic state and individual patient factors. A retrospective evaluation of adult thermal burn patients from April 2014 to April 2020 was conducted to assess voriconazole and posaconazole antifungal dosing regimens. The primary outcome was the incidence of attaining a therapeutic steady-state trough level on the patient’s initial voriconazole or posaconazole regimen. Of the 35 patients analyzed, 28 (80.0%) patients achieved a therapeutic level during azole therapy. However, only 13 (46.4%) patients achieved a therapeutic level on their first azole regimen. The median time to therapeutic level was 8.0 + 21.1 days from the start of azole therapy. Optimal dosing strategies for azole therapy in patients with thermal burns remains undefined. Further assessment is needed to delineate patient-specific factors that can contribute to subtherapeutic azole levels in thermal burn patients and the overall clinical impact of population-specific dosing regimens.

scholarly journals Clofazimine pharmacokinetics in patients with TB: dosing implications

2020 ◽  
Vol 75 (11) ◽  
pp. 3269-3277 ◽  
Author(s):  
Mahmoud Tareq Abdelwahab ◽  
Sean Wasserman ◽  
James C M Brust ◽  
Neel R Gandhi ◽  
Graeme Meintjes ◽  
...  
Keyword(s):  
Body Fat ◽  
Plasma Concentrations ◽  
Compartment Model ◽  
Pharmacokinetic Parameters ◽  
Pharmacokinetic Data ◽  
Drug Resistant ◽  
Elimination Half ◽  
Dosing Regimens ◽  
Dosing Strategies ◽  
Fat Fraction

Abstract Background Clofazimine is in widespread use as a key component of drug-resistant TB regimens, but the recommended dose is not evidence based. Pharmacokinetic data from relevant patient populations are needed to inform dose optimization. Objectives To determine clofazimine exposure, evaluate covariate effects on variability, and simulate exposures for different dosing strategies in South African TB patients. Patients and methods Clinical and pharmacokinetic data were obtained from participants with pulmonary TB enrolled in two studies with intensive and sparse sampling for up to 6 months. Plasma concentrations were measured by LC-MS/MS and interpreted with non-linear mixed-effects modelling. Body size descriptors and other potential covariates were tested on pharmacokinetic parameters. We simulated different dosing regimens to safely shorten time to average daily concentration above a putative target concentration of 0.25 mg/L. Results We analysed 1570 clofazimine concentrations from 139 participants; 79 (57%) had drug-resistant TB and 54 (39%) were HIV infected. Clofazimine pharmacokinetics were well characterized by a three-compartment model. Clearance was 11.5 L/h and peripheral volume 10 500 L for a typical participant. Lower plasma exposures were observed in women during the first few months of treatment, explained by higher body fat fraction. Model-based simulations estimated that a loading dose of 200 mg daily for 2 weeks would achieve average daily concentrations above a target efficacy concentration 37 days earlier in a typical TB participant. Conclusions Clofazimine was widely distributed with a long elimination half-life. Disposition was strongly influenced by body fat content, with potential dosing implications for women with TB.

scholarly journals Pharmacokinetic Study of Human Immunodeficiency Virus Protease Inhibitors Used in Combination with Amprenavir

2001 ◽  
Vol 45 (12) ◽  
pp. 3663-3668 ◽  
Author(s):  
Brian M. Sadler ◽  
Catherine Gillotin ◽  
Yu Lou ◽  
Joseph J. Eron ◽  
William Lang ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Steady State ◽  
Protease Inhibitors ◽  
Pharmacokinetic Study ◽  
Peak Plasma ◽  
Peak Plasma Concentration ◽  
Plasma Concentrations ◽  
Pharmacokinetic Parameters ◽  
Open Label ◽  
Immunodeficiency Virus

ABSTRACT In an open-label, randomized, multicenter, multiple-dose pharmacokinetic study, we determined the steady-state pharmacokinetics of amprenavir with and without coadministration of indinavir, nelfinavir, or saquinavir soft gel formulation in 31 human immunodeficiency virus type 1-infected subjects. The results indicated that amprenavir plasma concentrations were decreased by saquinavir soft gel capsule (by 32% for area under the concentration-time curve at steady state [AUCss] and 37% for peak plasma concentration at steady state [C max,ss]) and increased by indinavir (33% for AUCss). Nelfinavir significantly increased amprenavir minimum drug concentration at steady state (by 189%) but did not affect amprenavir AUCss orC max,ss. Nelfinavir and saquinavir steady-state pharmacokinetics were unchanged by coadministration with amprenavir compared with the historical monotherapy data. Concentrations of indinavir, coadministered with amprenavir, in plasma decreased in both single-dose and steady-state evaluations. The changes in amprenavir steady-state pharmacokinetic parameters, relative to those for amprenavir alone, were not consistent among protease inhibitors, nor were the changes consistent with potential interactions in CYP3A4 metabolism or P-glycoprotein transport. No dose adjustment of either protease inhibitor in any of the combinations studied is needed.

scholarly journals The Effect of Undaria pinnatifida Fucoidan on the Pharmacokinetics of Letrozole and Tamoxifen in Patients With Breast Cancer

2016 ◽  
Vol 17 (1) ◽  
pp. 99-105 ◽  
Author(s):  
Shreya Tocaciu ◽  
Lesley J. Oliver ◽  
Ray M. Lowenthal ◽  
Gregory M. Peterson ◽  
Rahul Patel ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Steady State ◽  
High Performance ◽  
Undaria Pinnatifida ◽  
Plasma Concentrations ◽  
Concomitant Administration ◽  
Open Label ◽  
Concurrent Use ◽  
Charged Aerosol ◽  
Hormonal Therapies

Background: Although the use of complementary and alternative medicines is widespread in cancer patients, clinical evidence of their benefits is sparse. Furthermore, while they are often assumed to be safe with regard to concurrent use of anticancer therapies, few studies have been carried out to investigate possible interactions. Fucoidans are a group of sulfated carbohydrates, derived from marine brown algae, which have long been used as dietary supplements due to their reported medicinal properties, including anticancer activity. The aim of this study was to investigate the effect of co-administration of fucoidan, derived from Undaria pinnatifida, on the pharmacokinetics of 2 commonly used hormonal therapies, letrozole and tamoxifen, in patients with breast cancer. Methods: This was an open label non-crossover study in patients with active malignancy taking letrozole or tamoxifen (n = 10 for each group). Patients took oral fucoidan, given in the form of Maritech extract, for a 3-week period (500 mg twice daily). Trough plasma concentrations of letrozole, tamoxifen, 4-hydroxytamoxifen, and endoxifen were measured using HPLC-CAD (high-performance liquid chromatography charged aerosol detector), at baseline and after concomitant administration with fucoidan. Results: No significant changes in steady-state plasma concentrations of letrozole, tamoxifen, or tamoxifen metabolites were detected after co-administration with fucoidan. In addition, no adverse effects of fucoidan were reported, and toxicity monitoring showed no significant differences in all parameters measured over the study period. Conclusions: Administration of Undaria pinnatifida fucoidan had no significant effect on the steady-state trough concentrations of letrozole or tamoxifen and was well tolerated. These results suggest that fucoidan in the studied form and dosage could be taken concomitantly with letrozole and tamoxifen without the risk of clinically significant interactions.

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 ◽  
...  
Keyword(s):  
Steady State ◽  
Healthy Adult ◽  
Controlled Trial ◽  
Phase 1 ◽  
Plasma Concentrations ◽  
Parameter Estimates ◽  
Open Label ◽  
Combination Drug ◽  
Period 2 ◽  
Adult Volunteers

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.)

Penetration of Intravenous and Oral Ciprofloxacin into Sterile and Empyemic Human Pleural Fluid

1994 ◽  
Vol 28 (3) ◽  
pp. 313-315 ◽  
Author(s):  
Joe Joseph ◽  
Leigh M. Vaughan ◽  
Gurnam S. Basran
Keyword(s):  
Steady State ◽  
Pleural Fluid ◽  
Venous Blood ◽  
Plasma Concentrations ◽  
Prospective Trial ◽  
Pleural Effusions ◽  
Open Label ◽  
Plasma Ratio ◽  
Oral Ciprofloxacin ◽  
Oral Doses

OBJECIVE: To compare the penetration of oral and intravenously administered ciprofloxacin into infected (empyemic) and noninfected(sterile) human pleural fluid. DESIGN: Eleven men and 5 women (aged 29–76) were consecutivelyselected from adult patients referred to the respiratory unit forpleural effusion. In this open-label, prospective trial, 13 patients withsterile pleural effusions were nonrandomly assigned to receive eitherciprofloxacin 200 mg (single intravenous dose), 750 mg (single oraldose), or 750 mg (two oral doses per day for 3 days); 3 patients withinfected pleural effusions received 750 mg oral doses for 10 days. Simultaneous pleural fluid and venous blood specimens were drawnover 5 hours after single dose or when steady-state was attained, andciprofloxacin concentrations were measured by HPLC. RESULTS: Pleural fluid concentrations of ciprofloxacin equaledplasma concentrations 1.5 hours after 200 mg was givenintravenously and the pleural/plasma ratio remained ∼ 0.9 for 4hours. After a single 750-mg oral dose, pleural ciprofloxacinconcentrations rose from 0 to 1.4 ug/ml, over 5 hours with thehighest pleural fluid/plasma ratio (0.7) at 5 hours. Average steadystateciprofloxacin concentrations in sterile pleural fluid after 750mg administered twice daily for 3 days, ranged between 1.1 and 1.8ug/rnl, with ratios between 0.3 and 0.9 over 4 hours. In empyemicpleural fluid at the same dosage, average steady-state ciprofloxacinconcentrations ranged between 1.9 and 3.4 ug/ml, with ratiosbetween 1.0 and 2.0 over 5 hours. CONCLUSIONS: Oral ciprofloxacin penetrates into sterile andempyemic pleural fluid with concentrations 30–90 percent and100–200 percent of plasma concentrations, respectively.

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