scholarly journals Pharmacokinetics of BILR 355 after Multiple Oral Doses Coadministered with a Low Dose of Ritonavir

2008 ◽  
Vol 53 (1) ◽  
pp. 95-103 ◽  
Author(s):  
Fenglei Huang ◽  
Kristin Drda ◽  
Thomas R. MacGregor ◽  
Joseph Scherer ◽  
Lois Rowland ◽  
...  
Keyword(s):  
Steady State ◽  
Maximum Concentration ◽  
Dose Range ◽  
Dose Interval ◽  
Phase Ii Trials ◽  
Time Curve ◽  
Minimum Concentration ◽  
Oral Dosing ◽  
Repeated Dosing

ABSTRACT The pharmacokinetics and safety of BILR 355 following oral repeated dosing coadministered with low doses of ritonavir (RTV) were investigated in 12 cohorts of healthy male volunteers with a ratio of 6 to 2 for BILR 355 versus the placebo. BILR 355 was given once a day (QD) coadministered with 100 mg RTV (BILR 355/r) at 5 to 50 mg in a polyethylene glycol solution or at 50 to 250 mg as tablets. BILR 355 tablets were also dosed at 150 mg twice a day (BID) coadministered with 100 mg RTV QD or BID. Following oral dosing, BILR 355 was rapidly absorbed, with the mean time to maximum concentration of drug in serum reached within 1.3 to 5 h and a mean half-life of 16 to 20 h. BILR 355 exhibited an approximately linear pharmacokinetics for doses of 5 to 50 mg when given as a solution; in contrast, when given as tablets, BILR 355 displayed a dose-proportional pharmacokinetics, with a dose range of 50 to 100 mg; from 100 to 150 mg, a slightly downward nonlinear pharmacokinetics occurred. The exposure to BILR 355 was maximized at 150 mg and higher due to a saturated dissolution/absorption process. After oral dosing of BILR 355/r, 150/100 mg BID, the values for the maximum concentration of drug in plasma at steady state, the area under the concentration-time curve from 0 to the dose interval at steady state, and the minimum concentration of drug in serum at steady state were 1,500 ng/ml, 12,500 h·ng/ml, and 570 ng/ml, respectively, providing sufficient suppressive concentration toward human immunodeficiency virus type 1. Based on pharmacokinetic modeling along with the in vitro virologic data, several BILR 355 doses were selected for phase II trials using Monte Carlo simulations. Throughout the study, BILR 355 was safe and well tolerated.

scholarly journals Pharmacokinetics and Dialytic Clearance of Isavuconazole during In Vitro and In Vivo Continuous Renal Replacement Therapy

2019 ◽  
Vol 63 (12) ◽  
Author(s):  
M. Biagi ◽  
D. Butler ◽  
X. Tan ◽  
S. Qasmieh ◽  
K. Tejani ◽  
...  
Keyword(s):  
Steady State ◽  
Renal Replacement Therapy ◽  
Continuous Renal Replacement Therapy ◽  
Replacement Therapy ◽  
Organ Transplant ◽  
Solid Organ ◽  
Time Curve ◽  
Minimum Concentration

ABSTRACT The pharmacokinetics (PK) and dialytic clearance of isavuconazole in vitro and in 7 solid-organ transplant patients undergoing continuous renal replacement therapy (CRRT) were evaluated. In vivo, the mean (± standard deviation [SD]) plasma PK parameters of isavuconazole were as follows: maximum concentration of drug in serum (Cmax), 4.00 ± 1.45 mg/liter; minimum concentration of drug in serum (Cmin), 1.76 ± 0.76 mg/liter; half-life (t1/2), 48.36 ± 29.78 h; volume of distribution at steady state (Vss), 288.78 ± 182.11 liters, clearance at steady state (CLss), 4.85 ± 3.79 liters/h; and area under the concentration-time curve (AUC), 54.01 ± 20.98 mg · h/liter. Transmembrane clearance represented just 0.7% of the total isavuconazole clearance. These data suggest that isavuconazole is not readily removed by CRRT and no dose adjustments are necessary.

scholarly journals Evaluation of Daptomycin Exposure and Efficacy and Safety Endpoints To Support Risk-versus-Benefit Considerations

2015 ◽  
Vol 60 (3) ◽  
pp. 1600-1607 ◽  
Author(s):  
Sujata M. Bhavnani ◽  
Paul G. Ambrose ◽  
Jeffrey P. Hammel ◽  
Christopher M. Rubino ◽  
George L. Drusano
Keyword(s):  
Infective Endocarditis ◽  
Clinical Response ◽  
Clinical Success ◽  
Dose Range ◽  
Simulated Patients ◽  
Albumin Concentration ◽  
Disease Category ◽  
Time Curve ◽  
Minimum Concentration ◽  
Content Type

The choice of an antimicrobial agent must balance optimization of efficacy endpoints with the minimization of safety events. The risk versus benefit of daptomycin for patients withStaphylococcus aureusbacteremia with or without infective endocarditis receiving daptomycin at 6, 8, and 10 mg/kg of body weight/day was assessed. The relationships between the area under the concentration-time curve over 24 h (AUC)/MIC ratio and both clinical response and time to decreased susceptibility were evaluated using data from patients with such infections who received daptomycin at 6 mg/kg/day. Using these relationships, plus the previously identified relationship between the minimum concentration and an elevation in the creatine phosphokinase (CPK) concentration (CPK elevation) (S. M. Bhavnani, C. M. Rubino, P. G. Ambrose, and G. L. Drusano, Clin Infect Dis 50:1568–1574, 2010) and Monte Carlo simulation, the probability of each outcome by MIC for daptomycin at 6, 8, and 10 mg/kg/day was calculated. The function for exposure-response relationships for clinical response (P= 0.06) and time to decreased susceptibility (P= 0.01) resembled U and inverted U shapes, respectively. Multivariable analyses demonstrated AUC/MIC ratio, creatinine clearance, albumin concentration, and disease category to be predictors of clinical response. The results of simulations failed to demonstrate large improvements in the probabilities of clinical success among cohorts of simulated patients defined by the above-described predictive factors or the probability of decreased susceptibility at 30 days when the daptomycin dose was increased from 6 to 10 mg/kg/day. The probability of CPK elevation increased from 0.073 to 0.156 over this dose range. These data can be used to inform risk-versus-benefit decisions for daptomycin dose selection in patients withS. aureusbacteremia with or without infective endocarditis. The risk of CPK elevation, which is reversible, should be weighed in the context of the mortality and severe morbidity associated with these types of serious staphylococcal infections.

scholarly journals Polysaccharide peptide (PSP) extract from Coriolus versicolor decreased Tmax of tamoxifen and maintained biochemical serum parameters, with no change in the metabolism of tamoxifen in the rat

2020 ◽  
Author(s):  
Valentina Naumovski ◽  
Benjamin Kimble ◽  
Daunia Laurenti ◽  
Srinivas Nammi ◽  
Hisayoshi Norimoto ◽  
...  
Keyword(s):  
Single Dose ◽  
Maximum Concentration ◽  
Cytochromes P450 ◽  
Female Rat ◽  
Sprague Dawley ◽  
Serum Parameters ◽  
Chemotherapy Drugs ◽  
Sprague Dawley Rats ◽  
Repeated Dosing

Abstract Background: Natural products such as mushrooms are increasingly used as adjunct therapies in cancer to stimulate the immune system. However, little is known about their interaction with chemotherapy drugs. This study investigated whether a commercial polysaccharide peptide (PSP) extract of the mushroom Coriolus (C.) versicolor interacts with tamoxifen, a common chemotherapy drug used in breast cancer. Methods: The pharmacokinetic and biochemical parameters of tamoxifen in female Sprague-Dawley rats’ serum were determined after orally administering tamoxifen (20 mg/kg) at a single dose and repeated dosing with and without C. versicolor (340 mg/kg). Results: Although the area-under-curve and maximum concentration showed no significant differences in both the single dose and repeated dosing, time to reach maximum concentration (Tmax) increased by 228% and 93%, respectively, in the rats treated with C. versicolor (p<0.05). The repeated dosing of C. versicolor, when co-administered with repeated dosing of tamoxifen, maintained 19 out of 23 biochemical serum parameters in rats compared to control (p<0.05). Using hepatic female rat microsomes, an in vitro study showed that the extract (10 – 100 µg/mL) did not significantly alter the rate of tamoxifen depletion which is known to be mediated by cytochromes P450 (CYP450). Conclusions: These results indicate that C. versicolor may delay the intestinal absorption of tamoxifen and maintain biochemical serum parameters, without any change in tamoxifen’s metabolism. If clinical trials confirm this result, the timing of tamoxifen and C. versicolor administration would need to be considered to avoid potential drug interactions resulting from a delay in achieving the systemic level of the anti-cancer medication.

scholarly journals In VivoPharmacodynamics of Torezolid Phosphate (TR-701), a New Oxazolidinone Antibiotic, against Methicillin-Susceptible and Methicillin-Resistant Staphylococcus aureus Strains in a Mouse Thigh Infection Model

2011 ◽  
Vol 55 (7) ◽  
pp. 3453-3460 ◽  
Author(s):  
Arnold Louie ◽  
Weiguo Liu ◽  
Robert Kulawy ◽  
G. L. Drusano
Keyword(s):  
Staphylococcus Aureus ◽  
Dose Range ◽  
Dose Fractionation ◽  
Infection Model ◽  
Pharmacokinetic Studies ◽  
Time Curve ◽  
Methicillin Resistant ◽  
Content Type

ABSTRACTTorezolid phosphate (TR-701) is the phosphate monoester prodrug of the oxazolidinone TR-700 which demonstrates potentin vitroactivity against Gram-positive bacteria, including methicillin-susceptibleStaphylococcus aureus(MSSA) and methicillin-resistantS. aureus(MRSA). The pharmacodynamics of TR-701 or TR-700 (TR-701/700) againstS. aureusis incompletely defined. Single-dose pharmacokinetic studies were conducted in mice for TR-701/700. Forty-eight-hour dose range and 24-hour dose fractionation studies were conducted in a neutropenic mouse thigh model ofS. aureusinfection using MRSA ATCC 33591 to identify the dose and schedule of administration of TR-701/700 that was linked with optimized antimicrobial effect. Additional dose range studies compared the efficacies of TR-701/700 and linezolid for one MSSA strain and one community-associated MRSA strain. In dose range studies, TR-701/700 was equally bactericidal against MSSA and MRSA. Mean doses of 37.6 and 66.9 mg/kg of body weight/day of TR-701/700 resulted in stasis and 1 log CFU/g decreases in bacterial densities, respectively, at 24 h, and mean doses of 35.3, 46.6, and 71.1 mg/kg/day resulted in stasis and 1 and 2 log CFU/g reductions, respectively, at 48 h. Linezolid administered at doses as high as 150 mg/kg/day did not achieve stasis at either time point. Dose fractionation studies demonstrated that the area under the concentration-time curve over 24 h in the steady state divided by the MIC (AUC/MIC ratio) was the pharmacodynamic index for TR-701/700 that was linked with efficacy. TR-701/700 was highly active against MSSA and MRSA,in vivo, and was substantially more efficacious than linezolid, although linezolid's top exposure has half the human exposure. Dose fractionation studies showed that AUC/MIC was the pharmacodynamic index linked with efficacy, indicating that once-daily dosing in humans is feasible.

scholarly journals Pharmacokinetic and Pharmacodynamic Study of the Human Immunodeficiency Virus Protease Inhibitor Amprenavir after Multiple Oral Dosing

2001 ◽  
Vol 45 (1) ◽  
pp. 30-37 ◽  
Author(s):  
Brian M. Sadler ◽  
Catherine Gillotin ◽  
Yu Lou ◽  
Daniel S. Stein
Keyword(s):  
Human Immunodeficiency Virus ◽  
Steady State ◽  
Dose Range ◽  
Area Under The Curve ◽  
Pharmacokinetic Parameters ◽  
Pharmacokinetic Data ◽  
Protease Enzyme ◽  
Immunodeficiency Virus

ABSTRACT In a dose-ranging study of amprenavir (formerly 141W94), an inhibitor of the protease enzyme of human immunodeficiency virus (HIV) type 1, single-dose and steady-state pharmacokinetic parameters were estimated from plasma samples collected on day 1 and during week 3, respectively. Amprenavir was administered on either a twice-daily (b.i.d.) or three-times-daily dosage schedule to 62 HIV-infected adults, 59 of whom had pharmacokinetic data. Log-log regression analysis (the power model) revealed that the steady-state area under the curve (AUCss) and the maximum, minimum, and average concentrations at steady state (C max,ss,C min,ss, and C avg,ss, respectively) increased in a dose-proportional manner over the 300- to 1,200-mg dose range. Steady-state clearance was dose independent. AUCss/AUC0→∞ decreased linearly with dose and correlated significantly with treatment-associated decreases in α1-acid glycoprotein. After 3 weeks, the dose of 1,200 mg b.i.d. provided a median amprenavir Cmin,ss (0.280 μg/ml) that was higher than the median in vitro 50% inhibitory concentration for clinical HIV isolates (0.023 μg/ml), even after adjustment for protein binding. The median amprenavir C min,sswas also greater than the estimated in vivo trough concentration calculated to yield 90% of the maximum antiviral effect (0.228 μg/ml) over 4 weeks. A pharmacodynamic analysis of the relationship between steady-state pharmacokinetic parameters and safety revealed headache and oral numbness to be the only side effects significantly associated with C max. The pharmacodynamic relationship defined in this study supports the use of 1,200 mg b.i.d. as the approved dose of amprenavir.

scholarly journals In VivoPharmacodynamic Target Investigation of Two Bacterial Topoisomerase Inhibitors, ACT-387042 and ACT-292706, in the Neutropenic Murine Thigh Model against Streptococcus pneumoniae and Staphylococcus aureus

2016 ◽  
Vol 60 (6) ◽  
pp. 3626-3632 ◽  
Author(s):  
A. J. Lepak ◽  
P. Seiler ◽  
J. P. Surivet ◽  
D. Ritz ◽  
C. Kohl ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Streptococcus Pneumoniae ◽  
Dose Range ◽  
Free Drug ◽  
Infection Model ◽  
Topoisomerase Inhibitors ◽  
Time Curve ◽  
Content Type ◽  
Phenotypic Resistance

ACT-387042 and ACT-292706 are two novel bacterial topoisomerase inhibitors with broad-spectrum activity against Gram-positive and -negative bacteria, including methicillin-resistantStaphylococcus aureusand penicillin- and fluoroquinolone-resistantStreptococcus pneumoniae. We used the neutropenic murine thigh infection model to characterize the pharmacokinetics (PK)/pharmacodynamics (PD) of these investigational compounds against a group of 10S. aureusandS. pneumoniaeisolates with phenotypic resistance to beta-lactams and fluoroquinolones. Thein vitroactivities of the two compounds were very similar (MIC range, 0.03 to 0.125 mg/liter). Plasma pharmacokinetics were determined for each compound by using four escalating doses administered by the subcutaneous route. In treatment studies, mice had 107.4to 108CFU/thigh at the start of therapy with ACT-387042 and 106.7to 108.3CFU/thigh at the start of therapy with ACT-292706. A dose-response relationship was observed with all isolates over the dose range. Maximal kill approached 3 to 4 log10CFU/thigh compared to the burden at the start of therapy for the highest doses examined. There was a strong relationship between the PK/PD index AUC/MIC ratio (area under the concentration-time curve over 24 h in the steady state divided by the MIC) and therapeutic efficacy in the model (R2, 0.63 to 0.82). The 24-h free-drug AUC/MIC ratios associated with net stasis for ACT-387042 againstS. aureusandS. pneumoniaewere 43 and 10, respectively. The 24-h free-drug AUC/MIC ratios associated with net stasis for ACT-292706 againstS. aureusandS. pneumoniaewere 69 and 25, respectively. The stasis PD targets were significantly lower forS. pneumoniae(P< 0.05) for both compounds. The 1-log-kill AUC/MIC ratio targets were ∼2- to 4-fold higher than stasis targets. Methicillin, penicillin, or ciprofloxacin resistance did not alter the magnitude of the AUC/MIC ratio required for efficacy. These results should be helpful in the design of clinical trials for topoisomerase inhibitors.

scholarly journals Decrease in Brain Distribution of Fluvoxamine in Experimental Hyperlipidemic Rats

2011 ◽  
Vol 14 (3) ◽  
pp. 414 ◽  
Author(s):  
Keizo Fukushima ◽  
Shinji Kobuchi ◽  
Masakazu Shibata ◽  
Kanji Takada ◽  
Nobuyuki Sugioka
Keyword(s):  
Steady State ◽  
Plasma Concentration ◽  
Protein Binding ◽  
Intravenous Administration ◽  
Intraperitoneal Administration ◽  
Plasma Lipoprotein ◽  
Plasma Lipoproteins ◽  
Poloxamer 407 ◽  
Time Curve

ABSTRACT: Purpose. Many clinical reports and trials have suggested that fluvoxamine (FLV) reduces plasma lipoprotein levels. However, few studies have reported the effect of plasma lipoproteins on FLV pharmacokinetics. The aim of the present study was to investigate the affinities of FLV to plasma lipoproteins and the effect of plasma lipoproteins on the biodistribution of FLV using an experimental hyperlipidemic (HL) rat model. Methods. HL rats were prepared by intraperitoneal administration of Poloxamer-407 solution (1.0 g/kg). In vitro protein binding and distribution of FLV in plasma lipoproteins were determined in control and HL rats. In vivo pharmacokinetic study (intravenous administration of FLV, 5.0 mg/kg) and biodistribution analysis for brain and liver at a steady state (infusion, 1.5 mg/kg/hr, 6 hrs) were also performed. Results. The plasma protein binding of FLV was around 83% and 95% in control and HL rats, respectively, whereas the FLV recoveries in triglyceride-rich lipoprotein fractions were increased in HL. Therefore, the elevation of lipoproteins was likely responsible for the increase in protein binding in HL. After intravenous administration, the area under the plasma concentration vs. time curve (AUC) in HL was 3.9-fold greater than that in control rats, whereas the distribution ratio of FLV plasma concentration to the brain at a steady state was decreased to approximately 20% of that of the control. Conclusions. FLV has an affinity to plasma lipoproteins, and their elevation might decrease the FLV biodistribution to brain; the plasma lipoprotein levels could not be found to correlate positively with the FLV pharmacokinetic effect in brain, but rather may attenuate it. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

scholarly journals Serum pharmacology of amphotericin B applied in lipid emulsions.

1997 ◽  
Vol 41 (4) ◽  
pp. 728-732 ◽  
Author(s):  
V Heinemann ◽  
B Kähny ◽  
U Jehn ◽  
D Mühlbayer ◽  
A Debus ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Dose Range ◽  
Reticuloendothelial System ◽  
Subsequent Treatment ◽  
Pharmacokinetic Analysis ◽  
Lipid Emulsions ◽  
Time Curve ◽  
Lipid Aggregates

Application of amphotericin B in lipid emulsions (AmB/L) reduced membrane toxicity in vitro and decreased amphotericin B-associated toxic side effects in vivo when compared to that of amphotericin B applied in 5% glucose (AmB/G). Therefore, a comparative analysis of the pharmacological parameters of AmB/L and AmB/G was performed. Thirteen patients were analyzed, and nine of these patients received a subsequent treatment with AmB/G and AmB/L. In patients in both treatment groups amphotericin B showed a biphasic elimination from serum, with a prolonged terminal half-life of approximately 27 h. Patients treated with AmB/L showed significantly lower peak concentrations (44.2%; P = 0.008) and correspondingly lower area under the drug concentration-time curve (AUC) values (64.3%; P = 0.015) compared to the values for the same patients treated with AmB/G at a dose range of 0.6 to 1.5 mg/kg of body weight. The enhanced clearance of AmB/L may be due to a faster initial elimination of amphotericin B-lipid aggregates by the reticuloendothelial system. Lower peak concentrations and AUC values in serum and a correspondingly faster deposition of AmB/L in tissues may at least partly explain the lower toxicity of AmB/L. A comparative pharmacokinetic analysis with data for a single patient treated with AmB/L demonstrated that hemodialysis did not significantly affect the disposition of amphotericin B.

scholarly journals Use of anInVitroPharmacodynamic Model To Derive a Moxifloxacin Regimen That Optimizes Kill ofYersinia pestisand Prevents Emergence of Resistance

2010 ◽  
Vol 55 (2) ◽  
pp. 822-830 ◽  
Author(s):  
A. Louie ◽  
H. S. Heine ◽  
B. VanScoy ◽  
A. Eichas ◽  
K. Files ◽  
...  
Keyword(s):  
Drug Exposure ◽  
Dose Range ◽  
Human Infection ◽  
Pharmacodynamic Model ◽  
Dose Fractionation ◽  
Time Curve ◽  
Infection Models ◽  
Animal Infection ◽  
Emergence Of Resistance

ABSTRACTYersinia pestis, the causative agent of bubonic, septicemic, and pneumonic plague, is classified as a CDC category A bioterrorism pathogen. Streptomycin and doxycycline are the “gold standards” for the treatment of plague. However, streptomycin is not available in many countries, andY. pestisisolates resistant to streptomycin and doxycycline occur naturally and have been generated in laboratories. Moxifloxacin is a fluoroquinolone antibiotic that demonstrates potent activity againstY. pestisinin vitroand animal infection models. However, the dose and frequency of administration of moxifloxacin that would be predicted to optimize treatment efficacy in humans while preventing the emergence of resistance are unknown. Therefore, dose range and dose fractionation studies for moxifloxacin were conducted forY. pestisin anin vitropharmacodynamic model in which the half-lives of moxifloxacin in human serum were simulated so as to identify the lowest drug exposure and the schedule of administration that are linked with killing ofY. pestisand with the suppression of resistance. In the dose range studies, simulated moxifloxacin regimens of ≥175 mg/day killed drug-susceptible bacteria without resistance amplification. Dose fractionation studies demonstrated that the AUC (area under the concentration-time curve)/MIC ratio predicted kill of drug-susceptibleY. pestis, while theCmax(maximum concentration of the drug in serum)/MIC ratio was linked to resistance prevention. Monte Carlo simulations predicted that moxifloxacin at 400 mg/day would successfully treat human infection due toY. pestisin 99.8% of subjects and would prevent resistance amplification. We conclude that in anin vitropharmacodynamic model, the clinically prescribed moxifloxacin regimen of 400 mg/day is predicted to be highly effective for the treatment ofY. pestisinfections in humans. Studies of moxifloxacin in animal models of plague are warranted.

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