scholarly journals Pharmacokinetics of Benznidazole in Healthy Volunteers and Implications in Future Clinical Trials

2017 ◽  
Vol 61 (4) ◽  
Author(s):  
I. Molina ◽  
F. Salvador ◽  
A. Sánchez-Montalvá ◽  
M. A. Artaza ◽  
R. Moreno ◽  
...  
Keyword(s):  
Chronic Phase ◽  
Volume Of Distribution ◽  
University Hospital ◽  
Pharmacokinetic Parameters ◽  
Triple Quadrupole Mass Spectrometer ◽  
Open Label ◽  
Time Curve ◽  
Drug Of Choice ◽  
Median Volume ◽  
Median Area

ABSTRACT Despite its toxicity and low efficacy in the chronic phase, benznidazole is the drug of choice in Chagas disease. Scarce information about pharmacokinetics and pharmacodynamics of benznidazole has been published. We performed a phase I, open-label, nonrandomized pharmacokinetic study of benznidazole (Abarax) conducted with 8 healthy adult volunteers at the Infectious Diseases Department of the Vall d'Hebron University Hospital (Barcelona, Spain). The separation and detection of benznidazole were performed on a Waters Acquity ultraperformance liquid chromatography system (UPLC) coupled with a Waters Xevo TQ MS triple quadrupole mass spectrometer. The pharmacokinetic parameters were calculated based on a noncompartmental body model using Phoenix WinNonlin version 6.3 software. Furthermore, computational simulations were calculated for the multiple-dose administration at two dose regimens: 100 mg of benznidazole administered every 8 h and 150 mg of benznidazole administered every 12 h. After benznidazole administration, the median area under the concentration-time curve from time zero to time t (AUC0–t ) and extrapolated to infinity (AUC0–∞) were about 46.4 μg · h/ml and 48.4 μg · h/ml, respectively. Plasma benznidazole concentrations peaked at 3.5 h, with maximal concentrations of 2.2 μg/ml, and benznidazole exhibited a terminal half-life of 12.1 h. The median maximum concentration (C max) of benznidazole was lower in men than in women (1.6 versus 2.9 μg/ml), and median volume of distribution (V) as a function of bioavailability (F) was higher in men than in women (125.9 versus 88.6 liters). In conclusion, dose regimens (150 mg/12 h or 100 mg/8 h) reached a steady-state range concentration above of the minimum experimental therapeutic dose. Sex differences in the benznidazole pharmacokinetics were observed; mainly, men had lower C max and higher V/F than women.

scholarly journals Tigecycline Does Not Prolong Corrected QT Intervals in Healthy Subjects

2013 ◽  
Vol 57 (4) ◽  
pp. 1895-1901 ◽  
Author(s):  
Joan M. Korth-Bradley ◽  
Paul C. McGovern ◽  
Joanne Salageanu ◽  
Kyle Matschke ◽  
Anna Plotka ◽  
...  
Keyword(s):  
Healthy Subjects ◽  
Volume Of Distribution ◽  
Mixed Effects ◽  
Pharmacokinetic Parameters ◽  
Qtc Interval ◽  
Open Label ◽  
Time Curve ◽  
Linear Mixed Effects ◽  
Mixed Effects Modeling ◽  
Qt Intervals

ABSTRACTWe evaluated the effect of tigecycline (50-mg and 200-mg doses) on corrected QT (QTc) intervals and assessed safety and tolerability in a randomized, placebo-controlled, four-period crossover study of 48 (44 male) healthy volunteers aged 22 to 53 years. Fed subjects received tigecycline (50 mg or 200 mg) or placebo in a blinded fashion or an open-label oral dose of moxifloxacin (400 mg) after 1 liter of intravenous fluid. Serial electrocardiograms were recorded before, and for 96 h after, dosing. Blood samples for tigecycline pharmacokinetics were collected after each recording. QTc intervals were corrected using Fridericia's correction (QTcF). Pharmacokinetic parameters were calculated using noncompartmental methods with potential relationships examined using linear mixed-effects modeling. Adverse events were recorded. The upper limits of the 90% confidence interval for the mean difference between both tigecycline doses and placebo for all time-matched QTcF interval changes from baseline were <5 ms. The tigecycline concentrations initially declined rapidly and then more slowly. In the group given 50 mg of tigecycline, the pharmacokinetic parameters and means were as follows: maximum concentration of drug in serum (Cmax), 432 ng/ml; area under the concentration-time curve from time zero extrapolated to infinity (AUC0–∞), 2,366 ng · h/ml; clearance (CL), 21.1 liters/h; volume of distribution at steady state (Vss), 610 liters; and terminal half-life (t1/2), 22.1 h. Proportional or similar values were found for the group given 200 mg of tigecycline. Linear mixed-effects modeling failed to show an effect on QTcF values by tigecycline concentrations (P= 0.755). Tigecycline does not prolong the QTc interval in healthy subjects. This study has been registered at ClinicalTrials.gov under registration no. NCT01287793.

scholarly journals Pharmacokinetics, Safety, and Tolerability of Single-Dose Intravenous (ZTI-01) and Oral Fosfomycin in Healthy Volunteers

2017 ◽  
Vol 61 (9) ◽  
Author(s):  
E. Wenzler ◽  
E. J. Ellis-Grosse ◽  
K. A. Rodvold
Keyword(s):  
Single Dose ◽  
Oral Administration ◽  
Relative Bioavailability ◽  
Volume Of Distribution ◽  
Pharmacokinetic Parameters ◽  
Open Label ◽  
Time Curve ◽  
Blood And Urine Samples ◽  
Study Support ◽  
Tract Infections

ABSTRACT The pharmacokinetics, safety, and tolerability of intravenous (i.v.) fosfomycin disodium (ZTI-01) and oral fosfomycin tromethamine were evaluated after a single dose in 28 healthy adult subjects. Subjects received a single 1-h i.v. infusion of 1 g and 8 g fosfomycin disodium and a single dose of 3 g oral fosfomycin tromethamine in a phase I, randomized, open-label, three-period crossover study. Serial blood and urine samples were collected before and up to 48 h after dosing. The mean pharmacokinetic parameters ± standard deviations of fosfomycin in plasma after 1 g and 8 g i.v., respectively, were the following: maximum clearance of drug in serum (C max), 44.3 ± 7.6 and 370 ± 61.9 μg/ml; time to maximum concentration of drug in serum (T max), 1.1 ± 0.05 and 1.08 ± 0.01 h; volume of distribution (V), 29.7 ± 5.7 and 31.5 ± 10.4 liters; clearance (CL), 8.7 ± 1.7 and 7.8 ± 1.4 liters/h; renal clearance (CLR), 6.6 ± 1.9 and 6.3 ± 1.6 liters/h; area under the concentration-time curve from 0 to infinity (AUC0–∞), 120 ± 28.5 and 1,060 ± 192 μg·h/ml; and half-life (t 1/2), 2.4 ± 0.4 and 2.8 ± 0.6 h. After oral administration, the parameters were the following: C max, 26.8 ± 6.4 μg/ml; T max, 2.25 ± 0.4 h; V/F, 204 ± 70.7 liters; CL/F, 17 ± 4.7 liters/h; CLR, 6.5 ± 1.8 liters/h; AUC0–∞, 191 ± 57.6 μg · h/ml; and t 1/2, 9.04 ± 4.5 h. The percent relative bioavailability of orally administered fosfomycin was 52.8% in relation to the 1-g i.v. dose. Approximately 74% and 80% of the 1-g and 8-g i.v. doses were excreted unchanged in the urine by 48 h compared to 37% after oral administration, with the majority of this excretion occurring by 12 h regardless of dosage form. No new safety concerns were identified during this study. The results of this study support further investigation of i.v. fosfomycin in the target patient population, including patients with complicated urinary tract infections and pyelonephritis.

An Evaluation of the Potential for Pharmacokinetic Interaction between Tramadol and Cytochrome P450 2D6 Inhibitor Promethazine

2014 ◽  
Vol 989-994 ◽  
pp. 1041-1043
Author(s):  
Ping Liu ◽  
Liang Sun ◽  
Jian Zhang ◽  
Rui Chen Guo
Keyword(s):  
Single Dose ◽  
Plasma Concentration ◽  
Pharmacokinetic Interaction ◽  
Apparent Volume ◽  
Volume Of Distribution ◽  
Pharmacokinetic Parameters ◽  
Maximum Plasma ◽  
Open Label ◽  
Tramadol Hydrochloride ◽  
Time Curve

In this single-center, randomized, open-label, 3-way crossover study, subjects received each of the following: a single dose of Tramadol Hydrochloride Injection (THI) 35 mg, a single dose of Promethazine Hydrochloride Injection (PHI) 45 mg, and single dose of Compound Tramadol Hydrochloride Injection (CTHI) 80mg. Blood was collected and plasma was analyzed for the pharmacokinetic parameters (maximum plasma concentration [Cmax], time to Cmax [Tmax], area under the plasma concentration-time curve, plasma elimination half-life, clearance, and apparent volume of distribution) of Tramadol and Promethazine. In general, several pharmacokinetic interactions were observed between Tramadol and Promethazine in the present study.

scholarly journals Herb-Drug Interaction betweenEchinacea purpureaand Darunavir-Ritonavir in HIV-Infected Patients

2010 ◽  
Vol 55 (1) ◽  
pp. 326-330 ◽  
Author(s):  
José Moltó ◽  
Marta Valle ◽  
Cristina Miranda ◽  
Samandhy Cedeño ◽  
Eugenia Negredo ◽  
...  
Keyword(s):  
High Performance ◽  
Geometric Mean ◽  
Echinacea Purpurea ◽  
The Body ◽  
Pharmacokinetic Parameters ◽  
Root Extract ◽  
Open Label ◽  
Fixed Sequence ◽  
Time Curve ◽  
Sequence Study

ABSTRACTThe aim of this open-label, fixed-sequence study was to investigate the potential ofEchinacea purpurea, a commonly used botanical supplement, to interact with the boosted protease inhibitor darunavir-ritonavir. Fifteen HIV-infected patients receiving antiretroviral therapy including darunavir-ritonavir (600/100 mg twice daily) for at least 4 weeks were included.E. purpurearoot extract capsules were added to the antiretroviral treatment (500 mg every 6 h) from days 1 to 14. Darunavir concentrations in plasma were determined by high-performance liquid chromatography immediately before and 1, 2, 4, 6, 8, 10, and 12 h after a morning dose of darunavir-ritonavir on days 0 (darunavir-ritonavir) and 14 (darunavir-ritonavir plus echinacea). Individual darunavir pharmacokinetic parameters were calculated by noncompartmental analysis and compared between days 0 and 14 with the geometric mean ratio (GMR) and its 90% confidence interval (CI). The median age was 49 (range, 43 to 67) years, and the body mass index was 24.2 (range, 18.7 to 27.5) kg/m2. Echinacea was well tolerated, and all participants completed the study. The GMR for darunavir coadministered with echinacea relative to that for darunavir alone was 0.84 (90% CI, 0.63-1.12) for the concentration at the end of the dosing interval, 0.90 (90% CI, 0.74-1.10) for the area under the concentration-time curve from 0 to 12 h, and 0.98 (90% CI, 0.82-1.16) for the maximum concentration. In summary, coadministration ofE. purpureawith darunavir-ritonavir was safe and well tolerated. Individual patients did show a decrease in darunavir concentrations, although this did not affect the overall darunavir or ritonavir pharmacokinetics. Although no dose adjustment is required, monitoring darunavir concentrations on an individual basis may give reassurance in this setting.

scholarly journals Safety, toleration, and pharmacokinetics of intravenous azithromycin.

1996 ◽  
Vol 40 (11) ◽  
pp. 2577-2581 ◽  
Author(s):  
D R Luke ◽  
G Foulds ◽  
S F Cohen ◽  
B Levy
Keyword(s):  
Half Life ◽  
Active Drug ◽  
Slow Release ◽  
Volume Of Distribution ◽  
Pharmacokinetic Parameters ◽  
Time Curve ◽  
Concentration Time ◽  
Elimination Half ◽  
The Mean ◽  
Male Subjects

To date, the clinical pharmacology of large intravenous doses of azithromycin has not been described. In the present study, single 2-h intravenous infusions of 1, 2, and 4 g of azithromycin were administered to three parallel groups (in each group, six received active drug and two received placebo) of healthy male subjects. Toleration (assessed by scores of subject-administered visual analog scale tests spanning 0 [good] to 10 [poor]), safety, pharmacokinetics, and serum motilin levels were monitored for up to 240 h after the start of each intravenous infusion. Mean nausea scores of 0.0, 0.0, 1.0, and 0.5 and abdominal cramping scores of 0.0, 0.0, 0.4, and 0.4 for 12-h periods after doses of 0, 1, 2, and 4 g of azithromycin, respectively, suggested that azithromycin was well tolerated. Because of the standardized 1-mg/ml infusates, all subjects in the 4-g dosing group complained of an urgent need to urinate. There were no consistent trends in endogenous motilin levels throughout the study. The maximum concentration of azithromycin in serum (10 micrograms/ml after a 4-g dose) and the area under the concentration-time curve (82 micrograms.h/ml after a 4-g dose) were dose related. The mean pharmacokinetic parameters were an elimination half-life of 69 h, total systemic clearance of 10 ml/min/kg, and a volume of distribution at steady state of 33.3 liters/kg. The pharmacokinetic results suggest that the long half-life of azithromycin is due to extensive uptake and slow release of the drug from tissues rather than an inability to clear the drug. Single intravenous doses of up to 4 g of azithromycin in healthy subjects are generally well tolerated, and quantifiable concentrations may persist in serum for 10 days or more.

scholarly journals Lack of Effect of Zafirlukast on the Pharmacokinetics of Azithromycin, Clarithromycin, and 14-Hydroxyclarithromycin in Healthy Volunteers

1999 ◽  
Vol 43 (5) ◽  
pp. 1152-1155 ◽  
Author(s):  
Kevin W. Garey ◽  
Charles A. Peloquin ◽  
Paul G. Godo ◽  
Anne N. Nafziger ◽  
Guy W. Amsden
Keyword(s):  
Steady State ◽  
Healthy Subjects ◽  
High Performance ◽  
Pharmacokinetic Parameters ◽  
Steady State Concentration ◽  
Open Label ◽  
Time Curve ◽  
Data Analyses ◽  
Concentration Time ◽  
State Concentration

ABSTRACT This randomized, open-label, crossover study was conducted to investigate whether the coadministration of zafirlukast would affect the pharmacokinetics of azithromycin, clarithromycin, or 14-hydroxyclarithromycin (14-OHC). Twelve healthy subjects (six males and six females) received single 500-mg doses of azithromycin and clarithromycin with and without zafirlukast given to a steady-state concentration. Blood was collected prior to all macrolide doses and for 3 and 10 days after each clarithromycin and azithromycin dose, respectively. Serum was assayed for azithromycin, clarithromycin, and 14-OHC concentrations by validated high-performance liquid chromatography assay systems. Data analyses were done by noncompartmental and nonparametric methods. Analysis of the patients indicated that the addition of steady-state concentrations of zafirlukast did not significantly alter the pharmacokinetic parameters of or overall exposure (based on the area under the concentration-time curve) to azithromycin, clarithromycin, and 14-OHC. While zafirlukast is a known inhibitor of CYP3A4, it does not appear to exert a clinically or statistically significant pharmacokinetic effect on azithromycin, clarithromycin, or 14-OHC.

Pharmacokinetics of Moxifloxacin in Patients Undergoing Continuous Ambulatory Peritoneal Dialysis

2009 ◽  
Vol 29 (5) ◽  
pp. 575-579 ◽  
Author(s):  
Chrysanthi Skalioti ◽  
Thomas Tsaganos ◽  
Dimitrios Stamatiadis ◽  
Evangelos J. Giamarellos–Bourboulis ◽  
John Boletis ◽  
...  
Keyword(s):  
Peritoneal Dialysis ◽  
Continuous Ambulatory Peritoneal Dialysis ◽  
Peritoneal Fluid ◽  
Clinical Success ◽  
Pharmacokinetic Parameters ◽  
Maximum Plasma ◽  
Time Curve ◽  
Median Area ◽  
Fluid Penetration ◽  
End Stage

Objective To investigate the effect of continuous ambulatory peritoneal dialysis (CAPD) on plasma and peritoneal fluid concentration and pharmacokinetics of moxifloxacin after administration of one 400 mg dose orally to end-stage renal failure patients undergoing CAPD. Patients and Methods Blood and peritoneal samples were collected from 8 patients at standard time intervals and concentrations of moxifloxacin were estimated by HPLC analysis with fluorometric and ultraviolet detection. Pharmacokinetic parameters were estimated using standard noncompartmental methods. Results Median maximum plasma moxifloxacin concentration was 5.86 mg/L at a median time of 1.25 hours. In serum, median area under the concentration–time curve (AUC0→inf) was 157.95 ± 100.34 mg·hour/L, median t½ 25.00 hours, median clearance 2.54 L/hour, and median distribution volume 94.90 L. Median peritoneal fluid-to-plasma ratio of moxifloxacin ranged between 0.84 and 1.00, denoting adequate penetration and lack of considerable moxifloxacin removal during CAPD. Maximum moxifloxacin concentration/minimum inhibitory concentration (MIC) and AUC0→24/MIC ratios were above the cutoff points that indicate clinical success. Conclusion A single 400 mg oral dose of moxifloxacin is safe, presents rapid peritoneal fluid penetration, has similar plasma and peritoneal fluid pharmacokinetics, and should therefore be efficacious in the treatment of CAPD-induced peritonitis.

scholarly journals Steady-State Pharmacokinetics of Abacavir in Plasma and Intracellular Carbovir Triphosphate following Administration of Abacavir at 600 Milligrams Once Daily and 300 Milligrams Twice Daily in Human Immunodeficiency Virus-Infected Subjects

2009 ◽  
Vol 53 (4) ◽  
pp. 1532-1538 ◽  
Author(s):  
Graeme Moyle ◽  
Marta Boffito ◽  
Carl Fletcher ◽  
Chris Higgs ◽  
Phillip E. Hay ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
High Performance ◽  
Pharmacokinetic Parameters ◽  
Virologic Suppression ◽  
Open Label ◽  
Time Curve ◽  
Mixed Effect ◽  
Once Daily ◽  
Immunodeficiency Virus ◽  
And Gender

ABSTRACT Abacavir (ABC) is administered either at 600 mg once daily (ABC 600 mg QD) or 300 mg twice daily (ABC 300 mg BID) in anti-human immunodeficiency virus (anti-HIV) combination therapy. Although ABC plasma pharmacokinetics following each regimen has been well defined, no study has directly compared the regimens with respect to pharmacokinetics of ABC's active intracellular anabolite, carbovir-triphosphate (CBV-TP). In an open-label, two-period, crossover study, 34 HIV-infected male and female subjects stabilized on antiretroviral regimens containing either ABC 600 mg QD or ABC 300 mg BID received their usual doses on days −1 and 1 and then switched regimens for days 2 to 11. Serial blood samples collected on days 1 and 11 were assayed for plasma ABC and intracellular CBV-TP concentrations using validated high-performance liquid chromatography-tandem mass spectrometry methods. Pharmacokinetic parameters were calculated using noncompartmental methods. Analysis of variance with a mixed-effect model was performed for treatment and gender comparisons. In 27 evaluable subjects, the regimens provided bioequivalent ABC daily areas under the concentration-time curve from 0 to 24 h (AUC0-24) and comparable CBV-TP concentrations at the end of the dosing interval (C τ). As expected, ABC QD resulted in 109% higher ABC maximum concentrations of drug in plasma (C max) than did ABC BID. ABC QD also resulted in 32% higher CBV-TP AUC0-24 and 99% higher CBV-TP C max than did ABC BID. Females had a 38% higher weight-adjusted ABC AUC0-24 and 81% higher weight-adjusted CBV-TP AUC0-24 than did males. Virologic suppression was maintained during regimen switch, and no tolerability differences between regimens were observed. In conclusion, this study showed that ABC 600 mg QD and ABC 300 mg BID regimens led to similar intracellular CBV-TP C τ values, thus providing pharmacokinetic support for the interchangeability of these two regimens. Women had higher intracellular CBV-TP exposure than did men.

scholarly journals Absence of Effect of Rufloxacin on Theophylline Pharmacokinetics in Steady State

1998 ◽  
Vol 42 (9) ◽  
pp. 2359-2364 ◽  
Author(s):  
Martina Kinzig-Schippers ◽  
Uwe Fuhr ◽  
Marina Cesana ◽  
Carola Müller ◽  
A. Horst Staib ◽  
...  
Keyword(s):  
Steady State ◽  
Adverse Events ◽  
Compartment Model ◽  
Volume Of Distribution ◽  
Reversed Phase ◽  
Pharmacokinetic Parameters ◽  
Time Curve ◽  
Elimination Phase ◽  
Once Daily ◽  
Model Independent

ABSTRACT Several quinolone antibacterial agents are known to inhibit the metabolism of theophylline, with the potential to cause adverse events due to raised theophylline concentrations during coadministration. A randomized crossover study was therefore conducted with 12 healthy male volunteers (ages, 23 to 34 years; body weight, 64 to 101 kg) to evaluate a possible interaction between rufloxacin and theophylline. Both drugs were administered at steady state. Following the administration of an oral loading dose of 400 mg on day 1, rufloxacin was given orally at 200 mg once daily on days 2 to 7 during one period only. During both periods, 146 mg of theophylline was administered orally twice daily for 3 days (which were days 4 to 6 of the rufloxacin coadministration period) and intravenously once the next morning to test for an interaction. Theophylline and rufloxacin concentrations were measured by reversed-phase high-pressure liquid chromatography, the pharmacokinetics of theophylline at steady state following administration of the last dose were calculated by compartment-model-independent methods. To compare the treatments, analysis of variance-based point estimates and 90% confidence intervals (given in parentheses) were calculated for the mean ratios of the pharmacokinetic parameters from the test (rufloxacin coadministration) over those from the reference (theophylline without rufloxacin) period. These were as follows: maximum concentration at steady state, 1.01 (0.96 to 1.07); area under the concentration-time curve from 0 to 12 h, 0.98 (0.94 to 1.02); half-life, 0.99 (0.95 to 1.03); total clearance at steady state, 1.02 (0.99 to 1.06); and volume of distribution in the elimination phase, 1.01 (0.97 to 1.05). In conclusion, rufloxacin did not affect theophylline pharmacokinetics at steady state. Therefore, therapeutic coadministration of rufloxacin and theophylline is not expected to cause an increased incidence of theophylline-related adverse events.

Characterization of the Pharmacokinetics of rFVIII in Young Pre-School Children with Hemophilia, Including an Analysis of the Influence of Age and Body Weight.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3084-3084
Author(s):  
Victor Blanchette ◽  
Amy D. Shapiro ◽  
Raina Liesner ◽  
Fernando Hernandez ◽  
Anastassios D. Retzios ◽  
...  
Keyword(s):  
School Children ◽  
Pediatric Patients ◽  
Inverse Correlation ◽  
Volume Of Distribution ◽  
Pharmacokinetic Parameters ◽  
Pharmacokinetic Studies ◽  
Clotting Factors ◽  
Open Label ◽  
Bleeding Episodes

Abstract Commencement of prophylaxis at an early age for management of severe hemophilia A is widely recommended in order to prevent or minimize disabling arthropathy. Knowledge of the pharmacokinetics of replacement clotting factors is key to achieving optimal dosing regimens. However, the majority of pharmacokinetic studies on replacement FVIII have been conducted in older children and adults, and evidence on the pharmacokinetics of FVIII in pre-school children is primarily anecdotal. This study is the first to evaluate the pharmacokinetics of rFVIII in a large cohort of children &lt; 6 y of age. The evaluation was part of an open-label, multicenter study of 53 subjects with FVIII ≤ 2% and ≥ 50 prior FVIII exposure days. The mean age of the cohort was 3.1 ± 1.5 y (range, 1.1–6.0 y). Standard pharmacokinetic parameters were assessed in accordance with the guidelines for pediatric patients of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. A single dose was infused of 50 IU/kg of a recently-developed recombinant FVIII product, ADVATE rAHF-PFM, a full-length FVIII concentrate prepared without the addition of human or animal plasma proteins. In an intent-to-treat analysis of results from 52 subjects, mean plasma half-life (t1/2) was 9.7 ± 1.9 h, the adjusted in vivo recovery (IVR) was 1.9 ± 0.4 IU/dL/IU/kg, and clearance was 0.04 ± 0.01 dL/kg•h. These data contrast with those of a recent study of rAHF-PFM in individuals with a median age of 18 (range, 10–65) in which the t1/2 was 12.0 ± 4.3 y and IVR was 2.4 ± 0.5 (Tarantino et al, Haemophilia, 2004, in press). No previous studies have examined whether pharmacokinetic changes in t1/2 and IVR related to age or weight occur in young pediatric patients. There was no significant correlation between IVR and age (r = −0.09, p = 0.54); however, there was a moderate correlation between IVR and body mass index (BMI) (r =.049; p &lt; 0.001). There was also a weak correlation between t1/2 and age (r =0.34; p = 0.02). A significant inverse correlation was found between IVR and volume of distribution at steady state (Vss) (r = −0.82, p &lt; 0.001). Subsequent assessment of the safety, efficacy and immunogenicity of rAHF-PFM is ongoing in these patients. In an interim analysis, after a total of 3,698 infusions, no inhibitors or other adverse events related to rAHF-PFM have been reported (median exposure days = 74). Of 210 bleeding episodes, 92.4% required ≤ 2 infusions. Median numbers of annual total bleeding episodes (joint + non-joint) for patients on either standard (n = 17) or modified (n = 25) prophylaxis or on-demand treatment (n = 4) were 2.85, 2.31, and 20.07, respectively. This study demonstrates for the first time in pre-school children and toddlers detectable correlations in the pharmacokinetics of rFVIII between age and t1/2, and between IVR and BMI, and that ADVATE rAHF-PFM is efficacious, well-tolerated and non-immunogenic in young children. Further research is required to define factors affecting inter-individual variation in t1/2 of rFVIII and the accelerated pharmacokinetics in children &lt; 6 y old.

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