Pharmacokinetics of recombinant factor XIII in young children with congenital FXIII deficiency and comparison with older patients.

Congenital factor XIII (FXIII) deficiency is a rare bleeding disorder, which in its severe form is associated with a significant bleeding phenotype, requiring regular prophylactic therapy. A recently developed recombinant FXIII (rFXIII) has demonstrated safety and efficacy in children aged ≥6 years and adults (mentor1 trial). This article describes the mentor4 trial, which has assessed the pharmacokinetics (PK) and safety of rFXIII in younger children (1 to <6 years) with congenital FXIII deficiency, and compares extrapolated PK parameters with the mentor1 trial. Six children with congenital FXIII A-subunit deficiency received a single, 35 IU kg(-1) rFXIII dose. PK properties were similar in all the children, with a mean area under the concentration vs. 30-day time curve of 248.6 IU h(-1) mL(-1) , maximal FXIII activity (30 min) of 0.67 IU mL(-1) , and mean 30-day trough of 0.21 IU mL(-1) . All patients maintained FXIII activity above the lower target level (0.1 IU mL(-1) ). rFXIII half-life was 15.1 days (range, 10-25). No safety findings of clinical concern were observed. PK properties of rFXIII were similar in patients from both trials. The study demonstrated that a single dose of 35 IU kg(-1) rFXIII maintained plasma FXIII levels above 0.1 IU mL(-1) over a 30-day period in young children with congenital FXIII deficiency, and is, therefore, likely to provide adequate prophylaxis in this age group. The study extends the previous findings of the mentor1 trial and confirms that no dose adjustment is required for different age groups with congenital FXIII deficiency.

40K glycoPEGylated, recombinant FVIIa: 3-month, double-blind, randomized trial of safety, pharmacokinetics and preliminary efficacy in hemophilia patients with inhibitors.

BACKGROUND: A 40K glycoPEGylated, recombinant activated factor VII (rFVIIa) bypassing agent (N7-GP) with a prolonged half-life (15 h) compared with rFVIIa was developed as a potential candidate for bleed-preventive regimens in patients with hemophilia and inhibitors. OBJECTIVES: To evaluate the safety, pharmacokinetics and preliminary efficacy of multiple doses of N7-GP in congenital hemophilia A and B patients with high-titer inhibitors. PATIENTS/METHODS: In this global, prospective, randomized, double-blinded, phase 2 trial, 25, 100 or 200 µg kg(-1)  N7-GP was administered intravenously once every second day during a 3-month, bleed-preventive regimen and compared with a preceding 3-month observation period with on-demand treatment of bleeds with rFVIIa. The primary endpoint was adverse events; secondary endpoints were evaluation of immunogenicity, pharmacokinetics and efficacy. RESULTS AND CONCLUSIONS: Overall, 23 patients were randomized and dosed (n = 8/7/8 for 25/100/200 µg kg(-1) ). N7-GP was well tolerated, with a low frequency of adverse events. No serious adverse events, immunogenic or thromboembolic events related to N7-GP were reported. The pharmacokinetic properties of N7-GP were similar to those reported in phase 1. The annualized bleeding rate (ABR) decreased in the treatment period vs. the observation period at all N7-GP dose levels. However, a dose-response relationship in the reduction could not be established in the N7-GP dose range evaluated. The ABR was also reduced at two dose levels during the last part of the observation period, and increased notably in the follow-up period irrespective of previous N7-GP dose. The trial was registered at ClinicalTrials.gov ( REGISTRATION NUMBER: NCT00951405).

Safety and pharmacokinetics of a glycoPEGylated recombinant activated factor VII derivative: a randomized first human dose trial in healthy subjects.

BACKGROUND: Extensive research is currently ongoing to prolong the half-life of coagulation factors. One of these techniques is glycoPEGylation, which has also been applied to recombinant activated factor VII (rFVIIa), resulting in a rFVIIa derivative (N7-GP) with a prolonged terminal half-life (t(1/2) ). The main clinical purpose of N7-GP is to provide safe and effective prophylaxis to patients with hemophilia and inhibitors. The prolonged t(1/2) of N7-GP can potentially reduce the dosing frequency and thereby facilitate convenience and compliance, which are two significant barriers to effective prophylaxis. OBJECTIVES: To determine the safety and pharmacokinetics of single doses of N7-GP in healthy men. METHODS: A randomized, placebo-controlled, dose-escalation trial with five cohorts (N7-GP dose of 12.5-100 µg kg(-1) ) was performed. In each cohort, eight subjects were randomized to receive N7-GP (n = 6) or placebo (n = 2). RESULTS: The mean FVIIa activity was measurable for up to at least 72 h after dosing, and the overall mean t(1/2) for FVIIa activity was 15 h. The pharmacokinetics of N7-GP appeared to be dose-proportional in the dose range investigated. No serious adverse events (including thromboembolic events) were reported. The frequency of adverse events was similar in both the placebo and N7-GP groups. No neutralizing antibodies against N7-GP were detected. A pharmacologic effect was apparent from a dose-dependent statistically significant decrease in the mean prothrombin time in all N7-GP groups as compared with placebo. CONCLUSIONS: N7-GP had a plasma half-life of 15 h and a profile that makes it a potential candidate for prophylaxis in patients with hemophilia and inhibitors.

Digital X-ray radiogrammetry combined with semiautomated analysis of joint space widths as a new diagnostic approach in rheumatoid arthritis: a cross-sectional and longitudinal study.

OBJECTIVE: To evaluate digital x-ray radiogrammetry (DXR) and the Radiogrammetry Kit program as new diagnostic tools for quantifying disease-related periarticular osteoporosis and for measuring joint space narrowing according to the severity and duration of rheumatoid arthritis (RA). METHODS: Using DXR, we performed computerized calculations of bone mineral density (BMD) and the metacarpal index (MCI) in 258 patients with active RA. Using the Radiogrammetry Kit program, we also performed semiautomated measurements of joint space width (JSW) at the second through the fifth metacarpophalangeal (MCP) joints in these patients. RESULTS: All correlations between the different parameters of both techniques (BMD and the MCI as measured by DXR and MCP JSW as measured by the Radiogrammetry Kit) were significant (0.36 < or = R < or = 0.63; P < 0.01). As expected, a significant negative association was shown between the different MCP JSW results and the results of all scoring methods (-0.67 < or = R < or = -0.29). The BMD and the MCI measured by DXR both decreased significantly between Steinbrocker stage I and stage IV (by 32.7% and 36.6%, respectively; both P < 0.01). Reductions in the overall (mean) MCP JSW varied from 35.3% (Larsen score) to 52.9% (Steinbrocker stage). Over a period of 6 years, we observed relative decreases in BMD and the MCI as measured by DXR (32.1% and 33.3%, respectively), as well as in the overall (mean) MCP JSW (23.5%), and these were pronounced in early RA (duration <1 year). In addition, excellent reproducibility of DXR and Radiogrammetry Kit parameters was verified (coefficients of variation <1%). CONCLUSION: DXR with the integrated Radiogrammetry Kit program could be a promising, widely available diagnostic tool for supplementing the different RA scoring methods with quantitative data, thus allowing an earlier and improved diagnosis of RA and more precision in determining disease progression.

Metacarpal index and bone mineral density in healthy African-American women.

Bone mineral density (BMD) reference data of non-Caucasian women is scarce but greatly needed for African-American women. The objective of this study was to establish a metacarpal normative reference database for African-American women using digital X-ray radiogrammetry (DXR) and hand radiographs and compare these values to existing Caucasian data. Two hundred and fifty healthy African-American women between the ages of 20 and 79 years old, 14 of whom were excluded, were recruited to participate from four different clinical sites. The study population was recruited in approximately equal number into the following groups: 20-29, 30-39, 40-49, 50-59, 60-69 and 70-79 years of age. A radiograph was acquired of each subject's non-dominant hand. The radiographs were scanned and analyzed using radiogrammetric techniques, and the BMD, MCI (Metacarpal Index), bone width and cortical thickness were calculated. The regression curve that best fit the data was a second order polynomial. The BMD and MCI of young adult women (20-40 years of age) were used to calculate T-score parameters. The young reference BMD and MCI with their associated standard deviations were found to be 0.6045 g/cm2+/-0.0529 g/cm2 and 0.5096 and 0.0792, respectively. However, the MCI was found to be approximately 2.5% lower (-0.0118) compared to Caucasian women. The African-American metacarpal BMD was found to be 3.5% (0.0207 g/cm2) higher across all ages when compared to existing Caucasian reference data acquired in a similar way. The differences were found to be entirely due to larger bone size, cortical diameter and bone width in the African-American women.

Estimation of bone mineral density by digital X-ray radiogrammetry: theoretical background and clinical testing.

A new automated radiogrammetric method to estimate bone mineral density (BMD) from a single radiograph of the hand and forearm is described. Five regions of interest in radius, ulna and the three middle metacarpal bones are identified and approximately 1800 geometrical measurements from these bones are used to obtain a BMD estimate of the distal forearm, referred to as BMDDXR (from digital X-ray radiogrammetry, DXR). The measured dimensions for each bone are the cortical thickness and the outer width, in combination with an stimate of the cortical porosity. The short-term in vivo precision of BMDDXR was observed to be 0.60% in a clinical study of 24 women and the in vitro variation over 12 different radiological clinics was found to be 1% of the young normal BMDDXR level. In a cohort of 416 women BMDDXR was found to be closely correlated with BMD at the distal forearm measured by dual-energy X-ray absoptiometry (r = 0.86, p < 0.0001) and also with BMD at the spine, total hip and femoral neck (r = 0.62, 0.69 and 0.73, respectively, p<0.0001 for all). The annual decline was estimated from the cohort to be 1.05% in the age group 55-65 years. Relative to this age-related loss, the reported short-term precision allows for monitoring intervals of 1.0 years and 1.6 years in order to detect expected age-related changes with a confidence of 80% and 95%, respectively. It is concluded that the DXR method offers a BMD estimate with a good correlation with distal forearm BMD, a low variation between geographical sites and a precision that potentially allows for relatively short observation intervals.

Digital X-ray radiogrammetry: a new appendicular bone densitometric method with high precision.

The precision of any given method for measurement of bone mineral density (BMD) is important in relation to the interpretation of repeated measurements over time, e.g. to monitor the course of suspected osteoporosis or follow the effect of therapy. In the present study a new bone densitometer using the digital X-ray radiogrammetry (DXR) method (Pronosco X-posure Systemtrade mark) is investigated with respect to its short-term precision. The study was carried out on two groups of females, one consisting of 20 women between the ages of 30 and 40, and the other of 20 post-menopausal women above the age of 64. The mean age of the premenopausal women was 35.2 years and the mean DXR BMD was 0.578 g cm-2. The mean age of the post-menopausal women was 68.2 years and the mean DXR BMD was 0.489 g cm-2. The short-term precision of the two groups was evaluated using the coefficient of variation (CV%) and corresponding 90% confidence intervals. The coefficient of variation in the premenopausal group was 0.68% with a 90% confidence interval of 0. 57%-0.83%. The coefficient of variation in the postmenopausal group was 0.61% with a 90% confidence interval of 0.52-0.75%. It can be concluded from the present study that the short-term in vivo precision error of the DXR method is low in both pre- and post-menopausal women. When the results of the study are compared to data reported in the literature, the performance of the DXR method seems to be at least equivalent with peripheral DXA.