A population pharmacokinetic-pharmacodynamic analysis of single doses of clenoliximab in patients with rheumatoid arthritis.

Clenoliximab (IDEC-151) is a macaque-human chimeric monoclonal antibody (immunoglobulin G4) specific for the CD4 molecule on the surface of T lymphocytes. It is being studied in patients with rheumatoid arthritis in which T cell activation orchestrates inflammation and tissue damage. In this initial study in humans, the pharmacokinetics and pharmacodynamics of clenoliximab were investigated after single intravenous infusion. Blood was collected up to 12 weeks after dose administration to measure clenoliximab concentration, CD4+ T-cell count, CD4 antigen coating, and CD4 cell surface density. Clenoliximab displayed nonlinear pharmacokinetic behavior and caused an 80% reduction in CD4 density for up to 3 weeks, without depleting T cells. A pharmacokinetic-pharmacodynamic model was developed that described the relationship between antibody concentration, antigen coating, and the observed decreases in CD4 cell surface density. This was used to anticipate the effects of clenoliximab in untested regimens and optimize the design of future clinical trials.

The response of articular cartilage to weight-bearing against metal. A study of hemiarthroplasty of the hip in the dog.

Hemiarthroplasty of the hip and some other joints has been used for many years with satisfactory results, but the fate of articular cartilage when weight-bearing against metal has not been reported. Replacement of the head of the femur was carried out in one hip of each of 26 dogs, and the changes in acetabular cartilage studied at intervals of up to 24 weeks. There was early loss of proteoglycan, followed by surface damage to the cartilage, progressive degenerative changes, and growth of pannus from the articular margins. At 24 weeks after operation there was little remaining articular cartilage, while intense subchondral activity suggested that the bony skeleton was being remodelled to conform to the shape of the prosthesis. This study is not intended to suggest that hemiarthroplasty does not help patients.

Perceptions of mathematics ability versus actual mathematics performance: Canadian and Hong Kong Chinese children.

This study compared levels of mathematics achievement between Canadian and Hong Kong Chinese children and explored the relations between perceptions of children's competence and mathematics achievement. The Canadian sample was made up of 125 4th-grade children who were randomly selected from five schools in Calgary. A comparative sample of 128 children was drawn from five Chinese-speaking schools in Hong Kong. Parents, teachers and children rated children's competence and a mathematics achievement test was given to the children. Hong Kong Chinese children outperformed their Canadian peers in the mathematics test. However, ratings of children's scholastic/mathematical abilities by Canadian respondents were significantly higher than those by Hong Kong Chinese informants. The Harter Self-Perception Profile Scale revealed that the aspects of themselves considered most important for sense of general self-worth were for Canadian children: physical appearance and social acceptance, for Hong Kong children: behavioural conduct and scholastic competence. Discussion centres on the contributions that expectations and evaluations of competence and self-worth make to the large difference in the mean levels of mathematics achievement between children in the two cultures.

A retrospective study of Moore and Thompson hemiarthroplasty. A review of 599 surgical cases and an analysis of the technical complications.

In a retrospective review of 580 patients with 599 hemiarthroplasties of the hip, 454 operations (75.8%) were carried out as primary procedures for fresh intracapsular fractures, and 145 operations (24.2%) were performed as salvage procedures. The three-month mortality rate was 5.0%, and the dislocation rate was 5.3%. The early results were assessed by roentgenograms alone; head size, neck length, stem-shaft angle, and calcar seating were measured on preoperative and postoperative films. Anteversion and retroversion could not be accurately assessed. Using an arbitrary rating system, the results were graded as excellent on the basis of four anatomical criteria: good, on the basis of three; fair, of two; and poor, on only one or none. Only 173 prostheses (26.3%) were graded as excellent and 103 (27.3%) as good. At least 70 (25.3%) were just fair, and 31 (11.2%) were poor. Inappropriate neck length was present in 55.0% of the dislocated prostheses, incorrect head size in 25.0%, varus of the prosthesis in 20.0%, and poor calcar seating in 25.0%. Thus, technical errors account for a significant number of imperfect hemiarthroplasties of the hip. Careful attention to detail should decrease the incidence of errors and improve end-results.

Disposition of metabolically radiolabeled CE9.1--a macaque-human chimeric anti-human CD4 monoclonal antibody--in transgenic mice bearing human CD4.

IDEC-CE9.1 is a macaque/human chimeric IgG1 monoclonal antibody (mAb) directed against the human T-lymphocyte receptor, CD4. CE9.1 is highly specific for the human receptor and is known to cross-react only with chimpanzee CD4. Thus, limited in vivo investigations have been performed that would be expected to reflect the behavior of this mAb in humans. CE9.1 was metabolically radiolabeled using [3H]leucine, and studies of the distribution and pharmacokinetics of [3H]CE9.1 were performed in transgenic mice bearing either the hCD4 receptor in place of the mouse receptor (CD4+), or no CD4 receptor (CD4-). Single-dose studies were performed after intravenous administration of approximately 0.4 and 100 mg/kg. The disposition of CE9.1 was highly dependent on the presence and distribution of the hCD4 receptor. After a low intravenous dose to CD4+ mice, rapid loss of [3H]CE9.1 from plasma (mean residence time < 1 hr) was accompanied by accumulation of radioactivity in the spleen (a maximum of 18% of the administered dose at 2 hr). By contrast, no significant uptake of radiolabel was observed in the spleen of CD4- mice after a low intravenous dose (< 1%), and plasma radioactivity exceeded 40% of the administered dose at 24 hr. Significant accumulation of radiolabel was observed in the liver of both CD4+ and CD4- mice (maximum of 9-13%), suggesting this process was not CD4-receptor-mediated. After a high intravenous dose to CD4+ mice, the mean residence time of CE9.1 was approximately 24 hr, and dose-normalized plasma area under the concentration vs. time curve was within a factor of 2 of that observed in CD4- mice. Spleen radioactivity was < 1% after a high intravenous dose to CD4+ mice, whereas in the liver, the profile of radioactivity was similar in CD4+ mice at 0.4 and 100 mg/kg.

Early versus delayed operative management of closed tibial fractures.

Fractures of the tibial shaft are the most common long bone fractures. Operative treatment of isolated closed tibial shaft fractures frequently is delayed in favor of treatment of life threatening injuries. A retrospective chart review of 200 tibial fractures was performed. These injuries were managed by two surgeons at a Level 1 trauma center between 1989 and 1996. Strict inclusion criteria identified 54 patients with an isolated closed tibial fracture. Postoperative hospital stay and complication rates were recorded. At a mean followup of 3.6 years, a quality of life questionnaire was administered via telephone calls to these patients. Two patient groups were identified: Group 1, 21 patients (< 12-hour surgical delay); and Group 2, 33 patients (> 12-hour surgical delay). Both groups were similar for baseline characteristics. Group 2 patients remained an extra 4.6 days in the hospital. A Kaplan-Meier analysis revealed that by the eighth postoperative day, all Group 1 patients were discharged from the hospital, whereas 47.8% of Group 2 patients remained in the hospital. Plate fixation was associated with a greater incidence of complications when compared with intramedullary nail internal fixation. Complication rates were significantly greater in the delayed surgical group. A multiple regression analysis revealed that surgical delay and postoperative complications accounted for 35% of the total variance in postoperative hospital stay. Time to surgical treatment was not prognostic of long term quality of life. Surgical delay results in longer postoperative hospital stays, greater complication rates, and increased total cost to the health care system.

Organ injuries associated with femoral fractures: implications for severity of injury in motor vehicle collisions.

OBJECTIVE: To determine if motor vehicle collisions (MVCs) resulting in femoral fractures were associated with a different injury severity and pattern of injury compared with crashes in which victims did not sustain femoral fractures. METHODS: Retrospective review of seriously injured motor vehicle occupants admitted to a regional trauma unit (Hamilton General Hospital) during a 69-month period (April 1991 to December 1996) for whom detailed crash details were known. RESULTS: Data for 733 motor vehicle occupants with Injury Severity Scores greater than 12 were available; 112 occupants (15.3%) sustained femoral fractures, and 621 occupants (84.7%) did not sustain femoral fractures. Victims with femoral fractures had a significantly higher mean Injury Severity Score (29.4 compared with 25.3 for non-femoral fracture group; p<0.001). The femoral fracture group had a higher incidence of bowel (p<0.012) and hemopneumothorax (p<0.02) injuries as well as an increased incidence of upper and lower extremity (p<0.001) and pelvic (p<0.05) fractures. CONCLUSION: The presence of a femoral fracture is strongly associated with the pattern and severity of injuries sustained by occupants in MVCs. A high index of suspicion is warranted in identifying associated organ injuries in MVC victims with concomitant femoral fractures.

Pharmacokinetics and pharmacodynamics of a humanized monoclonal antibody to factor IX in cynomolgus monkeys.

The pharmacokinetics and pharmacodynamics (PK/PD) of a humanized anti-Factor IX IgG1 monoclonal antibody (SB 249417, FIX mAb) were studied in Cynomolgus monkeys. Single i.v. bolus doses of 1, 3, or 10 mg/kg of FIX mAb were administered. The total FIX mAb concentration, activated partial thromboplastin time (aPTT), and Factor IX activity were monitored for up to 4 weeks after dosing. In the monkey, FIX mAb had a plasma clearance of 0.6 ml/h/kg and a steady-state volume of distribution of approximately 70 ml/kg. The elimination phase half-life (3.8 days) was considerably less than other humanized IgG1 mAbs in the monkey, for which there is no binding to endogenous antigen. The suppression of Factor IX activity and the prolongation of aPTT were rapid and dose dependent. The time for aPTT values to return to basal levels (25-170 h) increased with increasing dose. A mechanism-based PK/PD model consistent with the stoichiometry of binding (2:1) was developed to describe the Factor IX activity and aPTT response time course. The model incorporated Factor IX synthesis and degradation rates that were interrupted by the sequestration of Factor IX by the antibody. aPTT values were related to free Factor IX activity. This model was able to describe the PD profiles from the three dose levels simultaneously. The estimated Factor IX half-life was 11 h and the third-order association rate constant was 3.96 x 10(3) microM(-2) h(-1). The PK/PD modeling was useful in summarizing the major determinants (endogenous and antibody-ligand binding) controlling FIX mAb-related effects.

Comparative pharmacodynamics of keliximab and clenoliximab in transgenic mice bearing human CD4.

Keliximab and clenoliximab are monkey/human chimeric CD4 monoclonal antibodies (mAbs) of the IgG1 and IgG4 isotypes, respectively. The pharmacokinetics (PK) and pharmacodynamics (PD) of these mAbs were evaluated in transgenic mice bearing human CD4 molecules on their T cells after a single i.v. administration at three dose levels (5-125 mg/kg). The PK of keliximab and clenoliximab were similar, dose-dependent, and adequately described by a two-compartment model with saturable elimination from both compartments. The enumeration of circulating CD4(+) T cells and density of CD4 on their surface were determined as the PD effects. An indirect response model was proposed to characterize the PD effects. With the increase in mAb dose, the maximum intensity (R(max)) of PD effects was increased, and the time to reach R(max) shifted to later times. At all three dose levels, keliximab caused a relatively rapid decline in the number of circulating CD4(+) T cells, which then recovered gradually. In contrast, clenoliximab at the lowest dose (5 mg/kg) did not produce a significant effect on CD4(+) T cell counts compared with the placebo group. At high doses, clenoliximab caused a significant decrease in the number of CD4(+) T cells. Keliximab appeared to be more potent and efficient in depleting CD4(+) T cells. Both mAbs produced similar down-modulation of CD4 at corresponding dose levels. The findings of this study are consistent with the results of a recent clinical trial that emphasize the importance of this transgenic mouse model for evaluating PK/PD to support clinical development of anti-human CD4 mAbs.

Preclinical pharmacokinetic evaluation of the respiratory syncytial virus-specific reshaped human monoclonal antibody RSHZ19.

A preclinical evaluation of RSHZ19, a respiratory syncytial virus-specific reshaped human monoclonal antibody (IgG1 framework), has included pharmacokinetic studies in rats, adult cynomolgus macaques, and infant baboons after intravenous (iv), subcutaneous, or intramuscular (im) administration. After iv administration to rats and monkeys (1 mg/kg dose), a biphasic decline in plasma concentration was observed. The dominant terminal phase was characterized by an 11-day half-life in rats and a 21- to 24-day half-life in monkeys. Plasma clearances of 0.3 ml/hr/kg in the rat and 0.1-0.2 ml/hr/kg in the monkey were estimated. In the macaque, based on area under the curve, no evidence of significant nonlinearity in the pharmacokinetics was observed over a 200-fold dose range (1-200 mg/kg). In rat and monkey, absorption after extravascular administration was rapid relative to elimination (apparent half-lives < or = 24 hr), and bioavailability was high (> or = 82%). After iv or im administration to macaques (> or = 40 mg/kg), 1 of 3 animals in each group developed anti-RSHZ19 antibodies, and this resulted in rapid elimination of RSHZ19 from plasma. After the administration of a second im dose to macaques, no additional animals developed anti-RSHZ19 antibodies. Multiple-dose iv kinetics (5-day repeat dose) in infant baboons were modeled accurately by adult macaque data, suggesting that these species handled RSHZ19 similarly. The pharmacokinetic characteristics of RSHZ19 should support a convenient regimen for treatment or prophylaxis of human respiratory syncytial virus infection.