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Safety, Tolerability, Pharmacokinetics, and Immunogenicity of Motavizumab, a Humanized, Enhanced-Potency Monoclonal Antibody for the Prevention of Respiratory Syncytial Virus Infection in At-Risk Children

Abarca, Katia MD*; Jung, Elizabeth MD; Fernández, Pilar MD; Zhao, Liang PhD§; Harris, Brian MS§; Connor, Edward M. MD§; Losonsky, Genevieve A. MD§ for the Motavizumab Study Group

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The Pediatric Infectious Disease Journal: April 2009 - Volume 28 - Issue 4 - p 267-272
doi: 10.1097/INF.0b013e31818ffd03
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Abstract

Respiratory syncytial virus (RSV) is a significant respiratory pathogen of infants and young children that causes annual epidemics of bronchiolitis and pneumonia worldwide. Approximately 2% of infected infants require hospitalization.1,2 Premature infants, infants with chronic lung disease (CLD) of prematurity, and infants with hemodynamically significant congenital heart disease who are infected with RSV have hospitalization rates estimated to be 4 to 5 times higher than healthy children.3

There are currently no licensed vaccines to prevent RSV in children, and treatment options for RSV-infected individuals are limited.4 Monthly administration of RSV-specific antibody has been shown to be effective in the prevention of serious RSV disease in high-risk infants.5 Palivizumab (Synagis®, MedImmune, Gaithersburg, MD), a humanized monoclonal antibody directed against the F glycoprotein of RSV, was first licensed in the United States in 1998 and is currently in use in more than 60 countries.6 Prophylaxis of high-risk children with palivizumab 15 mg/kg monthly is associated with an overall reduction in RSV hospitalization rates of approximately 50% compared with placebo.5,7

Motavizumab (MEDI-524, MedImmune) is an enhanced-potency, RSV-specific monoclonal antibody developed by in vitro affinity maturation of the complementary determining regions of the heavy and light chains of palivizumab. Preclinical data indicate that motavizumab has an approximately 70-fold higher affinity for the F protein of RSV than palivizumab and is approximately 20-fold more potent than palivizumab in microneutralization studies.8 In the cotton rat model, motavizumab has 50 to 100 times greater anti-RSV activity in the lower respiratory tract compared with palivizumab9 and in this same model, at similar serum drug concentrations, motavizumab reduces RSV viral load in the upper respiratory tract of the cotton rat where palivizumab has minimal effect.8

The investigation described here was the first assessment of motavizumab in children. It was designed to evaluate the safety, pharmacokinetics, and immunogenicity of escalating, monthly intramuscular (IM) injections of motavizumab in high-risk children and included an assessment of tolerability and immunogenicity after sequential seasonal dosing.

MATERIALS AND METHODS

The first year of this study was a phase I/II, multicenter, open-label, dose-escalation study conducted in the United States (9 sites), Chile (4 sites), and Brazil (3 sites) during the respective RSV seasons in the northern and southern hemispheres (RSV season 1). Children were to receive between 2 and 5 doses of motavizumab (3 or 15 mg/kg) at 30-day intervals, depending on when during the RSV season a child was enrolled. During the second consecutive RSV season, at 4 sites in Chile and 2 sites in Brazil, children who received at least 3 doses of motavizumab in the previous season were randomized to receive monthly IM injections of motavizumab or palivizumab (15 mg/kg). Safety, tolerability, pharmacokinetics, and immunogenicity of motavizumab were evaluated. The study was conducted in accordance with the Declaration of Helsinki, and protocols were approved by the Institutional Review Board or Independent Ethics Committee at each study site. Parents or guardians of children provided written informed consent before participation.

Patient Population

Children were eligible to participate in the first year of the study if (1) their gestational age was between 32 and 35 weeks and they were ≤6 months of chronologic age or (2) they were ≤24 months of age and had CLD of prematurity requiring treatment with stable or decreasing doses of diuretics, steroids, or bronchodilators within the previous 6 months. Children were excluded if they had any of the following: hospitalization at the time of entry (unless discharge was expected within 3 days of study entry); birth hospitalization of >6 weeks’ duration (for children without CLD) or birth hospitalization >12 weeks’ duration (for children with CLD); chronic oxygen therapy or mechanical ventilation at the time of study entry (including continuous positive airway pressure); congenital heart disease; evidence of infection with hepatitis A, B, or C virus; known renal impairment; hepatic dysfunction; chronic seizure disorder; immunodeficiency or human immunodeficiency virus infection or mother with known infection; laboratory findings in blood obtained within 7 days before study entry for blood urea nitrogen or creatinine >1.5 times the upper limit of normal for age; aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >1.5 times the upper limit of normal for age; hemoglobin <9.5 g/dL, white blood cell count <4000 cells/mm3, or platelet count <120,000 cells/mm3; acute illness or progressive clinical disorder; active infection, including acute RSV infection; previous reaction to immunoglobulin intravenous (IGIV), blood products, or other foreign proteins; treatment with palivizumab; current or previous (within 120 days) treatment with immunoglobulin products (eg, RSV-IGIV [RespiGam®, MedImmune], IGIV) or any investigational agents; current participation in any investigational study; or previous participation in any investigational study using RSV vaccines or monoclonal antibodies.

Children were eligible to participate in the second RSV season if they received ≥3 doses of motavizumab (3 or 15 mg/kg) in the previous RSV season and were ≤24 months of age at enrollment.

Monoclonal Antibodies, Dosing, and Treatment Group Assignment

Motavizumab and palivizumab were provided in sterile vials containing 100 mg of sterile liquid product per 1 mL. In both seasons, the drugs were stored at 2°C to 8°C and administered by IM injection into the anterolateral aspect of the thigh.

During the open-label, dose-escalation phase in season 1, dosing was initiated at 3 mg/kg in 6 children without CLD. After all 6 children had been observed for at least 7 days after injection and there were no safety concerns, the dose of motavizumab was increased to 15 mg/kg in 6 additional children without CLD. An additional 18 children were enrolled at 15 mg/kg after all 6 patients in the initial cohort had been observed for at least 7 days and no safety concerns emerged. Dosing of children with CLD (motavizumab 15 mg/kg) began after all 30 previously enrolled children had received at least 1 dose of motavizumab and were observed for at least 7 days with no safety concerns.

During the second RSV season, treatment assignments were double-blind. The only individuals who had access to information that identified a patient's treatment allocation were the independent monitor, who reviewed only the pharmacy records, and the study pharmacist located at the study site. Children were randomly assigned 1:1 to receive motavizumab or palivizumab if their parent/legal guardian provided informed consent and they met all eligibility criteria. The randomization schedule was stratified by site with a block size of 4. Immediately after assignment to a treatment group, participants received their first dose of 15 mg/kg motavizumab or palivizumab (study day 0) followed by a dose every 30 days thereafter for a total of 4 to 5 injections.

Safety and Monitoring

For season 1, a physical examination and medical history were performed at screening (within 7 days before initial dosing); on the first day of dosing; and on days 2, 7, and 30 after dosing. Blood samples were collected for ALT, AST, blood urea nitrogen, creatinine, and a complete blood count with differential and platelets at screening on days 7, 30, and 37 and 30 days after the final dose of motavizumab. Blood was collected for the determination of immunogenicity and motavizumab serum concentrations on the day of each injection before dosing on days 2 (for serum motavizumab concentration only), 30, 37, and 60 after dose 1 and 30 and 90 days after administration of the final dose of motavizumab. Children who had motavizumab detected in serum or a titer of antimotavizumab antibodies of ≥1:40 at 90 days after the last dose had additional follow-up at 150 days after the last dose (for antimotavizumab antibody determinations). Adverse events (AEs) were defined as any adverse change from baseline that occurred after the first study injection through 30 days after the final dose. AEs and serious AEs (SAEs) were collected from the period immediately after the first administration of study drug through 30 days after the final dose. Clinical AEs and SAEs were graded by severity (levels 1, 2, 3, and 4, defined as mild, moderate, severe, and life threatening, respectively); laboratory AEs were defined by fold-differences above normal values in the central laboratory. All AEs were judged by the site investigators for their potential relationship to study drug (none, remote, possible, probable, definite). SAEs were those that resulted in death; were life threatening; resulted in inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability or incapacity; or were an important medical event that may not have resulted in death, threat to life, or required hospitalization but based on appropriate medical judgment, may have jeopardized the patient and may have required medical or surgical intervention to prevent 1 of the outcomes listed above.

In season 2, children were evaluated 30 minutes before and after injections and were followed up through 90 to 120 days after the last dose. Blood was collected before doses 1, 2, and 5 and at 2, 30, and 90 to 120 days after the last dose. AEs and SAEs were collected from the period immediately after the first administration of study drug through study day 120 for children who received 4 doses and study day 150 for children who received 5 doses of study drug.

Pharmacokinetic and Immunogenicity Assays

Serum concentrations of motavizumab were determined by a qualified enzyme-linked immunosorbent assay (ELISA), which was linear over a concentration range of 1.56 to 50.0 μg/mL. Positive controls were prepared by adding known quantities of motavizumab to pooled normal human serum. Reference standards, ranging from 0.391 to 200 μg/mL motavizumab, were prepared by adding motavizumab to pooled normal human serum. Concentrations of motavizumab in the unknown samples were determined relative to the motavizumab standard curve. Results were analyzed using Softmax Pro 3.1.2 software (Molecular Devices Corporation, Sunnyvale, CA). Samples with calculated concentrations below the lower limit of quantitation (LOQ) of the assay (<1.56 μg/mL) were reported as <LOQ. A similar procedure was used to quantify serum palivizumab concentrations. The LOQ for the palivizumab assay was <10 μg/mL.

Antimotavizumab antibody binding assays were performed using a qualified ELISA similar to that described above. Positive controls were prepared by spiking normal human serum with a goat polyclonal antimotavizumab reagent. Six unique motavizumab-naive human serum samples were used to generate a lower threshold value for each plate. Samples with an optical density greater than the lower threshold value were considered positive for antimotavizumab. Positive unknown samples were titered on a second plate beginning with the original sample and 2-fold serial dilutions with normal human serum in duplicate. The end point titer was defined as the highest serum dilution tested that yielded a positive response. Because all samples were diluted 1:10 before performing the assay, the lowest dilution value for which a positive result could be obtained was 1:10. A similar procedure was used to detect antipalivizumab-binding antibodies.

For functional characterization of the antibody response, predose and postdose serum samples from antidrug antibody–positive subjects were diluted minimally 1:15 with cell culture medium, heat-inactivated at 56°C to eliminate complement activity, and sterile filtered. Diluted predose and postdose serum samples were spiked with an equal volume of 1 of 3 concentrations of motavizumab. Sample/drug solutions were incubated for 1 hour at 37°C, an equal volume of RSV A virus was added and incubated for 1 hour at 37°C. An equal volume of sample/spiked drug/RSV mixture was then added to triplicate wells of HEp-2 cells, resulting in a final serum dilution of 1:120 (0.83% serum) in the assay plates and incubated for 6 days at 37°C to allow for cell killing. Cell viability was assessed using CellTiter-Blue™ (Promega, Madison, WI) fluorescent viability reagent. Antidrug antibody–positive postdose samples spiked with motavizumab that showed >50% neutralization of spiked drug activity compared with their corresponding predose spiked samples were classified as positive for neutralizing antibody activity.

Pharmacokinetic Analysis

Median observed serum concentrations and associated fifth and 95th percentiles were calculated for each nominal time point. A 2-compartment structural pharmacokinetic model was used to describe motavizumab concentration profiles. Post hoc individual pharmacokinetic parameters were estimated using a population approach of the nonlinear mixed effects model. Expected median concentrations after monthly IM administration of motavizumab 15 mg/kg in this patient population were simulated based on model-derived individual pharmacokinetic parameters. Half-life (t1/2) was calculated using the following equation: t1/2= ln(2)/kelim, where kelim is the elimination constant, calculated as (ln[C30]–ln[C90])/t, C is the concentration of motavizumab at 30 or 90 days after dose 5, and t is the time interval between the 2 measurements.

RESULTS

Patients

A total of 217 children were enrolled in year 1. The first 40 children were enrolled in the United States in late winter of 2004, near the end of the RSV season in the Northern Hemisphere. The remaining 177 children were enrolled in South America during the 2004 RSV season in the Southern Hemisphere. Baseline characteristics of children who participated in season 1 are presented in Table 1. For all children enrolled in the study, the mean age at initial enrollment was 3.0 months and the mean weight was 4.1 kg. Thirty-two children (14.7%) with CLD were enrolled, all of whom received 15 mg/kg. Of the 217 children, 211 (97.2%) received motavizumab 15 mg/kg, and 205 (94.5%) patients completed the study through final follow-up at 90 days after the final dose. One hundred twelve children (51.6%) received 5 doses of motavizumab, 101 children (46.5%) received 2 to 4 doses, and 4 children (1.8%) received 1 dose of motavizumab.

TABLE 1
TABLE 1:
Baseline Demographics and Characteristics

In season 2, 136 children who participated during the previous season were randomized between May 31, 2005 and June 30, 2005, to 1 of 2 treatment groups (motavizumab [n = 66] or palivizumab [n = 70]) at 6 sites in South America (4 in Chile and 2 in Brazil). A total of 131 patients (96.3%) completed the second season of the study. Two patients in the motavizumab treatment group (1 lost to follow-up and 1 withdrew consent) and 3 patients in the palivizumab group (all withdrew consent) did not complete the study. Baseline demographics for season 2 were similar and balanced between the motavizumab and palivizumab groups (Table 1).

Safety

Season 1

In season 1, 9 AEs deemed unrelated to study drug by the site investigators were reported among 4 of the 6 children who received motavizumab 3 mg/kg. One of these events was an SAE (inguinal hernia). Among the 211 children who received motavizumab 15 mg/kg, 47 children (22.3%) experienced at least 1 AE considered related to study drug by the site investigators. The most common (≥1%) related AEs were injection site erythema and elevated serum transaminases (Table 2). Transient (typically resolved in <1 day) mild injection site erythema was reported in approximately 13% of children. Overall, 21 children (9.7%) had elevations in ALT and AST (11 children), AST alone (8 children), or ALT alone (2 children) that met AE criteria, 14 of which were considered to be potentially related to study medication. All elevations were noted during protocol-specified testing in clinically asymptomatic children. Eight of the 14 AEs were level 1 or level 2 in severity, and 6 children had asymptomatic level 3 or 4 elevations of ALT values (n = 6; range, 182–328 U/L) and/or AST (n = 1; 333 U/L). Three patients were identified after the fifth (last) dose of motavizumab; 2 patients showed improvement on repeat sampling 7 days later (the third child did not have repeat testing). One child had elevated serum transaminases at enrollment before receipt of the initial dose of motavizumab. However, repeat testing 21 days after the first dose of motavizumab showed improvement in transaminase values. Two children had transaminase elevations identified after the second dose, and both resolved despite continued dosing.

TABLE 2
TABLE 2:
Incidence of Treatment-Related Adverse Events Occurring in ≥1% of the Study Population

Although fever was commonly reported (n = 35, 16.1%), only 1 event of fever occurred temporally related to dosing and did not recur with subsequent doses. Fourteen subjects had fever attributable to diphtheria-pertussis-tetanus and oral poliovirus vaccine immunizations; 13 subjects had fever events attributable to respiratory or gastrointestinal infections. Seven subjects had fever events without etiology, all of which were level 1 or 2 and lasted 1 or 2 days, except for 1 event of fever (level 1) that lasted 23 days. Ten children (4.6%) experienced irritability; all but 1 event were mild in severity. Three children experienced 4 occurrences of transient irritability considered to be related to study drug. These cases of transient irritability occurred on the day of doses 1, 2, 4, and 5. Rash was seen in 4 children (1.8%). Two of these 4 cases of rash were considered to be related to study drug after dose 2 and 5; both events were level 1 in severity and resolved within 1 day. Two children (0.9%) experienced urticaria beginning 10 to 29 days after dose 3; both AEs were considered unrelated to study drug and did not recur with subsequent doses.

Other than noted above, additional laboratory evaluations did not reveal medically significant drug-related abnormalities. Generally mild and transient anemia was the most commonly reported hematologic finding (48.3% of children in the 15-mg/kg dose group). The timing of the anemia was consistent with physiologic anemia of prematurity. Three children had moderate neutropenia that was reported to be potentially drug related. The events resolved with continued dosing; some had alternative etiologies (viral infections) and none resulted in treatment discontinuation.

In all, 10.4% of children in the 15-mg/kg group experienced an SAE. Most were typical hospitalizations for this population and were not considered to be related to study drug. One child was diagnosed with idiopathic thrombocytopenic purpura that was considered to be possibly related to study medication and had a transient significant decrease in platelets 21 days after dose 4 that fully resolved within 11 days of onset without treatment. Tests for cytomegalovirus, parvovirus, and Epstein-Barr virus infection were negative.

One death was reported during the study safety follow-up period and deemed not related to study drug by the site investigator: a 13-day-old child (35 weeks’ gestation) who presented with apnea, acidosis, and oliguria secondary to RSV bronchopneumonia requiring mechanical ventilation and pressor support 7 days after receipt of the first dose of motavizumab. After approximately 2 days in stable condition with improvement in ventilation, the patient self-extubated, developed asystole after reintubation and sedation, and could not be resuscitated. An autopsy revealed bronchopneumonia, emphysema, and end organ hemorrhage including the liver and suprarenal areas. No autopsy cultures were performed.

Season 2

In season 2, 56 (84.8%) motavizumab-treated children and 62 (88.6%) palivizumab-treated children experienced at least 1 AE. A total of 12 patients in each of the motavizumab (18.2%) and palivizumab (17.1%) groups experienced at least 1 AE considered to be related to study drug (Table 2). The most common of these was injection site erythema (motavizumab, 15.2%; palivizumab, 11.4%). These events were transient (lasting 1–2 days), were mild in severity, and appeared not to be associated with dose number. A total of 5 children (motavizumab, 4 [6.1%]; palivizumab, 1 [1.4%]) experienced 6 SAEs; 5 of which were judged to be unrelated to study drug. The 1 related SAE was an acute hypersensitivity event consisting of periorbital edema with upper chest rash, occurring within 15 minutes of the third dose of motavizumab with no associated respiratory distress, which decreased within 15 minutes of receipt of IM antihistamine; dosing was discontinued and the event fully resolved without recurrence. The patient was a 16.3-month-old female, 34 weeks gestational age, with a history of atopic dermatitis. This patient experienced no AEs consistent with acute hypersensitivity in season 1 and had no evidence of antidrug antibody after the first season of dosing. There were no deaths reported during the safety follow-up period for season 2.

Similar numbers of motavizumab (n = 2) and palivizumab (n = 2) patients had either ALT and/or AST increases recorded as AEs. Although lower than the rates observed in season 1, they were not statistically different. These events in the motavizumab group were judged not to be clinically significant by the site investigator, and values returned to normal within the 30 days after the final dose. One event in the motavizumab group was considered possibly related to study drug. An increase in blood urea nitrogen was noted in 4 patients who received palivizumab and none who received motavizumab. The events were all observed in samples taken before dose 2. All were mild in severity, were associated with normal creatinine levels, and were considered not related to study medication.

Pharmacokinetics of Motavizumab

In season 1, a small number of children (n = 6) received motavizumab 3 mg/kg IM. Mean serum trough concentrations were 7.9 μg/mL after the first dose and increased after subsequent doses. Figure 1 shows the observed individual and median serum concentrations and their fifth and 95th percentiles, as well as the predicted median serum concentration-time curve of motavizumab for patients treated with 15 mg/kg using individual pharmacokinetic parameters derived from the 2-compartment model. Mean serum trough concentrations were 50.2 μg/mL after the first 15-mg/kg dose and increased to 95.9 μg/mL after the fifth dose. The mean ± SD t1/2 calculated after the last dose among children who received 5 doses was 24.4 ± 5.7 days. The observed steady-state accumulation of serum trough concentrations is consistent with the estimated t1/2 of motavizumab and dosing frequency. Children who displayed evidence of antibody responses to motavizumab displayed lower mean trough serum concentrations of motavizumab at 30 days after the final dose compared with children without detectable antibody. However, there were few observations at each time point, and there was marked variability in drug concentrations such that individual values in patients with detectable antibodies were within the range of those seen in patients without detectable antibody (Table 3).

FIGURE 1.
FIGURE 1.:
Motavizumab serum concentrations in patients receiving monthly intramuscular doses of 15 mg/kg during season 1. Circles indicate observed drug concentrations. Solid squares indicate observed median serum concentrations at each nominal time point. Error bars indicate fifth and 95th percentiles of observed concentrations. Numbers adjacent to the median symbols represent the number of pharmacokinetic observations at each time point. A solid line indicates simulated median serum concentrations.
TABLE 3
TABLE 3:
Serum Trough Concentrations for Patients With and Without Detectable Antimotavizumab Antibodies

In season 2, serum trough concentrations of motavizumab were detectable in all subjects approximately 30 days after dose 1. The mean serum trough values and ranges of motavizumab after the first and fourth dose (54.6 μg/mL, range: 16.5–87.2 μg/mL; 86.2 μg/mL, range: 37.5–148 μg/mL, respectively) were similar to those observed in the first season (50.2 μg/mL, range: 2.76–106 μg/mL; 86.2 μg/mL, range: 0–194 μg/mL, respectively). The mean motavizumab concentration in all subjects was 12.2 μg/mL (range, 1.7–26.2 μg/mL) by 90 to 120 days after the final dose. There were no appreciable differences in serum drug concentrations in the 2 subjects with antimotavizumab antibodies before dosing in season 2 compared with those children without detectable antidrug antibodies.

Immunogenicity of Motavizumab

In season 1, 7 (3.3%) children in the 15-mg/kg group had antimotavizumab-binding antibody detected; 3 (1.4%) at 30 days after dose 5, and 4 (1.9%) at 90 days after the final dose (1 each after 3 or 4 doses, and 2 after 5 doses). Titers ranged from 1:80 to 1:2560. At the 150-day post–final dose follow-up, no new patients were identified with antimotavizumab activity. Children with antimotavizumab reactivity did not have any significant AEs concomitant with this observation. Antimotavizumab-binding antibody was detected in the child (described above) with transient idiopathic thrombocytopenic purpura at 90 days after the final dose (titer, 1:640), approximately 2 months after the event had resolved. Antimotavizumab antibody responses were further characterized; 6/7 subjects with antibody to motavizumab had evidence that these responses neutralized motavizumab. In season 2, no treatment group–specific antibody responses were detected during the study or at 90 to 120 days after dosing.

DISCUSSION

Motavizumab is an investigational anti-RSV humanized monoclonal antibody that is being developed for the prevention of serious RSV disease in high-risk children. Before this study, motavizumab (3, 15, and 30 mg/kg) was evaluated in a phase I study of 30 healthy adult volunteers; no safety issues were identified (data on file). This study provides the first data for the IM administration of motavizumab in pediatric patients. The first season of the study assessed initial clinical safety in a small number of children given 3 mg/kg followed by a larger group of children given the target dose of 15 mg/kg.

No serious dose-limiting toxicities were identified that were thought to be related to motavizumab. Most AEs were mild or moderate in severity and were consistent with those observed for patients with underlying conditions common in this high-risk population. Transient mild injection site reactions (ie, injection site erythema) were reported in 13.4% of patients. This rate differs from results seen in the IMpact study of palivizumab (1.2% and 1.4% in patients receiving placebo and palivizumab, respectively).5 However, results from a much larger recent phase III study showed rates of 2.7% and 3.3% in patients receiving palivizumab and motavizumab, respectively (data not shown), suggesting that the higher injection site reaction rate observed in this study may be a consequence of the small sample size. The most notable finding was that approximately 10% of motavizumab recipients had elevations of serum transaminases identified by protocol-defined laboratory testing. In contrast, results from the IMpact study demonstrated that levels of AST (placebo, 1.6%; palivizumab, 3.6%) and ALT (placebo, 2.0%; palivizumab, 2.3%) were elevated in a subset of patients5 and the larger phase III study showed rates of 1.9% and 1.8% in patients receiving palivizumab and motavizumab, respectively (data not shown), again suggesting that the higher rates observed in this study may be a consequence of the small sample size. These elevations were not associated with clinical symptoms and were transient.

The incidence of motavizumab immunogenicity observed in year 1 of this study is somewhat lower than that observed in previous studies with palivizumab in which 8% to 15% of patients displayed immune reactivity to palivizumab.10,11 Antimotavizumab immune reactivity was detected in 3% (n = 7) of patients and seen only after the completion of dosing (after dose 5 or 90 days after final dose). When immune reactivity was observed, drug concentrations were not detectable in some children. It is not clear whether this was a result of immunogenicity or related to the time point after dosing at which the blood sample was obtained. The finding of immune reactivity was not associated with any AE. One child with a diagnosis of idiopathic thrombocytopenic purpura had antimotavizumab-binding activity that was first identified approximately 2 months after complete resolution of the event (approximately 90 days after dose 4), making it unlikely that the thrombocytopenia was a drug-induced immune-mediated event.

In this study, motavizumab trough serum concentrations were measured monthly. The pattern of mean trough serum concentrations of motavizumab throughout this study was consistent with what one would expect with an IgG1 monoclonal antibody. Serum concentrations increased after each subsequent dose as expected. The mean t1/2 of motavizumab after a single intravenous or IM dose of motavizumab in healthy adults ranged from 13.7 to 18.5 days (data on file). The predicted serum t1/2 of motavizumab in children who received 15 mg/kg was approximately 24 days. This pharmacokinetic profile is consistent with palivizumab, which has a mean t1/2 of 19 to 27 days.11

Because high-risk children may require repeated RSV immunoprophylaxis doses over successive seasons, safety, tolerability, and immunogenicity of motavizumab were evaluated in children who received immunoprophylaxis during a second consecutive season. Repeated dosing with motavizumab or palivizumab during a second season was well tolerated. Antimotavizumab-binding activity was not detected through 90 to 120 days after the final dose in any patient who received motavizumab for a second season. Serum trough motavizumab concentrations were similar to those achieved in the first season in patients who received 15 mg/kg motavizumab. These studies provide the first clinical data on the safety of motavizumab when given for a second season.

Motavizumab has been shown in preclinical evaluations to have enhanced potency against RSV. Based on these findings, further clinical evaluation of motavizumab for the prevention of serious RSV disease in high-risk children is warranted.

ACKNOWLEDGMENTS

The authors thank the clinical research staff at all of the participating study sites and all of the children and families who participated in this study; Gabriel Robbie, PhD, of MedImmune for assistance with data analysis; Pam Mattes, PhD, Rhonda Croxton, PhD, Jeannie M. Fiber, PhD, and Gerard P. Johnson, PhD, for medical writing and editorial assistance in preparing this manuscript.

The Motavizumab Study Group—-Brazil: Otavio Cintra, Hospital das Clinicas da Faculdade de Medicina de Ribeirao Preto, Ribeirao Preto; Manuel Pereira, Hospital de Clinicas de Porto Alegre, Porto Alegre; Renato Stein, Pontificia Universidade Catolica do Rio Grande do Sul, Porto Alegre. Chile: Katia Abarca, Hospital Clínico Pontificia Universidad Católica de Chile, Santiago; Pilar Fernández, Hospital Clínico Universidad de Chile, Santiago; Christina Lindemann, Hospital San José, Independencia; Patricia Mena, Hospital Dr. Sótero del Río, Santiago. United States: Penelope Dennehy, Rhode Island Hospital, Providence, RI; Jeffrey Gerdes, Pennsylvania Hospital, Philadelphia, PA; Elizabeth Jung, St. John's Mercy Medical Center, St. Louis, MO; David Kaufman, University of Virginia Hospital, Charlottesville, VA; Leonard Krilov, Winthrop University Hospital, Mineola, NY; Jay Lieberman, Miller Children's Hospital, Long Beach, CA; Cody Meissner, New England Medical Center, Boston, MA; Mark Polak, West Virginia University Hospital, Morgantown, WV; Pablo Sanchez, University of Texas Southwest Medical Center at Dallas, Dallas, TX; Robert Schelonka, University of Alabama at Birmingham, Birmingham, AL; Yolande Smith, Georgetown University Medical Center, Washington, DC; Jean Steichen, University of Cincinnati College of Medicine, Cincinnati, OH; Whit Walker, Greenville Hospital System, Greenville, SC; Robert Welliver, Women & Children's Hospital of Buffalo, Buffalo, NY; Ram Yogev, Children's Memorial Hospital, Chicago, IL.

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Keywords:

clinical trial; motavizumab; palivizumab; pediatric; respiratory syncytial virus

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