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BIOLOGICS |
From the Developmental and Metabolic Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland (Dr Ries, Dr Brady, Dr Schiffmann); The Hospital for Sick Children, Toronto, Canada (Dr Clarke); Center for Lysosomal Storage Diseases, Children's Hospital, University of Mainz, Mainz, Germany (Dr Whybra, Dr Beck); Royal Free Hospital, London, United Kingdom (Dr Mehta); and Research, Shire HGT, Cambridge, Massachusetts (Dr Loveday). Dr Ries's current affiliation is Shire HGT, Cambridge, Massachusetts. Dr Loveday's current affiliation is Altus Pharmaceuticals, Cambridge, Massachusetts.
Address for correspondence: Dr Raphael Schiffmann, National Institutes of Health, Building 10, Room 3D03, 9000 Rockville Pike, Bethesda, MD 20892-1260; e-mail: RS4e{at}nih.gov.
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ABSTRACT |
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 TOP ABSTRACT MATERIAL AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Key Words: Fabry disease • lysosomal disorders • enzyme replacement therapy
-galactosidase A (GALA) that leads to failure to catabolize lipids containing -D-galactosyl moieties1 such as globotriaosylceramide (Gb3), digalactosyl ceramide, and blood group B, B1, and P1 glycolipids that accumulate in a variety of different types of cells.1-4 Progressive kidney failure, cardiac dysfunction, and stroke are documented complications in adult patients with Fabry disease.5-7 The majority of male children and adolescents with Fabry disease suffer from neuropathic pain, hypohidrosis, and enteropathic symptoms, leading to a reduced quality of life compared with peers.8,9 Females with Fabry disease, children as well as adults, express a heterogeneous spectrum of the disease with variable severity.8,10-12 The effects of enzyme replacement therapy (ERT) for Fabry disease have been documented in adult hemizygous patients.13,14 In these patients, ERT reduced glycolipid storage in various organs and tissues, decreased pain, improved peripheral nerve function and sweating, and appeared to reduce cardiac hypertrophy.15,16 ERT has also been safely applied to female patients with Fabry disease.17 The pathologies of Fabry disease are progressive, and if ERT is initiated late in the course of the disease, renal and cardiac function may continue to deteriorate despite therapy. Indeed, some patients experience strokes or develop white matter lesions despite ERT.18-20 Children with Fabry disease are mainly free from major organ complications, such as cardiac or renal involvement and stroke.9 Therefore, initiating treatment in childhood might prevent these secondary complications.
Until now, succinct data on enzyme and substrate turnover as well as kinetics of enzyme replacement therapies for Fabry disease have not been available for a pediatric population. We therefore conducted a multicenter clinical study to determine pharmacokinetic (PK) and pharmacodynamic parameters in pediatric Fabry patients following single and repeated IV infusions of agalsidase alfa administered every other week (EOW).
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MATERIAL AND METHODS |
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TOPABSTRACTMATERIAL AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Adult Patients
First-dose PK results from 18 adult male and 15 adult female Fabry patients were used as a comparison to the pediatric pharmacokinetics. Data were obtained from 10 men who participated in a randomized clinical study performed at the NIH in Bethesda, Maryland,14 and from 8 men who participated in a randomized clinical study performed at the Royal Free Hospital, London, United Kingdom.22 In both studies, the male patients had been treated with placebo during the double-blind phase of the studies, and pharmacokinetics were determined following the first dose during the open-label phase of the studies. The 15 women participated in an open-label study performed at the University of Mainz, Mainz, Germany.17 The study protocols were approved by the local institutional review boards of the NIH, Royal Free Hospital, or the University of Mainz. All patients gave their written informed consent to participate in these studies.
Enzyme Infusions and Blood Sampling
All patients were treated with 0.2 mg/kg of agalsidase alfa as a nominal 40-minute intravenous infusion administered EOW. During each patient's first infusion of agalsidase alfa, blood samples were taken prior to dosing and at selected time points during and after infusion (at approximately 20, 40, 50, 60, and 90 minutes and 2, 3, 4, and 8 hours following initiation of infusion) for PK analysis. For the adult PK studies, the duration of blood sampling was extended to 24 hours. The PK study was repeated after 6 and 24 months of agalsidase alfa treatment in the pediatric patients and after 6 or 12 months in the adult male patients. No follow-up PK study was performed in the female patients.
-Galactosidase A Activity and Plasma Gb3 and Analysis
Blood samples were processed to serum and sent frozen to Shire HGT for analysis of -galactosidase A activity. The enzyme assay used 4-methylumbelliferyl--D-galactopyranoside as the substrate and was modified from the method by Bishop and Desnick.23 The lower limit of detection for each assay was 1 U/mL. One unit (U) of enzyme activity was defined as the hydrolysis of 1 nanomole of substrate per hour at 37°C. Plasma Gb3 levels were measured at Shire HGT by high-performance liquid chromatography (HPLC) as previously described.24
Test Article
Agalsidase alfa is a form of human GALA produced in a genetically engineered continuous human cell line.14 The purified enzyme has the same amino acid sequence as the native human enzyme.25 The patients were dosed with various lots of agalsidase alfa. The specific activity of the lots ranged from 2.61·106 to 3.33·106 U/mL (average, 2.88·106 U/mL). The average dose administered to each patient was 0.57·106 U/kg (range, 0.49 to 0.68·106 U/kg). Four of 5 girls were enrolled at a single site where 1 lot of agalsidase alfa with the highest specific activity was used. Therefore, on average, girls received a slightly larger dose than boys (0.64 ± 0.07 vs 0.55 ± 0.05 U/kg·106, P = .005).
Pharmacokinetic Analysis
Pharmacokinetic analysis was performed at Shire HGT using WinNonlin Professional software (Pharsight Corporation, Mountain View, California). Each patient's serum activity-concentration profile was analyzed using a noncompartmental model.
Individual predose serum GALA levels (baseline) for the 19 male patients were 
1 U/mL for both weeks 1 and 25. The baseline values for the 5 female patients ranged from 4 to 14 U/mL during week 1 and 4 to 10 U/mL during week 25. These individual predose values were subtracted from the measured values before performing the PK analysis. For female patients, adjusted values less than predose values were not used for the analysis; for male patients, adjusted values <2 U/mL were not used for analysis. These cutoff levels affected only the 6-hour time point for 2 of 19 boys and for 4 of 5 girls.
To perform the PK analysis, the nominal dose (0.2 mg/kg) was converted to measured enzyme activity based on the volume of drug administered and the specific activity of each lot (total U/patient), and actual blood sampling times (instead of nominal sampling times) were used. The following pharmacokinetic parameters were calculated using the noncompartmental model: area under the curve extrapolated to infinity (AUC [min·U/mL]), maximum measured serum enzyme activity (Cmax [U/mL]), terminal elimination half-life (t
[
z] [min]), serum clearance of administered dose (Dose/AUC; CL [mL/min]), serum clearance normalized for body weight (CL [mL/min/kg]), apparent volume of distribution at steady state (MRT·CL; Vss [L]), and Vss normalized for body weight (Vss [% BW]).
Antibody Analysis
Serum samples taken at baseline and at weeks 9, 17, and 25 or 26 from the 24 pediatric patients were screened for anti-agalsidase alfa antibodies using an IgG screen and a multiple-screen (IgG, IgA, IgM, and IgE) enzyme-linked immunosorbent assay (ELISA) method. A positive response was defined as an absolute absorbance greater than 0.04 units and a time point/baseline ratio 
2.0.
Pharmacokinetic vs Pharmacodynamic Analysis
The percent reduction in plasma Gb3 concentration was used as an estimate of the efficacy of agalsidase alfa, and the relationship between percent reduction in plasma Gb3 and calculated pharmacokinetic parameters was evaluated by linear regression. Because female patients in these clinical studies had normal or nearly normal levels of plasma Gb3 (as expected based on the observation that most female Fabry patients have substantial but subnormal GALA activity26), reduction of plasma Gb3 was compared only in male pediatric patients and adult male patients.
Statistical Analysis
Methods of descriptive statistics were applied. Measures of central tendency were compared by t test, analysis of variance (ANOVA), and corresponding post hoc test as appropriate. The analyses were 2-tailed at a significance level of .05. All values are expressed as mean ± standard deviation (SD).
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RESULTS |
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TOPABSTRACTMATERIAL AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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First-Dose Pharmacokinetics in Children (Week 1)
Agalsidase alfa had a biphasic serum elimination profile in all 24 pediatric patients (the mean serum profile is shown in Figure 1). Cmax coincided with the end of the actual drug infusion in each patient, with a few exceptions. Calculated pharmacokinetic parameters are presented in Table I. Serum clearance and Vss were similar in the male and female patients, but t was significantly longer in male (70.8 ± 12.7 minutes) than in female (50.2 ± 10.2 minutes, P = .003, t test) pediatric patients. Serum clearance tended to decrease with age in this pediatric population (P = .051), and the trend line approached the adult values, as shown in Figure 2. Age had no significant influence on t (data not shown, P = .42). Mean AUC was higher in girls than in boys. However, this difference was primarily due to the fact that girls received an average higher dose of enzyme activity than boys (see above). Correcting for the difference in administered enzyme activity eliminated the statistical difference between the genders (P = .102, data not shown).
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First-Dose Pharmacokinetics in Adults
Agalsidase alfa had a biphasic serum elimination profile following a single intravenous infusion in the 18 adult male and the 15 adult female Fabry patients and was eliminated from the serum of most patients by 24 hours (Figure 1). As expected, Cmax coincided with the end of the 40-minute infusion period. Mean serum clearance in the adult males was 2.5 ± 0.7 mL/min/kg and was 2.1 ± 0.64 mL/min/kg in the adult females. The difference in clearance among the adult male and female Fabry patients was not statistically significant (t test), although t was slightly but significantly longer in men than in women (Table II). The mean serum clearance of agalsidase alfa in the adults was significantly slower than that seen in the pediatric population (2.3 ± 0.7 mL/min/kg vs 3.7 ± 1.5 mL/min/kg, P < .0001, t test). As was shown in the children, women had a larger AUC than men, primarily due to the fact that they received slightly higher doses (in terms of enzyme activity) than the men (data not shown).
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Repeat-Dose Pharmacokinetics (Week 25/26)
Predose serum concentrations of agalsidase alfa in male pediatric patients during week 25 (14 days after the previous dose) were 1 U/mL, confirming the lack of accumulation of agalsidase alfa in serum. The calculated PK parameters are presented in Table III. The 5 female pediatric patients and 11 of the 19 male pediatric patients had repeat-dose serum profiles nearly identical to their initial serum profiles (Figure 3A). In the remaining 8 male patients, terminal elimination of agalsidase alfa was slower during week 25 compared to week 1 (Figure 3B). For these 8 male patients, first-dose mean t was 66 minutes (range, 34-87 minutes), which increased to a mean value of 150 minutes (range, 112-256 minutes) during week 25. One male pediatric patient had an 80% reduction in Cmax (measured enzyme activity) at week 25 in comparison to week 1. Because of previous infusion reactions, his infusion time had been increased from 40 minutes to 1 hour, which accounts for a portion, but not all, of the decrease in Cmax during week 25. This patient had a transient IgG anti-agalsidase alfa antibody response at week 9, but antibodies to agalsidase alfa were not detected at either week 17 or at the time of the week 25 PK analysis.
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In the adult males, a substantial increase in t was demonstrated by 7 of the 18 patients during repeat PK analysis performed after 6 or 12 months of agalsidase alfa treatment. In these 7 patients, mean t increased from 111 minutes (range, 87-130 minutes) to 314 minutes (range, 161-470 minutes). No repeat PK analysis was done with the female patients.
Repeat-Dose Pharmacokinetics (2 Years)
Eleven pediatric patients (10 boys, mean age = 12.4 years [range, 10.3-16.8 years], 1 girl, age = 10.7 years) completed 2 years of agalsidase alfa therapy and had a successful PK study performed at that time. The calculated PK parameters are presented in Table III. Three of these patients had demonstrated a slower t at the week 25 measurement than during the initial infusion. Compared to their week 25 determination, the 2-year t was longer in 1 patient (144 minutes at week 25 vs 230 minutes at year 2), was shorter in 1 patient (137 vs 104 minutes), and was relatively unchanged in 1 patient (112 vs 119 minutes). None of the other 8 patients demonstrated a slower terminal elimination t after 2 years of dosing compared with their initial determination.
Antibodies
One male patient was positive for IgG antibodies at week 9 with a titer of 1:100. These antibodies were neutralizing, inhibiting in vitro enzyme activity by 87%. Although the patient tested IgG negative at week 25 of the study, the patient again tested IgG positive after 1.5 and 2 years of agalsidase alfa treatment. No other pediatric patient tested positive for anti-agalsidase alfa IgG antibodies at any time. No IgE antibodies were detected at any time.
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The pharmacokinetics of agalsidase alfa did not influence the reduction in plasma Gb3 in boys. For example, no relationship between AUC and decrease in plasma Gb3 in boys was evident (Figure 4). A similar lack of correlation between reduction in plasma Gb3 and serum clearance, terminal elimination half-life, or Vss was also found (data not shown). The relationship between the reduction in plasma Gb3 was similarly not related to pharmacokinetic parameters in adult male Fabry patients (Figure 4; other data not shown).
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DISCUSSION |
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TOPABSTRACTMATERIAL AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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The interpretation of the calculated PK parameters for agalsidase alfa and other enzymes targeted to lysosomes is different from that for conventional drugs. Agalsidase alfa is presumed to be removed from circulation via binding to cell surface MP6 receptors and subsequent transport to its site of action in cellular lysosomes.28 Once transported to the lysosomes, no reversibility of tissue uptake or release into the circulation occurs because of the efficiency of the M6P receptor in sequestering this enzyme within the lysosome. Agalsidase alfa is activated by the low pH in the lysosomes and is subsequently degraded in the lysosomes. Therefore, because of this 1-way transit into the lysosomes, plasma AUC does not accurately reflect total exposure as it does with conventional drugs. As shown in this study, differences in AUC do not correlate with differences in pharmacodynamic response (Figure 4). Similarly, the faster plasma clearance seen following the initial dose in children compared to adults (Tables II and III) should not be used as evidence that higher doses should be used in children. Again, because agalsidase alfa is sequestered within lysosomes, calculations of serum clearance rate only measure removal from serum and not whole-body clearance. Thus, it is likely that in children, faster, more efficient M6P-mediated removal of agalsidase alfa from the plasma into lysosomes may account for the difference in clearance seen in children and adults.
To produce a consistent pharmacodynamic effect in patients, the critical factors are tissue uptake and tissue half-life of agalsidase alfa. The tissue half-life of agalsidase alfa in the liver of Fabry patients has been estimated to be in excess of 2 days.24 In GALA knockout mice, peak concentrations of agalsidase alfa in liver, kidney, and spleen are seen about 1 hour after dosing and do not decline substantially in the first 24 hours.25 This substantially longer half-life in tissue compared to serum is characteristic of lysosomal enzymes used in enzyme replacement therapy24,30 and is why an extended dosing interval (e.g., EOW) can be effective.
In the pediatric patients, terminal elimination half-lives were less than 4 hours in all patients following either single or repeated doses, indicating that agalsidase alfa would not accumulate in the patient's sera following repeated weekly or EOW dosing. The PK parameters of CL and Vss were similar in boys and girls, and although mean t following the initial dose of agalsidase alfa was significantly longer in girls than in boys, all individual values measured in the girls were within the range observed in boys. The difference in t between boys and girls may be an artifact of the presence of endogenous GALA in girls, which may have influenced the calculation of terminal t when baseline values were subtracted from the low serum activities seen at times later than 4 hours postdosing. Other than this apparent difference in t among boys and girls, these results are consistent with a lack of difference in PK results between male and female adult Fabry patients dosed with agalsidase alfa.
Overall, single-dose PK parameters in pediatric patients were similar to results in adult Fabry patients. However, mean serum clearance was significantly increased in the 24 pediatric patients compared with adult Fabry patients. The effect of age was also seen within the pediatric population (Figure 2). This increase in serum clearance correlated with a lower Cmax in these patients and may reflect a more rapid removal of agalsidase alfa into tissues and organs via M6P receptors. Support for this tentative conclusion is based on the observation that younger children have increased organ/body weight ratios compared to adults. For example, the ratio between liver volume and body weight continually declines until about 16 years of age, when it levels off.31 Similar decreases have been reported for spleen and kidney.32 These differences in organ weight/body weight ratios could suggest an increased number of M6P receptors per kilogram of body weight in younger children, thus leading to a more rapid removal of administered agalsidase alfa from serum via M6P receptors. Alternatively, young children may have an increased turnover rate of M6P receptors, resulting in a more rapid uptake of infused enzyme.
The explanation for the increase in t at week 25 for 8 of the 19 male pediatric patients and in 7 of 18 adult male Fabry patients after 12 or 18 months is not known. Most of the adult males had developed IgG antibodies to agalsidase alfa that interfered with the in vitro assay of enzyme activity, and this interference may have contributed to the large variability in the calculated PK parameters seen after 12 to 18 months of dosing. This explanation cannot be invoked for the pediatric patients because only 1 of the 8 boys who showed an increase in t at week 25 was IgG anti-agalsidase alfa antibody positive. It is possible that with long-term enzyme replacement therapy, M6P receptors may be down-regulated in some of the adult or pediatric patients with Fabry disease. However, this modest increase in terminal elimination half-life did not appear to affect efficacy, at least in terms of pharmacodynamics. Younger pediatric patients (who had an 80% increase in serum clearance of agalsidase alfa compared to male adult patients) had the same pattern of plasma Gb3 reduction compared to older pediatric patients and male adult patients. Thus, consistent with the mode of action of agalsidase alfa (degradation of Gb3 in lysosomes), the increased serum clearance in the younger pediatric patients had no effect on the pattern or extent of reduction of plasma Gb3 levels.
In conclusion, most PK parameters of agalsidase alfa in pediatric patients following single and repeated dosing were similar to PK results found in adult Fabry patients. The exception was that serum clearance was age dependent in the pediatric population. Based on the assumption of ubiquitous distribution of M6P receptors on most somatic cells throughout the body, it is unlikely that the tissue biodistribution pattern of agalsidase alfa was altered by more rapid removal from serum in the younger patients. Furthermore, despite this apparent difference in pharmacokinetics, the pharmacodynamics in these younger children was not different compared to older pediatric Fabry patients or adults; therefore, the standard dose of 0.2 mg/kg in pediatric patients should provide the same metabolic effects in vivo as in adults.
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ACKNOWLEDGEMENTS |
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TOPABSTRACTMATERIAL AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Financial disclosure: This study was funded in part by the Intramural Program of the National Institutes of Health, NINDS. Shire HGT participated in the planning of the studies described in this article and provided financial support for their conduct and statistical analysis.
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REFERENCES |
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TOPABSTRACTMATERIAL AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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15. Schiffmann R, Floeter MK, Dambrosia JM, et al. Enzyme replacement therapy improves peripheral nerve and sweat function in Fabry disease. Muscle Nerve. 2003;28: 703-710.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
16. Weidemann F, Breunig F, Beer M, et al. Improvement of cardiac function during enzyme replacement therapy in patients with Fabry disease: a prospective strain rate imaging study. Circulation. 2003;108: 1299-1301.
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