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QUANTITATIVE CLINICAL PHARMACOLOGY |
From the Université de Montréal, Montréal, Québec, Canada (Ms Seng Yue); Savient Pharmaceuticals Inc, East Brunswick, NJ (Dr Huang, Mrs Alton, Dr Maroli, Dr Waltrip, Dr Wright); and MDS Pharma Services, St-Laurent, Québec, Canada (Dr Di Marco).
Address for reprints: Corinne Seng Yue, MSc, Université de Montréal, Faculté de pharmacie, Pavillon Jean Coutu, 2940 Chemin de la polytechnique, Montreal, Quebec, H3T 1J4 Canada; e-mail: corinne.seng.yue{at}umontreal.ca.
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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Key Words: Uricase • pharmacokinetics • pharmacodynamics • population modeling • uric acid • PEG
Pegloticase is a recombinant mammalian uricase (urate oxidase) being developed to control the clinical consequences of hyperuricemia in patients with treatment-failure gout. This recombinant uricase has been modified by covalent attachment of methoxy polyethylene glycol (m-PEG), and is expected to have a relatively long circulating life with less potential to induce an immune response than the non-PEGylated protein when administered to patients. The therapeutic effect of this drug is to decrease uric acid concentrations in the blood to well below the solubility limit. This may not only limit continued MSU crystal accumulation, but potentially may also bring existing crystal accumulations into solution for enzymatic degradation and excretion, thereby preventing the continued accumulation in joints and tissues that lead to acute attacks and other long-term clinical consequences, including destruction of joints, bones, cartilage, and tissue.
Single-dose intravenous (IV) infusions of pegloticase (at doses ranging from 0.5 mg to 12 mg) were administered to 24 patients (6 cohorts of 4 patients each) in an IV phase 1 study.3 Plasma uricase activity and plasma urate concentration were monitored for 21 days after dosing. Adverse events and the immunoglobulin G (the IgG antibody) response to pegloticase were followed for up to 35 days. The variability in the half-lives was so great that it was not possible to determine the effect of dose on half-life. A dose of 2 mg or greater of PEG-uricase decreased uric acid levels below the solubility level of 7 mg/dL in serum from 24 to 192 hours. The lowest IV dose of PEG-uricase that consistently reduced uric acid levels to the therapeutic target of <6 mg/dL was 4 mg, with duration of effect persisting less than 2 weeks after infusion. A 1-compartment pharmacokinetics-pharmacodynamics (PK/PD) model and a sigmoidal maximum effect attributed to drug (Emax) inhibitory effect model effectively explained the relationship between plasma pegloticase and uric acid. The PK/PD modeling results indicated that pegloticase doses of 2 mg or greater were required to maintain mean pegloticase levels above IC50 (drug concentration producing 50% of maximum inhibition at effect site) and consequently uric acid levels below its solubility limit of 7 mg/dL in serum for up to 1 week. In the dose range 0.5 mg to 12 mg, mean maximum plasma concentration (Cmax) values for PEG-uricase appeared dose proportional. There were no clinical allergic reactions in the 24 subjects treated.
This phase 2 study was designed to evaluate the efficacy, PK profile, and safety of pegloticase administered repeatedly by IV infusion. Pegloticase doses that were expected to maintain uric acid levels below the therapeutic target of 6 mg/dL were examined at 2 dosing intervals (ie, 4 mg every 2 weeks, 8 mg every 2 weeks, 8 mg every 4 weeks, and 12 mg every 4 weeks) in order to determine the optimal dose and dosing frequency to control uric acid levels in the population of patients with treatment-failure gout. Intravenous administration was selected in order to minimize local cutaneous response that had been observed with subcutaneous administration.
The current article describes the PK and PD of pegloticase in serum using a population PK/PD approach.
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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The primary objectives of this study were to assess the effect of multiple doses of pegloticase on uric acid levels, time to normalization of uric acid, for example, 
6 mg/dL uric acid in plasma, and duration of normalization of uric acid in order to determine the dose(s) and dosing interval(s) of pegloticase to be evaluated in future clinical trials. The secondary objective was to characterize the PK of multiple doses of pegloticase in this patient population.
Outpatients of either gender were included in the study if they were at least 18 years of age, diagnosed with symptomatic gout and hyperuricemic (screening serum uric acid 
8 mg/dL) uncontrolled by conventional therapy due to medical contraindication, lack of response, or intolerance. Subjects were also willing and able to give informed consent and adhere to visit/protocol schedules. Women of childbearing potential must have had a negative serum pregnancy test and were required to use an approved birth control method during their participation in the protocol.
Patients were excluded from the study if there was unstable coronary artery disease or uncontrolled hypertension, history of end stage renal disease requiring dialysis, history of liver disease (defined by baseline serum transaminase elevation >3x the upper limit of normal in the absence of any other known cause), immunosuppressive therapy required by organ transplantation, concurrent use of prednisone at a dose >10 mg every day (or equivalent) at or within 1 week before dosing, concurrent use of uric acid–lowering agents, prior treatment with pegloticase or other recombinant uricase, an acute gout flare within 1 week prior to first treatment with pegloticase (exclusive of chronic synovitis/arthritis) requiring use of medication that violates the protocol, glucose-6-phosphate dehydrogenase deficiency, a history of anaphylactic reaction to a recombinant protein or porcine derivatives, lactation, administration of an investigational drug within 4 weeks prior to study drug administration or plans to take an investigational agent during the study, known allergy to urate oxidase or PEGylated products, or any other medical or psychological condition which, in the opinion of the investigator, might create undue risk to the patient or interfere with the patient's ability to comply with the protocol requirements. Table I summarizes patient demographics.
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Patients were assigned to 1 of 4 dosing groups of intravenous pegloticase: 4 mg every 2 weeks, 8 mg every 2 weeks, 8 mg every 4 weeks, or 12 mg every 4 weeks. Depending on their treatment assignment, each patient received either 3 or 6 IV infusions of pegloticase given during 30 to 60 minutes. Treatment duration was approximately 12 weeks for each group; therefore, patients receiving pegloticase every 2 weeks completed 6 cycles of treatment while those treated every 4 weeks received 3 treatment cycles.
Pegloticase PK was determined through analysis of serum samples drawn at protocol-specified time points. Pegloticase PD was determined by measuring uric acid levels in plasma during each treatment cycle. For patients treated every 2 weeks, blood samples were collected on days 1 and 8 of every treatment cycle, as well as on days 2 and 4 for cycles 1 and 6. Additional sampling occurred following cycle 6, on days 8, 15, 22, 29, and 56. For patients treated every 4 weeks, samples were collected on days 1, 8, 15, and 22 of each cycle in addition to collections on days 2 and 4 of cycles 1 and 3. During the last cycle, samples were also collected on days 29 and 56. Table II outlines the specific blood sampling times.
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Safety and tolerability were evaluated throughout the study, including vital signs, electrocardiograms, physical examination, clinical laboratory evaluations (hematology, blood chemistry, human chorionic gonadotropin) and the occurrence of clinical adverse events. Immune response to pegloticase was assessed by measuring antibody levels to pegloticase. The sampling times for antibody assays were identical to the sampling times for PK assessments, since the same samples were used for both measurements. The previous uric acid–lowering treatment could have been reinstituted 56 days after the last dose administration. Including screening and washout activities, a patient's participation was expected to be up to 18 weeks.
Study restrictions included the use of uric acid–lowering agents such as allopurinol or probenecid during the course of the study. However, flares that may have developed were treated at the discretion of the investigator. Patients were also prohibited from using other investigational drugs during this period.
Analytical Assays
Serum pegloticase and plasma uric acid were determined using similar validated methods described as follows. The analysis of both parameters used an enzymatic activity assay where pegloticase or uricase catalyzed the conversion of uric acid to allantoin, hydrogen peroxide (H2O2), and carbon dioxide. In the presence of horseradish peroxidase (HRP), H2O2 reacted with a 1:1 stoichiometry with the Amplex Red reagent (Invitrogen Molecular Probes, Carlsbad, California) to generate the red-fluorescence oxidation product resorufin. The resorufin generated was measured fluorimetrically and correlated to the amount of pegloticase in the human serum samples or the amount of uric acid in the human acidified plasma samples.
For the determination of uric acid, plasma samples were immediately precipitated with an equivalent volume of 10% trichloroacetic acid (TCA) and frozen at the clinical site. After centrifugation of the acidified plasma, the clarified supernatant was neutralized with tris 1.0 molar (M), pH 8.5. Pegloticase was assayed in serum (acidified plasma was used only for uric acid determination). For the uric acid assay, the fluorescent reaction was started with the addition of the reagent (HRP, uricase, and Amplex UltraRed [Invitrogen Molecular Probes] in tris 0.1 M, pH 7.4). For the pegloticase assay, the fluorescent reaction was started with the addition of the reagent (HRP, uric acid, and Amplex UltraRed in tris 0.1 M, pH 7.4). The plates were then incubated at 37°C for approximately 40 minutes. After the incubation, the plate was read on a fluorescence microplate reader with excitation wavelength set at 540 nm and emission wavelength set at 590 nm. The amount of pegloticase in a serum sample was derived from pegloticase standards of a known concentration used in the same assay, and the amount of uric acid in a plasma sample was derived from uric acid standards of a known concentration used in the same assay.
Validation of the pegloticase method in human serum included specificity (selectivity and dilution linearity), working calibration range (0.600-10.000 µg/mL), intra- and interassay precision and accuracy (+25%), the stability of quality controls at room temperature, short- and long-term stability, and stability after 3 freeze-thaw cycles. For the human serum pegloticase assay, samples were diluted 40-fold prior to the assay to avoid interference seen in the human serum matrix during validation; 25 µL of the diluted sample was assayed.
Validation of the uric acid method in human acidified plasma included specificity (selectivity and dilution linearity), working calibration range (5.00-100.00 µg/mL), intra- and interassay precision and accuracy (+25%), the stability of quality controls at room temperature, short- and long-term stability, and stability after 3 freeze-thaw cycles. Immediately after taking blood from a subject, the processed plasma sample was treated with 10% trichloroacetic acid, which precipitated pegloticase. The resulting acidified plasma (25 µL) was analyzed for uric acid.
Antibody response was measured using a validated, qualified enzyme-linked immunosorbent assay (ELISA) method for the detection of IgG and IgM antibodies against pegloticase in human serum. Pegloticase was coated on the microtiter plate wells, and a surrogate antibody (rabbit antipegloticase antiserum) was used as a positive control in the assays. The method validation included negative cut-off, immunodepletion, specificity and recovery, intra- and interassay precision, stability, drug interference, and prozone effect. The study samples were diluted 1:30 in assay buffer in order to minimize the interference observed during validation with certain lots of serum from donors with gout. IgG and IgM were detected using a cocktail of goat antihuman IgG and goat antihuman IgM conjugated to HRP. A suitable substrate (tetramethylbenzidine) was added that generated a chromophore in the presence of the enzyme, which was proportional to the human IgG and IgM antibody concentration.
Population PK/PD Analysis
Actual dosing and sampling times were used for the compartmental population modeling of serum pegloticase and plasma uric acid. Only patients with detectable concentrations of active pegloticase and uric acid following drug administrations were included in the analysis. Samples that were hemolyzed or that did not meet acceptance criteria were not included in the PK analysis. Serum concentrations of pegloticase that were below the limit of quantitation were set to missing for the population PK modeling. Plasma concentrations of uric acid that were below the limit of quantitation were set to 0.25 mg/dL (half of the lower limit of quantitation [LLOQ]) for the population PD modeling.
Multiple compartmental models were first constructed for serum pegloticase concentrations using ADAPT-II (Biomedical Simulations Resource at the University of Southern California, Los Angeles, California).4 The model discrimination process was performed by comparing the Akaike Criterion (AIC) values and by looking at pertinent graphical representations of goodness of fit (eg, fitted and observed concentrations versus time; weighted residuals versus observedvalues). All relevant PK parameters were calculated and reported.
Following the determination of the final structural model in ADAPT-II, population PK/PD analysis was performed with IT2S (State University of New York at Buffalo, Buffalo, New York) using the relevant PK parameters obtained in ADAPT-II as prior estimates.5 The impact of covariates could be evaluated by coding the variable into the equations defining the compartmental model or by assessing them graphically in a post hoc analysis.
Covariates investigated for inclusion in the model included age, gender, race, body weight, ideal body weight, and antibody levels.
Once the structural PK model for serum pegloticase was determined, various PK/PD models were evaluated using ADAPT-II. Based on the criteria described above, the model that best fit the uric acid data was selected to conduct population PK/PD analyses in IT2S.
All serum pegloticase concentrations and plasma uric acid concentrations were fitted using a weighting procedure of Wj=1/
j2 where the variance j2 was calculated for each observation using the equation Sj2= (a + b x Yj)2 where a and b are the intercept and slope of each variance model. The slope is the residual variability proportional to each concentration, and the intercept is the additional component of the residual variability. These residual variability parameter estimates were updated iteratively during the population PK analysis until stable values were found.
Overall, a total of 498 serum concentrations of pegloticase and 769 plasma concentrations of uric acid were fitted simultaneously from a total of 40 patients. Only patients with detectable concentrations of both serum pegloticase and plasma uric acid were included in the population PK/PD analysis. One 34-year-old Caucasian man did not have available pegloticase concentrations; therefore, this patient was excluded from the PK/PD analysis.
Monte Carlo Simulations
Once the final PK/PD model, including covariates, was selected, Monte Carlo simulations were performed in order to predict serum pegloticase and plasma uric acid concentrations following the administration of various dosing regimens. Several dosing strategies were evaluated by simulation in order to determine the dosages required to maintain uric acid levels below 6 mg/dL to support future development studies. An infusion duration of 2 hours was simulated because infusion reactions had been noted in earlier phase studies, and this duration was under consideration for ongoing clinical development.
Monte Carlo simulations were performed using a population of 160 patients receiving 4 different regimens, which were the proposed phase 3 dose regimens. The first simulated regimen consisted of a 2-hour IV infusion of pegloticase (8 mg) administered every 2 weeks for 18 months. The second simulated regimen consisted of an 8-mg 2-hour IV infusion of pegloticase administered every 2 weeks for 6 months followed by administration every 4 weeks for another 12 months. The third simulated regimen consisted of an 8-mg 2-hour IV infusion of pegloticase administered every 4 weeks for a total of 18 months. The fourth and last simulated regimen comprised an 8-mg 2-hour IV infusion of pegloticase administered every 4 weeks for 6 months, followed by administration every 2 weeks for 12 months.
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RESULTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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The structural model that best described the PK of pegloticase was a 1-compartment model with linear elimination. An interoccasion variability (IOV) factor was added to the clearance (CL) in an attempt to improve the quality of fit. The IOV term allowed the systemic CL of pegloticase on the last cycle, that is, a second "occasion," to be slightly different than that observed on the first cycle within patients. However, the IOV term did not improve the quality of fit in a statistically significant manner and therefore the 1-compartment model was retained as the best model.
Using the predetermined 1-compartment PK model, various PD models were tested using ADAPT-II. In each of the models tested, plasma uric acid, the PD biomarker, was correlated to the PK of pegloticase. Selection of the best PK/PD model was based on minimization of the AIC as well as visual inspection of the quality of the fit.
In both the direct and indirect models tested, the sigmoidal Emax model did not provide a statistically significant improvement in comparison with the Emax model. Similarly, the indirect models did not provide a superior quality of fit in comparison with the direct models. Therefore, the model that best described the PK/PD relationship between serum pegloticase and plasma uric acid was the direct model. In this model, uric acid levels decreased with increasing pegloticase concentrations according to the following equation (Equation 1):
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The final PK/PD model is depicted in Figure 1.
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Neither age nor gender was a significant covariate for PK or PD parameters. Most patients were white, non-Hispanic, and therefore it was difficult to assess the effect of race on the PK and PD parameters of pegloticase. In addition, the "Asian or Pacific Islander" and "other" categories were only represented by 1 patient each. However, results suggest that there were no significant trends related to race.
Antibody levels were determined for each of the patients at various time points following dosing. Because each patient's antibody levels changed as a function of time, it was necessary to take this into account when developing the PK/PD model and assessing the impact of this covariate on the PK and PD parameters of pegloticase.
In order to assess the potential influence of fluctuating antibody levels on the PK and PD parameters of pegloticase, 2 different approaches were used. The first method included antibody level in the model as a covariate that changed with time. For time points where no antibody level was available, it was assumed the antibody level was the same as the previously detected level. In other words, the last observation carried forward (LOCF) technique was applied to this method.6 The second approach consisted of modeling the antibody levels in ADAPT-II and included the fitted antibody levels as a covariate in the PK/PD model.
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Quality of Fit and PK Parameter Estimates
Figure 2 presents an example of a fitted PK/PD profile.
Overall, individual plasma concentrations of pegloticase and uric acid were adequately fitted using this model, with r2 values of 0.8093 and 0.4662, respectively. Weighted residuals for pegloticase and uric acid did not show any bias over time.
Mean values for the PK and PD parameters of pegloticase along with interindividual variability (CV%), median, and range are presented in Table III.
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Monte Carlo Simulations
Results of the Monte Carlo simulations are presented in Figure 3. Overall, the predicted uric acid levels remained well below 6 mg/dL for all treatment regimens. This suggests that a regimen of 8 mg given every 2 weeks or every 4 weeks would be effective in maintaining uric acid concentrations at target levels.
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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Various software is available to perform population PK and PD analyses. The use of IT2S (State University of New York at Buffalo) for this particular analysis was based on the authors' familiarity with the software, as well as its flexibility for modeling more complicated PK/PD relationships. Although the final PK/PD model chosen to describe pegloticase and its effects on uric acid was not complex in itself, more elaborate models were evaluated in order to test the effect of antibody levels.
Although a thorough and detailed description of IT2S is beyond the scope of this article, its main features are presented below. Essentially, individual estimates and their covariances are used to estimate population characteristics using an "iterative 2-stage" approach, which, as the name suggests, is divided into 2 stages. First, an approximate a priori population model is used as a set of prior distributions for Bayesian estimation of individual parameters for all subjects. The individual parameters thus obtained are used to calculate a new set of population parameters, which is the second step. The population parameters from the second step are then used as prior distributions to perform the Bayesian estimation of the first step, and these 2 steps are repeated iteratively until there is essentially no difference between the old and new prior distributions.5,10,11 All patient data is fit simultaneously. Since IT2S estimates population PK/PD parameters based on individual subject parameters, post hoc PK/PD population parameters are presented in Table III.
In comparison with other software that estimates population parameters without requiring estimates of individual parameters, IT2S requires an initial set of prior distributions.10,11 For this analysis, the software ADAPT-II (Biomedical Simulations Resource) was employed in order to obtain prior distributions.4 Once the final model was determined in ADAPT-II using the criteria previously described, the model was used to fit patient data separately to obtain individual patient parameters. The population characteristics of each parameter were then estimated as the empirical mean and variance of the individual estimates.
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Among the various models tested, the simplest model that best described the serum concentrations of pegloticase was a 1-compartment model with linear elimination. The effect of serum pegloticase on the plasma concentrations of uric acid was best described by a direct inhibitory Emax model, ie, a model where increasing concentrations of serum pegloticase are associated with decreasing concentrations of plasma uric acid. The inclusion of a parameter representing maximal inhibitory effect is understandable, since the PD activity of pegloticase is enzymatic. That is to say, pegloticase's ability to convert uric acid would be governed not only by its inherent enzymatic activity, but also by the binding of the substrate to the active site. Although sigmoidal inhibitory models were tested (indirect response models), the clockwise hysteresis (for a typical patient after one 8-mg infusion of pegloticase), depicted in Figure 4, shows the lack of an indirect effect and therefore confirms the selection of a direct inhibitory Emax model.12
The mean Emax value for pegloticase was 82.5% with low intersubject variability, indicating that in most patients uric acid concentrations were decreased by approximately 83%. This was consistent with the marked suppression of uric acid observed in the population; many of the uric acid values fell below the limit of quantitation after single and repeated IV infusions of pegloticase.
The mean IC50 value of 0.104 µg/mL, a value which is below the LLOQ of serum pegloticase (0.6 µg/mL), indicates that very low levels of pegloticase are able to provide 50% of the maximal suppression of uric acid levels. Similarly, the mean IC90 value of 0.932 µg/mL demonstrates that levels of pegloticase slightly above the LLOQ are sufficient to attain most of the maximal suppressive effect (90% of the effect) of pegloticase. During the modeling process, no constraints were placed upon IC50 values in order to force them to be greater than quantifiable values, which allowed the mean value IC50 to be well below the LLOQ. Although the coefficient of variation associated with this parameter is approximately 65%, which could imply a lack of precision for this parameter estimate, this result is likely related to the wide range of uric acid values rather than a lack of accuracy. Uric acid values ranged from undetectable to 18.56 mg/dL (with a coefficient of variation of 114%), while pegloticase values ranged from undetectable to 8.887 µg/mL (coefficient of variation of approximately 60%).
In the PK/PD model, weight was the only covariate that influenced PK parameters CL and Vc. The inclusion of weight in the PK model suggests that in order to obtain more accurate estimates of CL and Vc, this demographic variable needs to be taken into consideration. However, of primary interest from a clinical perspective, there were no covariate effects on the PD parameters. This indicates that the PD properties of pegloticase, as characterized by Emax and IC50, are not influenced by such parameters as weight, age, or gender. Consequently, no dosage adjustments are required for covariates, which facilitates prescribing practices.
The residual variabilities reported for PK and PD parameters represent variability that is not explained by the model, including interindividual variability, the experimental "noise" of the analytical method, and errors arising from PK modeling itself. As previously mentioned, significant variability in the pegloticase and uric acid concentrations was observed, which could explain the residual variability values presented in Table III, as well as the elevated interindividual variability associated with certain PK and PD parameters.
The PEGylation of uricase was expected to prolong the terminal elimination half-life of the enzyme, and this was the case in this study.13 The mean terminal elimination half-life of pegloticase in serum was approximately 2 weeks long, ranging from 170 hours (
7 days) to 1049 hours ( 44 days). This is in accordance with previously published data. Based on phase 1 data, Ganson and colleagues estimated half-life values ranging from 10.5 to 19.9 days following subcutaneous administration of pegloticase.8 Sundy et al reported a mean half-life (±SD) of 300 hours (±21), or 12.5 days (±0.9) following IV infusions of the product.3 The terminal elimination half-life of pegloticase is significantly longer than that of a non-PEGylated urate oxidase, rasburicase, which has a terminal elimination half-life of approximately 19 hours.14,15
Despite the variability associated with the PK/PD model and certain parameter estimates, the population PK/PD analysis provides enough evidence to show that pegloticase is effective in rapidly reducing uric acid concentrations to very low levels. In addition to providing marked suppression of uric acid levels for prolonged periods, the PD effect of pegloticase appears to be independent of any demographic factors. The long terminal elimination half-life of the compound also confers an added benefit compared to agents with shorter plasma half-life values. Since effects on uric acid are directly related to pegloticase concentrations, therapeutic drug levels could be maintained with relatively low doses and infrequent dosing.
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CONCLUSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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The PK and PD characteristics of pegloticase make it an attractive therapeutic option for gout patients whose uric acid levels and symptoms cannot be managed by conventional treatments. Phase 3 studies that are currently under way should provide further evidence of its clinical benefits, as well as confirm the choice of dose regimen and dosing frequency suggested by this analysis.
Financial disclosure: There were no conflicts of interest, financial or otherwise, for authors affiliated with Université de Montréal or MDS Pharma Services. All authors who are employees of Savient Pharmaceuticals, Inc. are also shareholders.
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REFERENCES |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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1. Becker MA, Levinson DJ. Clinical gout and the pathogenesis of hyperuricemia. In: Koopman WJ, ed. Arthritis and Allied Conditions. 13th ed. Baltimore, MD: Williams and Wilkins; 1997: 2041-2071.
2. Sundy JS, Becker MA, Baraf HSB, et al. A phase 2 study of multiple doses of intravenous poly(ethylene glycol) (PEG)-uricase in patients with hyperuricemia and treatment-failure gout. Ann Rheum Dis. 2006;65(S2): 71.
3. Sundy JS, Ganson NJ, Kelly SJ, et al. Pharmacokinetics and pharmacodynamics of intravenous PEGylated recombinant mammalian urate oxidase in patients with refractory gout. Arthritis Rheum. 2007;56(3): 1021-1028.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
4. D'Argenio DZ, Schumitzky A. ADAPT-II Users Manual. Los Angeles, CA: Biomedical Simulations Resource, University of Southern California; 1997.
5. Forrest A, Hawtoff J, Egorin MJ. Evaluation of a new program for population PK/PD analysis applied to simulated phase I data. Clin Pharmacol Ther. 1991;49(2): 153.
6. Hu C, Sale ME. A joint model for nonlinear longitudinal data with informative dropout. J Pharmacokinet Pharmacodyn. 2003;30(1): 83-103.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
7. Sherman MR, Saifer MGP, Perez-Ruiz F. PEG-uricase in the management of treatment-resistant gout and hyperuricemia. Adv Drug Deliv Rev. 2008;60(1): 59-68.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
8. Ganson NJ, Kelly SJ, Scarlett E, Sundy JS, Hershfield MS. Control of hyperuricemia in subjects with refractory gout, and induction of antibody against poly(ethylene glycol) (PEG), in a phase I trial of subcutaneous PEGylated urate oxidase. Arthritis Res Ther. 2006;8(1): R12.[CrossRef][Medline] [Order article via Infotrieve]
9. Baraf HSB, Kim S, Matsumoto AK, Maroli AN. Resolution of tophi with intravenous PEG-uricase in refractory gout. Arthritis Rheum. 2005;52(suppl 9): S105.[CrossRef]
10. Ette EI, Williams PJ. Population pharmacokinetics II: estimation methods. Ann Pharmacother. 2004;38(11): 1907-1915.
11. Steimer JL, Mallet A, Golmard JL, Boisvieux JF. Alternative approaches to estimation of population pharmacokinetic parameters: comparison with the nonlinear mixed-effect model. Drug Metab Rev. 1984;15(1-2): 265-292.[Web of Science][Medline] [Order article via Infotrieve]
12. Gabrielsson J, Weiner D. Pharmacokinetic & Pharmacodynamic Data Analysis: Concepts and Applications. 4th ed. Stockholm, Sweden: Swedish Pharmaceutical Press; 2007.
13. Harris JM, Chess RB. Effect of pegylation on pharmaceuticals. Nat Rev Drug Discov. 2003;2(3): 214-221.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
14. Fasturtec [package insert]. Ottawa, Ontario, Canada: Canadian Pharmacists' Association; 2007.
15. Cammalleri L, Malaguarnera M. Rasburicase represents a new tool for hyperuricemia in tumor lysis syndrome and in gout. Int J Med Sci. 2007;4(2): 83-93.[Medline]
[Order article via Infotrieve]
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