2016 年 39 巻 5 号 p. 705-711
Rasburicase has a strong and fast effect for reducing blood levels of uric acid. However, there have been no reports of theoretical analysis for the rational dose and interval of administration. Thus we constructed a pharmacokinetic and pharmacodynamic model to determine changes in uric acid level after rasburicase administration at various doses and regimens. The time courses of uric acid level predicted using our model were in good agreement with observed data, indicating adequate performance for our model. The therapeutic effects after a single infusion at various rates of generation of uric acid were predicted. The maximum effect was not a large difference, in spite of the generation rate. Then, the therapeutic effects of repeated administrations were predicted. The effect did not change when rasburicase was administered at more than the usual dose. Besides, as the administration interval increased, the difference between minimum and maximum level of uric acid became greater. However, in all doses and regimens, adequate therapeutic effects were obtained. In conclusion, the model was found useful for predicting therapeutic effect of rasburicase and individually determining rational dosage regimen of rasburicase.
Tumor lysis syndrome (TLS) occurs when a tumor rapidly lyses from the effects of chemotherapy and has been frequently reported to occur after the initial chemotherapy treatment,1,2) with an incidence of about 5% reported in patients treated for a hematopoietic organ tumor.3) Nucleic acid released in a large amount due to TLS is subsequently decomposed to a large amount of uric acid, which induces crystallization, leading to renal disorder.
Allopurinol, a uric acid production-inhibitory agent, is orally administered for prevention and treatment of hyperuricemia caused by TLS. However, several problems with that treatment have been noted. Uric acid present prior to chemotherapy cannot be decomposed by allopurinol administration,4) which is generally performed 2–3 d prior to the start of chemotherapy.5) Also, obstructive uropathy is likely to develop, as xanthine crystals are formed from xanthine accumulation and their decomposition to uric acid by xanthine oxidase is inhibited by the action of allopurinol.4,6) Dose reduction of inhibitors of purine synthesis, such as 6-mercaptopurine and azathioprine, is required when used in combination with allopurinol.4,7) Furthermore, it is difficult to administer allopurinol to patients who have difficulty with oral administration.
Rasburicase is a recombinant uric acid oxidase originally produced by introducing an Aspergillus flavus-derived uric acid oxidase gene to a Saccharomyces cerevisiae strain.8) For its pharmacological action, rasburicase reduces the level of uric acid, as it oxidizes and decomposes uric acid to allantoin.9) Rasburicase has a stronger and faster effect for reducing uric acid as compared to allopurinol. Moreover, since it is given as an injection, rasburicase can be administered to patients who have difficulty with oral administration. Furthermore, no dose reduction is necessary even for those with reduced renal function.10)
In Japan, rasburicase is normally administered intravenously once a day at a dose of 0.20 mg/kg for a maximum of 7 d based on clinical trials, though a single infusion of 0.15 mg/kg was reported to be effective.11,12) The package insert recommends that administration should be limited to the minimum time required, while taking into consideration inter-individual variability in efficacy. There have been no reports presented of theoretical analysis of the minimum required duration of administration, thus it is considered important to perform theoretical evaluations of dose, regimen, and the effects of rasburicase. In the present study, we constructed a pharmacokinetic and pharmacodynamic model to determine the time courses of uric acid level after rasburicase administration, for examination of the effects of the drug in a theoretical manner with a variety of doses and regimens.
Data regarding the time course of serum concentration following a single infusion of rasburicase at 0.15 and 0.20 mg/kg for Japanese patients who participated in a phase II clinical study were obtained from the Japanese package insert.13) Clinical response was evaluated by uric acid level, and the data sources used for analysis were Japanese leukemia and malignant lymphoma patients who participated in the phase II clinical study.13) We also obtained data from that study for values representing uric acid level before and at 4, 8, 24, 48, 72, 96, 104, 120, and 168 h after administration (0.15 or 0.20 mg/kg, once a day) of rasburicase for Japanese patients. At this point, we converted the graphic data to numerical value by measuring the graph directly.
Analysis of Time Courses of Serum Concentration of RasburicasePreviously reported findings obtained from the package insert showed that the clearance of rasburicase is unchanged by increasing the dose (range 0.05 to 0.20 mg/kg), while linear relationships can be observed among dose administered, maximum serum concentration, and area under the curve.
The serum concentration data were obtained from a 0.5 h infusion. Therefore, in the present study, the time courses of serum concentrations after a single infusion of rasburicase were analyzed using the following Eq. 1 during infusion (t≦0.5) and Eq. 2 after infusion (t>0.5).
 | (1) |
 | (2) |
The R values were analyzed using the following Eq. 3.
 | (3) |
where D (mg/kg), Wt (kg), and T (h) represent dose (0.20 or 0.15 mg/kg), weight, and infusion time (0.5 h), respectively. At this point, previously reported median weight values (0.15 mg/kg: 57.1 kg, 0.20 mg/kg: 54.5 kg) in the phase II clinical study were adopted.13) Then, we calculated the R values (0.15 mg/kg: 17.1 mg/h, 0.20 mg/kg: 21.8 mg/h).
To estimate the pharmacokinetic parameters of Vd and ke in patients receiving the drug, the serum concentration of rasburicase after a single infusion at a dose of 0.15 or 0.20 mg/kg was simultaneously fitted to Eqs. 1 and 2 using the nonlinear least squares method. The nonlinear least squares program MLAB (Civilized Software, Inc.) was used for analysis.
Analysis of Clinical Response to Rasburicase Using a Pharmacokinetic and Pharmacodynamic ModelA model derived from the pharmacokinetic profile of rasburicase and turnover rate of uric acid is shown in Fig. 1. With this model, we assumed that rasburicase oxidizes and decomposes uric acid to allantoin. In addition, rasburicase becomes free after generating allantoin and is used again in the reaction.
Disappearance from the body of rasburicase occurs by ke. Uric acid is generated at a rate constant of ks (mg·dL−1·h−1) and eliminated at a rate constant of kT (h−1), then is oxidized by rasburicase at a reaction rate constant of kox (mL·µg −1·h−1) and decomposed to allantoin. Thus, the concentration of the uric acid of CU (mg/dL) was represented as follows:
 | (4) |
Furthermore, the value for CU in the absence of rasburicase [CU(0)] was expressed using the following Eq. 5:
 | (5) |
At this point, previously reported CU(0) values (0.15 mg/kg: 5.18 mg/dL, 0.20 mg/kg: 5.56 mg/dL) in the phase II clinical study were adopted. To estimate the values for kox and kT, we simultaneously fitted CU data from patients repeatedly administered rasburicase for 5 d at a dose of 0.15 or 0.20 mg/kg to Eqs. 1 to 5.
Predicton of Therapeutic Effects of RasburicaseBased on our analytical results, uric acid levels over time were predicted to investigate the appropriate administration of rasburicase in consideration of individual differences. Seven and half milligram per deciliter or lower uric acid levels were considered to be a marker for therapeutic effect, as it has been reported that an additional dose is necessary when the level exceeds that value.11) In the first prediction, we considered patients who had a CU(0) value of 7.5, 10, 12.5, or 15 mg/dL, and were given a single infusion of rasburicase at 0.20 mg/kg. In the second, the patients had a CU(0) value of 7.5 or 15 mg/dL, and were given rasburicase daily during a 5-d administration at a dose of 1.5, 3.0, 4.5, 6.0, 7.5, 11, or 15 mg. These doses were the quantity of rasburicase with a RASURITEK® i.v. injection of 1.5 mg/vial (1, 2, 3, or 4 vials), that of 7.5 mg/vial (1 or 2 vials), or the usual dose (0.20 mg/kg) for a patient weighing 55.3 kg (median weight of all patients in the phase II clinical study). For the third prediction, the patients had a CU(0) value of 7.5 or 15 mg/dL and were given rasburicase daily, every 2nd day, or every 3rd day during a 5-d administration at a dose of 0.20 mg/kg.
For these predictions, we considered that the kt value obtained in the above mentioned analyses did not change, and that was calculated by using kt, CU(0), and Eq. 5. In addition, we assumed that the calculated ks value was also maintained.
The time courses of serum concentrations of rasburicase following a single infusion at a dose of 0.15 or 0.20 mg/kg for patients with leukemia or malignant lymphoma, along with fitted curves based on the nonlinear least squares method are shown in Fig. 2. The fitted curves were well matched to observed data. The estimated Vd (L) value (±standard deviation (S.D.)) was 2.2 (±0.018) and the ke (h−1) value (±S.D.) was 0.066 (±0.0014).
Symbols represent actual data (mean±S.D.).13) The lines shown are fitted curves simultaneously calculated using the nonlinear least squares method.
Time courses of uric acid level following repeated administrations of rasburicase as well as fitted curves based on the simultaneous nonlinear least squares method are shown in Fig. 3. The fitted curves were well matched to observed data.
Symbols represent actual data (mean).13) The lines shown are fitted curves simultaneously calculated using the nonlinear least squares method.
The estimated kox (mL·µg −1·h−1) value (±S.D.) was 0.193 (±0.012) and the kT (h−1) was 0.0139 (±0.0008). Then, the ks (mg·dL−1·h−1) values calculated from Eq. 5 were 0.0720 (0.15 mg/kg) and 0.0773 (0.20 mg/kg).
Prediction of Therapeutic Effects of RasburicaseBy using the obtained pharmacokinetic and pharmacodynamic parameters, the therapeutic effects of rasburicase were predicted. First, the therapeutic effects of a single infusion of rasburicase in patients with CU(0) values of 7.5, 10, 12.5, or 15 mg/dL were predicted. At this point, the ks value of those patients was 0.10, 0.14, 0.17, or 0.21 mg·dL−1·h−1, respectively. The maximum therapeutic effect expressed by the minimum level of uric acid (Emax) was 0.18–0.36 mg/dL, which was not a large difference. Furthermore, the time required for uric acid to reach a minimum level (TEmax) was 8 h. Meanwhile, the time until an additional administration was necessary (blood level greater than 7.5 mg/dL) were 582 h [CU(0): 7.5 mg/dL], 153 h [CU(0): 10 mg/dL], 117 h [CU(0): 12.5 mg/dL], and 100 h [CU(0): 15 mg/dL] (Fig. 4, Table 1).
Gray area indicates the need for a second dose.
| CU(0) (mg/dL) | ks (mg·dL−1·h−1) | Emax (mg·dL−1) | TEmax (h) | Time to additional dosage (h) (Time to Emax≥7.5 mg/dL) |
|---|---|---|---|---|
| 7.5 | 0.10 | 0.18 | 8 | 582 |
| 10 | 0.14 | 0.24 | 8 | 153 |
| 12.5 | 0.17 | 0.30 | 8 | 117 |
| 15 | 0.21 | 0.36 | 8 | 100 |
Second, the therapeutic effects of repeated administrations of rasburicase at a dose of 1.5, 3.0, 4.5, 6.0, 7.5, 11, or 15 mg in patients weighing 55.3 kg with a CU(0) value of 7.5 or 15 mg/dL were predicted. There was no difference when rasburicase was administered at more than the usual dose, in spite of individual differences for rate of generation of uric acid. On the other hand, the effect of rasburicase became weaker as the dose was lowered. However, with all of the predictions, the CU value was reduced sufficiently (Fig. 5).
Gray area indicates the need for a second dose.
Third, we examined the therapeutic effects of rasburicase when repeatedly administered with 3 different regimens at a dose of 0.20 mg/kg. Our results showed that as the administration interval increased, the difference between minimum and maximum level of uric acid from 24 to 120 h after the initial dose (Erange) became greater. Notably, the minimum uric acid level ranged from 0.11 to 0.16 mg/dL in patients who had a CU(0) value of 7.5 and 0.22 to 0.32 mg/dL in those with a CU(0) value of 15 mg/dL, which were not significant differences. On the other hand, the maximum uric acid level varied greatly from 0.38 to 2.3 mg/dL in patients who had a CU(0) level of 7.5 and from 0.76 to 4.6 mg/dL in those with a CU(0) level of 15 mg/dL. However, in all predictions, the uric acid level dropped below 1 mg/dL after each administration and never exceeded 7.5 mg/dL (Fig. 6).
Gray area indicates the need for a second dose.
Rasburicase, used as a therapeutic agent for hyperuricemia associated with chemotherapy, is administered intravenously at 0.20 mg/kg once a day for a maximum of 7 d in Japan. However, a single infusion of 0.15 mg/kg has been reported to be effective,11,12) thus we considered it important to perform theoretical evaluations of dose and regimen. We collected the data which are the serum concentration and uric acid level after administration of rasburicase for Japanese patients. Then, we constructed a pharmacokinetic and pharmacodynamic model to determine changes in uric acid level over time after rasburicase administration for Japanese patients, and also examined the effects of various doses and regimens. The time courses of uric acid level predicted with our model were in good agreement with observed data,13) indicating adequate performance for our model. We also obtained the following results.
First, the therapeutic effects of rasburicase when administered to patients with a CU(0) value of 7.5, 10, 12.5, or 15 mg/dL were predicted (Fig. 4). At this point, the CU(0) values exceeding 7.5 mg/dL were reported as 29 of 80 patients in the previous report.11) Then, we estimated the CU(0) values which were raised by 2.5 mg/dL progressively to 15 mg/dL of the double of 7.5 mg/dL so as to investigate the therapeutic effects of rasburicase when administered to patients with different CU(0) values. The prediction resulted in an Emax value range of 0.18–0.36 mg/dL, which were not significantly different. In all cases, the TEmax was 8 h, while the time until an additional administration was necessary (CU: exceeding 7.5 mg/dL) were 582 h [CU(0): 7.5 mg/dL], 153 h [CU(0): 10 mg/dL], 117 h [CU(0): 12.5 mg/dL], and 100 h [CU(0): 15 mg/dL]. Therefore, it is suggested that similar clinical responses are provided regardless of the rate of generation of uric acid immediately following an administration of rasburicase. Furthermore, these results suggested that the inter-individual variability in clinical response increased over time, because of the difference in rate of generation of uric acid.
We considered that the uric acid level elevated along with drug elimination, as ks is thought to maintain the blood level of CU(0). On the basis of the ke value, the half-life of rasburicase was calculated to be about 10.5 h. Thus, in patients with a CU(0) level of 15 mg/dL, the blood level of rasburicase at 52.5 h after infusion drops to about 3% of the level just following the initial infusion and uric acid to 2.7 mg/dL, indicating that 47 h is needed until the uric acid level reaches 7.5 mg/dL. Accordingly, we concluded that some time is needed to recover once uric acid drops to a level of 7.5 mg/dL even after elimination of rasburicase, and that recovery time is increased with a lower CU(0) value and higher dosage.
Second, the therapeutic effects of repeated administrations of rasburicase at a dose of 1.5, 3.0, 4.5, 6.0, 7.5, 11, or 15 mg in patients with a CU(0) value of 7.5 or 15 mg/dL were predicted. Our results suggested that the effect did not change when rasburicase was administered at more than the usual dose, while it becomes weaker at lower doses. However, the clinical significance of an immediate reduction of CU was unidentified at the time of approval of rasburicase. Clinically significant TLS can occur in a spontaneous manner, though it is most often seen at 48–72 h after initiation of chemotherapy.14,15) It is necessary for the level of uric acid to decrease to adequate level during that period. In this prediction, CU was reduced with all doses and a sufficient effect was obtained, in spite of individual differences for the rate of generation of uric acid.
Finally, we predicted the therapeutic effects of a dose of 0.20 mg/kg with repeated administrations at 3 different regimens (Fig. 6). Our findings suggested that the Erange increased when the interval was increased for up to 120 h after administration. Notably, the minimum uric acid level ranged from 0.11 to 0.16 mg/dL in patients who had a CU(0) value of 7.5 and 0.22 to 0.32 mg/dL in those with a CU(0) value of 15 mg/dL, which were not significantly different. On the other hand, the maximum varied greatly from 0.38 to 2.3 mg/dL in patients who had a CU(0) value of 7.5 and from 0.76 to 4.6 mg/dL those with a CU(0) value of 15 mg/dL. However, in all cases, the level of uric acid dropped below 1 mg/dL after each administration and never exceeded 7.5 mg/dL (Fig. 6). Thus, we considered that the response rate of uric acid (ks·CU·CRas) is much higher than the rate of generation of uric acid rate after administration of rasburicase.
At this point, it was considered that the values of pharmacokinetic parameters (Vd and t1/2) were valid because the values of Cmax, AUC and accumulation index of rasburicase, which were calculated by using these parameters, were comparable with the actual values (data not shown).
Though our study did not consider the inter/intrasubject variability of rasburicase, our results suggested that clinical efficacy is affected by dose and regimen of rasburicase rather than rate of generation of uric acid. Therefore, even if that generation rate changes during chemotherapy, the clinical efficacy of rasburicase is not largely affected. Though the number of patients in Fig. 2 (n=21) and Fig. 3 (n=50) was different, these data were obtained from the same phase II clinical study. In addition, it was confirmed that the results of the pharmacokinetic study (n=21) of rasburicase were comparable with those of the clinical study in non-Japanese patients. Therefore, we considered that it was valid to analyze the time courses of uric acid level (Fig. 3) by using pharmacokinetic parameters provided by Fig. 2.
As for applying our findings to clinical practice, the clinical efficacy of rasburicase in individual patients can be predicted by determining the CU(0) value, and then using the model and parameters presented in this study. By monitoring CU and administering rasburicase based on this model, it would be possible to reduce the dose and to increase the administration interval of rasburicase. Then, the financial burden of patients can be reduced.
In conclusion, the present model was useful for predicting therapeutic effect of rasburicase. Then, based on this model and the value for CU in the absence of rasburicase [CU(0)], it would be possible to individually determine rational dosage regimen of rasburicase.
The authors declare no conflict of interest.
