Cancer Chemother Pharmacol (2003) 52: 417–423
`DOI 10.1007/s00280-003-0674-0
`
`O R I GI N A L A R T IC L E
`
`Patrick Thompson Æ Frank Balis Æ Baruti M. Serabe
`Stacey Berg Æ Peter Adamson Æ Renee Klenke
`Alberta Aiken Æ Roger Packer Æ Daryl J. Murry
`Regina Jakacki Æ Susan M. Blaney
`Pharmacokinetics of phenylacetate administered
`as a 30-min infusion in children with refractory cancer
`
`Published online: 15 July 2003
`Ó Springer-Verlag 2003
`
`Abstract Purpose: Phenylacetate (PAA), a deaminated
`metabolite of phenylalanine, suppresses tumor growth
`and induces differentiation in preclinical tumor models.
`We performed a pharmacokinetic study, as part of a
`phase I trial, of PAA in children with refractory cancer.
`Methods: PAA was administered as a 30-min i.v. infu-
`sion at a dose of 1.8 or 2.5 g/m2. Serial plasma samples
`
`This work was supported in part by the National Institutes of
`Health (M01-RR00188), and the General Clinical Research Center,
`Baylor College of Medicine.
`
`P. Thompson
`Department of Pediatrics,
`Baylor College of Medicine, Houston, TX, USA
`
`F. Balis Æ P. Adamson Æ A. Aiken
`Pediatric Oncology Branch,
`National Cancer Institute, Bethesda, MD, USA
`
`B. M. Serabe Æ S. Berg Æ R. Klenke Æ D. J. Murry Æ S. M. Blaney
`Texas Children’s Cancer Center,
`Baylor College of Medicine, Houston, TX, USA
`
`R. Packer
`Department of Hematology-Oncology,
`Children’s National Medical Center, Washington, DC, USA
`
`R. Jakacki
`Division of Hematology-Oncology,
`Riley Hospital for Children, Indianapolis, IN, USA
`S. M. Blaney (&)
`Texas Children’s Cancer Center, 6621 Fannin, MC 3-3320,
`Houston, TX 77030, USA
`E-mail: sblaney@txccc.org
`Tel.: +1-832-8221482
`Fax: +1-832-8254299
`
`were collected for up to 24 h after the end of the infusion
`in 27 children. The concentrations of PAA and its inac-
`tive metabolite, phenylacetylglutamine (PAG), were
`measured using a reverse-phase high-performance liquid
`chromatography
`assay with ultraviolet detection.
`Results: PAA and PAG concentrations were best de-
`scribed by a two-compartment model (one compartment
`for each compound) with capacity-limited conversion of
`PAA to PAG. The half-life of PAA was 55±18 min at
`the 1.8 g/m2 dose and 77±22 min at the 2.5 g/m2 dose.
`The half-life of PAG was 112±53 min at the 1.8 g/m2
`dose and 135±75 min at the 2.5 g/m2 dose. The clear-
`ance of PAA was 66±33 ml/min per m2 at the 1.8 g/m2
`dose and 60±24 ml/min per m2 at the 2.5 g/m2 dose. The
`Michaelis-Menten constants describing the conversion of
`PAA to PAG in the model (Vm and Km) were (means±
`SD) 18.4±13.8 mg/m2 per min and 152±155 lg/ml,
`respectively. The volumes of distribution for PAA and
`PAG (Vd-PAA and Vd-PAG) were 7.9±3.4 l/m2 and
`34.4±16.1 l/m2, respectively. The first-order elimination
`rate
`constant
`for PAG (ke-PAG) was
`0.0091±
`0.0039 min)1. Conclusions: The capacity-limited con-
`version of PAA to PAG has important implications for
`the dosing of PAA, and the pharmacokinetic model
`described here may be useful for individualizing the
`infusion rate of the drug in future clinical trials.
`
`Keywords Pharmacokinetic Æ Phenylacetate Æ
`Pediatric Æ Phenylacetylglutamine
`
`Present address: B. M. Serabe
`Medcenter One Health Systems, Bismarck, ND, USA
`
`Introduction
`
`Present address: P. Adamson
`Children’s Hospital Philadelphia, Philadelphia, PA, USA
`
`Present address: D. J. Murry
`Purdue University, Indianapolis, IN, USA
`
`Present address: R. Jakacki
`Children’s Hospital Pittsburgh, Pittsburgh, PA, USA
`
`Phenylacetate (PAA), a deaminated metabolite of
`phenylalanine, is normally present in the mammalian
`circulation in micromolar concentrations [1]. In pre-
`clinical studies, exposure to millimolar concentrations of
`PAA can induce tumor cytostasis and differentiation in a
`variety of tumor cell lines, including malignant gliomas,
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`418
`
`carcinoma, malignant
`hormone-refractory prostate
`lymphoblastic leukemia,
`melanoma, neuroblastoma,
`and adenocarcinomas of the breast, colon and lung [2, 3,
`4, 5, 6, 7, 8]. Postulated mechanisms for PAA-induced
`cytostasis and tumor differentiation include: alterations
`in lipid metabolism, regulation of gene expression
`through DNA hypomethylation and transcriptional
`activation,
`inhibition of protein isoprenylation, and
`glutamine depletion [5]. These unique mechanisms of
`action, combined with preclinical evidence of antitumor
`activity, have led to the clinical development of PAA as
`a potential anticancer agent.
`PAA has been administered in high doses to children
`with hyperammonemia due to inborn errors of urea
`synthesis [9, 10]. PAA is eliminated by conjugation with
`glutamine to yield phenylacetylglutamine (PAG), which
`is subsequently excreted in the urine [11, 12]. Mobiliza-
`tion of glutamine-associated nitrogen is believed to lead
`to the observed improvements in hyperammonemia. In
`children with urea cycle defects who received PAA doses
`of 2 mmol/kg (about 8 g/m2), PAA elimination was
`found to follow first-order kinetics with a t1/2 of 254 min
`[10]. In adults who received PAA as an anticancer agent,
`the pharmacokinetic behavior of PAA after adminis-
`tration of a 30-min bolus infusion was described by a
`one-compartment model, with capacity-limited elimina-
`tion [13, 14].
`In the present study, we investigated the pharmaco-
`kinetics of PAA in children with refractory cancers who
`received a 30-min infusion of PAA as part of a phase I
`clinical trial. We developed a pharmacokinetic model
`that describes the disposition of PAA and the formation
`and elimination of the metabolite, PAG.
`
`Patients and methods
`
`Patient eligibility
`
`Children between 2 and 21 years of age with histologically con-
`firmed cancer refractory to standard therapy or with surgically
`inoperable plexiform neurofibromas with the potential to cause
`significant morbidity were eligible for the study. Other eligibility
`criteria included: (a) adequate renal, hepatic, pulmonary and car-
`diovascular function; (b) recovery from the toxic effects of all prior
`therapy; (c) an ECOG performance status £ 2; (d) a life expectancy
`of at least 8 weeks; and (e) the presence of a permanently indwelling
`central venous access device. Patients were excluded if they: (a) were
`pregnant or lactating; (b) had a significant systemic illness; (c) had a
`pre-existing grade 2 neurocortical toxicity; or (d) had an amino
`aciduria or organic acidemia. Patients receiving dexamethasone
`were required to be on a stable or decreasing dose for at least
`2 weeks prior to study entry. Informed consent was obtained from
`the patient or parent in accordance with individual institutional
`policies prior to entry onto this study. Toxicities were evaluated
`using version 1 of the NCI Common Toxicity Criteria [15]. Table 1
`summarizes the characteristics of patients enrolled in the study.
`
`Dosage and drug administration
`
`PAA was supplied by the Investigational Drug Branch, National
`Cancer Institute (Bethesda, Md.) as a 50% (500 mg/ml) solution of
`sodium PAA in sterile water. The appropriate dose of the drug was
`
`Table 1 Patient demographics
`
`Total number of patients
`Age (years)
`Median
`Rangea
`Weight (kg)
`Mean±SD
`Range
`Body surface area (m2)
`Mean±SD
`Range
`
`27
`
`10
`1.4–20
`
`36±24
`9.9–93.5
`
`1.17±0.47
`0.48–2.3
`
`aTwo patients <2 years of age enrolled by special exemption
`
`diluted in 30 ml sterile water. PAG for HPLC standards was supplied
`by Elan Pharmaceutical and Research Company (Gainesville, Ga.).
`In order to characterize PAA pharmacokinetics, a 30-min i.v.
`infusion was administered 1 day prior to the start of a 28-day
`i.v. bolus dose was 1.8 g/m2
`continuous infusion. The initial
`(n=13), which was approximately 80% of the bolus dose admin-
`istered in phase I clinical trials in adults. The dose was subsequently
`increased to 2.5 g/m2 (n=14) due to the rapid plasma elimination
`of PAA and lack of toxicity at the lower dose. The continuous i.v.
`dose received by patients varied from 7 to 12 g/m2 per day. The
`results of the phase I clinical trial will be reported separately.
`
`Pharmacokinetic studies
`
`Blood samples were obtained prior to the start of the infusion, at
`15 min during the infusion, at the end of the infusion, and at 5, 15,
`30 min, and 1, 2, 4, 6, 8, 10 and 24 h following the completion of
`the infusion. Samples were drawn from a site separate from the
`infusion site. Blood samples were collected into heparinized tubes,
`placed on ice, and centrifuged to separate the plasma. Plasma was
`stored at )80°C until the day of analysis.
`
`Analytical method
`
`Plasma PAA and PAG concentrations were measured using a
`previously reported reverse-phase high-pressure liquid chromato-
`graph (HPLC) assay with minor modification [13]. Plasma (200 ll)
`was transferred to a 1.7-ml Eppendorf tube (Brinkmann Instru-
`ments, Westbury, N.Y.). Protein was precipitated by adding 180 ll
`100% methanol (EM Science, Gibbstown, N.J.) and 20 ll 40%
`zinc sulfate (Sigma Chemical Company, St. Louis, Mo.). The
`sample was vortexed, centrifuged (4500 g for 5 min) and the
`supernatant (150 ll) transferred to an autosampler vial maintained
`at 10°C until HPLC injection. The injection volume was 20 ll.
`Recovery was 85±7.7% for PAA and 90±16% for PAG.
`The HPLC system consisted of a Waters model 600 automated
`gradient controller, a Waters programmable ultraviolet multiwave-
`length detector model 490E and a Waters model 717 autosampler
`(Waters Corporation, Milford, Mass.). The analytical column was a
`Waters C-18 Novapak, 3.9·300 mm (Millipore Corporation, Mil-
`ford, Mass.) maintained at 60°C with a column heater. Mobile phase
`A was 5% acetonitrile acidified with 0.005 M phosphoric acid and
`mobile phase B was acetonitrile acidified with 0.005 M phosphoric
`acid. A linear gradient from 100% A to 70% A/30%B over 20 min
`was used. The total flow rate was 1 ml/min. The column was then
`washed with 50% A/50% B for 10 min and allowed to equilibrate
`with 100% A for 10 min between injections. The total run time was
`40 min. PAA and PAG were monitored at 208 nm. Retention times
`for PAA and PAG were 18 and 12.5 min, respectively.
`Standard curves in donor plasma were prepared for each HPLC
`run. Standard curves were linear over the ranges 5 to 750 lg/ml for
`PAA and 10 to 750 lg/ml for PAG. The interday coefficient of
`variation was less than 12%.
`
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`Fig. 1 Capacity-limited model for the pharmacokinetic disposition
`of PAA in children with refractory cancer. There are separate
`compartments for PAA and PAG and capacity-limited conversion
`of PAA to PAG. Box 1 represents the PAA compartment and box 2
`the PAG compartment. K0 represents the infusion of PAA. Vmax
`and Km are the Michaelis-Menten constants for capacity-limited
`kinetics and ke-PAG is the first-order elimination rate constant for
`PAG. Vd-PAA and Vd-PAG represent the volumes of distribution for
`PAA and PAG
`
`Fig. 2 First-order model for the pharmacokinetic disposition of
`PAA in children with refractory cancer. There are separate
`compartments for PAA and PAG and capacity-limited conversion
`of PAA to PAG. Box 1 represents the PAA compartment and box 2
`the PAG compartment. K0 represents the infusion of PAA. k12 is
`the first-order rate constant for the conversion of PAA to PAG,
`and ke-PAG is the first-order elimination rate constant for PAG.
`Vd-PAA and Vd-PAG represent the volumes of distribution for PAA
`and PAG
`
`Pharmacokinetic and statistical analysis
`
`Pharmacokinetic sampling was carried out in 27 patients. Non-
`compartmental methods were used to calculate the area under the
`concentration versus time curve (AUC), the model-independent
`total body clearance (ClTB), and model-independent steady-state
`volume of distribution (VdSS) for PAA. AUC was also determined
`for PAG. For both compounds the AUC was derived by the linear
`trapezoidal method and extrapolated to infinity by adding the
`quotient of the final plasma concentration divided by the terminal
`rate constant. For PAA the ClTB was determined by dividing the
`dose by the AUC, and the VdSS for PAA was calculated using the
`area under the moment curve. The terminal half-lives for PAA and
`PAG were calculated from the slope of the best-fit line through the
`last three or four data points.
`The pharmacokinetic models depicted in Figs. 1 and 2 were
`fitted to the plasma concentration versus time data from the indi-
`vidual patient data sets using MLAB software (Civilized Software,
`Bethesda, Md.). Both models incorporated single compartments
`for PAA and PAG, with either first-order or capacity-limited
`conversion of PAA to PAG, and subsequent first-order elimination
`for PAG.
`
`Model with capacity-limited conversion of PAA to PAG
`
`dX1
`
`dX2
`
`The differential equations that describe the model are as follows:
`dt ¼ Infusion VmaxX1
`dt ¼ VmaxX1
`K mþX1 KeX2
`K mþX1
`C2 ¼ X2
`Km ¼
`K m V1
`Where:
`X1
`X2
`C1
`C2
`V1
`V2
`
`C1 ¼ X1
`
`V1
`
`V2
`
`Amount of PAA
`Amount of PAG
`Concentration of PAA
`Concentration of PAG
`Volume of distribution PAA
`Volume of distribution PAG
`
`419
`
`K*m
`
`Half-saturation constant (Michaelis-Menten parameter)
`expressed on a mass basis
`Vmax Maximum velocity (Michaelis-Menten parameter) ex-
`pressed on a mass basis
`Half-saturation constant expressed on a concentration
`basis
`First-order elimination rate constant for PAG
`
`Km
`
`Ke
`
`Model with first-order conversion of PAA to PAG
`
`dX1
`
`dX2
`
`The differential equations that describe the model are as follows:
`dt ¼ Infusion k12X1
`dt ¼ k12X1 KeX2
`C1 ¼ X1
`C2 ¼ X2
`
`V1
`
`V2
`
`Where:
`X1
`X2
`C1
`C2
`V1
`V2
`k12
`ke
`
`Amount of PAA
`Amount of PAG
`Concentration of PAA
`Concentration of PAG
`Volume of distribution PAA
`Volume of distribution PAG
`First-order rate constant for conversion of PAA to PAG
`First-order elimination rate constant for PAG
`
`The completed model fits were compared in two ways: (1) by
`evaluating the sum of residual squared error (weighted by the in-
`verse concentration squared), and (2) by calculating the Akaike
`Information Criteria [16].
`The capacity-limited and first-order kinetic models were further
`evaluated by comparing their ability to predict the steady-state
`concentrations observed in the continuous i.v. infusions. The model
`parameters derived for each patient from the bolus data were used
`to predict the steady-state levels of PAA and PAG for the con-
`tinuous infusion.
`Since most of the children enrolled in this study had primary
`CNS tumors, additional analysis was done retrospectively to at-
`tempt to determine whether dexamethasone or anticonvulsants,
`medications that
`this patient population commonly receives,
`interfered with the metabolism or clearance of PAA. To evaluate
`this issue pharmacokinetic parameters were compared between the
`group receiving medication and the group that was not. A two-
`sided t-test was performed to determine significance.
`
`Results
`
`Model-independent pharmacokinetic parameters
`
`for
`Model-independent pharmacokinetic parameters
`PAA and PAG are provided in Table 2 for both bolus
`dose levels tested.
`
`Model fit: comparison of capacity-limited kinetics
`and first-order kinetics
`
`Representative concentration versus time curves of
`model-predicted and actual PAA and PAG concentra-
`tions following administration of either a 1.8 g/m2 or a
`2.5 g/m2 30-min i.v. infusion are shown in Fig. 3. The
`figure shows experimental data for two typical patients
`and model fits generated with both the capacity-limited
`and first-order pharmacokinetics. Overall the capacity-
`
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`Parameter
`
`Units
`
`Dose (g/m2)
`
`PAA
`
`PAG
`
`Maximum concentration
`AUC
`ClTB
`Vd-ss
`t1/2
`Maximum concentration
`AUC
`t1/2
`
`lg/ml
`lgÆmin/ml
`ml/min/m2
`l/m2
`min
`lg/ml
`lgÆmin/ml
`min
`
`1.8
`
`2.5
`
`253±51
`32,200±12,500
`66.4±33.4
`5.3±1.1
`55±19
`55±18
`18,800±12,000
`112±53
`
`359±121
`49,800±23,800
`59.9±24.0
`6.6±2.9
`77±22
`67±29
`24,000±12,700
`135±75
`
`420
`
`Table 2 Model-independent
`PAA and PAG pharmaco-
`kinetic parameters for both
`doses tested. Values are
`means±SD
`
`Fig. 3a, b Serum concentrations
`of PAA (s) and PAG (M) are
`shown for representative
`patients following (a) a 1.8-g/m2
`i.v. bolus of PAA over 30 min,
`and (b) a 2.5-g/m2 i.v. bolus
`over 30 min. The solid lines
`represent the model fit with
`capacity-limited kinetics, and
`the dashed lines represent the
`model fit with first-order
`kinetics
`
`limited model fitted the patient data very well, with a
`mean r2 of 0.939±0.082.
`Comparison to the first-order model showed that
`capacity-limited kinetics provided a lower
`sum of
`residual squares in 22 of 27 patients and a lower AIC
`in 20 of 27 patients. Additionally, for three of the
`seven patients whose concentration versus time data
`were fitted best by a first-order model, it was difficult
`to fit the experimental data to the capacity-limited
`
`late data
`kinetic model because there were fewer
`points (concentrations at 4 h post-infusion were below
`the lower limit of quantitation for the assay).
`
`Model-dependent pharmacokinetic parameters
`
`Tables 3 and 4 show the mean and median pharmaco-
`kinetic parameters determined from this study for the
`
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`Table 3 Model-dependent PAA
`and PAG pharmacokinetic
`parameters (results based on
`patients enrolled at both doses
`and results normalized on body
`surface area and mass)
`
`Table 4 Model-dependent PAA
`and PAG pharmacokinetic
`parameters at each dose tested
`
`421
`
`Parameter
`
`Units
`
`Mean
`
`Median
`
`SD
`
`CV (%)
`
`Area basis
`
`Mass basis
`
`Km
`Vmax
`ke-PAG
`Vd-PAA
`Vd-PAG
`Km
`Vmax
`ke-PAG
`Vd-PAA
`Vd-PAG
`
`mg/l
`mg/m2/min
`min)1
`l/m2
`l/m2
`mg/kg
`mg/kg/h
`h)1
`l/kg
`l/kg
`
`152
`18.4
`0.0091
`7.97
`35.0
`33.0
`34.9
`0.54
`0.27
`1.15
`
`99.0
`13.8
`0.0087
`6.74
`31.9
`25.3
`24.1
`0.52
`0.23
`1.06
`
`155
`13.8
`0.0039
`3.29
`16.0
`23.3
`22.8
`0.24
`0.13
`0.56
`
`101.9
`74.8
`43.2
`41.2
`45.6
`70.5
`65.2
`43.2
`48.4
`48.7
`
`Dose (g/m2)
`
`Parameter
`
`Units
`
`Mean
`
`Median
`
`SD
`
`CV (%)
`
`1.8
`
`2.5
`
`Km
`Vmax
`ke-PAG
`Vd-PAA
`Vd-PAG
`Km
`Vmax
`ke-PAG
`Vd-PAA
`Vd-PAG
`
`mg/l
`mg/m2/min
`min)1
`l/m2
`l/m2
`mg/l
`mg/m2/min
`min)1
`l/m2
`l/m2
`
`142
`18.3
`0.0087
`6.84
`35.3
`161
`18.6
`0.0094
`9.02
`34.7
`
`89.7
`13.5
`0.0089
`6.43
`39.1
`118
`15.0
`0.0084
`6.97
`28.3
`
`155
`14.7
`0.0041
`1.25
`9.2
`144
`12.8
`0.0038
`4.13
`20.3
`
`109.2
`80.3
`47.1
`18.3
`26.1
`89.4
`68.8
`40.4
`45.8
`58.5
`
`capacity-limited model. The results are expressed in two
`sets of units
`to facilitate comparison with other
`published data on PAA [13, 14]. Using the same
`units as previously published adult data, the model-
`dependent PAA pharmacokinetic parameters (Km, Vmax
`and Vd-PAA) in children were 152±155 lg/ml, 35.0±
`16 mg/kg per h, and 0.27±0.13 l/kg, respectively. These
`values are similar to previously reported parameters in
`adults: Km 105±44.5 lg/ml, Vmax 24.1±5.2 mg/kg per
`h, and Vd-PAA 19.2±3.3 l [13]. Assuming a 70-kg adult,
`the PAA volume of distribution for adults is approxi-
`mately 0.27±0.047 l/kg.
`As shown in Table 3, the variabilities of Vmax and Km
`are large. However, the variability decreased if the seven
`data sets which were fitted better by the first-order
`model than the capacity-limited model were disregarded.
`Based on the subset of 20 patients in whom the capacity-
`limited model was superior, Km was 92.9±42.4 lg/ml
`and Vmax 26.9±12.2 mg/kg per h. Other model-depen-
`dent parameters for this subset of patients did not sig-
`nificantly differ from the mean values for the complete
`study group.
`
`Estimation of continuous infusion drug levels using
`bolus pharmacokinetic parameters
`
`Both the capacity-limited and first-order kinetic mod-
`els were used to predict steady-state levels for patients
`receiving continuous i.v. infusions. This was done by
`using the model parameters for each patient derived
`from the bolus data to predict the steady-state levels
`of PAA and PAG during the continuous infusion.
`Figures 4 and 5 show the predicted PAA levels for
`
`the average measured
`both models plotted against
`steady-state levels for patients receiving continuous
`infusions of 7 and 9 g/m2 per day, respectively. Each
`data point represents one patient and the 45° line
`represents perfect agreement between the model and
`the data.
`
`Effect of concurrent medications
`
`Since most of the children enrolled in this study had
`primary CNS tumors, we retrospectively attempted to
`determine whether dexamethasone or anticonvulsants,
`medications that this patient population commonly re-
`ceives, interfered with the metabolism or clearance of
`PAA. There were no statistically significant relationships
`between concomitant administration of dexamethasone
`(n=12), phenytoin (n=4), or both (n=2) and the AUC
`for PAA or PAG. Likewise, there were no correlations
`between concomitant administration of these medica-
`tions and CLTB for PAA. However, potential interac-
`tions may not have been detected because of
`the
`relatively small number of patients who were receiving
`concomitant anticonvulsants.
`
`Discussion
`
`Pharmacokinetics of PAA following bolus
`dose administration
`
`Early studies of the plasma pharmacokinetics of PAA
`following bolus dose administration of 2 mmol/kg
`(about 270 mg/kg or 8 g/m2) performed in children with
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`422
`
`Fig. 4 Predicted steady-state
`concentrations of PAA using
`the capacity-limited (d) and
`first-order model (m) plotted
`against the average measured
`steady-state concentration for
`patients receiving a continuous
`i.v. infusion of PAA at 7 g/m2
`per day
`
`Fig. 5 Predicted steady-state
`concentrations of PAA using
`the capacity-limited (d) and
`first-order model (m) plotted
`against the average measured
`steady-state concentration for
`patients receiving a continuous
`i.v. infusion of PAA at 9 g/m2
`per day
`
`disorders of urea cycle synthesis showed first-order drug
`elimination [10]. The nonlinear nature of PAA elimina-
`tion may not have been recognized because relatively
`few post-infusion plasma samples were analyzed for
`PAA. However, the data from this pediatric study sug-
`gest that PAA elimination is nonlinear because the
`capacity-limited model described the data better than
`the first-order elimination model in 20 of 27 patients,
`based on residual sum of squares and AIC. In addition,
`model-dependent parameters derived from this study are
`consistent with those published for capacity-limited
`kinetics of PAA in adults (Km 105±44.5 lg/ml, Vmax
`24.1±5.2 mg/kg per h, and Vd-PAA 19.2±3.3 l).
`The model-independent parameters calculated for the
`two PAA dose levels studied are consistent with capac-
`ity-limited kinetics. At the higher PAA dose (2.5 g/m2),
`the increase in AUC was slightly greater than predicted
`based on the incremental increase in dose (55% versus
`40%) while the clearance was slightly decreased (about
`10%). The differences noted were not
`statistically
`
`significant, however, probably because most drug con-
`centrations measured, even at the higher dose level, fell
`below the Km (i.e., in the ‘‘linear’’ range of the capacity-
`limited model). Using the mean capacity-limited model
`parameters, we would predict that a dose increase from
`1.8 g/m2 to 2.5 g/m2 would result in a 63% increase in
`AUC and a 15% decrease in clearance, nearly identical
`to that actually observed. Thus, the model-independent
`parameters are consistent with the capacity-limited
`model proposed.
`
`Pharmacokinetics of continuous PAA infusion
`
`The good agreement between model predictions and
`measured steady-state levels in patients receiving con-
`tinuous infusions of PAA supports the value of using
`models derived from the bolus data. However, the re-
`sults do not help distinguish which model
`is most
`appropriate for PAA pharmacokinetics. As shown in
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`

`

`Figs. 4 and 5, steady-state levels for the 7 g/m2 per day
`and 9 g/m2 per day infusion rates can generally be well
`predicted using bolus pharmacokinetic parameters with
`either the capacity-limited or first-order models. For one
`patient receiving 9 g/m2 per day, the capacity-limited
`model was significantly better because it predicted the
`observed high steady-state level. In general, though,
`comparison of the two models using the continuous
`infusion data was limited by the fact that the achieved
`steady-state levels were typically below the Km of PAA.
`Unfortunately, patients receiving the highest doses of
`the continuous infusion (which in some cases achieved
`concentrations in excess of the Km) were enrolled after
`completion of the bolus study.
`
`Conclusions
`
`We present here the first pharmacokinetic model of PAA
`to include parameters for the formation and elimination
`of the metabolite PAG in children with refractory can-
`cer. The overall results of this study suggest that the
`model most consistent with the experimentally observed
`pharmacokinetics of PAA includes a capacity-limited
`conversion of PAA to PAG. Additionally, this study
`also showed that models developed from bolus phar-
`macokinetic studies of PAA may be useful in predicting
`the steady-state levels achieved during a continuous i.v.
`infusion.
`The nonlinear nature of PAA pharmacokinetics and
`the significant interpatient variability in clearance will
`present a challenge in making uniform dosing recom-
`mendations using traditional dosing schemes that are
`based on body weight or surface area. Pharmacokinetic
`and pharmacodynamic studies should be an integral part
`of future clinical trials in order to maximize the potential
`therapeutic efficacy and minimize the toxicity of PAA.
`
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