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Clinical Cancer Research 13, 4832-4839, August 15, 2007. doi: 10.1158/1078-0432.CCR-07-0475
© 2007 American Association for Cancer Research
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Cancer Therapy: Clinical

Oxaliplatin Pharmacokinetics and Pharmacodynamics in Adult Cancer Patients with Impaired Renal Function

Chris H. Takimoto1,2, Martin A. Graham4, Graham Lockwood4, Chee M. Ng1, Andrew Goetz1, Dennis Greenslade4, Scot C. Remick5, Sunil Sharma6, Sridhar Mani8, Ramesh K. Ramanathan9, Timothy W. Synold10, James H. Doroshow10, Anne Hamilton7, Daniel L. Mulkerin11, Percy Ivy3, Merrill J. Egorin8 and Jean L. Grem2

Authors' Affiliations: 1 Institute for Drug Development, Cancer Therapy and Research Center, San Antonio, Texas; 2 Medicine Branch at Navy, National Naval Medical Center, National Cancer Institute; 3 Investigational Drug Branch, Cancer Therapy Evaluation Program, Division of Cancer Treatment and Centers, National Cancer Institute, Bethesda, Maryland; 4 Department of Global Metabolism and Pharmacokinetics, Sanofi-Aventis, Malvern; Pennsylvania; 5 Case Western Reserve University, Cleveland, Ohio; 6 Memorial Sloan-Kettering Cancer Center; 7 New York University, New York, New York; 8 Montifiore Hospital, Albert Einstein College of Medicine, Bronx, New York; 9 Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, Pennsylvania; 10 City of Hope, Duarte, California; and 11 University of Wisconsin, Madison, Wisconsin

Requests for reprints: Chris H. Takimoto, Institute for Drug Development, Cancer Therapy and Research Center, 14960 Omicron Drive, San Antonio, TX 78245-3217. Phone: 210-450-3800; Fax: 210-677-0058; E-mail: ctakimot{at}idd.org.


   Abstract
Top
 Abstract
Materials and Methods
 Results
 Discussion
 References
 
Purpose: To characterize the pharmacokinetics and pharmacodynamics of oxaliplatin in cancer patients with impaired renal function.

Experimental Design: Thirty-four patients were stratified by 24-h urinary creatinine clearance (CrCL) into four renal dysfunction groups: group A (control, CrCL, ≥60 mL/min), B (mild, CrCL, 40-59 mL/min), C (moderate, CrCL, 20-39 mL/min), and D (severe, CrCL, <20 mL/min). Patients were treated with 60 to 130 mg/m2 oxaliplatin infused over 2 h every 3 weeks. Pharmacokinetic monitoring of platinum in plasma, plasma ultrafiltrates, and urine was done during cycles 1 and 2.

Results: Plasma ultrafiltrate platinum clearance strongly correlated with CrCL (r2 = 0.712). Platinum elimination from plasma was triphasic, and maximal platinum concentrations (Cmax) were consistent across all renal impairment groups. However, only the ß-half-life was significantly prolonged by renal impairment, with values of 14.0 ± 4.3, 20.3 ± 17.7, 29.2 ± 29.6, and 68.1 h in groups A, B, C, and D, respectively (P = 0.002). At a dose level of 130 mg/m2, the area under the concentration time curve increased in with the degree of renal impairment, with values of 16.4 ± 5.03, 39.7 ± 11.5, and 44.6 ± 14.6 µg·h/mL, in groups A, B, and C, respectively. However, there was no increase in pharmacodynamic drug-related toxicities. Estimated CrCL using the Cockcroft-Gault method approximated the measured 24-h urinary CrCL (mean prediction error, –5.0 mL/min).

Conclusions: Oxaliplatin pharmacokinetics are altered in patients with renal impairment, but a corresponding increase in oxaliplatin-related toxicities is not observed.

Oxaliplatin is a novel diaminocyclohexane platinum derivative approved for the treatment of patients with advanced colorectal cancer. The major dose-limiting side effects of oxaliplatin are acute and chronic peripheral neuropathies, although mild myelosuppression and moderate nausea and vomiting are also common (1, 2). Oxaliplatin is not ototoxic or nephrotoxic, and it does not require extensive i.v. hydration before its administration (1).

Oxaliplatin is stable in water, but in saline solutions, it rapidly converts to highly reactive monochloroplatinum, dichloroplatinum, and diaquoplatinum biotransformation products (3) that can immediately interact with tissues, proteins, and other plasma constituents (4). The volume of distribution of oxaliplatin-associated platinum in plasma ultrafiltrates is quite large, over 300 L, and the kinetics of elemental platinum in plasma after oxaliplatin administration shows three distinct phases. Initially, there is a short {alpha}-phase half-life of 0.25 to 0.33 h followed by a longer ß-phase half-life of ~16 h. Finally, highly sensitive analytic methods, such as inductively coupled plasma mass spectroscopy, can detect a prolonged {gamma}-half-life of 240 to 600+ h (4, 5). Within the first 48 h after drug administration, over 50% of the administered platinum is excreted into the urine, consistent with the kidneys being a major route of platinum elimination (4). After repeated dosing, oxaliplatin can accumulate in erythrocytes; however, this intracellular binding within RBC is thought to be irreversible (6, 7).

Because of the potential importance of renal excretion in oxaliplatin elimination, we conducted a dose-escalating multicenter pharmacologic trial of oxaliplatin in adult cancer patients with variable degrees of renal dysfunction under the sponsorship of the National Cancer Institute's Organ Dysfunction Working Group. In this study, full doses of single-agent oxaliplatin of 130 mg/m2 administered on an every 3-week schedule were clinically well tolerated by cancer patients with mild-to-moderate renal impairment, defined as a measured 24-h urinary creatinine clearance (CrCL) >20 mL/min. The full safety and efficacy results of this study have been published elsewhere (8). Here, we describe in detail the pharmacokinetics and pharmacodynamics of oxaliplatin as determined by elemental platinum in plasma, plasma ultrafiltrates, and urine collected from renally impaired cancer patients participating in an organ dysfunction study. This represents the largest reported clinical pharmacology trial of oxaliplatin in patients with a broad range of renal impairment.


   Materials and Methods
Top
 Abstract
 Materials and Methods
Results
 Discussion
 References
 
Patient selection. Thirty-four of 37 adult solid tumor patients enrolled in a clinical study of oxaliplatin in patients with renal dysfunction (8) also participated in the current pharmacokinetic and pharmacodynamic study. Patients were treated at nine separate institutions, and all patients satisfied the study eligibility criteria, which included a histologically confirmed diagnosis of an advanced malignancy for which other therapies were no longer effective, age ≥18 years, Eastern Cooperative Oncology Group performance status of 0 to 2 (Karnofsky, ≥60%), life expectancy ≥4 weeks, adequate bone marrow reserve as evidenced by a leukocyte count ≥3,000/µL or an absolute neutrophil count ≥1,500/µL, and a platelet count ≥100,000/µL. Adequate hepatic function was required, as shown by a total bilirubin within normal institutional limits and transaminase (aspartate aminotransferase and alanine aminotransferase) values ≤1.5 times the upper limit of normal. Prior chemotherapy with any agent except oxaliplatin was permitted. At least 4 weeks had to have elapsed since any prior treatment with chemotherapy or radiation therapy, and a 6-week period was required after any prior platinum-based chemotherapy. The Institutional Review Board for each participating institution approved the protocol, and written informed consent was obtained from all patients. The underlying cause of renal dysfunction was not assessed or documented. Additional eligibility criteria, the laboratory evaluation schedule, and the full clinical toxicity and efficacy findings of this trial have been published elsewhere (8).

Treatment protocol. Patients were stratified into one of four groups based on their measured CrCL (Table 1 ). Group A patients (CrCL, ≥60 mL/min) were considered pharmacologic controls, and the remaining patients were assigned to groups B (CrCL, 40-59 mL/min), C (CrCL, 20-39 mL/min), or D (CrCL, <20 mL/min), representing the mild, moderate, and severe renal dysfunction groups, respectively. Two separate 24-h urine collections for measuring uncorrected CrCL were required, with the most recent done within 1 week of starting on study. Stratification into the study groups was based on the most recent 24-h CrCL that did not deviate from an earlier measurement by >25%. If the two measurements differed by >25%, additional 24-h CrCLs were obtained until the above criteria were satisfied. The original CrCL assessments used for patient stratification were not corrected for body surface area. However, because some nephrologists and clinical pharmacologists have recommended standardizing CrCL to a uniform body size of 1.73 m2 (9), all summary CrCLs in this report have been corrected for body surface area. However, we have maintained the initial patient stratification scheme based on uncorrected CrCL to retain clarity in the dosing schemes. Correction for body surface area was achieved by dividing the absolute measured CrCL by the patient's actual body surface area and multiplying the result by 1.73 m2.


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  		Table 1. Patient demographics (N = 34)

 
The Cancer Treatment Evaluation Program in the Division of Cancer Treatment Diagnosis and Centers of the National Cancer Institute (Bethesda, MD) supplied oxaliplatin as a sterile freeze-dried powder for i.v. infusion in glass vials containing 50 or 100 mg of drug and lactose monohydrate as an excipient. Oxaliplatin was provided to the National Cancer Institute under a Cooperative Research and Development Agreement (CRADA no. 0640) with Sanofi-Synthelabo. Oxaliplatin was diluted into an infusion solution of 250 to 500 mL of 5% dextrose in water and administered within 8 h of preparation. This solution was infused over 2 h through a peripheral or central venous catheter every 3 weeks. Immediately following drug administration, the infusion line was flushed with dextrose 5% in water. All patients were treated with a prophylactic antiemetic regimen in common use for platinum-based chemotherapy, which typically consisted of a serotonin (HT3) receptor antagonist given i.v. with dexamethasone.

Different starting doses of oxaliplatin (60-130 mg/m2) were used in each renal dysfunction group (Table 1). Group A patients were treated at the recommended single-agent dose of oxaliplatin at 130 mg/m2 every 3 weeks without further escalation. In group B, the dose levels were 105 and 130 mg/m2; in group C, the dose levels were 80, 105, and 130 mg/m2; and in group D, the planned dose levels were 60, 80, 105, and 130 mg/m2. These starting dose levels were selected because preliminary information on oxaliplatin pharmacokinetics in patients with mild-to-moderately impaired renal function showed a 43% decrease in ultrafilterable platinum clearance and a corresponding increase in the area under the concentration time curve (AUC) compared with patients with control renal function. No dose escalation >130 mg/m2 was permitted in any group. Three to six patients were enrolled per dose level in each renal dysfunction group, and a minimum of six patients were treated at the highest dose level deemed tolerable in each organ dysfunction group, except for group A where at least 12 patients were enrolled to serve as pharmacokinetic controls.

Sample processing and analytic methodology. Blood samples for plasma and plasma ultrafiltrate platinum concentrations were obtained during cycles 1 and 2 at the following times: before infusion and at 2 h (end of infusion), 2.25, 2.50, 2.75, 3, 5, 8, 24, 48, 168, 336, and 504 h after the start of the infusion. Eight milliliters of blood were drawn into Vacutainer tubes containing sodium heparin anticoagulant, kept on ice, and centrifuged within 1 h at 1,000 x g at 4°C to isolate plasma. One milliliter of plasma was frozen for total platinum analysis and the remaining plasma was loaded into an Amicon Centrifree micropartition filter (Millipore) with a molecular weight cutoff of 30,000 and centrifuged at 3,000 x g for 30 min at 4°C. The protein-free ultrafiltrates and plasma specimens were frozen and stored at –20°C until shipped to the analytic facilities of Sanofi-Aventis Research. Two complete 24-h urine sample collections were done from 0 to 24 and 24 to 48 h after treatment during cycles 1 and 2 and stored at 4°C. After the total volume of urine for each collection period was recorded, a 10-mL aliquot was stored frozen at –20°C for platinum analysis.

Total elemental platinum in plasma, plasma ultrafiltrate, and urine was assayed using a highly sensitive inductively coupled plasma mass spectroscopy analytic method (10). This method was validated with an accuracy and precision within ±15% over the concentration range of 1 to 250 ng/mL in plasma ultrafiltrate and 0.1 to 10 µg/mL in plasma. The lower limit of quantification of platinum in urine was 0.1 µg/m.

Pharmacokinetic analysis. Oxaliplatin-associated platinum concentrations in plasma and ultrafiltrates were analyzed using noncompartmental pharmacokinetic analytic methods. The individual AUC to the last measured concentration was calculated using the linear trapezoidal rule, and the AUC0-inf was determined by extrapolation to infinity. The extrapolated portion of the AUC was calculated by dividing the last measured concentration by the terminal rate constant for each matrix (11). Nominal sampling times were used in all pharmacokinetic calculations. The elimination rate constant was estimated by linear regression analysis of the terminal phase of drug elimination. All calculations were done using WinNonLin Professional, version 3.1 (Pharsight Corp.). The volume of distribution at steady state (Vss) was calculated from the formula: Vss = CL (AUMC / AUC) where AUMC is the area under the first moment curve (12). Clearance was calculated by dividing dose by the AUC (11). The maximum platinum concentrations were determined by inspection of the platinum concentration data at the end of the 2-h drug infusion. Renal clearance was calculated from the following equation: CLr = Aut / AUC0-48 where CLr is renal clearance, Aut is total amount of platinum eliminated in the urine from 0 to 48 hour, and AUC0-48 is the area under the plasma ultrafiltrate versus time curve from 0 to 48 h.

Platinum ultrafiltrate concentration data were analyzed using a three-compartment, open model done as implemented in WinNonLin Professional, version 3.1. The {alpha}-, ß-, and {gamma}-phase rate constants were estimated using a 1/y weighting scheme.

In group C, patients were treated at three different oxaliplatin dose levels allowing for the formal assessment of dose proportionality. The dose proportionality of AUC was examined using the intercept test (13) and by measuring the variability in the dose-normalized AUC using the nonparametric Kruskal-Wallis statistic (14).

Pharmacodynamic analysis. Pharmacodynamic relationships were examined by graphical analysis of the plots of AUC or maximal concentration (Cmax) versus the percentage change in blood counts occurring during cycle 1 including leucocytes, neutrophils, and platelets. This was defined as follows: percentage change in count = [(pretreatment count – nadir count) x 100] / pretreatment count.

Pharmacodynamic scatter plot graphs were inspected visually for any evidence of correlation and linear, maximum-effect, and sigmoid maximum-effect models were fitted to the data using WinNonLin, version 3.1 to estimate the corresponding pharmacodynamic variables. Model selection was determined using graphical analysis and residual plots. Growth factor support was not permitted during cycle 1.

Statistical analysis. Descriptive statistics (mean, SD) were calculated for all pharmacokinetic variables, with the exception that harmonic means and pseudostandard deviations were used as summary statistics for half-lives (15). The relationship between plasma ultrafiltrate platinum clearance and measured CrCL was examined by linear regression. Correlations were evaluated using the Spearman's rank-order test.

The {alpha}-, ß-, and {gamma}-half-lives were analyzed by the following linear, mixed-effect model: half-life = Group + Dose + Cycle + Group*Dose + Group*Cycle + Subject(Group*Dose).

Subject(Group*Dose) was considered a random term and Group, Dose, and Cycle (and interactions) were considered fixed terms using the SAS MIXED procedure (SAS Institute, Inc.). Nonsignificant (P > 0.05) interaction terms were removed and the model was refit using only the main and significant interaction terms. Differences among groups were assessed by the P value for the Group main effect. If the Group*Dose interaction was significant, group comparisons were done only for the 130 mg/m2 dose groups. The severe group D group was removed from all statistical analyses because it contained only one subject.

Interoccasion variability in pharmacokinetics was analyzed by comparing the cycle 1 versus cycle 2 log-transformed Vss and CL values using a paired, two-tailed t test with significance defined by a P value of <0.05. Pharmacodynamic variability was assessed by comparing the nadir in blood counts in the renal impairment groups B and C with group A control patients using a simple t test.

Individual estimates of the CrCL were also obtained with the Cockcroft-Gault formula using actual body weight (16):CrCL in mL/min = (140 – age in years) x (actual weight in kg) / (72 x serum creatinine in mg/dL).

For females, the same formula was used multiplied by a factor of 0.85. The precision and bias of the estimated CrCL were compared with the measured CrCL as the reference standard using the method of Sheiner and Beal (17).


   Results
Top
 Abstract
 Materials and Methods
 Results
Discussion
 References
 
Study population and patient demographics. Plasma, plasma ultrafiltrates, and urine samples were collected and analyzed from 34 patients during cycle 1 and from 29 patients during cycle 2 of therapy. Demographic and dosing information for these patients is summarized in Table 1.

Plasma ultrafiltrate platinum pharmacokinetics. Plasma ultrafiltrate platinum represents free, unbound, low-molecular-weight circulating platinum species. Noncompartmental analytic methods were used to estimate pharmacokinetic variables for unbound platinum in plasma ultrafiltrates collected from 30 patients during cycle 1 and from 25 patients during cycle 2 (Table 2 ). At the highest dose level of 130 mg/m2, peak concentrations (Cmax) were consistent in all patients treated at 130 mg/m2, regardless of the degree of renal impairment. At this dose level, the mean first cycle Cmax values were 1.31 ± 0.19, 1.31 ± 0.51, and 1.39 ± 0.58 in groups A, B, and C, respectively (Table 2). Platinum clearance from plasma ultrafiltrates during cycles 1 and 2 was strongly correlated with the measured CrCL (r2 = 0.7117; Fig. 1A ) consistent with renal excretion of unbound platinum. Pretreatment blood samples at the start of cycle 2 showed trace amounts of platinum in plasma ultrafiltrates, but the overall Cmax and AUCs were not substantially altered from cycle 1 to cycle 2 (Table 2).


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  		Table 2. Pharmacokinetic variables for platinum in plasma ultrafiltrate and urine (mean ± SD)

 

Figure 1
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  		Fig. 1. Plots of platinum clearance from plasma ultrafiltrate during cycles 1 (bullet) and 2 ({circ}; A), {alpha}-rate constant (B), ß-rate constant (C), and {gamma}-rate constant (D), plotted versus baseline CrCL.

 
In all patient groups, the elimination of platinum from plasma ultrafiltrates was triphasic (Fig. 2A ). During the early distribution {alpha}-phase (Fig. 1B) and the terminal {gamma}-elimination phase (Fig. 1D), changes in ultrafilterable platinum concentrations were independent of renal function. The initial plasma ultrafiltrate {alpha}-half-lives were 0.183 ± 0.049, 0.132 ± 0.079, 0.162 ± 0.064, and 0.222 h in groups A (n = 12), B (n = 8), C (n = 10), and D (n = 1), respectively (P = 0.16). Similarly, the terminal plasma ultrafiltrate {gamma}-half-lives were also relatively constant, consisting of 288 ± 215, 295 ± 108, 362 ± 215, and 286 h in groups A, B, C, and D, respectively (P = 0.16). In contrast, the plasma ultrafiltrate ß-rate constants were significantly decreased in patients with renal impairment (Fig. 1C), corresponding to prolonged ß-half-life values of 14.0 ± 4.3, 20.3 ± 17.7, 29.2 ± 29.6, and 68.1 h in groups A, B, C, and D, respectively (P = 0.002). No significant changes in the Vss or CL were observed in any cohort when cycle 2 was compared with cycle 1 (data not shown).


Figure 2
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  		Fig. 2. Dose-normalized platinum concentrations in plasma ultrafiltrates (A) and plasma (B) during cycle 1 in patients grouped by renal dysfunction. Points, mean; bars, SD.

 
Plasma platinum pharmacokinetics. Total plasma platinum represents both bound and unbound circulating platinum species. Noncompartmental pharmacokinetic data of total platinum in plasma were obtained from 29 patients in cycle 1 and 25 patients in cycle 2 (Table 3 ). In general, platinum concentrations were 3- to 10-fold higher in total plasma than in ultrafiltrates, consistent with high plasma protein binding (Fig. 2B). The ratio of unbound to bound Cmax platinum concentrations did not change in each renal function group, with mean values of 0.354 ± 0.085, 0.341 ± 0.179, 0.336 ± 0.109, and 0.407 in groups A (n = 10), B (n = 9), C (n = 9), and D (n = 1), respectively. Thus, renal dysfunction did not alter acute oxaliplatin protein binding. In contrast to the ultrafiltrate fraction, clearance of platinum from total plasma correlated less well with CrCL (r2 = 0.712 for ultrafiltrate versus 0.154 for total plasma). The pharmacokinetics of total platinum in plasma was also characterized by triphasic elimination. The {alpha}-half-lives were 0.196 ± 0.201, 0.137 ± 0.142, 0.162 ± 0.157, and 0.178 h, and the terminal {gamma}-half-lives were 226 ± 105, 255 ± 158, 184 ± 97, and 451 h in groups A (n = 12), B (n = 10), C (n = 11), and D (n = 1), respectively. In contrast to the ultrafiltrate data, the ß-half-lives of total platinum in plasma did not consistently change with renal impairment, showing values of 18.6 ± 11.0, 22.0 ± 12.9, 18.2 ± 13.2, and 29.5 h in groups A, B, C, and D, respectively (P = 0.604). In cycle 2, the total plasma platinum Vss and CL did not significantly differ from the cycle 1 variables for any cohort (data not shown).


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  		Table 3. Pharmacokinetic variables of platinum in plasma (mean ± SD)

 
Pharmacokinetics in urine. Urinary excretion of platinum was analyzed in 27 patients in cycle 1 and 23 patients in cycle 2 (Table 2). Urinary recovery of platinum in the first 24 h was ~40% in patients with control renal function but decreased to 20% or less in patients with moderate or severe renal impairment. The mean cycle 1 renal clearance of platinum from ultrafiltrate in the control patients in group A was 3.73 L/h/m2, which is close to the average measured CrCL of 3.16 L/h/m2 (91.2 mL/min/1.73 m2) in this group, consistent with the principal method of unbound platinum elimination being glomerular filtration.

Dose proportionality. In group C patients with moderate renal dysfunction, three different dose levels were administered, which allowed for an analysis of dose proportionality within this renal dysfunction group. Overall, 3 patients were treated at 80 mg/m2, 2 patients at 105 mg/m2, and 6 patients at 130 mg/m2. Weighted linear regression of the AUC of ultrafiltrable platinum as a function of dose level generated an intercept that did not significantly deviate from zero (AUC intercept, 0.121; 95% confidence interval, –73.834-74.077), consistent with dose proportional kinetics (13). In addition, a nonparametric ANOVA Kruskal-Wallis test of these three dose level groups showed no difference in the dose-normalized plasma ultrafiltrate AUCs across the dose levels in this renal dysfunction group (P = 0.905; ref. 14). Although the number of patients treated at each dose level is small, these data are consistent with oxaliplatin pharmacokinetics being dose proportional within the moderate renal dysfunction group. Thus, dose normalization of the concentrations versus time plots can be used to summarize these data within each renal dysfunction group (Fig. 2).

Pharmacodynamic analysis. Pharmacodynamic correlations were restricted by the low incidence of drug-induced toxicities of single-agent oxaliplatin (8). In the early single-agent phase I studies of oxaliplatin, the reported dose-limiting toxicities were sensory neuropathy (18), and nausea and vomiting (19). However, these adverse events were not prominent in the current study (8). The most common myelosuppressive toxicity observed across all study cohorts was mild thrombocytopenia; however, this pharmacodynamic effect did not correlate with AUC or Cmax (data not shown). When the incidence of cytopenias was compared across the renal impairment groups in patients treated with the same oxaliplatin dose of 130 mg/m2, there were no significant differences compared with control patients. In groups A (n = 12), B (n = 7), and C (n = 6), the mean nadir neutrophil counts in cycle 1 were 4.72 ± 2.48, 4.80 ± 1.79 (P = 0.935), and 4.65 ± 1.69 (P = 0.953) x 103/µL, respectively. Similarly, for groups A, B, and C, the nadir hemoglobin levels were 10.8 ± 1.8, 10.4 ± 2.2 (P = 0.69), and 9.3 ± 1.7 (P = 0.104) g/dL, respectively, and the nadir platelet counts were 324 ± 232, 223 ± 117 (P = 0.836), and 187 ± 105 (P = 0.278) x 103/µL, respectively. None of these blood count nadirs were significantly different from controls for any renal impairment group. Thus, the increase in systemic platinum exposure associated with renal impairment did not increase the incidence of drug-related adverse events.

Measured versus estimated CrCL. Patients were stratified into different renal dysfunction groups by their measured 24-h CrCL. These measurements were compared with the Cockcroft-Gault formula using absolute body weight (16), which is much easier to implement at the bedside. Overall, the predictive performance of the calculated CrCL relative to the measured assessment was generally good, although the calculated values underestimated the measured CrCL with a bias (mean prediction error) of –5.0 mL/min and a precision (root mean squared error) of 12.7 mL/min (17).


   Discussion
Top
 Abstract
 Materials and Methods
 Results
 Discussion
References
 
We conducted a pharmacokinetic, pharmacodynamic, and dose-escalating trial of single-agent oxaliplatin in adult cancer patients with renal impairment (8). This is the largest study of oxaliplatin kinetics in cancer patients with a broad range of renal impairment and it is the first study to analyze which phases of platinum clearance are most affected by renal impairment. In patients with mild-to-moderate renal impairment, as defined by measured CrCL >20 mL/min, full doses of oxaliplatin at 130 mg/m2 were well tolerated with no increase in drug-related toxicity (8). Despite this clinical tolerability, the overall clearance of unbound platinum from plasma ultrafiltrates was markedly reduced in patients with renal failure, an observation noted in prior pharmacokinetic studies of oxaliplatin (7). Overall, the clearance of unbound platinum from plasma ultrafiltrates and the total urinary platinum excreted over 24 h both strongly correlated with measured CrCL (Fig. 1A). Thus, at any constant dose of oxaliplatin, renally impaired patients are exposed to greater amounts of circulating ultrafilterable platinum; however, no pharmacodynamic increase in clinical toxicity is observed.

Recent advances in our understanding of the complex clinical pharmacology of oxaliplatin may explain how renal dysfunction alters oxaliplatin pharmacokinetics with a correspondingly minimal effect on pharmacodynamics. Most pharmacologic studies of oxaliplatin, including the present one, only measure the total amount of platinum present in biological matrices. However, total circulating platinum is actually a complex mixture of active and inactive platinum species. In saline solutions, oxaliplatin undergoes rapid chemical activation (3) to form unstable biotransformation products that interact with tissues, proteins, and other plasma constituents (Fig. 3 ; refs. 4, 5, 20). This phenomenon was described in an elegant study by Allain et al. (21) that characterized the distribution of platinum in plasma and blood in three subjects following a 2-h infusion of 130 mg/m2 oxaliplatin. One hour after the end of the infusion, the majority of unbound platinum consisted of inactive low-molecular-weight platinum conjugates of glutathione, L-methionine, and L-cysteine; only 12% or less of the unbound platinum was unchanged oxaliplatin. After 3 h, free oxaliplatin comprised <5% of the unbound circulating platinum. Thus, shortly after the end of an oxaliplatin infusion, the majority of platinum circulating in plasma and plasma ultrafiltrates consists of inactive biotransformation products.


Figure 3
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  		Fig. 3. Schematic of oxaliplatin biotransformation, distribution, and excretion.

 
These reports coupled with the observations made in our current study have led to the following hypothesis. During the first hour following oxaliplatin treatment, the active drug is cleared rapidly from plasma ultrafiltrate via protein binding, tissue distribution, cellular sequestration, and reactions with plasma constituents, ultimately forming inactive platinum adducts (Fig. 3). These processes are independent of renal function and represent the {alpha}-phase of platinum disappearance. Our data showing constant {alpha}-phase half-lives (Fig. 1B) and Cmax values at 130 mg/m2 across each renal dysfunction group (Tables 2 and 3) support this hypothesis. In contrast, within an hour after the end of the infusion, the majority of unbound platinum is in the form of inactive, low-molecular-weight conjugates that are cleared by glomerular filtration. This ß-phase of drug elimination lasts for 72 h or longer and strongly correlates with CrCL (Fig. 1C). Because these adducts are biologically inactive, the increase in systemic platinum exposure associated with renal impairment does not enhance drug-related toxicities. Finally, platinum sequestered in cellular and tissue compartments is released slowly back into the systemic circulation as low-molecular-weight platinum species during the prolonged {gamma}-terminal elimination phase. These late-occurring processes are rate limited by tissue and protein degradation and are unrelated to renal function (Fig. 1D). Formal testing of this complex hypothesis is not possible in our current clinical study because oxaliplatin biotransformation products are not stable in frozen plasma and must be assayed in real time (21). Nonetheless, our proposed hypothesis explains how renal impairment can alter oxaliplatin pharmacokinetics with a minimal effect on oxaliplatin pharmacodynamics.

Our findings are in close agreement with previously published data on the clinical pharmacology of oxaliplatin. The estimated pharmacokinetic variables found in our control group A are comparable with those summarized in a comprehensive review of oxaliplatin pharmacokinetics (4). Furthermore, in the only previously published study of oxaliplatin in renal dysfunction, 10 patients with an estimated CrCL <60 mL/min (median CrCL, 42 mL/min; range, 27-57 mL/min) were compared with 13 control patients with an estimated CrCL >60 mL/min (median CrCL, 70.5 mL/min; range, 63-136 mL/min; ref. 7). Following a single dose of oxaliplatin at 130 mg/m2, the renally impaired patients had a lower systemic clearance of unbound platinum compared with controls (14.23 ± 6.04 versus 25.70 ± 8.53 L/h, respectively; P = 0.005). No increase in acute toxicity was observed; however, the majority of patients in this study were only treated with one cycle of oxaliplatin.

Finally, our study used the 24-h urinary CrCL to stratify patients with renal impairment. Because rapid bedside estimation of CrCL is more convenient, we compared the predictive performance of the well-known Cockcroft-Gault formula (16) using actual body weight to our measured CrCL assessment in this population of cancer patients. In agreement with other studies comparing these two specific methods of assessing renal function in cancer patients (22–24), the predictive performance of the calculated Cockcroft-Gault CrCL values approximated the measured CrCL determination (mean prediction error bias, –5.0 mL/min).

In summary, renal impairment decreases plasma ultrafiltrate platinum clearance and enhances systemic platinum exposure in cancer patients treated with single-agent oxaliplatin. However, no corresponding pharmacodynamic increase in clinical toxicities is observed and oxaliplatin dose reductions are not necessary. These observations are consistent with the hypothesis that the active forms of oxaliplatin are eliminated within the first hour after infusion by clearance mechanisms independent of renal function. Later, during the ß-phase of platinum elimination, biologically inactive low-molecular-weight platinum is excreted via glomerular filtration, which may explain why renal impairment does not enhance oxaliplatin-related toxicities. Additional pharmacokinetic-pharmacodynamic modeling efforts are ongoing to define specific oxaliplatin kinetics variables that predict clinically relevant drug-related toxicities.


   Acknowledgments
 
We thank Dr. William G. Price, Jr. (Theradex, Princeton, NJ), Ronald Knight and Dr. Paul Juniewicz (Sanofi-Synthelabo, Malvern, PA), and Drs. Bennett Kaufman and Carolyn Nagler (TRI/PSI, Bethesda, MD) for their invaluable support in the conduct of this study and Dr. Jane H. Ransom Ph.D. (TRI International, Bethesda, MD) for her efforts in compiling the clinical study report for this project.


   Footnotes
 
Grant support: National Cancer Institute grants U01CA069853, U01CA062502, U01CA069856, U01CA076642, U01CA062505, U01CA062491, and U01CA069855.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 2/27/07; revised 4/18/07; accepted 5/29/07.


   References
Top
 Abstract
 Materials and Methods
 Results
 Discussion
 References
 

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