Cancer Chemother Pharmacol (2014) 73:1009–1020 DOI 10.1007/s00280-014-2436-6

Original Article

Rate and extent of oxaliplatin absorption after hyperthermic intraperitoneal administration in peritoneal carcinomatosis patients Carlos Pérez‑Ruixo · José E. Peris · Vanesa Escudero‑Ortiz · Pedro Bretcha‑Boix · José Farré‑Alegre · Juan José Pérez‑Ruixo · Belén Valenzuela 

Received: 11 February 2014 / Accepted: 4 March 2014 / Published online: 25 March 2014 © Springer-Verlag Berlin Heidelberg 2014

Abstract  Purpose To determine the rate and extent of hyperthermic intraperitoneal oxaliplatin (HIO) absorption in peritoneal carcinomatosis patients treated with cytoreductive surgery (CRS) and the effect of the isotonic carrier solution on HIO absorption parameters. Methods  Full pharmacokinetic profiles collected in peritoneum and plasma from 57 subjects treated with CRS followed by 30 min of HIO were pooled with sparse plasma concentrations collected from 50 patients with solid tumors treated with intravenous oxaliplatin. Pharmacokinetic data were jointly analyzed with nonlinear mixed-effect model

C. Pérez‑Ruixo · J. E. Peris  Pharmacy and Pharmaceutical Technology Department, University of Valencia, Valencia, Spain C. Pérez‑Ruixo  Consulting Projects for Research, Valencia, Spain V. Escudero‑Ortiz · P. Bretcha‑Boix · J. Farré‑Alegre · B. Valenzuela  Platform of Oncology, Hospital Quirón Torrevieja, Alicante, Spain

(NONMEM VII software). The effect of carrier solution (icodextrin 4 % vs. dextrose 5 %) and selected patient covariates on oxaliplatin pharmacokinetics was investigated. Model evaluation was performed using predictive checks and nonparametric bootstrap. Results An open linear two-compartment disposition model with linear absorption from peritoneum to plasma was used to characterize the oxaliplatin pharmacokinetics in peritoneum and plasma. No patient-related covariates were associated with oxaliplatin pharmacokinetics. The volume of distribution in the peritoneum (Va) exponentially decreased due to the carrier solute absorption. The reduction in Va was 1.76-fold faster when HIO was administered in dextrose 5 %, relative to icodextrin 4 %. For HIO durations of 30 min, the rate of oxaliplatin absorption ranges from 0.84 to 0.96 h−1 for icodextrin 4 % and from 0.86 to 1.09 h−1 for dextrose 5 %. The extent of HIO absorption was 38 %, regardless of the carrier solution. Conclusions Hyperthermic intraperitoneal oxaliplatin absorption is fast and incomplete. The small difference in oxaliplatin exposure between both carrier solutions evaluated is not clinically relevant for HIO durations of 30 min.

V. Escudero‑Ortiz · P. Bretcha‑Boix · J. Farré‑Alegre · B. Valenzuela  Cathedra of Multidisciplinary Oncology, UCAM Catholic University of San Antonio, Murcia, Spain

Keywords  Oxaliplatin bioavailability · Peritoneal carcinomatosis · Pharmacokinetics · NONMEM® · Hyperthermic intraperitoneal chemotherapy · Cytoreductive surgery

J. J. Pérez‑Ruixo  Pharmacokinetics and Drug Metabolism, AMGEN, Valencia, Spain

Introduction

B. Valenzuela (*)  Personalized Pharmacotherapy Unit, Platform of Oncology, Hospital Quiron Torrevieja, Partida de la Loma s/n, 03180 Torrevieja, Alicante, Spain e-mail: [email protected]

A multimodal approach consisting of cytoreductive surgery (CRS) with hyperthermic intraoperative intraperitoneal chemotherapy (HIPEC) is used for the loco-regional treatment of peritoneal carcinomatosis (PC) from several

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primary tumors such as colorectal [1–3], ovarian [4–6], gastric [7, 8], pseudomyxoma peritonei [9, 10], and malignant peritoneal mesothelioma [11, 12]. Randomized phase II [13], phase III [14], and meta-analysis studies [15] have evidenced that CRS followed by HIPEC increases the longterm survival of patients with PC, with an acceptable rate of morbidity and mortality [16]. One of the most used drugs in HIPEC is oxaliplatin because it penetrates into the tumor [17], has a temperature-dependent cytotoxicity [18] and a low diffusion into the subperitoneal space and capillary endothelial, which might avoid excessive systemic exposure [19]. Therefore, hyperthermic intraperitoneal oxaliplatin (HIO) has the potential to maximize the cytotoxic exposure of the tumor cells in peritoneum, while limits its systemic exposure, which depends on the rate and extent of oxaliplatin absorption from peritoneum to plasma [20]. Oxaliplatin pharmacokinetics in peritoneum and plasma has been simultaneously characterized in cancer patients with PC treated with CRS followed by HIO [19, 21–25]. Peritoneal concentrations decline exponentially with a halflife ranging from 0.5 to 2.2 h, while plasma concentrations increase to reach the peak (Cmax) shortly after the end of the intraperitoneal administration. After treatment with HIO, oxaliplatin plasma concentrations decline in a bi-exponential fashion resembling to the pharmacokinetic profiles observed after intravenous (IV) administration, with an apparent oxaliplatin plasma clearance (Cl/F) that substantially varies across studies (range 1.61–3.71 L × h−1) [19, 23]. Although the time course of plasma concentrations following HIO has been well described by an open two-compartment disposition model with nonspecific distribution to a peripheral compartment, linear elimination from the central compartment, and first-order absorption from peritoneum to plasma [19, 24], the extent of oxaliplatin absorption from peritoneum to plasma has not been determined yet. Furthermore, different isotonic carrier solutions, used to administer oxaliplatin into the peritoneal cavity, might potentially impact the rate of oxaliplatin absorption, but not its extent [26]. Carrier solutes crossing through the permeable peritoneal barrier may decrease the oxaliplatin volume of distribution in peritoneum, which results in increased drug concentrations that might directly impact the rate of oxaliplatin absorption. Actually, a 12–15 % reduction in oxaliplatin volume of distribution in peritoneum has been associated with similar increases in the apparent HIO absorption rate in patients receiving HIO diluted in 5 % dextrose relative to 4 % icodextrin [24]. Icodextrin, an α-14-linked glucose polymer of 12,000–20,000 Da, diluted at 4 % is an isotonic high molecular weight solution widely used for peritoneal dialysis that has also been employed as carrier solution for HIO. Isotonic high molecular weight solutions, such as icodextrin, are not absorbed and can

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maintain the intraperitoneal fluid volume longer, which may reduce the rate and the extent of oxaliplatin absorption, thus reducing the risk of toxicity and increasing the drug concentrations in peritoneum, therefore achieving higher cytotoxic effect in the peritoneal surface. However, the absence of a direct association between the changes in the oxaliplatin volume of distribution in peritoneum, when oxaliplatin is administered with 4 % icodextrin solution, and the extent of oxaliplatin absorption has not been confirmed yet. Consequently, we aimed to simultaneously determine the rate and the extent of HIO absorption in PC patients with CRS by jointly analyzing the time course of oxaliplatin in peritoneum after HIO administration and the time course of oxaliplatin in plasma after intravenous and HIO administrations. Additionally, we test the hypothesis that the volume of the carrier solution instilled in the peritoneum changes over the time as a consequence of the carrier solute absorption. Most likely, this change is related to the molecular weight of the carrier solute and affects the rate, but not the extent of oxaliplatin absorption. Lastly, the effect of patient- and treatment-related covariates as potential sources of variability in oxaliplatin pharmacokinetics was also explored. This information is expected to be useful to balance HIO cytotoxic activity and its risk of hematological toxicity and peripheral sensory neuropathy, which are also the dose-limiting toxicities after IV oxaliplatin administration [20].

Methods Study design and subject eligibility criteria Data from three single arms observational studies involving a total of 107 patients were available for the analysis. Thirty-six (33.7 %) PC patients out of 107 patients were treated with CRS followed by HIO diluted in icodextrin 4 % (Cohort A), twenty-one (19.6 %) PC patients underwent CRS followed by HIO diluted in dextrose 5 % (Cohort B), and fifty (46.7 %) patients with solid tumors were treated with IV oxaliplatin. For Cohorts A and B, patients’ eligibility criteria, CRS procedure and HIO treatment at 42 °C have been extensively described elsewhere [19, 24]. In these two cohorts, the primary tumor type was colorectal (n  = 20), ovarian (n  = 18), appendiceal (n = 10), gastric (n = 5), endometrial (n = 3), and primary papillary (n = 1). For Cohort C, patients were eligible if they had histological or cytological confirmation of malignant solid tumor, potentially amenable to oxaliplatin. Other eligibility criteria included an age between 18 and 80 years, World Health Organization performance status of 0–2, and anticipated life

Cancer Chemother Pharmacol (2014) 73:1009–1020

expectancy longer than 3 months. Patients were required to have a negative pregnancy test (only for female patients with reproductive potential) and normal hepatic and renal function, defined as alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 times the upper limit of normality (×ULN) and bilirubin ≤1.5 × ULN and serum creatinine ≤1.5  × ULN. An acceptable bone marrow function, defined as hemoglobin >10 g × dL−1, neutrophil count >1.5 × 109 L−1, and platelets >100.0 × 109 L−1, was also needed. Patients with one or more of the following criteria were not selected: peripheral neuropathy grade >2, allogeneic transplant, prior extensive radiation therapy (>25 % of bone marrow reserve), prior bone marrow transplantation or high-dose chemotherapy with bone marrow or stem cell rescue, participation in a clinical trial involving an investigational drug in the past 30 days or concurrent enrollment in another observational study, and any coexisting medical condition that was likely to interfere with study procedures and/or results. These patients were treated with IV oxaliplatin on a biweekly dosing regimen, with a mean dose of 61 mg × m−2 (30–117 mg × m−2) administered over 1–2 h (mean = 1.5 h). According to the primary tumor type, oxaliplatin was administered in combination with other IV anticancer therapy, including 5-fluorouracil (42 %), irinotecan (17 %), gemcitabine (10 %), docetaxel (6 %), doxorubicin (3 %), or pemetrexed (2 %) among others. The primary tumor type was colorectal (n = 20), gastric (n = 11), pancreas (n = 9), appendiceal (n = 3), esophagus (n = 2) and others (n = 5). The studies were conducted in accordance with principles for human experimentation as defined in the International Conference on Harmonization for Good Clinical Practice guidelines and the principles of the Declaration of Helsinki. The studies were approved by the corresponding Investigational Review Board, and informed consent was obtained from each subject after being advised of the potential risks and benefits, as well as the investigational nature of the studies. Sample collection and bioanalytical method In Cohorts A and B, an intensive sampling schedule was used as described elsewhere [19, 24]. For Cohort C, samples were collected in Sarstedt lithium-heparin monovette® tubes, from the opposite arm where drug was administered, around 1.5, 2.5, and 6 h after the beginning of the HIO procedure. All samples were centrifuged at 3,500 rpm for 10 min and stored at −80 °C until analysis. Samples were digested with nitric acid at 0.65 %, and total platinum in peritoneum and plasma was measured using an analytical method previously described, validated over the range of 0.5–30 mg × L−1 for plasma samples and 5–300 mg × L−1 for peritoneal fluid samples with a lower

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limit of quantification of 0.5 mg × L−1 [19, 24]. The mean intra- and interassay coefficients of variation were lower than 9.5 and 7.7 %, respectively. Before conducting the pharmacokinetic analysis, total platinum concentrations of each sample were transformed into oxaliplatin concentrations according to their molecular weights. Although the unbound oxaliplatin fraction is usually considered to be the active drug, the absence of proteins to which oxaliplatin can bind in the peritoneal fluid and the high correlation determined between unbound and total platinum plasma concentrations for oxaliplatin (r2 = 0.98) [27] justifies that total oxaliplatin concentrations in peritoneum and plasma were used to conduct this population pharmacokinetic analysis, similarly to what was recently reported in other publications in the same target population [19, 23]. Population pharmacokinetic analysis Software Nonlinear mixed-effects modeling using the first-order conditional estimation (FOCE) method implemented in NONMEM version 7.1.2. software package (ICON, Hanover, MD) [28] was used to conduct the model-based analysis and simulations. ADVAN 13 and the differential equations solver routine were used during the analysis. Compilations were achieved using gfortran compiler 4.6.2, for Windows Vista™ 64 bits. PsN 3.4.2 tool was used to conduct a stratified nonparametric bootstrap. Graphical and all other statistical analyses were performed using S-PLUS 6.1 Professional Edition (TIBCO Software Inc., Palo Alto, CA, USA). Structural model As a consequence of the carrier solute absorption, the volume of distribution in the peritoneum (Va) during the HIO administration was assumed to change according to a firstorder process characterized by kvol [29, 30]. At the beginning of the HIO administration, the volume of carrier solution instilled in the peritoneum (Vi) was assumed to be the oxaliplatin Va, as described in Eq. (1):

dVa = −kvol · Va ; dt

where Va (t = 0) = Vi

(1)

Oxaliplatin amount in peritoneal fluid (A) evidenced a monoexponential decay that was parameterized in terms of peritoneum to plasma clearance (Cla) and Va as follows:

Cla dA =− ·A dt Va

(2)

We assumed that only a fraction (F) of the oxaliplatin amount that disappears from the peritoneal fluid is

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absorbed. The F was estimated by simultaneously analyzing peritoneal concentrations after HIO administration with plasma concentrations obtained after IV and HIO administrations. Consequently, the rate and extent of HIO absorption in PC patients with CRS were determined by Cla/Va and F, respectively. The oxaliplatin disposition in plasma was characterized by an open two-compartment pharmacokinetic model [19, 24], parameterized in terms of systemic clearance (Cl), intercompartmental flow (Clp), central volume of distribution (Vc), and peripheral volume of distribution (Vp). Consequently, the time course of oxaliplatin amount in plasma (C) and peripheral (P) compartment was described by Eqs. (3) and (4) as follows:

Clp Clp Cla Cl dC = ·A·F− ·C− ·C+ ·P dt Va Vc Vc Vp

(3)

Clp Clp dP = ·C− ·P dt Vc Vp

(4)

Statistical model The interindividual (or between subjects) variability (IIV) in the pharmacokinetic model parameters was assumed to follow the log-normal distribution, and consequently, an exponential error model was used. However, an additive error model in the logit domain was used to constrain F to be between 0 and 1 at individual level. Residual variability in oxaliplatin peritoneal and plasma concentrations was evaluated using an additive error model after natural logarithmic transformation of the observations and model predictions. The magnitude of interindividual and residual variability was expressed approximately as a coefficient of variation. Model selection criteria The improvement of the fit obtained for each model was assessed by the likelihood ratio test for nested models, the reduction in the IIV and residual variability, the precision and the correlation in parameter estimates, and the examination of diagnostic plots and shrinkage [31]. Covariate analysis The covariates included in the analysis were carrier solution, age, body surface area, sex, creatinine clearance (calculated according to Cockcroft–Gault equation), liver metastases, PC index, and complete cytoreduction. The effect of selected covariates on model parameters was explored following the forward inclusion (p < 0.05) and backward elimination (p < 0.01) process as described

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elsewhere [32]. Dichotomous covariates were incorporated into the model as index variables, whereas continuous covariates were evaluated using power equations after centering on the median. Model qualification Nonparametric bootstrap stratified by cohort [33], normalized prediction distribution errors (NPDE) [34, 35], and visual predictive check (VPC) were employed to internally evaluate the pharmacokinetic model developed. VPCs are presented with three solid red lines displaying the 5th, 50th, and 95th percentiles of the observed values, and the associated shaded area represents the 95 % confidence interval (95 % CI) for the corresponding model-based predicted percentiles computed from 1000 Monte Carlo replicates obtained by simulating the design of the underlying dataset with the final model. Model‑based simulations Based on the model developed, deterministic simulations based on a standard HIO dose of 420 mg × m−2 were used to explore the effect of the HIO duration with respect to (1) the time course of the Va and oxaliplatin peritoneal concentration; (2) the amount of oxaliplatin disappeared from peritoneum and absorbed from peritoneum to plasma; and (3) the oxaliplatin plasma concentration profile and the area under the plasma concentration–time curve (AUC0−t). Results A descriptive statistics of the patient baseline characteristics stratified by cohort are shown in Table 1. Similar distribution of patient covariates and treatment characteristics was found across the three cohorts analyzed, except for albumin (p = 0.03). A total of 253 and 797 oxaliplatin concentrations from peritoneum and plasma, respectively, were available to characterize the rate and extent of oxaliplatin absorption in cancer patients with PC treated with HIO after CRS. After the IV administration in Cohort C patients, the mean (SD) of plasma Cmax was 3.79 (1.07) mg × L−1 and the oxaliplatin plasma concentrations decayed in a bi-exponential fashion, which suggested that a two-compartment pharmacokinetic model was suitable to describe oxaliplatin plasma disposition. After the HIO administration, the mean (SD) of peritoneum Cmax was 174 (40) and 267 (66) mg × L−1 for Cohorts A and B, respectively, which reflects the slight differences between the two cohorts with respect to the dose and the Vi (Table  1). In both cohorts, the oxaliplatin peritoneal concentrations showed a rapid, exponential decrease during the duration of the procedure, which supported the use of a linear

Cancer Chemother Pharmacol (2014) 73:1009–1020 Table 1  Patient and treatment characteristics at baseline stratified by cohort

* Continuous variables are expressed as mean (standard deviation), whereas categorical variables are expressed as percentage (%) †

  Creatinine clearance was calculated using the Cockroft– Gault’s formula, and values higher than 150 mL × min−1 were truncated to 150 mL × min−1

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Patient characteristics

Cohort A (N = 36)

Cohort B (N = 21)

Cohort C (N = 50)

Age (years) Body weight (kg) Body surface area (m2) Sex (%)  Male  Female ALT (IU × L−1) AST (IU × L−1) Alkaline phosphatase (IU × L−1) Total bilirubin (mg × dL−1) Serum albumin (g × L−1) Total protein (g × L−1) Creatinine clearance (mL × min−1)† Hemoglobin (g × dL−1) Leukocyte count (×109 L−1) Neutrophil (×109 L−1) Platelets (×109 L−1) Liver metastases  Yes (%)  No (%) Oxaliplatin dose (mg × m−2) Infusion duration (min) Volume carrier solution (L) Peritoneal carcinomatosis index Complete cytoreduction  Yes (%)  No (%) Number of concentrations  Peritoneum

58 (12) 69.3 (12.1) 1.7 (0.2)

58 (11) 69.8 (13.9) 1.8 (0.2)

62 (11) 71.1 (14.2) 1.8 (0.2)

38.9 61.1 34 (13) 31 (15) 100 (23) 0.6 (0.3) 43.7 (5.8) 66.9 (11.9) 80.5 (29.1) 12.1 (1.5) 7.7 (3.7) 4.9 (3.5) 290 (151)

33.3 66.7 32 (10) 26 (8) 105 (7) 0.5 (0.2) 43.3 (2.6) 71.2 (7.9) 83.0 (25.6) 12.1 (1.2) 8.3 (3.8) 5.3 (3.6) 287 (88)

56.0 44.0 36 (9) 33 (9) 105 (13) 0.5 (0.3) 35.6 (9.2) 72.0 (8.9) 74.0 (22.3) 12.1 (1.6) 8.2 (3.9) 5.5 (3.6) 335 (163)

13.9 86.1 364.5 (32.4) 37.6 (8.3) 3.9 (0.8) 12.3 (12.3)

9.5 90.5 410.9 (81.0) 32.4 (4.4) 3.7 (0.7) 10.4 (9.5)

12.0 84.0 60.9 (15.1) 90.0 (18) – –

72.2 27.8

95.2 4.8

– –

166

87

–

429

233

135

 Plasma

model to characterize the oxaliplatin disappearance from peritoneum and its absorption from peritoneum to plasma. The mean (SD) of plasma Cmax was 5.58 (1.79) and 6.14 (2.15) mg × L−1 for Cohort A and B, respectively, which was slightly smaller than the plasma Cmax reached after 2-h IV infusion of 130 mg × m−2 (labeled dose) [36] and suggested an incomplete oxaliplatin absorption. The population pharmacokinetic model described in methods characterized the peritoneum and plasma oxaliplatin concentration profiles from the three cohorts reasonably well. The volume of the carrier solution instilled in the peritoneum changed over the time because kvol was estimated to be 0.37 h−1, which was significantly different than 0 (ΔMVOF  = 55.557; df  = 1; p < 0.001). Furthermore, the type of carrier solution evaluated (dextrose 5 % vs. icodextrin 4 %) was associated with differences in kvol (ΔMVOF = 4.189; df = 1; p = 0.040). In fact, the ratio of dextrose 5 % to icodextrin 4 % kvol, φ, was estimated to be

1.76 (95 % CI 1.06–2.82). No significant effect of the carrier solution on Cla (ΔMVOF = 0.023; df = 1; p = 0.882) and F (ΔMVOF = 0.050; df = 1; p = 0.823) was found. Furthermore, within the range of values analyzed, the effect of age, body surface area, sex, creatinine clearance, liver metastases, PC index, and complete cytoreduction on pharmacokinetic model parameters was found to be negligible. The final parameter estimates of the population model characterizing the pharmacokinetics of oxaliplatin in peritoneum and plasma after HIO and IV administrations and the results of the nonparametric bootstrap analysis are presented in Table 2. Except for Vc, IIV was estimated for the model parameters and the shrinkage was lower than 37 % in Cohorts A and B, while was higher than 60 % in Cohort C due to the sparse sampling scheme implemented in this cohort. Although only 53 % of bootstrap replicates minimized successfully, there was <5 % difference in the mean parameter estimates obtained from successful and nonsuccessful

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Cancer Chemother Pharmacol (2014) 73:1009–1020

10.0

5.0

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Population Prediction, mg/L

0.5

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Population Prediction, mg/L

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Fig. 1  Goodness of fit plots for the oxaliplatin population pharmacokinetic model

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Normalized Prediction Distribution Error

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Oxaliplatin concentrations, mg/L

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0.5

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Normalized Prediction Distribution Error

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10.0

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Peritoneum

Cohort A Cohort B

0.6

0.8

1.0

Time, h

2

15.9–19.6

1

17.4 (11.7)

17.7 (12.1)

Oxaliplatin concentrations, mg/L

 σ

0

43.7–101.3 13.5–33.2 31.2–64.2 36.8–60.7 15.4–65.6 27.1–47.1

-1

64.7 (46.8) 22.6 (43.8) 47.4 (39.8) 48.6 (27.2) 40.4 (58.5) 36.7 (28.4)

-2

21.2–28.2 32.2–36.2

Normalized Prediction Distribution Error

24.6 (7.80) 33.9 (3.21)

24.6 (8.16) 33.9 (4.60) Vp (L) Interindividual variability (CV %) 67.7 (34.6)  ωkvol 24.1 (35.5)  ωCla 49.5 (34.3)  ωF 50.0 (54.7)  ωCl 40.1 (43.8)  ωClp 36.7 (58.2)  ωVp Residual variability (CV %)

2

0.91–1.19 9.69–12.1

1

1.05 (7.78) 10.8 (6.80)

0

1.03 (8.03) 10.8 (9.45)

-1

1.06–2.82 2.75–3.98 0.30–0.44

-2

0.19–0.64

1.73 (28.9) 3.35 (10.5) 0.37 (11.9)

Normalized Prediction Distribution Error

0.38 (33.9)

2

0.33 (31.2) 1.76 (29.2) 3.27 (6.03) 0.38 (7.81)

1

95 % CI

0

Mean (RSE)

-1

Estimate (RSE)

5.0

F Cl (L × h−1) Vc (L) Clp (L × h−1)

Nonparametric bootstrap

1.0

kvol (h−1) Φ Cla (L × h−1)

Original dataset

0.5

Model parameters

replicates; thus, the 95 % CI were computed from all bootstrap runs, regardless of the successful minimization, as previously suggested [37]. The precision of the parameter estimates was good with relative standard error (RSE) for fixed and random effects lower than 35 and 60 %, respectively. Figure 1 displays the goodness of fit plots for the population pharmacokinetic model describing the oxaliplatin peritoneal and plasma concentrations for the three cohorts analyzed. The observed versus model predicted plots did not show any trend that evidences model inadequacy. Similarly, the distribution of NPDE as a function of the population predictions and time showed a normal random scatter around 0, indicating the absence of significant bias or model misfit [34, 35]. Actually, the mean and standard deviation of the NPDE for peritoneal concentrations was 0.04 (95 % CI −0.16–0.10) and 1.06 (95 % CI 0.97–1.16), respectively, while the mean and standard deviation of the NPDE for plasma concentration was 0.04 (95 % CI −0.02 to 0.10) and 0.91 (95 % CI 0.88–0.98). These results confirm the model accuracy and precision because the mean and standard deviation of the NPDE for both peritoneal and plasma concentrations were very close to 0 and 1, respectively. The results of the VPC depicted in Fig. 2 evidence the model developed is appropriate to describe the time course

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Table 2  Parameter estimates (relative standard errors) and nonparametric bootstrap analysis of the oxaliplatin population pharmacokinetic model

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Peritoneum Concentrations, mg/L

Cohort A

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Peritoneum Concentrations, mg/L

Cohort B

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Time, h Plasma Concentrations, mg/L

Cohort

C

Time, h

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4 Time, h

6

8

Fig. 2  Visual predictive check stratified by cohort (solid red lines display the 5th, 50th, and 95th percentiles of the observed values, and the associated shaded area represents the 95 % confidence interval)

of peritoneal and plasma oxaliplatin concentrations and their associated variability in both cancer patients with solid tumors and PC patients after CRS.

The predicted time course of Va as a function of the HIO duration and the carrier solution used evidenced a different exponential decrease over time for dextrose 5 % and

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0.5

1.0

1.5

2.0

200 100

150

Oxaliplatin Dose = 700 mg, Vi = 4L, Icodextrin Oxaliplatin Dose = 700 mg, Vi = 4L, Dextrose

50

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0

Vi = 4L, Icodextrin 4% Vi = 4L, Dextrose 5%

Oxaliplatin Peritoneum Concentrations, mg/L

A

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Cancer Chemother Pharmacol (2014) 73:1009–1020

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Oxaliplatin Volume in Peritoneum, L

1016

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HIO Duration 0.5 h with Icodextrin 4% HIO Duration 0.5 h with Dextrose 5% HIO Duration 2 h with Icodextrin 4% HIO Duration 2 h with Dextrose 5%

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Oxaliplatin Plasma Concentrations, mg/L

Disappeared from Peritoneum, Icodextrin 4% Disappeared from Peritoneum, Dextrose 5% Absorbed from Peritoneum, Icodextrin 4% Absorbed from Peritoneum, Dextrose 5%

60

80

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100

Time, h

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Time, h

Fig. 3  Typical time course of the oxaliplatin peritoneal volume of distribution (a), oxaliplatin peritoneal concentration (b), relative amount of oxaliplatin dose disappeared from peritoneum and absorbed from peritoneum to plasma (c), and oxaliplatin plasma concentration (d)

icodextrin 4 % (Fig. 3a). While the Va following a HIO administration with icodextrin 4 % had a 15 and 48 % reduction after a HIO duration of 0.5 and 2 h, respectively, the Va following HIO administration with dextrose 5 % was reduced by 25 and 58 % after a HIO duration of 0.5 and 2 h, respectively. The changes of Va over time were translated into changes in oxaliplatin peritoneal concentrations, which initially were higher for HIO performed with dextrose 5 %, relative to icodextrin 4 %. In fact, after a 0.5 h of HIO, the peritoneal concentrations were reduced by a 24 and 17 % when administered with icodextrin 4 % and dextrose 5 %, respectively. However, after a 1.5 h of HIO duration, the oxaliplatin concentrations in peritoneum became similar (59 mg × L−1) for the two carrier solutions evaluated. Afterward, the oxaliplatin peritoneal concentrations became higher when icodextrin 4 % was used instead of dextrose 5 %. Actually, after 2 h of HIO administered with icodextrin 4 %, the oxaliplatin peritoneal concentration (26 mg × L−1) was approximately 30 % higher than the

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peritoneum concentration obtained when dextrose 5 % carrier solution was used (Fig. 3b). These results are a direct consequence of the changes on the oxaliplatin absorption rate due to the changes in Va. In this context, Fig. 3c shows the time course of the percentage of oxaliplatin dose disappeared from peritoneum, as well as the percentage of oxaliplatin dose absorbed from peritoneum to plasma, as a function of the HIO duration. After a HIO duration of 0.5 h, the percentage of oxaliplatin dose disappeared from peritoneum was 34 and 36 % for icodextrin 4 % and dextrose 5 %, respectively; while after 2 h of HIO, the percentage of oxaliplatin dose disappeared from peritoneum was 90 and 95 % for icodextrin 4 % and dextrose 5 %, respectively. Therefore, as the HIO duration gets prolonged, the percentage of oxaliplatin dose disappeared from peritoneum asymptotically tends to 100 %, regardless of the carrier solution used, while the percentage of oxaliplatin dose absorbed from peritoneum to plasma asymptotically tends to the estimate of the oxaliplatin absolute bioavailability,

Cancer Chemother Pharmacol (2014) 73:1009–1020

38 %. Figure 3d compares the plasma concentration–time profile for HIO durations of 0.5 and 2 h as a function of the carrier solution and suggests that extending the HIO duration with icodextrin 4 % from 0.5 to 2 h will result in a 25 and 251 % increase in plasma Cmax and AUC0−∞, respectively; if the HIO duration is prolonged from 0.5 to 2 h when dextrose 5 % carrier solution is used, a 29 and 253 % increase in plasma Cmax and AUC0−∞ will be observed. Discussion The oxaliplatin plasma pharmacokinetics after IV administration has previously been investigated in several studies [22, 38–40]. After the IV administration in Cohort C, the oxaliplatin (dose normalized) Cmax was consistent with the (dose normalized) Cmax observed in a previous study [36]. The oxaliplatin concentration–time profile was well described by an open two-compartment distribution model with nonspecific distribution to peripheral compartment and first-order elimination from the central compartment as reported elsewhere [22]. The steady-state volume of distribution (Vss) estimated to be 44.7 L was similar to 45.5 L previously reported [41]. The estimate of oxaliplatin Cl, 1.03 L × h−1, was consistent with the range of Cl values published (0.80–1.13 L × h−1) [42, 43]. The initial (t1/2α) and the terminal (t1/2β) disposition half-lives were estimated to be 0.23 and 30.8 h, respectively, which are slightly shorter than those values previously reported (0.46 and 39.4 h, respectively) under the coadministration of taxanes, which slightly prolongs the residence of oxaliplatin in systemic circulation [44]. The IIV in model parameters was also consistent with the values published in the literature [22, 41]. Furthermore, consistent with other publications, no effect of age, body surface area, sex, liver metastases, PC index, and complete cytoreduction on oxaliplatin pharmacokinetic parameters was found [19, 24]. Notably, no effect of creatinine clearance (Clcr) on oxaliplatin clearance was found in patients with normal to moderate renal function (Clcr > 45 mL × min−1). This finding is consistent with the results of other studies and reflected in the drug label, which indicates that starting oxaliplatin dose should only be reduced in patients with severe renal impairment (Clcr < 30 mL × min−1) [22, 45], where a 21 % reduction in oxaliplatin clearance is expected. Taken together, these findings confirm that the population pharmacokinetic model developed describes well the oxaliplatin plasma concentrations following IV administration and, consequently, justifies the use of the Cohort C as a reference IV cohort to estimate the oxaliplatin rate and extent of absorption following HIO administration. After correcting the differences in the oxaliplatin dose and Vi, the remainder difference in the peritoneal Cmax

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between the two carrier solutions evaluated is due to the difference in kvol, which determines the different oxaliplatin Va at the time the drug is dosed. Actually, Va was estimated to be 97 and 95 % of the Vi for icodextrin 4 % and dextrose 5 %, respectively (Fig. 3a, b). According to the three-pore model [46], the higher kvol for dextrose 5 %, relative to icodextrin 4 %, is probably due to the net absorption of the dextrose, since the peritoneal barrier allows the diffusion of low molecular weight solutes, such as dextrose, across “small” (radius ≈ 45 Å) and (protein permeable) “large” (radius  ≈ 250 Å) pores, which contribute substantially to induce the osmotic ultrafiltration through the “water-only” pores or aquaporins [47]. In this context, isotonic high molecular weight solutions, such as icodextrin, are able to maintain the intraperitoneal fluid volume longer because its diffusion only occurs through the “large” pores and does not induce the osmotic ultrafiltration. Since the volume of distribution in the peritoneal cavity changes over time according to a linear process characterized by a half-life of 2.10 h for patients treated with icodextrin 4 % and 1.19 h for patients treated with dextrose 5 %, the oxaliplatin elimination rate from peritoneum becomes time dependent. At the beginning of HIO administration, the oxaliplatin disappearance rate from peritoneum was estimated to be 0.84 and 0.86 h−1 for icodextrin 4 % and dextrose 5 %, respectively. After 0.5 and 2 h of HIO administration, the oxaliplatin disappearance rate from peritoneum increases by 33 and 217 % in patients receiving dextrose 5 %, while a 17 and 93 % increase is predicted in patients receiving icodextrin 4 %, respectively. In absence of IV data, the oxaliplatin disappearance from peritoneum is assumed to be equivalent to the oxaliplatin absorption from peritoneum to plasma and, consequently, the oxaliplatin disappearance rate from peritoneum estimated in the current analysis is consistent with the apparent oxaliplatin absorption rate reported in other HIO studies [23, 48, 49]. This assumption might hold for short (30 min), but not for long (2 h) infusion of 4 % icodextrin where the chloride concentration in 4 % icodextrin solutions (0.096 M) might alter the oxaliplatin molecule. The current population pharmacokinetic study design allowed us to characterize the extent of HIO absorption in PC patients treated with CRS for first time. The standard crossover design widely used for bioavailability studies could not be used in this particular case because the toxicity of HIPEC only warrants the administration of a single dose in cancer patients and, consequently, a parallel study design was used. The similarity of the patient characteristics at baseline across the three cohorts analyzed, and the lack of any significant association between patient characteristics and oxaliplatin pharmacokinetic parameters warrants the comparability of the pharmacokinetic parameters across the three cohorts evaluated and diminishes the risk of masking

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potential differences among them in the absence of randomization. By simultaneously analyzing the time course of oxaliplatin in peritoneum after HIO administration (Cohorts A and B) with the oxaliplatin plasma concentrations after IV (Cohort C) and HIO administration (Cohorts A and B), the extent of the oxaliplatin absorption during the HIO duration was determined to be 38.0 % (95 % CI 29.9–43.9 %). The HIO administration delivers very high local concentrations of oxaliplatin inside the abdominal cavity, which increases the oxaliplatin penetration in superficial local tissue, facilitates the oxaliplatin covalent binding into the tumor and normal cells, and may presumably be the determinant of the incomplete oxaliplatin absorption [17], given the total oxaliplatin is physically and chemically stable in the two carrier solutions evaluated [50, 51]. Furthermore, the extent of the oxaliplatin absorption determined in this analysis is equivalent to the HIO absolute bioavailability; however, since not all the oxaliplatin dose administered is available for absorption (because part of the dose is removed from the peritoneal cavity at the end of the HIO procedure), estimating the absolute bioavailability as the ratio of plasma AUC following HIO and IV administrations is misleading and should be avoided, especially for short HIO duration. In fact, deterministic simulations confirm that, for a given dose, the ratio of oxaliplatin plasma AUC following 0.5 h of HIO duration to oxaliplatin plasma AUC following IV administration is 0.135 and 0.142 for icodextrin 4 % and dextrose 5 %, respectively, while the ratio of oxaliplatin plasma AUC following 2 h of HIO duration to oxaliplatin plasma AUC following IV administration is 0.339 and 0.359 for icodextrin 4 % and dextrose 5 %, respectively. These findings also suggest that the small relative difference in oxaliplatin exposure between the two carrier solutions evaluated is not clinically relevant, which is consistent with previous modelbased pharmacokinetic and pharmacodynamic assessments for short HIO duration. In order to extend this conclusion to long HIO durations, additional clinical studies should be conducted to confirm or refute this finding [24, 52].

Conclusions In summary, a population model-based approach was used to determine the rate and extent of HIO absorption in PC patients treated with CRS. The oxaliplatin volume of distribution in peritoneum decreased over time as a consequence of the carrier solute absorption. The reduction was faster when HIO was administered in dextrose 5 %, relative to icodextrin 4 %. For 30 min of HIO duration, the rate of oxaliplatin absorption ranges from 0.84 to 1.57 h−1 for dextrose 4 % and from 0.86 to 2.59 h−1 for icodextrin 4 %. In addition, the extent of HIO absorption (absolute bioavailability) was determined to be 38 %, regardless of the carrier

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solution. These findings confirm that the relatively small difference in peritoneum and plasma oxaliplatin exposure between the two carrier solutions evaluated is not likely to be clinically relevant because no major differences in toxicity were observed. Acknowledgments The authors would like to thank the patients and their families, as well as the medical, nursing, and laboratory staff of the Hospital Quirón Torrevieja who participated in the present study. This work was supported by Consellería de Sanidad of Comunidad Valenciana. Grant GE-079/11. Conflict of interest  Carlos Pérez-Ruixo, José E. Peris, Vanesa Escudero-Ortiz, Pedro Bretcha-Boix, José Farré-Alegre, Juan José Pérez-Ruixo, and Belén Valenzuela have indicated no potential conflicts of interest, other than those reflected in their affiliations. Consulting Projects for Research provides consulting services to Hospital Quiron Torrevieja.

References 1. Ceelen WP (2013) Current management of peritoneal carcinomatosis from colorectal cancer. Minerva Chir 68:77–86 2. Newman NA, Votanopoulos KL, Stewart JH, Shen P, Levine EA (2012) Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for colorectal cancer. Minerva Chir 67:309–318 3. Sugarbaker PH, Ryan DP (2012) Cytoreductive surgery plus hyperthermic perioperative chemotherapy to treat peritoneal metastases from colorectal cancer: standard of care or an experimental approach? Lancet Oncol 13:362–369 4. Helm CW (2012) Current status and future directions of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in the treatment of ovarian cancer. Surg Oncol Clin N Am 21:645–663 5. Mulier S, Claes JP, Dierieck V, Amiel JO, Pahaut JP, Marcelis L, Bastin F, Vanderbeeken D, Finet C, Cran S, Velu T (2012) Survival benefit of adding hyperthermic intraperitoneal chemotherapy (HIPEC) at the different time-points of treatment of ovarian cancer: review of evidence. Curr Pharm Des 18:3793–3803 6. Dovern E, de Hingh IH, Verwaal VJ, van Driel WJ, Nienhuijs SW (2010) Hyperthermic intraperitoneal chemotherapy added to the treatment of ovarian cancer. A review of achieved results and complications. Eur J Gynaecol Oncol 31:256–261 7. Wu XJ, Yuan P, Li ZY, Bu ZD, Zhang LH, Wu AW, Zong XL, Li SX, Shan F, Ji X, Ren H, Ji JF (2013) Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy improves the survival of gastric cancer patients with ovarian metastasis and peritoneal dissemination. Tumour Biol 34:463–469 8. Ströhlein MA, Bulian DR, Heiss MM (2011) Clinical efficacy of cytoreductive surgery and hyperthermic chemotherapy in peritoneal carcinomatosis from gastric cancer. Expert Rev Anticancer Ther 11:1505–1508 9. Chua TC, Moran BJ, Sugarbaker PH, Levine EA, Glehen O, Gilly FN, Baratti D, Deraco M, Elias D, Sardi A, Liauw W, Yan TD, Barrios P, Gómez Portilla A, de Hingh IH, Ceelen WP, Pelz JO, Piso P, González-Moreno S, Van Der Speeten K, Morris DL (2012) Early- and long-term outcome data of patients with pseudomyxoma peritonei from appendiceal origin treated by a strategy of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. J Clin Oncol 3:2449–2456 10. Cioppa T, Vaira M, Bing C, D’Amico S, Bruscino A, De Simone M (2008) Cytoreduction and hyperthermic intraperitoneal

Cancer Chemother Pharmacol (2014) 73:1009–1020 chemotherapy in the treatment of peritoneal carcinomatosis from pseudomyxoma peritonei. World J Gastroenterol 14:6817–6823 11. Yan TD, Deraco M, Baratti D, Kusamura S, Elias D, Glehen O, Gilly FN, Levine EA, Shen P, Mohamed F, Moran BJ, Morris DL, Chua TC, Piso P, Sugarbaker PH (2009) Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for malignant peritoneal mesothelioma: multi-institutional experience. J Clin Oncol 27:6237–6242 12. Baratti D, Kusamura S, Cabras AD, Bertulli R, Hutanu I, Deraco M (2013) Diffuse malignant peritoneal mesothelioma: long-term survival with complete cytoreductive surgery followed by hyperthermic intraperitoneal chemotherapy (HIPEC). Eur J Cancer 49:3140–3148 13. Verwaal VJ, van Ruth S, de Bree E, van Sloothen GW, van Tinteren H, Boot H, Zoetmulder FA (2003) Randomized trial of cytoreduction and hyperthermic intraperitoneal chemotherapy versus systemic chemotherapy and palliative surgery in patients with peritoneal carcinomatosis of colorectal cancer. J Clin Oncol 21:3737–3743 14. Yang XJ, Huang CQ, Suo T, Mei LJ, Yang GL, Cheng FL, Zhou YF, Xiong B, Yonemura Y, Li Y (2011) Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy improves survival of patients with peritoneal carcinomatosis from gastric cancer: final results of a phase III randomized clinical trial. Ann Surg Oncol 18:1575–1581 15. Cao C, Yan TD, Black D, Morris DL (2009) A systematic review and meta-analysis of cytoreductive surgery with perioperative intraperitoneal chemotherapy for peritoneal carcinomatosis of colorectal origin. Ann Surg Oncol 16:2152–2165 16. Ung L, Chua TC, Morris DL (2013) Cure for peritoneal metastases? An evidence-based review. ANZ J Surg 83:821–826 17. Elias D, Bonnay M, Puizillou JM, Antoun S, Demirdjian S, El OA, Pignon JP, Drouard-Troalen L, Ouellet JF, Ducreux M (2002) Heated intraoperative intraperitoneal oxaliplatin after complete resection of peritoneal carcinomatosis: pharmacokinetics and tissue distribution. Ann Oncol 13:267–272 18. Atallah D, Marsaud V, Radanyi C, Kornprobst M, Rouzier R, Elias D, Renoir JM (2004) Thermal enhancement of oxaliplatininduced inhibition of cell proliferation and cell cycle progression in human carcinoma cell lines. Int J Hyperth 20:405–419 19. Valenzuela B, Nalda-Molina R, Bretcha-Boix P, Escudero-Ortíz V, Duart MJ, Carbonell V, Sureda M, Rebollo JP, Farré J, Brugarolas A, Pérez-Ruixo JJ (2011) Pharmacokinetic and pharmacodynamic analysis of hyperthermic intraperitoneal oxaliplatininduced neutropenia in subjects with peritoneal carcinomatosis. AAPS J 13:72–82 20. Culy CR, Clemett D, Wiseman LR (2000) Oxaliplatin. A review of its pharmacological properties and clinical efficacy in metastatic colorectal cancer and its potential in other malignancies. Drugs 60:895–924 21. Elias D, Sideris L (2003) Pharmacokinetics of heated intraoperative intraperitoneal oxaliplatin after complete resection of peritoneal carcinomatosis. Surg Oncol Clin N Am 12:755–769 22. Massari C, Brienza S, Rotarski M, Gastiaburu J, Misset JL, Cupissol D, Alafaci E, Dutertre-Catella H, Bastian G (2000) Pharmacokinetics of oxaliplatin in patients with normal versus impaired renal function. Cancer Chemother Pharmacol 45:157–164 23. Ferron G, Dattez S, Gladieff L, Delord JP, Pierre S, Lafont T, Lochon I, Chatelut E (2008) Pharmacokinetics of heated intraperitoneal oxaliplatin. Cancer Chemother Pharmacol 62:679–683 24. Pérez-Ruixo C, Valenzuela B, Peris JE, Bretcha-Boix P, Escudero-Ortiz V, Farré-Alegre J, Pérez-Ruixo JJ (2013) Population pharmacokinetics of hyperthermic intraperitoneal oxaliplatin in patients with peritoneal carcinomatosis after cytoreductive surgery. Cancer Chemother Pharmacol 71:693–704

1019 25. Mahteme H, Wallin I, Glimelius B, Påhlman L, Ehrsson H (2008) Systemic exposure of the parent drug oxaliplatin during hyperthermic intraperitoneal perfusion. Eur J Clin Pharmacol 64:907–911 26. Mohamed F, Sugarbaker PH (2003) Carrier solutions for intraperitoneal chemotherapy. Surg Oncol Clin N Am 12:813–824 27. Brouwers EE, Huitema AD, Beijnen JH, Schellens JH (2008) Long-term platinum retention after treatment with cisplatin and oxaliplatin. BMC Clin Pharmacol 17(8):7 28. Beal SL, Sheiner LB, Boeckman AJ (eds) (1989–2006) NONMEM users guides. ICON Development Solutions, Ellicott City 29. Lee PR, Code CF, Scholer JF (1955) The influence of varying concentrations of sodium chloride on the rate of absorption of water from the stomach and small bowel of human beings. Gastroenterology 29:1008–1016 30. Love AH, Mitchell TG, Phillips RA (1968) Water and sodium absorption in the human intestine. J Physiol 195:133–140 31. Savic RM, Karlsson MO (2009) Importance of shrinkage in empirical Bayes estimates for diagnostics: problems and solutions. AAPS J 11:558–569 32. Mandema JW, Verotta D, Sheiner LB (1992) Building population pharmacokinetic–pharmacodynamic models. I: models for covariate effects. J Pharmacokinet Biopharm 20:511–528 33. Efron B, Tibshirani R (1993) An introduction to the bootstrap. Chapman and Hall/CRC Press, London 34. Brendel K, Comets E, Laffont C, Laveille C, Mentré F (2006) Metrics for external model evaluation with an application to the population pharmacokinetics of gliclazide. Pharm Res 23:2036–2049 35. Nguyen TH, Comets E, Mentré F (2012) Extension of NPDE for evaluation of nonlinear mixed effect models in presence of data below the quantification limit with applications to HIV dynamic model. J Pharmacokinet Pharmacodyn 39:499–518 36. Graham MA, Lockwood GF, Greenslade D, Brienza S, Bayssas M, Gamelin E (2000) Clinical pharmacokinetics of oxaliplatin: a critical review. Clin Cancer Res 6:1205–1218 37. Matthews I, Kirkpatrick C, Holford N (2004) Quantitative justification for target concentration intervention–parameter variability and predictive performance using population pharmacokinetic models for aminoglycosides. Br J Clin Pharmacol 58:8–19 38. Bastian G (1994) Report on the pharmacokinetic of oxaliplatin in patients with normal and impaired renal function. Ann Oncol 5:126 39. Kochi M, Fujii M, Kanamori N, Kaiga T, Okubo R, Mihara Y, Takayama T (2011) Pharmacokinetics of oxaliplatin in gastrointestinal cancer patients with malignant ascites. J Chemother 23:28–31 40. Burz C, Berindan-Neagoe IB, Balacescu O, Tanaselia C, Ursu M, Gog A, Vlase L, Chintoanu M, Balacescu L, Leucuta SE, Irimie A, Cristea V (2009) Clinical and pharmacokinetics study of oxaliplatin in colon cancer patients. J Gastrointest Liver Dis 18:39–43 41. Bekaii-Saab TS, Liu J, Chan KK, Balcerzak SP, Ivy PS, Grever MR, Kraut EH (2008) A phase I and pharmacokinetic study of weekly oxaliplatin followed by paclitaxel in patients with solid tumors. Clin Cancer Res 14:3434–3440 42. Graham MA, Gamelin E, Misset JL, Brienza S, Allain P, Boisdron-Celle M, Krikorian A, Greenslade D, Bayssas M (1998) Clinical pharmacokinetics of oxaliplatin. Proc Am Assoc Cancer Res 39:159 43. Allen J, Graham MA, Firth J, Woolfrey S, Greenslade D, Morrison JG, McDougall S, Ross P, Cunningham D (1998) Biotransformation and pharmacokinetic analysis of oxaliplatin in patients with advanced gastrointestinal cancer. Proc Am Assoc Cancer Res 39:159 44. Schuette W, Blankenburg T, Guschall W, Dittrich I, Schroeder M, Schweisfurth H, Chemaissani A, Schumann C, Dickgreber N,

13

1020 Appel T, Ukena D (2006) Multicenter randomized trial for stage IIIB/IV non-small cell lung cancer using every-3-week versus weekly paclitaxel/carboplatin. Clin Lung Cancer 7:338–343 45. Takimoto CH, Remick SC, Sharma S, Mani S, Ramanathan RK, Doroshow J, Hamilton A, Mulkerin D, Graham M, Lockwood GF, Ivy P, Egorin M, Schuler B, Greenslade D, Goetz A, Knight R, Thomas R, Monahan BP, Dahut W, Grem JL (2003) Dose-escalating and pharmacological study of oxaliplatin in adult cancer patients with impaired renal function: a National Cancer Institute Organ Dysfunction Working Group Study. J Clin Oncol 21:2664–2672 46. Rippe B, Stelin G (1989) Simulation of peritoneal solute transport during continuous ambulatory peritoneal dialysis (CAPD). Application of two-pore formalism. Kidney Int 35:1234–1244 47. Rippe B, Davies S (2011) Permeability of peritoneal and glomerular capillaries: What are the differences according to the pore theory? Perit Dial Int 31:249–258 48. Elias D, Raynard B, Bonnay M, Pocard M (2006) Heated intraoperative intraperitoneal oxaliplatin alone and in combination with intraperitoneal irinotecan: pharmacologic studies. Eur J Surg Oncol 32:607–613

13

Cancer Chemother Pharmacol (2014) 73:1009–1020 49. Stewart JH IV, Shen P, Russell G, Fenstermaker J, McWilliams L, Coldrun FM, Levine KE, Jones BT, Levine EA (2008) A phase I trial of oxaliplatin for intraperitoneal hyperthermic chemoperfusion for the treatment of peritoneal surface dissemination from colorectal and appendiceal cancers. Ann Surg Oncol 15:2137–2145 50. Elias D, Lefevre JH, Chevalier J, Brouquet A, Marchal F, Classe JM, Ferron G, Guilloit JM, Meeus P, Goéré D, Bonastre J (2009) Complete cytoreductive surgery plus intraperitoneal chemo hyperthermia with oxaliplatin for peritoneal carcinomatosis of colorectal origin. J Clin Oncol 27:681–685 51. Escudero-Ortiz V, Duart-Duart MJ, Pérez-Ruixo C, Valenzuela B, Pérez-Ruixo JJ (2014) Stability analysis of intraperitoneal administration of oxaliplatin and doxorubicin with hyperthermia. Farm Hosp (accepted) 52. Pérez-Ruixo C, Valenzuela B, Peris JE, Bretcha-Boix P, Escudero-Ortiz V, Farré-Alegre J, Pérez-Ruixo JJ (2013) Neutrophil dynamics in peritoneal carcinomatosis patients treated with cytoreductive surgery and hyperthermic intraperitoneal oxaliplatin. Clin Pharmacokinet 52:1111–1125