Population Pharmacokinetics and ...

Cancer Therapy: Clinical

Population Pharmacokinetics and Pharmacodynamics of Paclitaxel and Carboplatin in Ovarian Cancer Patients: A Study by the European Organization for Research and Treatment of Cancer-Pharmacology and Molecular Mechanisms Group and New Drug Development Group Markus Joerger,1,2 Alwin D.R. Huitema,1 Dick J. Richel,4 Christian Dittrich,5 Nikolas Pavlidis,6 Evangelos Briasoulis,6 Jan B.Vermorken,7 Elena Strocchi,8 Andrea Martoni,9 Roberto Sorio,10 Henk P. Sleeboom,11 Miguel A. Izquierdo,12 Duncan I. Jodrell,13 Hilary Calvert,14 AlanV. Boddy,14 Harry Hollema,15 Regine Fe¤ty,16 Wjf J.F.Van derVijgh,3 Georg Hempel,17 Etienne Chatelut,18 Mats Karlsson,19 Justin Wilkins,19 BrigitteTranchand,20,21,22 Ad H.G.J. Schrijvers,23 Christian Twelves,24 Jos H. Beijnen,1,2,25 and Jan H.M. Schellens2,25

Abstract

Purpose: Paclitaxel and carboplatin are frequently used in advanced ovarian cancer following cytoreductive surgery. Threshold models have been used to predict paclitaxel pharmacokineticpharmacodynamics, whereas the time above paclitaxel plasma concentration of 0.05 to 0.2 Amol/L (t C > 0.05-0.2) predicts neutropenia.The objective of this study was to build a population pharmacokinetic-pharmacodynamic model of paclitaxel/carboplatin in ovarian cancer patients. Experimental Design: One hundred thirty-nine ovarian cancer patients received paclitaxel (175 mg/m 2) over 3 h followed by carboplatin area under the concentration-time curve 5 mg/mL*min over 30 min. Plasma concentration-time data were measured, and data were processed using nonlinear mixed-effect modeling. Semiphysiologic models with linear or sigmoidal maximum response and threshold models were adapted to the data. Results: One hundred five patients had complete pharmacokinetic and toxicity data. In 34 patients with measurable disease, objective response rate was 76%. Neutrophil and thrombocyte counts were adequately described by an inhibitory linear response model. Paclitaxel t C > 0.05 was significantly higher in patients with a complete (91.8 h) or partial (76.3 h) response compared with patients with progressive disease (31.5 h; P = 0.02 and 0.05, respectively). Patients with paclitaxel t C > 0.05 > 61.4 h (mean value) had a longer time to disease progression compared with patients with paclitaxel t C > 0.05 < 61.4 h (89.0 versus 61.9 weeks; P = 0.05). Paclitaxel t C > 0.05 was a good predictor for severe neutropenia (P = 0.01), whereas carboplatin exposure (C max and area under the concentration-time curve) was the best predictor for thrombocytopenia (P < 10-4). Conclusions: In this group of patients, paclitaxel t C > 0.05 is a good predictive marker for severe neutropenia and clinical outcome, whereas carboplatin exposure is a good predictive marker for thrombocytopenia.

Authors’ Affiliations: 1Department of Pharmacy and Pharmacology, Slotervaart Hospital/The Netherlands Cancer Institute; 2Department of Medical Oncology, Antoni van Leeuwenhoek Hospital/The Netherlands Cancer Institute; 3 Free University Medical Center, Amsterdam, the Netherlands; 4Medical Spectrum Twente, Enschede, the Netherlands; 5LBI-ACR VIEnna and ACR-ITR VIEnna, KFJSpital,Vienna, Austria; 6Ioannina University Hospital, Ioannina, Greece; 7University Hospital Antwerp, Edegem, Belgium; 8Universita di Bologna; 9Policlinico S. OrsolaMalpighi, Bologna, Italy; 10National Cancer Institute, Aviano, Italy; 11Leyenburg Hospital, Den Haag, the Netherlands; 12Catalan Institute of Oncology, Barcelona, Spain; 13 University of Edinburgh, Edinburgh, United Kingdom; 14 Newcastle University, Newcastle upon Tyne, United Kingdom; 15University Medical Center, Groningen, the Netherlands; 16Centre R Gauducheau, Saint Herblain, France; 17 University of Mu«nster, Mu«nster, Germany; 18Centre Claudius Regaud, Toulouse, France; 19 Uppsala University, Uppsala, Sweden; 20 Ctr Leon Berard; 21Lyon University, Lyon, France; 22EA3738, CTO, Faculty of Medicine Lyon Sud, Oullins,

Clin Cancer Res 2007;13(21) November 1, 2007

France; 23European Organization for Research and Treatment of Cancer-New Drug Development Group, Brussels, Belgium; 24University of Leeds, Bradford NHS Trust and Beatson Oncology Centre, Glasgow, United Kingdom; and 25Division of Drug Toxicology, Department of Biomedical Analysis, Faculty of Pharmaceutical Sciences, Utrecht University, Utrecht, the Netherlands Received 1/11/07; revised 5/11/07; accepted 7/17/07. 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. Requests for reprints: Markus Joerger, Department of Medical Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands. Phone: 31-205129111; Fax : 31-204443920; E-mail: markus. joerger@ kssg.ch. F 2007 American Association for Cancer Research. doi:10.1158/1078-0432.CCR-07-0064

6410

www.aacrjournals.org

Downloaded from clincancerres.aacrjournals.org on September 13, 2015. © 2007 American Association for Cancer Research.

Paclitaxel and Carboplatin in Ovarian Cancer Patients

Ovarian cancer is still the most common cause of death from gynecologic cancer in the Western world. The combination of paclitaxel and carboplatin is seen as standard treatment for advanced ovarian cancer based mainly on three studies showing that paclitaxel plus carboplatin is equally effective to paclitaxel plus cisplatin with a superior safety profile and response rates of roughly two thirds in patients with measurable disease (1 – 3). Most patients with advanced ovarian cancer achieve a clinical complete remission following cytoreductive surgery and chemotherapy with paclitaxel and carboplatin. The same combination has also proven to be the most effective treatment regimen for late relapses of ovarian cancer (i.e., in patients who progress z6 months after completion of upfront therapy). Small-to-moderate gains in progression-free and overall survival were achieved with the paclitaxel/carboplatin combination therapy as opposed to carboplatin monotherapy in patients with late (z6 months) tumor relapses (4). Accordingly, the combination of a 3-h infusion of paclitaxel (175 mg/m2) followed by carboplatin area under the concentration-time curve (AUC) 5 mg/mL*min has been used as the control arm in clinical studies of first-line (5) and second-line treatment of platinum-sensitive or late relapses of ovarian cancer (6). Single-agent paclitaxel showed overall response rates of 28% in platinum-pretreated patients with advanced ovarian cancer (7). Paclitaxel is known for its nonlinear pharmacokinetics (8 – 11), and population pharmacokinetic models have mostly implemented saturable elimination and distribution to peripheral compartments (12 – 14). Carboplatin has less nonhematologic toxicity than cisplatin, and most randomized trials have reported comparable activity between cisplatin and carboplatin in chemotherapy-naive patients with advanced ovarian cancer (15). The exposure toxicity relationship of paclitaxel has been described by threshold models, whereas the time above a paclitaxel plasma concentration of between 0.05 and 0.2 Amol/L was correlated with hematologic toxicity (8, 12, 16 – 18). Two of these trials studied single-agent paclitaxel in patients with advanced ovarian cancer (8, 16). The study of Gianni et al. (8) studied 30 patients with relapsed ovarian or breast cancer and found a correlation between neutropenia and the duration that paclitaxel plasma concentration was z0.05 Amol/L, a relationship that was well described by a sigmoid maximum response (E max) model. In the study of Huizing et al. (16), the duration of paclitaxel plasma concentration z0.1 Amol/L (t C > 0.1) was correlated with neutropenia and leucopenia, suggesting that myelosuppression could be predicted by measuring the duration of paclitaxel plasma concentration z0.1 Amol/L. The combination of paclitaxel and carboplatin has been studied for its pharmacokinetic-pharmacodynamic relationship in patients with advanced non – small cell lung cancer, where a paclitaxel plasma concentration >0.1 Amol/L for more than 15 h was correlated with improved overall survival (19). In ovarian cancer, limited data suggest the absence of a pharmacokinetic interaction between paclitaxel and carboplatin (20), but there is a well-known pharmacodynamic interaction resulting in a platelet-sparing effect of paclitaxel in combination with carboplatin as first-line treatment (21, 22). However, studies implementing combined pharmacokinetic-pharmacodynamic assessment of the drug combination in an extended group of ovarian cancer patients have not been done to our knowledge. www.aacrjournals.org

Besides threshold models as used by Gianni et al. (8) and Huizing et al. (17, 19), more physiology-based modeling approaches have been adapted recently. Friberg et al. (23) described a semimechanistic (pharmacokinetic-pharmacodynamic) model of paclitaxel-induced myelosuppression by using nonlinear mixed-effects modeling. The semimechanistic modeling approach typically uses drug-related and system (patient)-related variables and is capable to explain and predict both the degree and duration of hematologic toxicity. Such more physiology-based models are often preferred because they generally are more predictive, with variables that refer to actual processes and conditions (23). The present study was initiated to build a population pharmacokineticpharmacodynamic model of paclitaxel and carboplatin in ovarian cancer patients and to quantitatively assess the relationship between pharmacokinetic, hematologic toxicity, and treatment response.

Materials and Methods Patient population, blood sampling, and bioanalysis. Twelve study centers participated in the trial (Appendix). All centers had approval from the local Medical Ethics Committee. Written informed consent was obtained from all patients. One hundred thirty-nine female patients with ovarian cancer were recruited between 1998 and 2001. Inclusion criteria for study participation included histologically or cytologically verified epithelial ovarian cancer, patients with microscopic local, locally advanced or metastatic disease, performance status (WHO scale) V2, life expectancy z3 months, absolute neutrophil count (ANC) z1,500/AL, platelets z100,000 AL, age z18, creatinine clearance z40 mL/min, serum bilirubin V26 Amol/L (1.5 mg/dL), and alanine aminotransferase and aspartate aminotransferase V2 the upper limit of normal (unless related to liver metastases, then aspartate aminotransferase and alanine aminotransferase may be 5 the upper limit of normal), and a minimum of 4 weeks (8 weeks in case of extensive prior radiotherapy) must have elapsed between the end of the prior radiotherapy and entry into the protocol. Patients may be premenopausal or postmenopausal. Patients may (but do not necessarily) have unidimensionally or bidimensionally measurable lesions. Patients must be able and willing to undergo pharmacokinetic analysis. Patients are excluded in case of prior chemotherapy for adjuvant or advanced disease; symptomatic brain and/or leptomeningeal disease; previous or current malignancies at other sites (with exception of adequately treated in situ carcinoma of the cervix uteri and basal or squamous cell carcinoma of the skin); active uncontrolled infection; women with childbearing potential not practicing adequate contraception, pregnancy, or lactation; and active clinically significant and/or treatment requiring cardiac arrhythmias and/or congestive heart failure. It was anticipated to include 150 patients in this trial. However, this was not based on a formal sample size calculation because several factors were uncertain a priori (e.g., the number of patients with evaluable disease). Furthermore, the number of patients was based on a reasonable estimate of the patient accrual per center in the study period. All patients received Cremophor EL – formulated paclitaxel (175 mg/m2) i.v. over 3 h immediately followed by a 30-min infusion of carboplatin AUC 5 mg/mL*min, with the initial dose calculated according to the method described by Calvert et al. (24), in which glomerular filtration rate was calculated using the Cockroft-Gault formula. This dose remained fixed for all cycles, unless toxicity necessitated any dose reduction. Standard premedication was administered, including 20 mg dexamethasone orally at 12 and 6 h before paclitaxel, 2 mg clemastine i.v., and a H2 receptor antagonist 30 min before paclitaxel, to prevent hypersensitivity reactions. Antiemetics were used according to local guidelines (metoclopramide, ondansetron, or granisetron). Cycles were

6411



Cancer Therapy: Clinical repeated at three-weekly intervals, and routine weekly hematologic assessments were done, including hemoglobin, leucocyte count, ANC, lymphocyte count, and thrombocyte count (PLT). Pharmacokinetic analysis was done during the first cycle of paclitaxel and carboplatin treatment. The samples for paclitaxel analysis were collected in heparinized tubes. The blood samples for paclitaxel were taken before the start of the infusion, at 1.5 h after the start, at the end of the infusion, and at 45 min and 2, 6, 9, 12, and 24 h after the end of the infusion. Whole blood was centrifuged immediately after withdrawal for 5 min (3,000 rpm, 4jC), and the plasma fraction was stored at -20jC until analysis. The plasma concentrations of paclitaxel were determined by a validated isocratic high-performance liquid chromatographic method with solid-phase extraction as the sample pretreatment procedure as described previously (17). The quantitation range of the high-performance liquid chromatographic method was 10 to 10,000 ng/mL (11.7-11,710 nmol/L). Within-day imprecision for paclitaxel was between 1.2% and 8.5% and accuracy was >95%. Bioanalysis of paclitaxel was done in European Organization for Research and Treatment of Cancer-Pharmacology and Molecular Mechanisms centers (see Appendix). The blood samples for carboplatin were taken before the start of the infusion, at the end of the infusion, and at 2, 5, and 9 h after the start of the infusion. Whole blood samples were collected in 5 mL heparin-containing tubes and centrifuged immediately after withdrawal for 5 min (3,000 rpm, 4jC). Plasma ultrafiltrate (pUF) was obtained by centrifuging the plasma fraction through a 30-kDa cutoff ultrafiltrate filter (Centriplus YM-30, Millipore Corp.) for 15 min (3,000 rpm, 20jC). The preparation of pUF from plasma was done immediately after blood collection to prevent the decrease of free carboplatin levels due to ex vivo binding of carboplatin to plasma proteins and erythrocytes. All samples were stored at -20jC until analysis. Carboplatin analysis was also done in European Organization for Research and Treatment of Cancer-Pharmacology and Molecular Mechanisms centers (see Appendix) according to a previously described atomic absorption spectroscopy assay (25). Bioanalysis of paclitaxel and carboplatin took place after extensive cross-validation of all involved centers. This was a two-step process. At first, all participating centers had to send their validation report of the assay to the coordinator of the bioanalytic steering committee (J.H.B.), who reviewed the reports according to international standards (19). Second, when the report of a site was considered appropriate, five blinded samples containing two blanks and three samples with spiked concentrations of carboplatin and paclitaxel were sent to the participating bioanalytic centers. The spiked samples contained concentrations in the lower quartile, in the middle, and in the upper quartile of the calibration curve of the respective assays. For paclitaxel, the concentrations were in the range of 20 to 10,000 Ag/L (23.4-11,710 nmol/L) and, for carboplatin, in the range of 556 to 5,568 Ag/L (1.5-15 Amol/L). The centers had to achieve the minimal acceptance levels for successful validation of their assay, which means that the deviations from the nominal value had to be 0.1/t C > 0.05 and objective tumor response, time to disease progression (TTP), and hematologic toxicity as assessed by common toxicity grading. Paclitaxel and carboplatin C max and AUC were similarly analyzed for their relation with objective tumor response and hematologic toxicity.


Results Patient population and treatment. From the 139 included patients, 1 patient received 1 paclitaxel/carboplatin cycle, 6 patients received 2 cycles, 3 patients received each 3, 4, and 5 cycles, 106 patients received 6 cycles, 6 patients received 7 cycles, 7 patients received 8 cycles, 1 patient received 9 cycles, and 3 patients received 10 cycles. A total of 104 patients had complete pharmacokinetic and toxicity data to be included into pharmacokinetic analysis. The remaining 35 patients had either incomplete pharmacokinetic assessments (including 4 patients with allergic reactions to paclitaxel, in whom paclitaxel infusion was stopped or paused) or incomplete hematologic assessments. From these 104 patients, 34 had measurable disease at the time of study treatment and 70 had nonevaluable disease. From 34 patients with measurable disease, 17 had a complete response, 9 had a partial response, and 2 had stable disease and 6 were patients with progressive disease, for an overall response rate of 76%. All 139 patients had surgical debulking of ovarian cancer, with gross residual disease in 48 patients, microscopic malignant disease in 82 patients, unknown disease status in 2 patients, and no tumor residuals in 7 patients. Patient characteristics were as follows: median age, 54 years (23.7-79.4); median weight, 59 kg (30.5-93); median serum albumin, 41 g/L (24-47); total bilirubin ( 0.1 was 17.8 h and, in patients with progressive disease, 14.0 h (Table 4). t C > 0.1 was not statistically higher in patients with at

6414




Fig. 1. Typical curves of neutrophil count (A) and thrombocyte counts (B) after administration of paclitaxel/carboplatin combination chemotherapy. Dashed lines, 25% and 75% percentiles.

least stable disease compared with patients with progressive disease (18.3 versus 14.0 h; P = 0.08). Mean t C > 0.05 was 61.4 h. Patients with a complete remission had a significantly higher t C > 0.05 compared with patients with progressive disease (91.9 versus 31.5 h; P = 0.02) as had patients with at least

stable disease compared with patients with progressive disease (78.3 versus 31.5 h; P = 0.05). No statistically significant differences were found between patients with at least stable disease compared with patients with progressive disease for paclitaxel and carboplatin exposure as assessed by C max and AUC (Table 4). As expected, TTP was longer in patients with at least stable disease compared with patients with progressive disease under paclitaxel/carboplatin treatment (71.6 versus 35.0 weeks; P = 0.04). t C > 0.1 was not correlated to TTP as assessed by Pearson correlation analysis (r = 0.04; P = 0.83), and patients with t C > 0.1 > 16.4 h had a TTP comparable with patients with t C > 0.1 < 16.4 h (73.1 versus 67.3 weeks; P = 0.66). t C > 0.05 was significantly correlated with TTP (r = 0.36; P = 0.03), and patients with t C > 0.05 above the mean of 61.4 h had a significantly higher TTP compared with patients with t C > 0.05 < 61.4 h (89.0 versus 61.9 weeks; P = 0.05). For hematologic toxicity, no significant difference was found for the grade of neutropenia or thrombocytopenia and exposure to paclitaxel as assessed by t C > 0.1, C max, or AUC. t C > 0.05 was significantly higher in patients with severe neutropenia (grade 3/4) compared with patients with absent or mild neutropenia (grade 1/2; 74.1 versus 50.3 h; P = 0.02), and t C > 0.05 was significantly higher in patients with any thrombocytopenia compared with patients without thrombocytopenia (82.2 versus 53.8 weeks; P = 0.02). Carboplatin C max and carboplatin pUF-AUC were highest in patients with severe thrombocytopenia (57.7 mg/L and 2.08 mg/mL*min, respectively) compared with patients with mild thrombocytopenia (47.8 mg/L and 1.76 mg/mL*min, respectively) and without thrombocytopenia (30.7 mg/L and 1.25 mg/mL*min, respectively; P < 10-4; Table 4). Significant correlations between paclitaxel t C > 0.05 and relative neutropenia as well as between AUC carboplatin and relative thrombocytopenia are shown in

Table 4. Mean derived pharmacokinetic variables and clinical outcome (objective response rate and TTP) Objective tumor response (units)

n

Paclitaxel pharmacokinetic variables tC

CR Partial remission SD PD CR/PR/SD versus PD* Neutrophil toxicity Absent Mild Severe Absent/mild versus severe neutropenia* Thrombocyte toxicity Absent Mild Severe Absent versus any *

> 0.1

(h) t C

> 0.05

Carboplatin pharmacokinetic variables

(h) C max (Mmol/L) AUC (Mmol/L*h)

C max (mg/L)

CpUF-AUC (mg/mL*min)

17 9 2 6

17.82 18.14 23.75 14.03 0.08

91.9 51.5 75.9 31.5 0.05

4.81 5.99 4.71 4.48 0.44

17.98 18.75 17.08 16.13 0.38

28.0 25.2 54.5 24.9 0.51

1.18 1.18 1.68 1.13 0.55

14 44 46

17.6 16.4 15.9 0.5

50.2 50.3 74.1 0.01

4.81 5.16 4.57 0.11

18.2 17.5 16.3 0.12

33.80 32.9 36.8 0.29

1.35 1.31 1.42 0.19

73 19 3

16.1 16.8 12.5 0.88

53.8 85.0 75.1 0.02

4.95 4.76 3.29 0.39

17.2 17.4 16.4 0.95

30.7 47.8 57.7 0.05, time above threshold paclitaxel concentration of 0.05 Amol/L; CpUF-AUC, carboplatin pUF-AUC; C max, maximum plasma concentration. *Student’s t test.


6415




Fig. 2. A, relative neutropenia as a function of duration of time that the plasma paclitaxel concentration is >0.05 Amol/L (R 2 = 0.16; Pearson correlation coefficient = 0.39; P < 10-3). B, relative thrombocytopenia as a function of carboplatin AUC (mg*min/mL; R 2 = 0.26; Pearson correlation coefficient = 0.51; P < 10-3).

Fig. 2. The correlations as depicted in Fig. 2 were calculated using linear regression analysis.

Discussion Optimization of doses and administration schedules for anticancer agents is desirable not only in the development of new drugs but also for established drugs and drug combinations. One important component in optimizing cancer therapy is to describe the hematologic toxicity of the drugs, which is dose limiting for most anticancer drugs, as a function of its pharmacokinetic behavior. Pharmacokinetic conditions with effect on the toxicity and efficacy of paclitaxel have been the topic of several publications (8, 12, 16, 18), but data are still very limited for the paclitaxel/carboplatin regimen (19, 21)


despite its common use. The establishment of a pharmacokinetic-pharmacodynamic relationship may enable the optimization of standard first-line treatment in ovarian cancer patients with the potential for higher response rates and/or less hematologic toxicity. We found an overall response rate of 76%, in accordance to what has been described in patients with advanced ovarian cancer receiving first-line treatment with paclitaxel/carboplatin (64% in ref. 2, 64% in ref. 32, and 78% in ref. 16). Mean time to progression of 70 weeks was slightly inferior to the 83 weeks as reported by Ozols et al. (3) with the paclitaxel/carboplatin drug regimen. However, the study by Ozols et al. included optimally resected ovarian cancer patients, whereas our series included 48 patients (35%) with gross residual disease after cytoreductive surgery, explaining the inferior TTP. The pharmacokinetic model provided estimates for carboplatin clearance (123 mL/min) that were in accordance with previously published data (33). For paclitaxel, maximal elimination capacity (VMEL) was estimated at 29 Amol/h, in accordance to our previous paclitaxel pharmacokinetic and covariate analysis in 168 solid tumor patients (37 Amol/h; ref. 28) but higher than previously described by Karlsson et al. (13 Amol/h for the saturable, noninstantaneous binding model; ref. 14). The higher paclitaxel elimination capacity in our previous pharmacokinetic analysis (28) compared with the present analysis is explained by the mixed gender distribution in the former and the female gender in the latter, backing our previous finding of a higher paclitaxel elimination capacity in males compared with females (28). The lower estimated paclitaxel elimination capacity in the study by Karlsson et al. is probably due to differences in the study population and might be a consequence of a better performance status and general health status with a higher paclitaxel elimination capacity in the present study and our previous report (28). Furthermore, effects of comedication may also be considered, although difficult to assess retrospectively. The pharmacokineticpharmacodynamic model adequately described neutrophil and thrombocyte counts after the administration of paclitaxel (175 mg/m2) followed by carboplatin AUC 5 mg/mL*min in 105 ovarian cancer patients with complete pharmacokinetic and toxicity data. The good agreement between final pharmacokinetic variables from the presented 105 ovarian cancer patients with a previously published paclitaxel pharmacokinetic model in a group of 168 solid tumor patients (28) suggests a lack of pharmacokinetic interaction between paclitaxel and carboplatin. This is in accordance to what has been described by Huizing et al. (16) in Caucasian and by Yamamoto et al. (34) in Japanese patients with advanced ovarian cancer. The sequence of drug administration (paclitaxel followed by carboplatin or vice versa) did not exert a significant effect on the level of observed neutropenia in 40 patients with advanced gynecologic malignancies (35). This was also found in 36 patients with metastatic non – small cell lung cancer, where neutropenia following paclitaxel/carboplatin was consistent with that observed in patients receiving paclitaxel alone (21). On the contrary, there is a clinically relevant pharmacodynamic interaction between paclitaxel and carboplatin, which results in a thrombocyte-sparing effect of paclitaxel (20, 36, 37). The paclitaxel-mediated, thrombocyte-sparing effect results in high tolerated carboplatin doses if given together with paclitaxel (21). The thrombocyte-sparing effect of paclitaxel was not

6416




found to be caused by pharmacokinetic interactions (20) but rather by an antagonistic interaction on thrombocyte precursor cells (36). Despite the platelet-sparing effect of paclitaxel, exposure to carboplatin remained the strongest predictor for thrombocyte toxicity by conventional descriptive analysis, as both C max and AUC were significantly lower in patients with mild versus severe or absent versus any (P < 10-4 for all comparisons; Table 4). Paclitaxel t C > 0.05 was significantly higher in patients with at least stable disease during treatment with paclitaxel/carboplatin compared with patients with progressive disease, and t C > 0.05 was also significantly correlated with severe neutropenia and with thrombocytopenia (Table 4). t C > 0.05 did not segregate between patients with mild or severe thrombocytopenia, but the latter group included only three patients. The presented threshold analysis as well as graphical plots of relative neutropenia/thrombocytopenia as a function of t C > 0.1/t C > 0.05 suggest t C > 0.05 to be a better surrogate for hematologic toxicity (Fig. 2) and objective response rate (Table 4) in patients with advanced ovarian cancer receiving paclitaxel/carboplatin. Basically, paclitaxel t C > 0.05 was the best predictor for treatment response and neutrophil toxicity, whereas carboplatin exposure was the best predictor for thrombocyte toxicity. We found a MTT of almost 6 days for blood neutrophils and 8 days for thrombocytes. For neutrophils, a similar MTT of 127 h (5.3 days) has been found for paclitaxel by Friberg et al. (23), also using a linear E drug model. No data on MTT for thrombocytes have been published for paclitaxel to our knowledge. van Kesteren et al. (38) estimated MTT for thrombocytes at 103 h (4.3 days) after the administration of the anticancer agent indisulam using a linear E drug model. The higher MTT for thrombocytes as found in the presented patient population may also reflect the thrombocyte-sparing effect of paclitaxel. Typical curves for blood counts as outlined in Fig. 1 found a neutrophil nadir of 1,090/AL at 11.5 days and a thrombocyte nadir of 200 103/AL at 15 days. Neutrophil nadir as found in this study is in accordance to what has been reported by Minami et al. (39) in 17 patients with advanced breast cancer. The authors modeled the time course of leukopenia following a 3-h infusion of 210 mg/m2 paclitaxel and found an estimated mean leucocyte nadir of 2,000/AL 11.7 days after drug administration, but they did not report the estimated neutrophil nadir. A leucocyte nadir of 2,000/AL as reported by Minami et al., however, would correspond to a neutrophil nadir of f1,200/AL if we assume a neutrophil fraction of 60%. A higher neutrophil nadir of 2,320/AL has been reported by Markman et al. (35) in 40 patients with advanced gynecologic malignancies receiving paclitaxel (175 mg/m2) over 3 h followed by carboplatin AUC (6 mg*min/mL). Comparable baseline neutrophil counts and lacking chemotherapy pretreatment in our and Markman’s patient group do not explain the difference in neutrophil nadir found. Nadir evaluation in the study by Markman et al. was done 8 to 10 days following the administration of paclitaxel/carboplatin and may have missed the true nadir in a significant part of patients. Simulation studies as done in the presented study are a potent tool for a more precise nadir assessment, but data validation is important to confirm appropriate simulation procedure. In conclusion, the presented inhibitory linear population pharmacokinetic-pharmacodynamic model predicted neutropenia and thrombocytopenia after the administration of


paclitaxel/carboplatin in patients with ovarian cancer. Paclitaxel t C > 0.05 was found to be a good predictive marker for severe neutropenia and clinical outcome, whereas carboplatin exposure was a good predictive marker for thrombocytopenia. Prospective studies should assess the value of therapeutic drug monitoring in this patient group.

Appendix A. Overview of study centers and investigators C. Dittrich, Ludwig Boltzmann-Institute of Applied Cancer Research, Vienna, Austria. J.B. Vermorken, University Hospital Antwerp, Edegem, Belgium. A. Van Oosterom and E. de Bruijn, UZ Gasthuisberg, Leuven, Belgium. D. de Valeriola and M. Piccart, Institut Jules Bordet, Brussels, Belgium. J. Kralovanszky and E. Toth Nat. Inst. Oncologie, Budapest, Hungary. P. Canal and E. Chatelut, Inst. Claudius Regaud, Toulouse, France. C. Ardiet and B. Tranchand, Centre Leon Be´rard, Lyon, France. J. Robert, Institut Bergonie, Bordeaux, France. P. Fumoleau, Centre G-F Leclerc, Dijon, France. R. Fe´ty, Centre R Gauducheau, Nantes Saint Herblain, France. N. Pavlidis and E. Briasoulis, Ioannina University Hospital, Ioannina, Greece. A. Hanauske, AK St. George, Hamburg, Germany. J. Boos and G. Hempel, University of Munster, Munster, Germany. A. Martoni and E. Piana, Policlinico S. OrsolaMalpighi, Bologna, Italy. R. Sorio and I. Robieux, National Cancer Institute, Aviano, Italy. G. Comella and P. Caponigro, National Tumor Institute, Naples, Italy. C.M. Camaggi and E. Strocchi, University of Bologna, Bologna, Italy. J.H.M. Schellens and M. van de Vijver, The Netherlands Cancer Institute, Amsterdam, the Netherlands. J.H. Beijnen, Slotervaart Hospital, Amsterdam, the Netherlands. E.G.E. De Vries and H. Hollema, University Medical Center, Groningen, the Netherlands. D.J. Richel, Medical Spectrum Twente, Enschede, the Netherlands. H.P. Sleeboom, Leyenburg Hospital, Den Haag, the Netherlands. J. Wanders and A.H.G.J. Schrijvers, NDDOOncology, Amsterdam, the Netherlands. W.J.F. van der Vijgh, Free University Medical Center, Amsterdam, the Netherlands, M.A. Izquierdo, Catalan Institute of Oncology, Barcelona, Spain. M. Karlsson, Uppsala University, Uppsala, Sweden. T. Cerny, Kantonsspital St.Gallen, St. Gallen, Switzerland. D.I. Jodrell, University of Edinburgh, Edinburgh, United Kingdom. A.H. Calvert, D.R. Newell, and A. Boddy, University of Newcastle upon Tyne, Newcastle upon Tyne, United Kingdom. Ch. Twelves, Glasgow University, Glasgow, United Kingdom. L.S. Murray, Glasgow University, Glasgow, United Kingdom. H.L. McLeod and J. Cassidy, University of Aberdeen, Aberdeen, United Kingdom. Centers that did bioanalysis of paclitaxel: E. de Bruijn, UZ Gasthuisberg, Leuven, Belgium. G. Hempel, University of Mu¨nster, Mu¨nster, Germany. E. Strocchi, Universita di Bologna, Bologna, Italy. J.H. Beijnen, Department of Pharmacy and Pharmacology, Slotervaart Hospital/The Netherlands Cancer Institute, Amsterdam, the Netherlands. M. Izquierdo, Catalan Institute of Oncology, Barcelona, Spain. A. Boddy, University of Aberdeen, Aberdeen, United Kingdom. Centers that did bioanalysis of carboplatin: R. Fe´ty, Centre R Gauducheau, Saint Herblain, France. E. Chatelut, Centre Claudius Regaud, Toulouse, France. W.J.F. van der Vijgh, Free University Medical Center, Amsterdam, the Netherlands. A. Boddy, University of Aberdeen, Aberdeen, United Kingdom.

6417




References 1. du BA, Luck HJ, Meier W, et al. A randomized clinical trial of cisplatin/paclitaxel versus carboplatin/paclitaxel as first-line treatment of ovarian cancer. J Natl Cancer Inst 2003;95:1320 ^ 9. 2. Neijt JP, Engelholm SA, Tuxen MK, et al. Exploratory phase III study of paclitaxel and cisplatin versus paclitaxel and carboplatin in advanced ovarian cancer. J Clin Oncol 2000;18:3084 ^ 92. 3. Ozols RF, Bundy BN, Greer BE, et al. Phase III trial of carboplatin and paclitaxel compared with cisplatin and paclitaxel in patients with optimally resected stage III ovarian cancer : a Gynecologic Oncology Group study. J Clin Oncol 2003;21:3194 ^ 200. 4. Parmar MK, Ledermann JA, Colombo N, et al. Paclitaxel plus platinum-based chemotherapy versus conventional platinum-based chemotherapy in women with relapsed ovarian cancer : the ICON4/AGOOVAR-2.2 trial. Lancet 2003;361:2099 ^ 106. 5. Vasey PA, Jayson GC, Gordon A, et al. Phase III randomized trial of docetaxel-carboplatin versus paclitaxel-carboplatin as first-line chemotherapy for ovarian carcinoma. J Natl Cancer Inst 2004;96: 1682 ^ 91. 6. Gonzalez-Martin AJ, Calvo E, Bover I, et al. Randomized phase II trial of carboplatin versus paclitaxel and carboplatin in platinum-sensitive recurrent advanced ovarian carcinoma: a GEICO (Grupo Espanol de Investigacion en Cancer de Ovario) study. Ann Oncol 2005;16:749 ^ 55. 7. Trope C, Hogberg T, Kaern J, et al. Long-term results from a phase II study of single agent paclitaxel (Taxol) in previously platinum treated patients with advanced ovarian cancer: the Nordic experience. Ann Oncol 1998;9:1301 ^ 7. 8. Gianni L, Kearns CM, Giani A, et al. Nonlinear pharmacokinetics and metabolism of paclitaxel and its pharmacokinetic/pharmacodynamic relationships in humans. J Clin Oncol 1995;13:180 ^ 90. 9. OhtsuT, Sasaki Y,TamuraT, et al. Clinical pharmacokinetics and pharmacodynamics of paclitaxel: a 3-hour infusion versus a 24-hour infusion. Clin Cancer Res 1995;1:599 ^ 606. 10. Rowinsky EK, Donehower RC. The clinical pharmacology of paclitaxel (Taxol). Semin Oncol 1993;20: 16 ^ 25. 11. Rowinsky EK, Wright M, Monsarrat B, et al. Clinical pharmacology and metabolism of Taxol (paclitaxel): update 1993. Ann Oncol 1994;5 Suppl 6:S7 ^ 16. 12. Henningsson A, Karlsson MO, Vigano L, et al. Mechanism-based pharmacokinetic model for paclitaxel. J Clin Oncol 2001;19:4065 ^ 73. 13. Henningsson A, Sparreboom A, Sandstrom M, et al. Population pharmacokinetic modelling of unbound and total plasma concentrations of paclitaxel in cancer patients. Eur J Cancer 2003;39:1105 ^ 14. 14. Karlsson MO, Molnar V, Freijs A, et al. Pharmacoki-

netic models for the saturable distribution of paclitaxel. Drug Metab Dispos 1999;27:1220 ^ 3. 15. Aabo K, Adams M, Adnitt P, et al. Chemotherapy in advanced ovarian cancer: four systematic meta-analyses of individual patient data from 37 randomized trials. Advanced Ovarian Cancer Trialists’ Group. Br J Cancer 1998;78:1479 ^ 87. 16. Huizing MT, Keung AC, Rosing H, et al. Pharmacokinetics of paclitaxel and metabolites in a randomized comparative study in platinum-pretreated ovarian cancer patients. J Clin Oncol 1993;11:2127 ^ 35. 17. Huizing MT,Vermorken JB, Rosing H, et al. Pharmacokinetics of paclitaxel and three major metabolites in patients with advanced breast carcinoma refractory to anthracycline therapy treated with a 3-hour paclitaxel infusion: a European Cancer Centre (ECC) trial. Ann Oncol 1995;6:699 ^ 704. 18. Wilson WH, Berg SL, Bryant G, et al. Paclitaxel in doxorubicin-refractory or mitoxantrone-refractory breast cancer: a phase I/II trial of 96-hour infusion. J Clin Oncol 1994;12:1621 ^ 9. 19. Huizing MT, Giaccone G, van Warmerdam LJ, et al. Pharmacokinetics of paclitaxel and carboplatin in a dose-escalating and dose-sequencing study in patients with non-small-cell lung cancer.The European Cancer Centre. J Clin Oncol 1997;15:317 ^ 29. 20. Fujiwara K,Yamauchi H, Suzuki S, et al. The plateletsparing effect of paclitaxel is not related to changes in the pharmacokinetics of carboplatin. Cancer Chemother Pharmacol 2001;47:22 ^ 6. 21. Belani CP, Kearns CM, Zuhowski EG, et al. Phase I trial, including pharmacokinetic and pharmacodynamic correlations, of combination paclitaxel and carboplatin in patients with metastatic non-small-cell lung cancer. J Clin Oncol 1999;17:676 ^ 84. 22. Bookman MA, McGuire WP, Kilpatrick D, et al. Carboplatin and paclitaxel in ovarian carcinoma: a phase I study of the Gynecologic Oncology Group. J Clin Oncol 1996;14:1895 ^ 902. 23. Friberg LE, Henningsson A, Maas H, et al. Model of chemotherapy-induced myelosuppression with parameter consistency across drugs. J Clin Oncol 2002; 20:4713 ^ 21. 24. Calvert AH, Newell DR, Gumbrell LA, et al. Carboplatin dosage: prospective evaluation of a simple formula based on renal function. J Clin Oncol 1989;7: 1748 ^ 56. 25. vanWarmerdam LJC, vanTellingenO,MaesRAA, et al. Validated method for the determination of carboplatin in biological fluids by Zeeman atomic absorption spectrometry. FreseniusJAnal Chem1995;357:1820 ^ 4. 26. Beal SL, Sheiner LB. NONMEM user’s guide. San Francisco: NONMEM Project Group, University of California. 1998. 27. Jonsson EN, Karlsson MO. XposeOan S-PLUS based population pharmacokinetic/pharmacodynam-


6418

ic model building aid for NONMEM. Comput Methods Programs Biomed 1999;58:51 ^ 64. 28. Joerger M, Huitema AD, van den Bongard DH, et al. Quantitative effect of gender, age, liver function, and body size on the population pharmacokinetics of paclitaxel in patients with solid tumors. Clin Cancer Res 2006;12:2150 ^ 7. 29. Huitema AD, Mathot RA, Tibben MM, et al. Validation of techniques for the prediction of carboplatin exposure: application of Bayesian methods. Clin Pharmacol Ther 2000;67:621 ^ 30. 30. Friberg LE, Freijs A, Sandstrom M, et al. Semiphysiological model for the time course of leukocytes after varying schedules of 5-fluorouracil in rats. J Pharmacol ExpTher 2000;295:734 ^ 40. 31. Sandstrom M, Lindman H, Nygren P, et al. Model describing the relationship between pharmacokinetics and hematologic toxicity of the epirubicin-docetaxel regimen in breast cancer patients. J Clin Oncol 2005; 23:413 ^ 21. 32. Bolis G, Scarfone G, Polverino G, et al. Paclitaxel 175 or 225 mg per meters squared with carboplatin in advanced ovarian cancer: a randomized trial. J Clin Oncol 2004;22:686 ^ 90. 33. Okamoto H, Nagatomo A, Kunitoh H, et al. Prediction of carboplatin clearance calculated by patient characteristics or 24-hour creatinine clearance: a comparison of the performance of three formulae. Cancer Chemother Pharmacol 1998;42:307 ^ 12. 34. Yamamoto R, Kaneuchi M, Nishiya M, et al. Clinical trial and pharmacokinetic study of combination paclitaxel and carboplatin in patients with epithelial ovarian cancer. Cancer Chemother Pharmacol 2002;50: 137 ^ 42. 35. Markman M, Elson P, Kulp B, et al. Carboplatin plus paclitaxel combination chemotherapy: impact of sequence of drug administration on treatment-induced neutropenia. Gynecol Oncol 2003;91:118 ^ 22. 36. Guminski AD, Harnett PR, deFazio A. Carboplatin and paclitaxel interact antagonistically in a megakaryoblast cell lineOa potential mechanism for paclitaxel-mediated sparing of carboplatin-induced thrombocytopenia. Cancer Chemother Pharmacol 2001;48:229 ^ 34. 37. Ishikawa H, Fujiwara K, Suzuki S, et al. Plateletsparing effect of paclitaxel in heavily pretreated ovarian cancer patients. Int J Clin Oncol 2002;7: 330 ^ 3. 38. van Kesteren C, Zandvliet AS, Karlsson MO, et al. Semi-physiological model describing the hematological toxicity of the anti-cancer agent indisulam. Invest New Drugs 2005;23:225 ^ 34. 39. Minami H, Sasaki Y,WatanabeT, et al. Pharmacodynamic modeling of the entire time course of leukopenia after a 3-hour infusion of paclitaxel. Jpn J Cancer Res 2001;92:231 ^ 8.



Population Pharmacokinetics and Pharmacodynamics of Paclitaxel and Carboplatin in Ovarian Cancer Patients: A Study by the European Organization for Research and Treatment of Cancer-Pharmacology and Molecular Mechanisms Group and New Drug Development Group Markus Joerger, Alwin D.R. Huitema, Dick J. Richel, et al. Clin Cancer Res 2007;13:6410-6418.

Updated version

Cited articles Citing articles

E-mail alerts Reprints and Subscriptions Permissions

Access the most recent version of this article at: http://clincancerres.aacrjournals.org/content/13/21/6410

This article cites 37 articles, 23 of which you can access for free at: http://clincancerres.aacrjournals.org/content/13/21/6410.full.html#ref-list-1 This article has been cited by 6 HighWire-hosted articles. Access the articles at: http://clincancerres.aacrjournals.org/content/13/21/6410.full.html#related-urls

Sign up to receive free email-alerts related to this article or journal. To order reprints of this article or to subscribe to the journal, contact the AACR Publications Department at [email protected]. To request permission to re-use all or part of this article, contact the AACR Publications Department at [email protected].
