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1 Multidisciplinary Oncology Center, 2 Division of Clinical Pharmacology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Experimental Design: TMZ levels were measured by high-performance liquid chromatography in plasma and CSF samples from 35 patients with newly diagnosed or recurrent malignant gliomas. The population pharmacokinetic analysis was performed with nonlinear mixed-effect modeling software. Drug exposure, defined by the area under the concentration-time curve (AUC) in plasma and CSF, was estimated for each patient and correlated with toxicity, survival, and progression-free survival.
Results: A three-compartment model with first-order absorption and transfer rates between plasma and CSF described the data appropriately. Oral clearance was 10 liter/h; volume of distribution (VD), 30.3 liters; absorption constant rate, 5.8 h–1; elimination half-time, 2.1 h; transfer rate from plasma to CSF (Kplasma
CSF), 7.2 x 10–4h–1 and the backwards rate, 0.76 h–1. Body surface area significantly influenced both clearance and VD, and clearance was sex dependent. The AUCCSF corresponded to 20% of the AUCplasma. A trend toward an increased KplasmaCSF of 15% was observed in case of concomitant radiochemotherapy. No significant correlations between AUC in plasma or CSF and toxicity, survival, or progression-free survival were apparent after deduction of dose-effect.
Conclusions: This is the first human pharmacokinetic study on TMZ to quantify CSF penetration. The AUCCSF/AUCplasma ratio was 20%. Systemic or cerebral exposures are not better predictors than the cumulative dose alone for both efficacy and safety.
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Temozolomide (TMZ), a novel oral imidazotetrazinone methylating agent has demonstrated a schedule-dependent antitumor activity in various advanced cancers, including malignant gliomas (7, 8, 9, 10, 11, 12) . After oral administration, TMZ is rapidly absorbed with almost 100% bioavailability and undergoes spontaneous hydrolysis at physiological pH into its active metabolite, 5-(3-methyl triazen-1-yl)imidazole-4-carboxamide (MTIC) (13) . This is then rapidly degraded into methyldiazonium, the methylating entity, and into an inactive metabolite 5-aminoimidazole-4-carboxamide (AIC), which is finally excreted by the kidney (13 , 14) . The cytotoxicity of MTIC is thought to be caused by methylation of the O6 position of guanine with additional alkylation at the N7 position (13 , 15) .
TMZ has demonstrated ubiquitous distribution into all tissues including the brain (7 , 13) . Its plasma pharmacokinetics is linear and predictable. However, there is only scarce information on the concentration profile of TMZ into the brain or cerebrospinal fluid (CSF; Refs. 16 , 17 ). Although TMZ is mainly used in the treatment of malignant brain tumors, a complete pharmacokinetic profile in the CSF, commonly used as a surrogate marker for central nervous system penetration, has never been described for this agent.
Here we report the TMZ pharmacokinetics in plasma and CSF from patients enrolled in two clinical trials. Because repeated lumbar punctures are not feasible for ethical and practical reasons, a population pharmacokinetic approach using the nonlinear mixed-effect modeling (NONMEM) computer program was used.
The objectives of this study are to characterize the population pharmacokinetics of TMZ in plasma and CSF along with the inter- and intra-individual variability, to evaluate their dependence toward demographic and clinical covariates, and to further explore the relationships between TMZ systemic and cerebral exposure and clinical outcomes in glioma patients.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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18 years, eastern cooperative oncology group performance status 
2 or Karnofsky performance status 70%, adequate hematological, renal, and hepatic functions, defined as absolute neutrophil count 1.5 x 109/liter; platelet count 100 x 109/liter; hemoglobin >90 g/liters; serum creatinine and total serum bilirubin 1.5 times the upper limit of normal; aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase <2.5 times the upper limit of normal. Exclusion criteria included any medical conditions that could interfere with the oral administration of TMZ or any previous or concurrent malignancies at other sites, with the exception of the cervix and nonmelanoma skin cancer. The clinical and pharmacokinetic protocols were reviewed and approved by the local ethics committee. TMZ was administered on one of the two following schedules:
Prophylactic antiemetics (4 mg/day ondansetron, 1 mg/day granisetron; 10–40 mg/day metoclopramide, 50 mg/day alizapride) were used only as required during concomitant radiotherapy plus TMZ therapy and routinely prescribed once a day before adjuvant or recurrent TMZ treatment. Anticonvulsants [cytochrome P-450 inducers (phenytoïne, carbamazepine); cytochrome P-450 inhibitors (valproïc acid); others (lamotrigine, gabapentine, clonazepam)], corticosteroids (dexamethasone, prednisone), antacids (omeprazole, ranitidine) or the cytoprotective agent, sucralfate, were administered as needed.
Pharmacokinetic Sampling and Processing.
Plasma and CSF concentrations of TMZ were analyzed in sparse samples collected on different occasions over a 17 months period. Venous blood samples (5 ml) were drawn into cooled lithium-heparinized tubes at three different times between 0.2 and 8.4 h after oral TMZ administration on the first (day 1) and last day (day 42–49) of the concomitant radiotherapy plus TMZ therapy (continuous schedule) and on day 1 and day 5 during first cycle of adjuvant or recurrent TMZ treatment (intermittent schedule). The exact time of TMZ administration as well as the time of blood and CSF sampling were carefully recorded. After collection, samples were immediately centrifuged (2000 rpm during 10 min at 4°C), the plasma was then acidified with 0.1 ml 1 M HCl and stored at –20°C until analysis. CSF was collected on two occasions through a lumbar puncture between 1.3 and 6.6 h after oral TMZ intake. A lumbar puncture was performed on day 1 of the concomitant radiochemotherapy (continuous schedule) and on the first day of the adjuvant or recurrent chemotherapy (intermittent schedule). In one patient, the presence of an Ommaya reservoir, implanted previously because of the development of an occlusive hydrocephalus, allowed the collection of sequential CSF samples. Processing of the CSF samples was analogous to the blood samples but did nor require centrifugation.
Blood and CSF Samples Analysis.
Quantitation of TMZ in plasma and CSF was performed by reversed-phase high-performance liquid chromatography analysis using a slight modification of our method described previously (20)
, to improve the sensibility of the method for the CSF samples analysis, for which lower TMZ levels were expected. The clean-up procedure involved a solid-phase extraction of biological sample (100 µl) on a 100 mg C18-endcapped cartridge (Chromabond, Macherey-Nagel, Düren, Germany). Matrix components were eliminated with 750 µl of 0.5% acetic acid. TMZ was subsequently eluted with 1250 µl of methanol. The resulting eluate was evaporated under nitrogen at room temperature, reconstituted in 100 and 200 µl of 0.5% acetic acid for CSF and plasma samples respectively, and analyzed by high-performance liquid chromatography.
The chromatographic system consisted of a HP 1050 isocratic/quaternary pump (Hewlett-Packard, Böblingen, Germany) connected to an HP 1050 autosampler and an HP 1050 UV diode-array detector set at UV 330 nm. Separations were performed on a Nucleosil 100–5 C18 AB column (125 x 4 mm inside diameter; Macherey-Nagel) equipped with an Nucleosil C18 AB (8 x 4 mm) guard column. The high-performance liquid chromatography mobile phase was methanol/0.5% acetic acid (7:93 v/v). The flow rate was 1 ml/min. The retention time for TMZ and ethazolastone were 2.7 and 6.8 min, respectively. A HP ChemStation A-O6-03 software loaded onto a Compaq Deskpro EP/SB was used for the data processing of the chromatograms.
The plasma calibration standards (0.4, 2, 4, 10, and 20 µg/ml) and control samples (1, 10, and 18 µg/ml) were prepared with 5 ml of blank human plasma, added to TMZ stock solution (prepared in 0.1 M HCl), acidified with 250 µl of 2 M HCl and completed ad 5.5 ml with 0.1 M HCl. The CSF calibration standards (0.1, 0.2, 0.5, 1, and 2 µg/ml) and controls (0.33, 0.5, and 1 µg/ml) were prepared with an artificial CSF solution [0.8 g/liter glucose, 0.2 g/liter albumin, 7.3 g/liter NaCl, and 1.9 g/liter NAHCO3 (adjusted to pH 7.5 with phosphate buffer)], added to various volumes of TMZ stock solution and acidified similarly to the plasma samples.
A linear response was observed for all calibration curves between 0.4 and 20 µg/ml and 0.1 to 2 µg/ml in plasma and CSF, respectively (r > 0.999). This method had a limit of quantitation of 0.2 µg/ml and 0.1 µg/ml in plasma and CSF, respectively, as well as an inter-assay variability and bias of <15%, in accordance with the recommendations of the Conference Report on Bioanalytical Method Validation (21) .
Model-Based Pharmacokinetic Analysis.
Population analysis was performed using the NONMEM computer program (version V with NM-TRAN version II) developed by Beal and Sheiner (22)
. NONMEM uses mixed (fixed and random) effects regression to estimate the population mean and the variability of pharmacokinetic parameters and to identify factors that may influence them. A three-compartment model with first order absorption from the gastrointestinal tract (Fig. 1)
was used to model TMZ in plasma and in CSF according to:
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The model was fitted to the data by using the first order method with the subroutine ADVAN5. NONMEM performs linearized maximum likelihood estimation by use of an objective function of minus twice the logarithm of the likelihood of the model. To determine the statistical significance between two models, we used the log-likelihood ratio test obtained by computing the difference in the minimum value of the objective function (the difference in the minimum value of the NONMEM objective function [–2
LL] for nested models is approximately 
2 distributed); Model selection criteria were a decrease of the objective function (OF) of 3.8 points for one additional parameter and 5.9 points for two additional parameters (P < 0.05) as well as comparison of regression diagnostic plots. Figures were generated with Prism (version 4.0; GraphPad Software Inc., San Diego, CA).
Pharmacodynamics.
Posthoc Bayesian estimates of the pharmacokinetic parameters were obtained for all patients and used to calculate the area under the curve concentration-time curve (AUC) in plasma (AUCplasma) and CSF (AUCCSF) according to the following relationships:
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Hematological toxicity, commonly defined by the percentage of decrease in platelet and absolute neutrophil count (ANC) from baseline to nadir (27
, 28)
, was observed during the first two cycles of the adjuvant or recurrent treatments (intermittent schedule). Percent decrease was calculated as follows, using neutrophil as example:
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The associations between both AUCplasma and AUCCSF and the two efficacy outcomes, survival and PFS observed at the time of this analysis, were assessed by the Spearman rank correlation test and by logistic regression. For this statistical analysis, a model was fitted to the clinical data, initially expressed in months, which was transformed into binary response, as follows: (a) 0 = alive; 1 = dead, in terms of survival after 9, 12, and 24 months and (b) 0 = progression-free; and 1 = disease progression for PFS after 6, 9, and 12 months.
The results were considered statistically significant at P < 0.05, whereas P < 0.1 was regarded to be indicative of possible trends. All statistical tests were performed with the Statistix program (version 7.0, 2000, Analytical software; Statistix, Tallahassee, FL).
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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, and the different comedications are summarized in Table 2
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. Because plasma concentrations decreased more quickly than in the CSF, the CSF/plasma ratio increased across the dosing interval (median, 30.1%; range, 2.1–65.2%). The CSF curve was essentially flat at approximately 1 µg/ml, likely attributable to slow influx and efflux rates from the CSF compartment (30)
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OF) = –36.4], but no inter-patient variability on VD and K32 could be detected. The model building steps for the covariate analysis are shown in Table 3
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OF > –5.5) and VD is influenced to a small but significant extent by BSA only (OF > –6.7). Because body weight and height influenced TMZ pharmacokinetics, we retained BSA, which reflects both these values, as a covariate on CL and VD in the model. All covariates (i.e., BSA on VD and CL, and gender on CL) remained statistically significant in the multivariate analysis.
Considering that corticosteroids could partially restore the integrity of the blood-brain barrier, thereby limiting drug delivery to the tumor, and on the other hand also reduce intracranial pressure by decreasing peritumoral vasogenic edema resulting in a increased drug delivery (6
, 31, 32, 33, 34)
, a relationship between corticotherapy and the two transfer rate constants, K23 and K32, were examined. No significant influence could be observed (OF = –0.1).
No other demographic covariates (age, creatinine clearance) showed any statistical influence on TMZ disposition. Coadministration of drugs, such as anticonvulsants, antiemetics, antacids, cytoprotective agents, or again corticosteroids, did not influence any pharmacokinetic parameters to a statistically relevant extent. However, a trend toward a 15% increase of the rate constant of CSF entry, K23, was observed in case of concomitant radiotherapy to TMZ (OF = –2.6).
The final population estimate of oral CL was 10.0 liter/h and increased to 11.9 liter/h in male patients and oral VD was 30.3 liters. These two parameters increased, respectively, to 14.2 liter/h and 50.2 liters on doubling BSA. Ka was 5.8 h–1, K23 was 7.2 x 10–4 h–1, and K32 was 0.76 h–1. The derived elimination half-life was 2.1 h, whereas the absorption half-life was very rapid (7 min). The inter-individual variability (CV%) in CL (4.7%) and K23 (16.6%) were relatively small compared with the high inter-individual variability in Ka (111%). A residual intra-individual variability of 21.4% was observed. The final population parameter estimates are presented in Table 4
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. The individual and population predictions were symmetrically distributed around the line of identity, suggesting adequate model predictions, without any troublesome pattern in the residuals, as seen on Fig. 4
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. For both types of schedules (continuous or intermittent), the AUCCSF represented 
20% of the AUC in plasma. The mean AUCplasma after a daily dose of 75 or 200 mg/m2/day was 12.1 ± 1.1 and 30.1 ± 6.1 mg/liter/h, respectively. In the CSF, the corresponding values were 2.5 ± 0.3 and 6.1 ± 1.2 mg/liter/h.
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The statistical analysis was then repeated with the AUCplasma and AUCCSF calculated with the daily dose (i.e., TMZ 75 or 200 mg/m2/day) and the dose per cycle (continuous schedule, 75 mg/m2/day x 42–49day; intermittent schedule, 200 mg/m2/day x 5 days). It failed to demonstrate any significant correlation between both AUCplasma or AUCCSF and survival or PFS, with P > 0.1 in all cases.
Finally, no significant correlations could be observed by logistic regression between AUCplasma or AUCCSF and both survival and PFS censored at 6, 9, 12, or 24 months (P > 0.19).
Myelosuppression, in particular delayed thrombocytopenia, is the primary dose-limiting toxicity of TMZ. Hematological toxicity observed in this study population (2–3% grade III/IV neutropenia, 5–6% grade III/IV thrombocytopenia) was in agreement with data reported previously (9, 10, 11, 12, 13) . The mean decrement in absolute neutrophil count between baseline to nadir was 49% (range, 0–93%) and 47% (range, 4–97%) for platelets. It was then examined whether AUCplasma was a predictor of hematological toxicity. No significant correlation between systemic TMZ exposure during the first two cycles of adjuvant or recurrent treatments (intermittent schedule) and the percentage of decrease in platelet (P = 0.812) nor absolute neutrophil count (P = 0.599) was observed.
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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They enable the description of complex pharmacokinetic behavior, the generation of individual estimates of pharmacokinetic parameters (e.g., CL, VD) or systemic exposure (AUCplasma), the assessment of inter-individual variability, and the identification of influent patients characteristics on drug disposition.
Very few studies evaluated the penetration of cytotoxic agents into the CSF. Except for anecdotic reports, no data are available today on the penetration of TMZ into the CSF in brain tumor patients. However, for agents with a presumed activity in the central nervous system, sufficient drug concentrations in the clinical situation are a prerequisite.
Our study provides the first description of the influence of population factors on TMZ pharmacokinetics in the plasma and the CSF. We demonstrate that TMZ oral clearance is only slightly influenced by BSA and gender and is associated with a remarkably small inter-patient variability (4.7%). The volume of distribution is influenced by BSA only. These results are in good agreement with Jen et al. (43) reporting an oral clearance of 11.2 liter/h with a 15% inter-patient variability and a similar influence of BSA and gender. In our study, neither individual determinants such as genetic background or organ failure nor comedications commonly used in gliomas patients (anticonvulsants, antiemetics, corticosteroids, antacids, and cytoprotective agent) altered TMZ oral clearance.
The AUC values estimated in our analysis revealed that CSF values corresponding to 20% ± 5% of those observed in plasma. These results are comparable to the limited information reported in preclinical studies with TMZ and the camptothecins, irinotecan and topotecan. The AUCCSF/AUCplasma ratio observed in nonhuman primate models were 33% ± 6% for TMZ, 14% ± 3% for irinotecan, and 32% ± 3% for topotecan (17 , 44 , 45) . Irinotecan and other camptothecins are currently in clinical trials as new treatments for malignant gliomas (46) .
This AUCCSF/AUCplasma ratio of 20% ± 5% is somewhat lower than the average CSF/plasma concentration ratio (mean, 29.4% ± 15%; increasing up to 40% until 4 h after TMZ intake) reported previously on the same study population (29) . This difference is constructed as AUCCSF/AUCplasma ratio integrates the entire dosing interval. The ratio of the AUCs estimates more accurately the penetration into the central nervous system than only a CSF/plasma ratio obtained with plasma and CSF concentrations (30) . A penetration of at least 20% of the AUCplasma into the CSF may be used as a benchmark for comparison with other agents with a presumed activity in the CSF.
The lack of a significant relationship between AUCplasma or AUCCSF beyond the cumulative dose and efficacy outcomes is likely to be explained by the very low inter-patient variability in TMZ pharmacokinetics, thus minimizing the predictive value added by AUC over the cumulative dose alone.
Similarly, AUCplasma was not a predictor of decrease of platelets or neutrophils. Detection of decrease in blood counts is obscured by the large normal fluctuation of leukocyte and platelet counts. Furthermore, severe hematological toxicity with the treatment of TMZ is rare and observed in <10% of patients only. Decrease in blood counts is also dependent on O6-methylguanine-DNA methyltransferase (MGMT) expression in hematopoietic stem cells (47) . This ubiquitous DNA repair enzyme, which removes methylating and chloroethylating lesions at the O6 position of guanine, is to a large extent variably expressed in peripheral blood mononuclear cells (48) and thus seems to be a stronger predictor for toxicity than systemic drug exposure.
It must be recognized that TMZ by itself is not the biologically active agent, but merely a prodrug which undergoes a spontaneous hydrolysis to generate the methylating agent MTIC. The determination of this compound in plasma and CSF could have a better chance to predict efficacy or safety outcomes and will be assessed in an additional investigation. Moreover, the biotransformation of TMZ may have a significant variability between organ, tissue, or cell compartments. This possibly limits the ability of blood or CSF concentrations to adequately reflect drug levels at target tissue sites.
Whether concomitant radiotherapy improves cerebral penetration of some chemotherapeutic agents by radiation-induced opening of the blood-brain barrier (49, 50, 51, 52) still deserves additional confirmation (6 , 53) .
Finally, TMZ appears to be one of the few anticancer agents for which dose individualization entirely based on BSA may be actually justified. This finding was also confirmed by Baker et al. (54) in a retrospective study on the role of BSA for the dosing of new anticancer agents. The AUC in plasma and CSF have shown a low inter-individual variability and could not be correlated with efficacy nor toxicity outcomes. The AUC in the CSF, considered as the only ethically accepted surrogate of the brain penetration, corresponds to approximately 20% of the systemic TMZ exposure.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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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.
Note: L. A. Decosterd and R. Stupp designed the study and contributed equally to this work.
Requests for reprints: Roger Stupp, Multidisciplinary Oncology Center, Centre Hospitalier Universitaire Vaudois, Rue du Bugnon, 46, CH-1011 Lausanne, Switzerland. Phone: 41-21-314-01-56; Fax: 41-21-314-07-37; E-mail: roger.stupp{at}chuv.hospvd.ch
Received 12/24/03; accepted 2/ 3/04.
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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) and cerebrospinal fluid (CSF; 
) concentration-time profiles of temozolomide (TMZ). Peak plasma (
