BACKGROUND:Early identification of patients at high risk for chemoresistance among those treated with methotrexate (MTX) for low-risk gestational trophoblastic neoplasia (GTN) is needed. We modeled human chorionic gonadotropin (hCG) decline during MTX therapy using a kinetic population approach to calculate individual hCG clearance (CL(hCG)) and assessed the predictive value of CL(hCG) for MTX resistance. PATIENTS AND METHODS:A total of 154 patients with low-risk GTN treated with 8-day MTX regimen were retrospectively studied. NONMEM was used to model hCG decrease equations between day 0 and day 40 of chemotherapy. Receiver operating characteristic curve analysis defined the best CL(hCG) threshold. Univariate/multivariate survival analyses determined the predictive value of CL(hCG) and compared it with published predictive factors. RESULTS:A monoexponential equation best modeled hCG decrease: hCG(t) = 3900 x e(-0.149 x t). Median CL(hCG) was 0.57 l/day (quartiles: 0.37-0.74). Only choriocarcinoma pathology [yes versus no: hazard ratio (HR) = 6.01; 95% confidence interval (CI) 2.2-16.6; P < 0.001] and unfavorable CL(hCG) quartile (< or =0.37 versus >0.37 l/day: HR = 6.75; 95% CI 2.7-16.8; P < 0.001) were significant independent predictive factors of MTX resistance risk. CONCLUSION:In the second largest cohort of low-risk GTN patients reported to date, choriocarcinoma pathology and CL(hCG) < or =0.37 l/day were major independent predictive factors for MTX resistance risk.

The aim here was to explore the potential of pharmacokinetic (PK)/pharmacodynamic (PD) and physiopathological parameters in explaining the primary effects of an anti-cancer treatment that targets cells in a specific cell cycle phase. The authors applied a theoretical multi-scale disease model of tumour growth that integrates cancer processes at the cellular and tissue scales. The mathematical model at the cell level relies on a dynamic description of cell cycle regulation while the model at the tissue level is based on fluid mechanics considerations. Simulations show that the number of target cells oscillates as the tumour grows after a first cycle of chemotherapy. Both treatment effect and tumour growth processes drive these oscillations. Nonetheless, results indicate that parameters related to physiopathological processes may have greater relevance than classical drug-related parameters in determining the efficacy of a chemotherapy treatment protocol. Physiopathological parameters, in particular those related to cell cycle regulation, may be integrated in PK/PD models aimed at optimising the delivery of phase-specific cytotoxic treatments.

.............................................................................................................................. 4 INTRODUCTION ...................................................................................................................... 5 METHODS ................................................................................................................................. 7 Search strategy ....................................................................................................................... 7 Data abstraction form building ............................................................................................... 7 Basic internal evaluation ........................................................................................................ 8 Advanced internal evaluation ................................................................................................. 9 External evaluation ............................................................................................................... 11 Metrics used for model evaluation ....................................................................................... 11 Subjective synthesis ............................................................................................................. 12 Statistical analysis ................................................................................................................ 13 RESULTS ................................................................................................................................. 14 General results ...................................................................................................................... 14 Basic internal evaluation ...................................................................................................... 14 Advanced internal evaluation ............................................................................................... 15 External evaluation ............................................................................................................... 16 Metrics used for model evaluation ....................................................................................... 16 Subjective synthesis ............................................................................................................. 17 DISCUSSION .......................................................................................................................... 17 CONCLUSION ........................................................................................................................ 21 REFERENCES ......................................................................................................................... 23 in se rm -0 01 59 12 4, v er si on 1 14 S ep 2 00 9

969 Purpose: Feasibility study for a new method to accurately assess PSA decrease in patients with prostate cancer after radical prostatectomy (PSA clearance (CLPSA)) and to identify relationships between PSA decrease profile and relapse free survival (RFS) . Indeed the current method used to describe PSA decrease after surgery (individual PSA half-life calculation, nadir) in patients with prostate tumors is source of biases and inaccuracies and may alter the prognostic value of PSA decline profile. We propose to apply the same population kinetic approach that is used in drug pharmacokinetic studies in order to estimate PSA clearance (CLPSA) which dynamically quantifies body PSA elimination. Method: This was a retrospective study on 67 consecutive patients undergoing radical prostatectomy in the same center from November 2000 to December 2006. Fifty five patients had at least 3 PSA dosages in the first month after the procedure (total 162 PSA dosages). A population model was investigated with NONMEM software. We searched for all patient covariates potentially increasing accuracy of the model. The prognostic factors regarding 2 year biochemical RFS (bRFS) were assessed using univariate (log-rank) and multivariate analysis (Cox model). Results: The best model describing PSA post-operative decrease was bi-compartmental. Only inclusion of “biochemical relapse” covariate (RLPS: Yes=1, No=0) statistically improved PSA elimination prediction. The final model was: [CLPSA= 0.0320 -0.0141 * RLPS]. There was a great agreement between predicted and observed PSA values. The significant prognostic factors associated with a better 2 year bRFS with univariate analysis were CLPSA >0.0234 (2 year bRFS=92.8% vs 66.7%, p=0.002) as well as preoperative PSA

Lors de la mise en place des essais cliniques en oncologie, plusieurs questions se posent tant au niveau scientifique qu'au niveau ethique. Au cours des dix dernieres annees, differentes approches ont ete proposees pour ameliorer la maniere de conduire les essais cliniques lors du developpement des medicaments anticancereux, dans le but de reduire le nombre de patients traites a des doses infratherapeutiques et d'optimiser l'information obtenue durant ces essais. Cette revue presente les differentes approches disponibles, de la phase I a la phase III, leurs avantages et leurs limites. Un compromis entre toutes ces methodes est suggere.

8537 Background: To analyze the pharmacokinetic (PK) parameters of etoposide in patients with malignant lymphomas receiving high dose chemotherapy (BEAM: carmustine, cytarabine, etoposide and melphalan) followed by ABMT. Methods: 91 patients were included in this open multicentre prospective study at first treatment line or at relapse. BEAM comprised etoposide 100 mg/m² twice daily for 4 days. We used a limited blood sampling strategy, allowing to estimate the patients’ PK parameters with acceptable precision. Individual etoposide concentrations versus time curves as well as individual etoposide clearance (etoCL) and Area Under the Curve (etoAUC) were modelized using the NONMEM program. The distribution of total etoAUC (over the 4-day treatment) was investigated according to population quartiles. Results: The inter-individual variability in etoCL was 26.3% (95% CI=20.6–30.9%). The median etoAUC was 906.5 mg/L.h for all patients (range: 547.5–2,271.6 mg/L.h) and was not influenced by treatment line. The total etoAUC upper bounds of 1st, 2nd and 3rd quartiles were 737.5, 906.5 and 1,096.2 mg/L.h respectively. No correlations were observed between body surface area and etoCL. Conclusions: Although all patients received the same etoposide dose calculated using body surface area, we observed a major inter-individual variability in AUC. Some patients had a more than 4 fold higher systemic exposure than other patients, which may have important consequences on treatment tolerance and efficacy. Data on clinical consequences of PK variability will be presented. Distribution of total etoAUC All patients 1st quartile (Q1) 2nd quartile(Q2) 3rd quartile(Q3) 4th quartile(Q4) Number of patients 91 23 23 22 23 Total etoAUC range [547,5–2271,6] [547.5–737.5] [737.5–906.5] [906.5–1096.2] [1096.2–2271.6] Ratio: Q25 etoAUC/Q75 etoAUC=0.67 No significant financial relationships to disclose.

What is already known about this subject • Major bleeds with low‐molecular‐weight heparin have been reported at curative and prophylactic dosages.• Enoxaparin clearance depends on body weight, and therefore weight‐adjusted dosing is recommended to minimize interindividual variability in drug exposure and the risk of haemorrhage in patients treated at curative doses.• Monitoring of this treatment is recommended in curative indications in patients at risk.• The need for monitoring of patients at risk receiving prophylactic doses of enoxaparin, in this case the elderly, remains unclear. What this study adds • Clearance of enoxaparin at prophylactic doses is predictably related to body weight and creatinine clearance in the elderly.• The simplified Modification of Diet in Renal Disease formula seems to be most discriminating and powerful in detecting any influence of glomerular filtration rate in the elderly.• The influence of these covariates does not seem to be sufficiently clinically relevant to support routine assessment in the elderly.AimsMajor bleeding complications with low‐molecular‐weight heparin (LMWH) treatment have been reported both in clinical studies and during postmarketing surveillance. Monitoring of antifactor Xa (anti‐Xa) activities is therefore recommended in special populations often predisposed to renal impairment. The PROPHRE.75 study was conducted to estimate the distribution parameters of anti‐Xa activity in the elderly.MethodsPROPHRE.75 was a prospective study of a cohort of consecutive patients aged >75 years and treated with 4000 IU of enoxaparin once daily for venous thromboembolism prophylaxis. Dosing history and measurements of anti‐Xa activity in sparse samples were recorded throughout treatment. The covariates included weight, gender, age, renal function, medical history and concomitant medication. Population parameters and interindividual variability were estimated using NONMEM® V software.ResultsAnti‐Xa activity was studied in 189 patients (mean age 82 ± 5 years, 22% weighing <50 kg, 50% presenting renal impairment according to the Cockcroft and Gault formula). A first‐order input two‐compartment model best fitted the data. Clearance was significantly related to body weight and creatinine clearance based on the simplified Modification of Diet in Renal Disease formula, central volume being related to body weight. According to individual Bayesian estimations, 4% of patients presented with a peak anti‐Xa activity >1.0 IU ml−1, but this group did not include the sole patient experiencing a major bleed (0.53%).ConclusionsSystematic monitoring of anti‐Xa activity in elderly patients treated with enoxaparin at prophylactic doses does not seem to be necessary to prevent the occurrence of major bleeding.

AIMS A descriptive survey of published population pharmacokinetic and/or pharmacodynamic (PK/PD) analyses from 2002 to 2004 was conducted and an evaluation made of how model building was performed and reported. METHODS We selected 324 articles in Pubmed using defined keywords. A data abstraction form (DAF) was then built comprising two parts: general characteristics including article identification, context of the analysis, description of clinical studies from which the data arose, and model building, including description of the processes of modelling. The papers were examined by two readers, who extracted the relevant information and transmitted it directly to a MySQL database, from which descriptive statistical analysis was performed. RESULTS Most published papers concerned patients with severe pathology and therapeutic classes suffering from narrow therapeutic index and/or high PK/PD variability. Most of the time, modelling was performed for descriptive purposes, with rich rather than sparse data and using NONMEM software. PK and PD models were rarely complex (one or two compartments for PK; E(max) for PD models). Covariate testing was frequently performed and essentially based on the likelihood ratio test. Based on a minimal list of items that should systematically be found in a population PK-PD analysis, it was found that only 39% and 8.5% of the PK and PD analyses, respectively, published from 2002 to 2004 provided sufficient detail to support the model-building methodology. CONCLUSIONS This survey allowed an efficient description of recent published population analyses, but also revealed deficiencies in reporting information on model building.

13013 Background: Mathematical modeling is a powerful approach to provide functional description of a real process. In medicine and biology, models are established on the basis of available clinical observations and biological covariates. Modeling applied in cancer treatment is a valuable tool to perform drug dosage adjustments. We used this methodology to regulate ET administration by predicting haematopoiesis and tumor growth in patients with MBC in a phase I trial. Methods: We developed a mechanistic model to describe leukopoiesis / thrombopoiesis / tumor growth in MBC patients under bimonthly ET + G-CSF. The model was first validated using data from clinical trials [Viens, Am J Clin Oncol. 2001;24:328, Chugai lenograstim database] and prospectively applied to individualize ET administration (dose rate and duration). The model optimizes the drug doses that could minimize the tumour burden while respecting a priori fixed constraints on deepness / duration of neutropenia and thrombocytopenia. First course administration was fixed ahead. At following courses, schedules were individually adjusted. At first dose level, patients received ET: 85/85 mg over a 48 h period with various, electronically- controlled infusion rates every 2 weeks. At dose level 2, doses were 100/100 mg. Results: Between 06/2005 and 06/2006, 3.5 median courses (range: 2–6) were administered to 6 patients (level 1: 3; level 2: 3). Rates of grade 3–4 neutropenia and thrombocytopenia were 47 and 0 % respectively. Observed toxicities were close to those predicted by the model. Predicted vs. observed neutrophil counts linear regression was significant (p<0.001). Moreover, 83 and 95 % weighted residuals were comprised between [-2; +2] at all courses and first course respectively. No grade 3–4 non-hematological toxicity was observed. Partial responses were noted in 2 patients (33%) and disease stabilization in 3 patients (50%). Conclusions: We report the preliminary results of the first trial using mechanistic modeling to improve cancer chemotherapy. Using this approach, we have successfully predicted the behavior of a complex biological system and individualized drugs administration in a phase I trial. No significant financial relationships to disclose.

Docetaxel is an antineoplastic agent widely used in therapeutics. The objective of this study was to develop and validate a routine assay, using liquid chromatography coupled to tandem mass spectrometry (LC/MS/MS), for the simultaneous quantification of docetaxel and its main hydroxylated metabolites in human plasma. A structural analogue, paclitaxel, was used as the internal standard. Determination of docetaxel and four metabolites (M1, M2, M3 and M4) was achieved using only 100 microL of plasma. Liquid-liquid extraction was used for sample preparation, with extraction efficiency of at least 90% for all analytes. Detection used positive-mode electrospray ionization in selected reaction monitoring mode. The lower limit of quantification (LLOQ) was 0.5 ng/mL for all analytes. The assay was linear in the calibration curve range 0.5-1000 ng/mL and acceptable precision and accuracy (<15%) were obtained with concentrations above the LLOQ. This method was sufficiently selective and sensitive for quantification of metabolites in plasma from cancer patients receiving docetaxel chemotherapy, and is suitable for routine analyses during pharmacokinetic studies.

2044 Background: Optimal duration of G-CSF prophylaxis after chemotherapy remains unknown. The study objectives were 1) to build a mixed - phenomenological/non-phenomenological - model describing the pharmacokinetic (PK) - pharmacodynamic (PD) relationships of D + E + lenograstim, including antitumor effect and haematological toxicity, 2) to predict using this model the optimal G-CSF administration schedule: duration and depth of neutropenia. Methods: The multicompartment model included D and E PK characteristics, tumor growth, blood progenitors maturation and elimination process, G-CSF effects and cytotoxicity. Clinical data regarding chemotherapy administration and blood cell counts were obtained in 65 pts (Viens et al, Am J Clin Oncol. 2001), as well as data on the PD effect of lenograstim in healthy volunteers (Chugaï laboratories). The PK parameters of D and E were found in previously published studies. The PD impact of D and E was extrapolated from in vitro studies testing those drugs separately and in combination. Data were included into the model and analyzed using MATLAB software. Results: We obtained a final model fitting the individual data. The impact of lenograstim on the depth and the duration of neutropenia was confirmed as we observed a 50% increase in the neutrophils Area Under the Curve at each cycle. The best schedule was lenograstim starting at day 5 for 5 consecutive injections. A 10-injections schedule did not add any benefit. Conclusions: Short-duration of G-CSF therapy might not be inferior to “classical” 10–15 days duration. Monitoring haematological toxicity using a mathematical model in the clinical setting seems feasible. No significant financial relationships to disclose.

BACKGROUND Patients with relapsing or refractory multiple myeloma have poor prognosis. Few compounds are active in these patients and response duration remains short. We report the results of an open phase II trial evaluating the efficacy and safety of fotemustine monotherapy. PATIENTS AND METHODS Twenty-one patients with relapsing (17) or refractory (four) multiple myeloma received fotemustine 100 mg/m(2) on an outpatient basis on days 1 and 8 of the induction cycle, followed after a 6-week rest period by fotemustine 100 mg/m(2) every 3 weeks until progression or unacceptable toxicity. Fotemustine pharmacokinetics during the first day of induction was compared between patients with normal or abnormal renal function. RESULTS Five of 20 eligible patients had an objective response giving an intention-to-treat response rate of 25% [95% confidence interval (CI) 6% to 44%] and a 35.7% response rate (95% CI 11% to 61%) in the 14 patients having received at least four injections of fotemustine. The median time to objective response was 8.9 months. The median times to progression and survival were 13.8 and 23.1 months, respectively, with a 2-year survival rate of 49%. The main toxicity was myelosuppression with grade 3-4 neutropenia and thrombocytopenia in 66% and 71% of patients, respectively. There was one toxic death by sepsis after induction. The pharmacokinetic parameters in renal-impaired patients were not significantly different from those in patients with normal renal function with a similar incidence of grade 3-4 toxicity in both groups. CONCLUSIONS Fotemustine as a single agent has definite activity in patients with relapsing or refractory multiple myeloma, with acceptable toxicity and can be administered at conventional doses in patients with mild or moderate renal impairment.

Aging is associated with multidimensional changes, including alterations in physiological functions, co-morbidities and poly-medications. These changes may lead to modifications in the absorption, distribution, metabolism and excretion of drugs. The lack of a scientific basis for optimal drug dosing in the elderly is a major problem. The development and validation of guidelines are therefore essential to improve treatment administration and monitoring in elderly patients. Even though it has been widely demonstrated that standard therapies used in adults may be of great benefit in the elderly, there may be a higher incidence of toxicity. This could be avoided by using dosage individualization based on a sound knowledge of the physiological factors implicated in the pharmacokinetic (PK) characteristics of the drugs administered and in their observed pharmacodynamic (PD) effects in each patient. The so-called "population modeling" approach renders such studies feasible by allowing the analysis of PK-PD relationships from sparse observational data.

BACKGROUND:Multiple myeloma is a malignant plasma cell disorder which still bears a dramatic prognosis. Renal insufficiency is a frequent and severe complication directly related to prognosis. The aim of our study was to establish whether an intermediate dose of intravenous melphalan, 25 mg/m2, could be safely and efficiently administered to patients with multiple myeloma and renal impairment.METHODS:Between January 1990 and April 2000, 45 patients with multiple myeloma received a single intravenous dose of melphalan, 25 mg/m2. Survival was analysed, as well as the duration of response and potential toxicity. In addition, a melphalan pharmacokinetic study was performed.RESULTS:The overall median survival was 45 +/- 43 months after diagnosis. Based on the Cockcroft and Gault formula, 79% patients had renal impairment. For the 28 stage III patients, survival was no different whether renal insufficiency was present or not. Twenty-five out of 34 patients had leukopenia for an average of 13.8 +/- 12 days, and the most frequent adverse effect was infection. The pharmacokinetic study showed that the melphalan area under the curve was positively correlated to the degree of renal insufficiency. However, this was not clinically relevant since patients with the most altered renal function, including those undergoing dialysis, did not present more episodes of leukopenia.DISCUSSION:The present study shows that renal impairment is not a contraindication for aggressive myeloma chemotherapy, even for patients undergoing dialysis. Intravenous melphalan, 25 mg/m2, is associated with good survival and acceptable side-effects. A randomised trial seems needed to compare this melphalan dose with standard melphalan/prednisone or combination chemotherapies.