Population pharmacokinetics and pharmacodynamics of cisplatinum during hyperthermic intraperitoneal chemotherapy using a closed abdominal procedure.

The aim of this work was to study the pharmacokinetics of cisplatinum during closed abdominal hyperthermic intraperitoneal chemotherapy (HIPEC) using a population pharmacokinetics approach. Forty patients were treated between January 2003 and December 2004. Peritoneal and blood concentrations of cisplatinum were used to develop a pharmacokinetic model of the peritoneal and plasma compartments using NONMEM software. Different covariables were analyzed to identify those that explain part of the interindividual variability of the pharmacokinetic parameters. Relationships between the area under the concentration-time curve (AUC) and hematological and renal toxicity and efficiency were explored. The pharmacokinetics of cisplatinum were modeled with a 3-compartment model. Estimations of the plasma and peritoneal pharmacokinetic parameters were obtained. No clinical or biological covariates correlated with these parameters. No direct relationship between the AUC of the peritoneal or plasma and toxicity or efficiency was demonstrated. The pharmacokinetics during HIPEC could be modeled with a 3-compartment model using a population pharmacokinetics approach. This work is the basis of further studies. Notably, studies including new patients will analyze the impact of abdominal cavity volume and the variation of the abdominal pressure during HIPEC on the pharmacokinetics of cisplatinum.

Predictive value of modeled AUC(AFP-hCG), a dynamic kinetic parameter characterizing serum tumor marker decline in patients with nonseminomatous germ cell tumor.

OBJECTIVE: The early decline profile of alpha-fetoprotein (AFP) and human chorionic gonadotropin (hCG) in patients with nonseminomatous germ cell tumors (NSGCT) treated with chemotherapy may be related to the risk of relapse. We assessed the predictive values of areas under the curve of hCG (AUC(hCG)) and AFP (AUC(AFP)) of modeled concentration-time equations on progression-free survival (PFS). METHODS: Single-center retrospective analysis of hCG and AFP time-points from 65 patients with IGCCCG intermediate-poor risk NSGCT treated with 4 cycles of bleomycin-etoposide-cisplatin (BEP). To determine AUC(hCG) and AUC(AFP) for D0-D42, AUCs for D0-D7 were calculated using the trapezoid rule and AUCs for D7-D42 were calculated using the mathematic integrals of equations modeled with NONMEM. Combining AUC(AFP) and AUC(hCG) enabled us to define 2 predictive groups: namely, patients with favorable and unfavorable AUC(AFP-hCG). Survival analyses and ROC curves assessed the predictive values of AUC(AFP-hCG) groups regarding progression-free survival (PFS) and compared them with those of half-life (HL) and time-to-normalization (TTN). RESULTS: Mono-exponential models best fit the patterns of marker decreases. Patients with a favorable AUC(AFP-hCG) had a significantly better PFS (100% vs 71.5%, P = .014). ROC curves confirmed the encouraging predictive accuracy of AUC(AFP-hCG) against HL or TTN regarding progression risk (ROC AUCs = 79.6 vs 71.9 and 70.2 respectively). Because of the large number of patients with missing data, multivariate analysis could not be performed. CONCLUSION: AUC(AFP-hCG) is a dynamic parameter characterizing tumor marker decline in patients with NSGCT during BEP treatment. Its value as a promising predictive factor should be validated.

Pharmacokinetically based estimation of patient compliance with oral anticancer chemotherapies: in silico evaluation.

BACKGROUND AND OBJECTIVES: More and more anticancer chemotherapies are now available as oral formulations. This relatively new route of administration in oncology leads to problems with patient education and non-compliance. The aim of this study was to explore the performances of the 'inverse problem', namely, estimation of compliance from pharmacokinetics. For this purpose, we developed and evaluated a method to estimate patient compliance with an oral chemotherapy in silico (i) from an a priori population pharmacokinetic model; (ii) with limited optimal pharmacokinetic information collected on day 1; and (iii) from a single pharmacokinetic sample collected after multiple doses. METHODS: Population pharmacokinetic models, including estimation of all fixed and random effects estimated on a prior dataset, and sparse samples taken after the first dose, were combined to provide the individual POSTHOC Bayesian pharmacokinetic parameter estimates. Sampling times on day 1 were chosen according to a D-optimal design. Individual pharmacokinetic profiles were simulated according to various dose-taking scenarios. To characterize compliance over the n previous dosing times (supposedly known without error), 2n different compliance scenarios of doses taken/not taken were considered. The observed concentration value was compared with concentrations predicted from the model and each compliance scenario. To discriminate between different compliance profiles, we used the Euclidean distance between the observed pharmacokinetic values and the predicted values simulated without residual errors. This approach was evaluated in silico and applied to imatinib and capecitabine, the pharmacokinetics of which are described in the literature, and which have quite different pharmacokinetic characteristics (imatinib has an elimination half-life of 17 hours, and alpha-fluoro-beta-alanine [FBAL], the metabolite of capecitabine, has an elimination half-life of 3 hours). 1000 parameter sets were drawn according to population distributions, and concentration values were simulated at several timepoints under various compliance patterns to compare with the predicted ones. In addition, several simulation scenarios were run in order to explore the impact of the quality of the error model, interoccasion variability (IOV), error in the number of pills taken, and the performance of the compliance estimation method. RESULTS: The best compliance estimate was obtained with pharmacokinetic samples taken 5 hours after the last dose. Performance of the method varied between simulation scenarios. In both the imatinib and capecitabine basic simulations, patient compliance was correctly estimated on the two last scheduled doses (with better results for imatinib). The magnitude of the error model also had a great impact on the quality of the compliance estimate. CONCLUSIONS: We highlight the effect of three parameters on the quality of compliance estimates based on limited pharmacokinetic information: the plasma elimination half-life, interdose interval and magnitude of the error model. Nevertheless, the pharmacokinetic method is not informative enough and should be used with electronic monitoring, which provides additional information on compliance. Our method will be used in a future phase IV clinical trial where the relationships between compliance, efficacy and tolerability will be assessed.

Etoposide pharmacokinetics and survival in patients with small cell lung cancer: a multicentre study.

PURPOSE: To investigate the prognostic value of systemic exposure to etoposide (Area Under the concentration Curve (AUC(VP16))) on overall survival (OS) in patients with small cell lung cancer (SCLC). PATIENTS AND METHODS: Data from 52 patients with limited stage (n=17) or metastatic (n=35) SCLC were analysed. They received at least two courses of etoposide (120mg/(m(2)day) on 3 days) combined with either doxorubicin-ifosfamide (AVI, n=29) or platinum compounds (carboplatin: n=16; cisplatin: n=7). Population pharmacokinetic-pharmacodynamic (PK-PD) study was performed using NON-linear Mixed Effect Model (NONMEM) and Splus software with univariate and multivariate analyses. RESULTS: Etoposide plasma concentration vs. time was described by a two compartment model. Etoposide clearance (CL) was significantly dependant on serum creatinine (Scr). Ifosfamide (IFO) coadministration increased etoposide clearance by 28% (median CL(VP16): 2.42L/h vs. 1.89L/h, p<0.0005) leading to a reduced systemic exposure (median AUC(VP16): 260mgh/L vs. 339mgh/L). No influence of body surface area (BSA) on CL(VP16) was observed. Median percent decrease of absolute neutrophil count (ANC) after the first chemotherapy course was greater when etoposide 24h concentration was above 0.33mg/L (88% vs. 0%, p=0.028). Median OS was significantly longer in patients treated without ifosfamide (11.0 months vs. 7.0 months, p=0.049) and in patients with CL(VP16)<2.22L/h (14 months vs. 7 months, p=0.013) and AUC(VP16)>254.8mgh/L (11 months vs. 7 months, p=0.048). The independent prognostic factors regarding OS were LDH, CL(VP16) and AUC(VP16). CONCLUSION: In this study it was found that CL(VP16) is reduced in patients with elevated serum creatinine, whilst ifosfamide coadministration increases CL(VP16) and reduces AUC(VP16), demonstrating the interaction between VP16 and ifosfamide. CL(VP16) and AUC(VP16) correlate significantly with overall survival of patients with SCLC patients receiving etoposide regimens.

Advantages of prostate-specific antigen (PSA) clearance model over simple PSA half-life computation to describe PSA decrease after prostate adenomectomy.

OBJECTIVES: A population kinetic approach based on PSA clearance (CL(PSA)) may be a more rational strategy to characterize prostate-specific antigen (PSA) decrease profile after prostate surgery than the commonly used method (half-life from mono/bi-exponential models). METHODS: We used 182 post-adenomectomy PSA concentrations from 56 benign prostatic hyperplasia patients to build, with NONMEM software, a multi-exponential and a CL(PSA) model for comparison. RESULTS: The best multi-exponential model was PSA(t)=4.96e(-)(0.269t)+3.10e(-)(0.16t)+0.746e(+)(0.0002t) with a stable median residual PSA at 0.64 ng/mL. The best model parametrized with clearance was CL(PSA)=0.0229()(AGE/69)(3.78). Akaike information criteria and standard errors favored the CL(PSA) model. Median peripheral zone and transitional zone productions were 0.034 ng/mL/cm(3) and 0.136 ng/mL/g. A threshold at 2 ng/mL on day 90 allowed for a diagnostic of biochemical relapse diagnostic. CONCLUSIONS: The population CL(PSA) model was superior to the multi-exponential approach for investigating individual post-adenomectomy PSA decreases.

[Pharmacology of anticancer drugs in the elderly: tools for dose-adjustment]. / Pharmacologie des agents anticancéreux chez le sujet âgé: une aide à l'adaptation des doses.

Life expectancy increasing and cancer incidence rising with age, geriatric and cancer care will become a significant medical, public health, challenge. It is possible that the lack of efficacy of cancer therapies in the elderly may simply be due to the fact that physicians reduce anticancer drug doses empirically, in order to avoid "putative" toxicities that might arise as a result of alterations of physiological functions or as a result of co-morbidities generally present within this population. However, many authors have demonstrated that some patients over 70 years old could tolerate and obtain same benefit from therapies as younger adults, when some who are frail need less aggressive therapies. It is imperative that decisions regarding the management of cancer in older persons should be based upon the individual needs and fitness of the patient, and not based on chronological age. The main difficulty is the lack of scientific references on optimal treatment-dosing in the elderly, and we cannot extrapolate, as it stands, the information from younger patient. Indeed, aging is associated with multidimensional changes, including alteration of physiological status, comorbidities and polymedications. These changes may lead to pharmacokinetic (PK) modifications, namely in absorption, distribution, metabolism and elimination of drugs as well as pharmacodynamic (PD) modifications. Prospective studies need to be implemented in the elderly in order to study in depth the PK and PD properties of the drugs used for these patients, and establish PK-PD relationships in this specific population. Such studies have been successfully conducted in the elderly, some of them leading to dose recommendations. This paper detail the different sources of PK-PD variability in the elderly, some practical considerations regarding the design of studies using the population approach, as well as some examples of studies performed in the elderly. We conclude with some recommendations in this population at risk.

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.

PURPOSE: Paclitaxel and carboplatin are frequently used in advanced ovarian cancer following cytoreductive surgery. Threshold models have been used to predict paclitaxel pharmacokinetic-pharmacodynamics, whereas the time above paclitaxel plasma concentration of 0.05 to 0.2 micromol/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.

Population pharmacokinetics and pharmacodynamics of doxorubicin and cyclophosphamide in breast cancer patients: a study by the EORTC-PAMM-NDDG.

AIMS: To investigate the population pharmacokinetics and pharmacodynamics of doxorubicin and cyclophosphamide in breast cancer patients. PATIENTS AND METHODS: Sixty-five female patients with early or advanced breast cancer received doxorubicin 60 mg/m(2) over 15 minutes followed by cyclophosphamide 600 mg/m(2) over 15 minutes. The plasma concentration-time data of both drugs were measured, and the relationship between drug pharmacokinetics and neutrophil counts was evaluated using nonlinear mixed-effect modelling. Relationships were explored between drug exposure (the area under the plasma concentration-time curve [AUC]), toxicity and tumour response. RESULTS: Fifty-nine patients had complete pharmacokinetic and toxicity data. In 50 patients with measurable disease, the objective response rate was 60%, with complete responses in 6% of patients. Both doxorubicin and cyclophosphamide pharmacokinetics were associated with neutrophil toxicity. Cyclophosphamide exposure (the AUC) was significantly higher in patients with at least stable disease (n = 44) than in patients with progressive disease (n = 6; 945 micromol . h/L [95% CI 889, 1001] vs 602 micromol . h/L [95% CI 379, 825], p = 0.0002). No such correlation was found for doxorubicin. Body surface area was positively correlated with doxorubicin clearance; AST and patient age were negatively correlated with doxorubicin clearance; creatinine clearance was positively correlated with doxorubicinol clearance; and occasional concurrent use of carbamazepine was positively correlated with cyclophosphamide clearance. CONCLUSIONS: The proposed inhibitory population pharmacokinetic-pharmacodynamic model adequately described individual neutrophil counts after administration of doxorubicin and cyclophosphamide. In this patient population, exposure to cyclophosphamide, as assessed by the AUC, might have been a predictor of the treatment response, whereas exposure to doxorubicin was not. A prospective study should validate cyclophosphamide exposure as a predictive marker for the treatment response and clinical outcome in this patient group.

[Issues of the study of patient compliance to treatment with oral anticancer chemotherapy: advantages of pharmacokinetics-pharmacodynamics modelisation]. / Les enjeux de l'observance pour les nouvelles chimiothérapies par voie orale: intérêt du modèle pharmacocinétique-pharmacodynamique.

Nowadays, more and more oral anticancer chemotherapies are developed either for cytotoxic or new targeted drugs. But this relatively new route of administration in oncology drives to new problems in treatment management and particularly to non-compliance, i.e. the deviance of the actual way patients take their treatment with the prescription. Population PK-PD models and Monte-Carlo simulations allow to study the impact of non-compliance on toxicities. After a brief review on recent developments about oral chemotherapies, this work presents a simulation where non-compliance, modelled with a two state Markov chain defining four compliance profiles from excellent to poor, is linked to two dose-toxicity (continuous or categorical) population models. Simulated patients with the lowest compliance level were less exposed to treatment and therefore experienced less toxicity with shorter events. Nevertheless treatment efficacy is also lower, and this loss of efficacy may compromise patient's outcome. These results foresee the necessity of global simulations, combining compliance, toxicity and efficacy modelling.

Exposure-effect population model of inolimomab, a monoclonal antibody administered in first-line treatment for acute graft-versus-host disease.

BACKGROUND AND OBJECTIVE: Inolimomab, a monoclonal antibody against interleukin (IL)-2Ralpha (CD25) has shown promising results in the treatment of corticosteroid-resistant acute graft-versus-host disease (GvHD). The objective of the present study was to characterise the pharmacokinetic and pharmacodynamic properties of inolimomab as first-line treatment in this condition. METHODS: The data came from 21 patients with acute GvHD (8 with an International Bone Marrow Transplant Registry [IBMTR] score of B, 11 with a score of C and 2 with a score of D) following haematopoietic stem cell transplantation after a median delay of 26 days (range 10-127 days). Inolimomab was administered at 0.1, 0.2, 0.3 or 0.4 mg/kg daily in association with methylprednisolone (2 mg/kg) for 8 or 16 days depending on the status at day 9. Then, for responder patients, administrations were continued three times weekly until day 28. Inolimomab concentrations and pharmacodynamic data (acute GvHD scores) were recorded during the study. The pharmacodynamic data were assessed in four grades according to the IBMTR and Glucksberg classification in parallel with Karnofsky scores. A population analysis was developed using a nonlinear mixed-effects model to define the pharmacokinetic model, to test covariates and, when apparent, to model the exposure-effect relationship by a proportional odds model. The modelling was finally qualified by a predictive check. RESULTS: The best pharmacokinetic model was two-compartmental. For each score, the most demonstrative exposure-effect graphics linked the cumulative area under the concentration-time curve to cumulated probabilities of observing a specific score. This relationship was identified as a maximum effect model for the skin (with two patient subpopulations: sensitive/less sensitive) and a linear model for the intestinal tract and liver. No covariate was identified as influencing any of these parameters. CONCLUSION: Inolimomab exposure-effect relationships as first-line treatment for acute GvHD have been identified and modelled. The discovered dose-effect relationship allows confirmation of the treatment response, thereby establishing the first step towards optimising the inolimomab dosage in future trials.

International Society of Geriatric Oncology Chemotherapy Taskforce: evaluation of chemotherapy in older patients--an analysis of the medical literature.

The elderly comprise the majority of patients with cancer and are the recipients of the greatest amount of chemotherapy. Unfortunately, there is a lack of data to make evidence-based decisions with regard to chemotherapy. This is due to the minimal participation of older patients in clinical trials and that trials have not systematically evaluated chemotherapy. This article reviews the available information with regard to chemotherapy and aging provided by a task force of the International Society of Geriatric Oncology (SIOG). Due to the lack of prospective data, the conclusions and recommendations made are a consensus of the participants. Extrapolation of data from younger to older patients is necessary, particularly to those patients older than 80 years, for which data is almost entirely lacking. The classes of drugs reviewed include alkylators, antimetabolites, anthracyclines, taxanes, camptothecins, and epipodophyllotoxins. Clinical trials need to incorporate an analysis of chemotherapy in terms of the pharmacokinetic and pharmacodynamic effects of aging. In addition, data already accumulated need to be reanalyzed by age to aid in the management of the older cancer patient.

Contribution of modelling chemotherapy-induced hematological toxicity for clinical practice.

Anticancer chemotherapies are responsible for numerous adverse events. Among these, hematological toxicity is one of the main causes for ending treatment. These toxicities decrease production of red blood cells (anemia), production of white blood cells (neutropenia or granulocytopenia), and production of platelets (thrombocytopenia), which may be life-threatening to the patient. Preventing such discontinuation would be valuable for treating patients more effectively. In order to achieve this goal, numerous mathematical and physiological or semiphysiological models have been developed. The complexity of models has increased over the years, from empiric E(max) models to mechanistic models including physiological mechanisms such as feedback control. This review discusses several approaches of modelling hematological toxicities illustrated with some examples: pharmacodynamic models for the hematological toxicity of 5-fluorouracil, epirubicin, melphalan, paclitaxel, topotecan, and indisulam.

Are population pharmacokinetic and/or pharmacodynamic models adequately evaluated? A survey of the literature from 2002 to 2004.

Model evaluation is an important issue in population analyses. We aimed to perform a systematic review of all population pharmacokinetic and/or pharmacodynamic analyses published between 2002 and 2004 to survey the current methods used to evaluate models and to assess whether those models were adequately evaluated. We selected 324 articles in MEDLINE using defined key words and built a data abstraction form composed of a checklist of items to extract the relevant information from these articles with respect to model evaluation. In the data abstraction form, evaluation methods were divided into three subsections: basic internal methods (goodness-of-fit [GOF] plots, uncertainty in parameter estimates and model sensitivity), advanced internal methods (data splitting, resampling techniques and Monte Carlo simulations) and external model evaluation. Basic internal evaluation was the most frequently described method in the reports: 65% of the models involved GOF evaluation. Standard errors or confidence intervals were reported for 50% of fixed effects but only for 22% of random effects. Advanced internal methods were used in approximately 25% of models: data splitting was more often used than bootstrap and cross-validation; simulations were used in 6% of models to evaluate models by a visual predictive check or by a posterior predictive check. External evaluation was performed in only 7% of models. Using the subjective synthesis of model evaluation for each article, we judged the models to be adequately evaluated in 28% of pharmacokinetic models and 26% of pharmacodynamic models. Basic internal evaluation was preferred to more advanced methods, probably because the former is performed easily with most software. We also noticed that when the aim of modelling was predictive, advanced internal methods or more stringent methods were more often used.

Evaluation of uncertainty parameters estimated by different population PK software and methods.

The uncertainty associated with parameter estimations is essential for population model building, evaluation, and simulation. Summarized by the standard error (SE), its estimation is sometimes questionable. Herein, we evaluate SEs provided by different non linear mixed-effect estimation methods associated with their estimation performances. Methods based on maximum likelihood (FO and FOCE in NONMEM, nlme in Splus, and SAEM in MONOLIX) and Bayesian theory (WinBUGS) were evaluated on datasets obtained by simulations of a one-compartment PK model using 9 different designs. Bootstrap techniques were applied to FO, FOCE, and nlme. We compared SE estimations, parameter estimations, convergence, and computation time. Regarding SE estimations, methods provided concordant results for fixed effects. On random effects, SAEM and WinBUGS, tended respectively to under or over-estimate them. With sparse data, FO provided biased estimations of SE and discordant results between bootstrapped and original datasets. Regarding parameter estimations, FO showed a systematic bias on fixed and random effects. WinBUGS provided biased estimations, but only with sparse data. SAEM and WinBUGS converged systematically while FOCE failed in half of the cases. Applying bootstrap with FOCE yielded CPU times too large for routine application and bootstrap with nlme resulted in frequent crashes. In conclusion, FO provided bias on parameter estimations and on SE estimations of random effects. Methods like FOCE provided unbiased results but convergence was the biggest issue. Bootstrap did not improve SEs for FOCE methods, except when confidence interval of random effects is needed. WinBUGS gave consistent results but required long computation times. SAEM was in-between, showing few under-estimated SE but unbiased parameter estimations.

Therapeutic drug monitoring for dose individualization of Cisplatin in testicular cancer patients based upon total platinum measurement in plasma.

Cisplatin (CDDP) is an anticancer agent widely used in testicular cancer, for which pharmacokinetic (PK)/pharmacodynamic relationships have usually been based upon measurement of its unbound fraction in plasma. Because it has been shown that free CDDP clearance can be related to patient's body surface area (BSA), dosage is mostly adjusted a priori using only this single parameter, with mixed results for accurately predicting CDDP exposure and reducing toxicities. In contrast, the authors present here an original, 5-day continuous infusion schedule, coupled to a daily Bayesian adaptive dosing with feedback strategy, based upon the rapid assay of total, rather than free, CDDP in plasma. Nineteen patients (66 therapeutic courses) were treated with platinum-based combinational therapy. Plasma samples were analyzed to allow real-time Bayesian estimation of individual PK parameters with subsequent prospective dose adjustment in order to reach a target Cmax (Cend) of 1.95 mg/L of total platinum. Performance of the Bayesian dosing method was evaluated by comparing target Cmax with achieved Cmax. The mean+/-SD Cmax achieved was 1.93+/-0.16 mg/L. No statistically significant difference was observed between experimental and target values (P>0.05, t test), and Cend achievement was done with an overall 6.6% precision, a performance to be compared with the initial 54% interpatient variability observed in CDDP clearance. A nonlinear mixed effect model population PK analysis was subsequently performed to identify retrospectively the covariates associated with PK parameters of total CDDP. It showed a good correlation (r=0.84, P=0.004) between total platinum clearance and therapeutic course number. A weaker correlation (r=0.59) was found between BSA and total CDDP clearance and, importantly, no additional relationship was established with BSA when successive therapeutic courses, and not only the first one, were considered. This highlights the critical importance of total drug accumulation on CDDP pharmacokinetics when several infusions are to be administered in a row and, therefore, the need for real-time dose individualization that takes into account the course number, rather than BSA. Finally, doses of CDDP administered during each course were significantly higher (+20%, P<0.01) than the ones classically normalized with BSA, thus leading to an overall greater drug exposure in the patients. It is noteworthy that despite these markedly higher doses, little severe toxicity was reported, and all of the patients presented in this study were still alive and disease free after a follow-up of up to 15 years.

Dose individualization of carboplatin after a 120-hour infusion schedule: higher dose intensity but fewer toxicities.

Carboplatin (CBDCA) is a widely used anticancer agent for which dose-effect and dose-toxicity relationships have been demonstrated, thus stressing the need for a controlled exposure to this drug. So far, carboplatin administration could only be individualized a priori following 2 classic methods, which are based on the evaluation of renal clearance: Calvert's and Chatelut's formulas. This study was designed to develop and evaluate the performance of an alternative CBDCA 120-hour schedule coupled to a Bayesian adaptive dosing with feedback strategy. Precision of the dosing method was assessed in 84 patients (256 courses performed during a 10-year period), by comparing CBDCA plasma concentrations observed at the end of the infusion with initial target values. A comprehensive monitoring of treatment-related toxicities also was performed. Finally, the authors compared doses actually delivered following the dose-tailoring method with the theoretical, standard, ones calculated retrospectively with Calvert's and Chatelut's formulas. No significant differences were found between experimental and theoretical concentrations. According to the target exposure chosen (3 levels), the mean doses administered to our patients were 517, 719, and 902 mg of CBDCA compared with 550, 509, and 538 or 657, 604, and 644 mg, which would have been given following Calvert or Chatelut formulas, respectively. These results showed that our Bayesian method led to the administration of up to 60% higher doses of carboplatin compared with those based only on the evaluation of renal clearance. Despite the markedly higher doses administered, no severe toxicities were reported in the patients treated following this new schedule. It is noteworthy that neither hematologic growth factors nor stem cells, usually associated with high-dose regimen, were used as support in this study. These data strongly suggest that it is possible to deliver higher dose- intensities of carboplatin, even in elderly, unselected patients, without increasing toxicities and with no growth factor support, provided that a therapeutic drug monitoring strategy with real-time tailored dosing is performed.

Pharmacology of cytotoxic agents: a helpful tool for building dose adjustment guidelines in the elderly.

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.

Intermediate-dose (25mg/m2) IV melphalan for multiple myeloma with renal failure.

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.

A simultaneous oral/intravenous population pharmacokinetic model for vinorelbine.

OBJECTIVES: To develop a population pharmacokinetic (PK) model for simultaneous analysis of oral and intravenous data, to compare the variability between the two routes of administration of vinorelbine, to search for the main patient characteristics that explain this variability, and to estimate the mean population bioavailability of oral vinorelbine. PATIENTS AND METHODS: A PK model was developed from 175 phase I/II patients (419 courses) treated by intravenous (20-45 mg/m2) and/or oral (60-100 mg/m2) vinorelbine given as monotherapy. Oral and intravenous PK data were simultaneously fitted using the NONMEM program, allowing the estimation of oral PK parameters such as the bioavailability factor in patients who received only the oral formulation. Covariates included demographic characteristics, biological markers, hematological parameters, liver metastases, early vomiting, and food intake. The population covariate model was developed from rich sampling data ( n=187 phase I courses) and then assessed from sparse sampling data ( n=232 phase II courses). RESULTS: A three-compartment model best described the combined oral/intravenous blood concentration-time data. The mean absolute bioavailability was 36%, with moderate interindividual (CV=20%) and intraindividual (CV=19%) variability. Bayesian clearance was accurately estimated in 180 of 187 patients. The clearance of oral and intravenous vinorelbine showed comparable variability at usual doses (25-30 mg/m2 intravenous; CV=26%; 60-80 mg/m2 oral, CV=33%) and was moderately increased when including maximum tolerated doses (20-45 mg/m2 intravenous, CV=27%; 60-100 mg/m2 oral, CV=36%). Several relevant covariate relationships influencing the total body clearance of vinorelbine were independent of the route of administration: body surface area (proportional relationship), platelet count above 400 x 10(9)/l (negative correlation), creatinine clearance (positive correlation), and elevated transaminases (negative correlation). Food intake induced a lag time in the absorption of oral vinorelbine. A weak and poorly estimated relationship was observed between elevated alkaline phosphatase levels and bioavailability, although hepatic markers such as GGT, LDH, total protein, and liver metastases and age had no effect on vinorelbine pharmacokinetics. CONCLUSIONS: By means of the simultaneous analysis of oral and intravenous data the bioavailability (F=36%) and its associated variability were estimated. At usual doses similar levels of variability were observed between oral and intravenous routes. As a result of the identification of covariates from phase I data and their confirmation from phase II data further explorations based on limited sampling strategies are now possible. The use of a simultaneous oral/intravenous model allows a better characterization of the PK profile of vinorelbine after administration by either vascular or oral route

Population pharmacokinetics model and limited sampling strategy for intravenous vinorelbine derived from phase I clinical trials.

AIMS: a) To characterize the pharmacokinetics of intravenous vinorelbine, b) to use a population analysis for the identification of patient covariates that might appreciably influence its disposition and c) to define a limited sampling strategy for further Bayesian estimation of individual pharmacokinetic parameters. METHODS: All data were collected from 64 patients (99 courses) entered in three different phase I trials that have been previously reported. All patients received vinorelbine as a 20 min infusion with dose levels ranging from 20-45 mg m-2. The population pharmacokinetic model was built in a sequential manner on a subset of two-thirds of the data, starting with a covariate-free model then progressing to a covariate model using the nonlinear-mixed effect methodology. The remaining one-third of the data were used to validate several sparse sampling designs. RESULTS: A linear three-compartment model characterized vinorelbine blood concentrations (n=1228). Two primary pharmacokinetic parameters (total clearance and volume of distribution) were related to various combinations of covariates. The relationship for total clearance (CLtotal (l h-1)=29.2xBSAx(1-0.0090 Plt)+6.7xWt/Crs) was dependent on the patient's body surface area (BSA), weight (Wt), serum creatinine (Crs) and platelet count before administration (Plt). The optimal limited sampling strategy consisted of a combination of three measured blood concentrations; the first immediately before the end of infusion or 20 min later, the second at either 1 h, 3 h or 6 h and the third at 24 h after drug administration. CONCLUSIONS: A population pharmacokinetic model and a limited sampling strategy for intravenous vinorelbine have been developed. This is the first population analysis performed on the basis of a large phase I database that has identified clinical covariates influencing the disposition of i.v. vinorelbine. The model can be used to obtain accurate Bayesian estimates of pharmacokinetic parameters in situations where extensive pharmacokinetic sampling is not feasable.