Biomedical subjects

France Mentré

Publications and source records attributed to France Mentré.

At least 19 recordsLinked to original sources

PubMed2007

Impact of modelling intra-subject variability on tests based on non-linear mixed-effects models in cross-over pharmacokinetic trials with application to the interaction of tenofovir on atazanavir in HIV patients.

We evaluated the impact of modelling intra-subject variability on the likelihood ratio test (LRT) and the Wald test based on non-linear mixed effects models in pharmacokinetic interaction and bioequivalence cross-over trials. These tests were previously found to achieve a good power but an inflated type I error when intra-subject variability was not taken into account. Trials were simulated under H0 and several H1 and analysed with the NLME function. Different configurations of the number of subjects n and of the number of samples per subject J were evaluated for pharmacokinetic interaction and bioequivalence trials. Assuming intra-subject variability in the model dramatically improved the type I error of both interaction tests. For the Wald test, the type I error decreased from 22, 14 and 7.7 per cent for the original (n = 12, J = 10), intermediate (n = 24, J = 5) and sparse (n = 40, J = 3) designs, respectively, down to 7.5, 6.4 and 3.5 per cent when intra-subject variability was modelled. The LRT achieved very similar results. This improvement seemed mostly due to a better estimation of the standard error of the treatment effect. For J = 10, the type I error was found to be closer to 5 per cent when n increased when modelling intra-subject variability. Power was satisfactory for both tests. For bioequivalence trials, the type I error of the Wald test was 6.4, 5.7 and 4.2 per cent for the original, intermediate and sparse designs, respectively, when modelling intra-subject variability. We applied the Wald test to the pharmacokinetic interaction of tenofovir on atazanavir, a novel protease inhibitor. A significant decrease of the area under the curve of atazanavir was found when patients received tenofovir.

Adenine↗

PubMed2007

Estimation of population pharmacokinetic parameters of saquinavir in HIV patients with the MONOLIX software.

In nonlinear mixed-effects models, estimation methods based on a linearization of the likelihood are widely used although they have several methodological drawbacks. Kuhn and Lavielle (Comput. Statist. Data Anal. 49:1020-1038 (2005)) developed an estimation method which combines the SAEM (Stochastic Approximation EM) algorithm, with a MCMC (Markov Chain Monte Carlo) procedure for maximum likelihood estimation in nonlinear mixed-effects models without linearization. This method is implemented in the Matlab software MONOLIX which is available at http://www.math.u-psud.fr/~lavielle/monolix/logiciels. In this paper we apply MONOLIX to the analysis of the pharmacokinetics of saquinavir, a protease inhibitor, from concentrations measured after single dose administration in 100 HIV patients, some with advance disease. We also illustrate how to use MONOLIX to build the covariate model using the Bayesian Information Criterion. Saquinavir oral clearance (CL/F) was estimated to be 1.26 L/h and to increase with body mass index, the inter-patient variability for CL/F being 120%. Several methodological developments are ongoing to extend SAEM which is a very promising estimation method for population pharmacockinetic/pharmacodynamic analyses.

Administration, Oral↗

PubMed2006

Metrics for external model evaluation with an application to the population pharmacokinetics of gliclazide.

PURPOSE: The aim of this study is to define and illustrate metrics for the external evaluation of a population model. MATERIALS AND METHODS: In this paper, several types of metrics are defined: based on observations (standardized prediction error with or without simulation and normalized prediction distribution error); based on hyperparameters (with or without simulation); based on the likelihood of the model. All the metrics described above are applied to evaluate a model built from two phase II studies of gliclazide. A real phase I dataset and two datasets simulated with the real dataset design are used as external validation datasets to show and compare how metrics are able to detect and explain potential adequacies or inadequacies of the model. RESULTS: Normalized prediction errors calculated without any approximation, and metrics based on hyperparameters or on objective function have good theoretical properties to be used for external model evaluation and showed satisfactory behaviour in the simulation study. CONCLUSIONS: For external model evaluation, prediction distribution errors are recommended when the aim is to use the model to simulate data. Metrics through hyperparameters should be preferred when the aim is to compare two populations and metrics based on the objective function are useful during the model building process.

Algorithms↗

PubMed2006

[Adherence intervention for HIV-infected patients receiving antiretroviral treatment. Implementation and initial assessment].

OBJECTIVE: To describe the implementation and initial results of a specific educational and counseling intervention to examine and improve adherence to antiretroviral therapy (ARV) in HIV-infected patients. METHOD: Four patient profiles were defined: 1) discontinuation and 2) failure: patients with virological failure (defined as two consecutive viral loads>200 copies/mL) at ARV discontinuation or under treatment, both seen after the fact; 3) preparation: naive patients seen before starting treatment, and 4) reinforcement: patients in treatment seen for counseling to prevent virological failure. A clinical psychologist, nurse and hospital pharmacist jointly conducted the session. Data collected include standardized information about the characteristics of HIV infection and ARV regimens, and demographic, behavioral, social and cultural indicators. CD4 cell counts and HIV viral loads were recorded at D0, M1, M3, M9 and M12. The effectiveness of the adherence intervention was defined separately for each patient profile based on some combination of taking or restarting an ARV regimen, virological response, and M12 follow-up. RESULTS: The study included 139 patients between November 1998 and April 2000. The intervention was defined as effective in 50% and 40% of the discontinuation (n=26) and failure (n=61) patients respectively, 84% of those with preparation profile (n=37) and 93% (14/15) of reinforcement patients. Only undetectable HIV viral load at M3 was significantly associated with the effectiveness of the adherence intervention for all 4 profiles. The preventive interventions (preparation and reinforcement) were less effective in patients from outside Europe (p=0.013). CONCLUSION: The adherence intervention was more effective in preventing virological failure than in restoring ARV effectiveness among patients who had already experienced virological failure. It should therefore be proposed primarily before starting ARV, to prevent failure in treatment-naive patients, especially those from outside Europe.

Adult↗

PubMed2006

Assessment of the drug susceptibility of Plasmodium falciparum clinical isolates from africa by using a Plasmodium lactate dehydrogenase immunodetection assay and an inhibitory maximum effect model for precise measurement of the 50-percent inhibitory concentration.

The extension of drug resistance among malaria-causing Plasmodium falciparum parasites in Africa necessitates implementation of new combined therapeutic strategies. Drug susceptibility phenotyping requires precise measurements. Until recently, schizont maturation and isotopic in vitro assays were the only methods available, but their use was limited by technical constraints. This explains the revived interest in the development of replacement methods, such as the Plasmodium lactate dehydrogenase (pLDH) immunodetection assay. We evaluated a commercially controlled pLDH enzyme-linked immunosorbent assay (ELISA; the ELISA-Malaria antigen test; DiaMed AG, Cressier s/Morat, Switzerland) to assess drug susceptibility in a standard in vitro assay using fairly basic laboratory equipment to study the in vitro resistance of malaria parasites to major antimalarials. Five Plasmodium falciparum clones and 121 clinical African isolates collected during 2003 and 2004 were studied by the pLDH ELISA and the [8-(3)H]hypoxanthine isotopic assay as a reference with four antimalarials. Nonlinear regression with a maximum effect model was used to estimate the 50% inhibitory concentration (IC(50)) and its confidence intervals. The two methods were observed to have similar reproducibilities, but the pLDH ELISA demonstrated a higher sensitivity. The high correlation (r = 0.98) and the high phenotypic agreement (kappa = 0.88) between the two methods allowed comparison by determination of the IC(50)s. Recently collected Plasmodium falciparum African isolates were tested by pLDH ELISA and showed drug resistance or decreased susceptibilities of 62% to chloroquine and 11.5% to the active metabolite of amodiaquine. No decreased susceptibility to lumefantrine or the active metabolite of artemisinin was detected. The availability of this simple and highly sensitive pLDH immunodetection assay will provide an easier method for drug susceptibility testing of malaria parasites.

Africa↗

PubMed2005

Absence of association between MDR1 genetic polymorphisms, indinavir pharmacokinetics and response to highly active antiretroviral therapy.

OBJECTIVE: The relationship between MDR1 single nucleotide polymorphisms (SNP) and the pharmacokinetic or pharmacodynamic responses to protease inhibitors has been recently challenged. AIM: The objective of the present study was to determine whether MDR1 genetic polymorphisms in exons 21 and 26 (G2677T/A and C3435T) are in association with indinavir (IDV) plasma concentrations and/or therapeutic response to highly active antiretroviral therapy (HAART) in HIV-infected patients treated with unboosted IDV containing regimens. METHODS: MDR1 genotyping was performed in a population of 139 HIV-1-positive patients followed during 72 weeks, as part of the previous study called ANRS 081 'Trianon'. The primary study was a randomized trial comparing over 72 weeks the efficacy of two antiretroviral drug combinations in a population of adult HIV-1-infected patients: group 1, [lamivudine (3TC) - stavudine (d4T) - IDV (800 mg three times daily)] and group 2, [Nevirapine (NVP) - d4T - IDV (1000 mg three times daily)]. RESULTS: MDR1 SNPs analyzed separately or combined into haplotypes did not show any significant association with IDV pharmacokinetics nor response to HAART. Mean modelled IDV peak and trough concentrations, as well as clearance modelled from pharmacokinetic model, after 8 weeks of therapy were not significantly different between patients carrying the wild-type haplotype GG-CC (at position 2677 and 3435 respectively) and others. CONCLUSIONS: Our results do not support an association between MDR1 genetic polymorphisms and modelled IDV clearance or clinical response to HAART.

Adult↗

PubMed2005

Prediction discrepancies for the evaluation of nonlinear mixed-effects models.

Reliable estimation methods for non-linear mixed-effects models are now available and, although these models are increasingly used, only a limited number of statistical developments for their evaluation have been reported. We develop a criterion and a test to evaluate nonlinear mixed-effects models based on the whole predictive distribution. For each observation, we define the prediction discrepancy (pd) as the percentile of the observation in the whole marginal predictive distribution under H(0). We propose to compute prediction discrepancies using Monte Carlo integration which does not require model approximation. If the model is valid, these pd should be uniformly distributed over (0, 1) which can be tested by a Kolmogorov-Smirnov test. In a simulation study based on a standard population pharmacokinetic model, we compare and show the interest of this criterion with respect to the one most frequently used to evaluate nonlinear mixed-effects models: standardized prediction errors (spe) which are evaluated using a first order approximation of the model. Trends in pd can also be evaluated via several plots to check for specific departures from the model.

Algorithms↗

PubMed2005

Non-linear mixed effects modeling - from methodology and software development to driving implementation in drug development science.

Few scientific contributions have made significant impact unless there was a champion who had the vision to see the potential for its use in seemingly disparate areas-and who then drove active implementation. In this paper, we present a historical summary of the development of non-linear mixed effects (NLME) modeling up to the more recent extensions of this statistical methodology. The paper places strong emphasis on the pivotal role played by Lewis B. Sheiner (1940-2004), who used this statistical methodology to elucidate solutions to real problems identified in clinical practice and in medical research and on how he drove implementation of the proposed solutions. A succinct overview of the evolution of the NLME modeling methodology is presented as well as ideas on how its expansion helped to provide guidance for a more scientific view of (model-based) drug development that reduces empiricism in favor of critical quantitative thinking and decision making.

Algorithms↗

PubMed2005

Evaluation by simulation of tests based on non-linear mixed-effects models in pharmacokinetic interaction and bioequivalence cross-over trials.

We propose tests based on non-linear mixed effects models (NLMEM) in pharmacokinetic interaction and bioequivalence cross-over trials comparing two treatments or two formulations. To compare the logarithm of the area under the curve (AUC) using these models, two approaches are studied: in the first one, concentration data are analysed globally, with and without the estimation of a treatment effect; and in the second one, they are analysed separately in each treatment group with the estimation of the individual parameters. Four tests for comparison of the logarithm AUC between two treatment arms are studied: a likelihood-ratio test (LRT), a Wald test and two tests, parametric and non-parametric, comparing the individual Empirical Bayes (EB) estimates. These tests are adapted to the case of equivalence, except the LRT which does not have any simple extension. We evaluate by simulation of the type I error and the power for both comparison and equivalence tests. They are compared to the standard tests recommended by the FDA and the EMEA, based on non-compartmental (NC) AUC. Trials for a usual PK model are simulated under H(0) and several H(1) using S-plus software and analysed with the nlme function. Different configurations of the number of subjects (n=12, 24 and 40) and of the number of samples per subject (J=10, 5 and 3) are studied. The type I error alpha of LRT and Wald comparison test in the 5000 replications of interaction cross-over trials is found to be 20.9 per cent and 21.7 per cent, respectively, in the original design (n=12, J=10), which is far superior to 5 per cent, and decreases when n increases. When n is fixed, alpha is found to increase with J. Power is satisfactory for both tests, after correction of the significance threshold. Results of EB and NC tests are similar with satisfactory powers and a type I error close to 5 per cent, except when J=3 for EB tests. Similar results are obtained for equivalence tests, except for EB and NC Student tests, which are not of a great interest. NC tests keep their place when the number of samples per subject J is large, but NLMEM seem useful for cross-over studies performed in special populations where J limited; the evaluation by Monte-Carlo simulations of empirical threshold seems however necessary because of the inflation of the type I error.

Area Under Curve↗

PubMed2005

Effects of intravenous polymaltose iron on oxidant stress and non-transferrin-bound iron in hemodialysis patients.

BACKGROUND: The use of intravenous iron to correct anemia in end-stage renal diseases (ESRD) has been suspected of catalyzing the production of activated oxygen species and promoting oxidative damage. We investigated the pro-oxidative potential of injected iron in hemodialysis patients. METHODS: In study A, 65 patients with ESRD were studied. 20 patients received weekly infusions of iron polymaltose (maltofer), whereas 45 patients had been off iron therapy for more than 2 months. In study B, 12 patients were investigated during two consecutive hemodialysis sessions, one session without and one session with infusion of 100 mg of maltofer over 4 h. Serum iron status, non-transferrin-bound iron (NTBI) and markers of oxidative stress were studied in blood samples from these patients. RESULTS: In study A, NTBI was detected in 41% of the patients and the proportion of NTBI-positive patients was the same whether or not they received iron therapy. In study B, the serum iron and transferrin saturation index increased during iron infusion and NTBI transiently appeared in some patients but markers of oxidative stress were not significantly affected. CONCLUSION: Although ESRD patients have a high prevalence of NTBI in their serum, no correlation could be established between the presence of NTBI and an increased oxidative stress. The slow infusion of maltofer does not promote a significant increase in the plasma concentration of oxidative stress markers. It may therefore be considered as a safe complement to erythropoietin therapy.

Adult↗

PubMed2005

Risk factors for Staphylococcus aureus infection in liver transplant recipients.

Staphylococcus aureus is the leading cause of bacterial infection in liver transplant recipients. Preoperative nasal carriage of methicillin-resistant S. aureus (MRSA) is associated with a high risk of infection. We conducted a retrospective cohort study in order to identify independent risk factors for early-onset S. aureus infection after liver transplantation. Patients were screened preoperatively for methicillin-susceptible S. aureus (MSSA) and MRSA nasal carriage. Risk factor analysis was performed by univariate analysis followed by stepwise logistic regression. Of the 323 patients included, 63 (19.5%) patients developed S. aureus infection (36 MRSA, 27 MSSA) within 1 month of surgery. Variables significantly associated with infection in the univariate analysis were MRSA and MSSA nasal carriage, alcoholic cirrhosis, absence of hepatocellular carcinoma, decreased prothrombin ratio, and presence of ascites. In the multivariate analysis, MRSA carriage (odds ratio [OR]: 20.9, P < 0.0001), MSSA carriage (OR: 3.4, P = 0.0004), alcoholic cirrhosis (OR: 2.4, P = 0.01) and decreased prothrombin ratio (OR: 1.2, P = 0.01) were independent predictors of infection. Molecular typing showed that the infecting isolate was identical to the isolate from the nose in most patients. In conclusion, preoperative nasal carriage of MRSA and MSSA is an independent risk factor for S. aureus infection in liver transplant recipients. The infection is most often of endogenous origin. Alcoholic cirrhosis and the severity of liver failure are also associated with a high risk of infection.

Adolescent↗

PubMed2005

Indinavir plasma concentration and adherence score are codeterminant of early virologic response in HIV-infected patients of the APROCO cohort.

To study the respective roles of indinavir concentrations and treatment adherence as predictors of early virologic response, we analyzed the patients of the APROCO cohort treated by indinavir 800 mg TID during the first 4 months. Minimum (Cmin), maximum (Cmax), and the ratio of the measured to expected concentrations (CR) were estimated for each patient at M4, from a population pharmacokinetic analysis of all data. The relationship among virologic success at M4 [plasma HIV RNA (VL) <500 copies/mL], baseline characteristics, estimated indinavir concentrations, and adherence score measured by a self-administered questionnaire, was analyzed by multivariate logistic regression. In the 216 studied patients, baseline median HIV RNA was 4.4 log10 copies/mL, and CD4 cell count was 309/mm. Virologic success was achieved in 195 (90%) patients; it was independently related to baseline viral load (OR = 0.524, CI 0.29-0.93; P = 0.03), antiretroviral treatment naive status (OR = 3.89, CI 1.29-11.76; P = 0.01), and indinavir Cmin (OR = 1.06, CI 1.02-1.10; P = 0.004) when adherence score was not included in the model, whereas full adherence was the only independent related factor when included in the model (OR = 8.8, 95% CI 2.85-27.3; P < 10). In the 168 fully adherent patients, virologic success was more frequent in patients with shorter duration of antiretrovirals at baseline (P = 0.03), lower baseline HIV RNA (P = 0.03), and higher indinavir CR (P < 10); the most discriminating Cmin cut-off was 194 ng/mL. Data on the relationship between indinavir plasma concentration and virologic success are therefore misleading without a concomitant assessment of adherence. These data suggest that any strategy of therapeutic drug monitoring must imply first a combined evaluation of plasma concentrations and adherence level and second an intervention target based on the results of both assessments.

Adult↗

PubMed2005

Bayesian estimation of cyclosporin exposure for routine therapeutic drug monitoring in kidney transplant patients.

AIMS: AUC-based monitoring of cyclosporin A (CsA) is useful to optimize dose adaptation in difficult cases. We developed a population pharmacokinetic model to describe dose-exposure relationships for CsA in renal transplant patients and applied it to the Bayesian estimation of AUCs using three blood concentrations. METHODS: A total of 84 renal graft recipients treated with CsA microemulsion were included in this study. Population pharmacokinetic analysis was conducted using NONMEM. A two-compartment model with zero-order absorption and a lag time best described the data. Bayesian estimation was based on CsA blood concentrations measured before dosing and 1 h and 2 h post dose. Predictive performance was evaluated using a cross-validation approach. Estimated AUCs were compared with AUCs calculated by the trapezoidal method. The Bayesian approach was also applied to an independent group of eight patients exhibiting unusual pharmacokinetic profiles. RESULTS: Mean population pharmacokinetic parameters were apparent clearance 30 l h(-1), apparent volume of distribution 79.8 l, duration of absorption 52 min, absorption lag time 7 min. No significant relationships were found between any of the pharmacokinetic parameters and individual characteristics. A good correlation was obtained between Bayesian-estimated and experimental AUCs, with a mean prediction error of 2.8% (95% CI [-0.6, 6.2]) and an accuracy of 13.1% (95% CI [7.5, 17.2]). A good correlation was also obtained in the eight patients with unusual pharmacokinetic profiles (r(2) = 0.96, P < 0.01). CONCLUSIONS: Our Bayesian approach enabled a good estimation of CsA exposure in a population of patients with variable pharmacokinetic profiles, showing its usefulness for routine AUC-based therapeutic drug monitoring.

Adult↗

PubMed2005

Population pharmacokinetic analysis of indinavir in HIV-infected patient treated with a stable antiretroviral therapy.

The objectives of this study were to build a population pharmacokinetic model that describe plasma concentrations of indinavir in human immunodeficiency virus (HIV)-infected patients with sustained virological response under a stable antiretroviral combination, and to characterize the effect of covariates and co-medications on indinavir pharmacokinetics. Data were obtained from 45 patients who received different dosages of indinavir: either indinavir alone t.i.d. (mostly 800 mg), either indinavir b.i.d. (mostly 800 mg) with a booster dose of 100 mg of ritonavir. Patients were required to have a baseline plasma HIV RNA <200 copies/mL and to have unchanged antiretroviral treatment for 6 months. Indinavir concentrations were measured at a first visit (one sample before drug administration and five after) and at a second visit 3 months later (before and 1 or 3 h after drug administration). A one-compartment model with first-order absorption and first-order elimination best described indinavir pharmacokinetics. For patients treated with indinavir alone, absorption rate constant was estimated to be 0.43/h, and oral clearance Cl/F was 33 L/h. For patients treated with indinavir plus ritonavir these estimates were 0.25/h and 19 L/h, respectively. Cl/F was found to increase by 1.45-fold in men and by 1.18-fold in patients also receiving zidovudine. Oral volume of distribution (V/F) was 24 L. The inter-individual and intra-individual variability were 117 and 205% for V/F, 42 and 58% for Cl/F, respectively. This population analysis in patients with sustained virological response, quantified the effect of ritonavir on the absorption rate constant and on the clearance of indinavir, showed an increase of Cl/F in men and can be used to draw reference curve for therapeutic drug monitoring.

Adult↗

PubMed2005

B-type natriuretic peptide and echocardiographic determination of ejection fraction in the diagnosis of congestive heart failure in patients with acute dyspnea.

BACKGROUND: Echocardiography and B-type natriuretic peptide (BNP) are diagnostic tests for congestive heart failure (CHF), but an emergency diagnosis can be difficult. OBJECTIVE: To assess the diagnostic performance of BNP testing and echocardiographic assessment of left ventricular systolic function, separately and combined, for the identification of CHF in patients with acute dyspnea. DESIGN: Prospective, multinational, multicenter study. SETTING: Patients presenting to emergency departments in seven hospitals between June 1999 and December 2000. PATIENTS: A total of 1,586 patients with acute dyspnea. MAIN OUTCOME MEASURES: Echocardiographic determination of ejection fraction (EF) and point-of care BNP measurement for the diagnosis of CHF. RESULTS: Seven hundred nine of the 1,586 patients underwent echocardiography; 492 patients (69.4%) had a final diagnosis of CHF. Patients with CHF were older (68.5 years vs 61.6 years, p < 0.0001), had a lower EF (39.5% vs 56.1%, p < 0.0001), and a higher BNP (683 pg/mL vs 129 pg/mL, p < 0.0001) than patients without CHF. Area under the receiver operating characteristic (ROC) curve for the diagnosis of CHF was significantly higher for BNP (0.89) than for EF (0.78; area under the ROC curve difference, 0.12; p < 0.0001). The sensitivity of BNP > or = 100 pg/mL for the diagnosis of CHF was 89%, and specificity was 73%. Values for EF < or = 50% had a sensitivity of 70% and a specificity of 77%. Multivariate logistic regression analysis showed that, in combination with clinical, ECG, and chest radiograph data, BNP > or = 100 pg/mL and EF < or = 50% remained independent predictors of CHF (odds ratios, 32.1 and 6.2, respectively). The proportions of patients who were correctly classified were 67% for BNP alone, 55% for EF alone, 82% for the two variables together, and 97.3% when clinical, ECG, and chest radiograph data were added. CONCLUSION: BNP measurement was superior to two-dimensional echocardiographic determination of EF in identifying CHF, regardless of the threshold value. The two methods combined have marked additive diagnostic value.

Acute Disease↗

PubMed2005

High variability of indinavir and nelfinavir pharmacokinetics in HIV-infected patients with a sustained virological response on highly active antiretroviral therapy.

OBJECTIVES: To describe plasma concentrations of indinavir alone or combined with ritonavir, and of nelfinavir and its active metabolite M8, and to measure their variabilities in HIV-infected patients treated with a stable antiretroviral regimen and experiencing a sustained virological response for at least 12 months. PATIENTS AND METHODS: In this prospective trial, blood samples were drawn during a 6-hour time interval between two doses at enrolment to assess protease inhibitor (PI) pharmacokinetic parameters, and 4 months later to assess plasma trough and peak concentrations. Safety and adherence assessments and laboratory data were collected during an 8-month period. PI pharmacokinetic characteristics were analysed using a non-compartmental approach. Inter- and intrapatient variabilities were estimated using a linear mixed-effect model. The impact of different covariates on plasma trough concentrations was investigated. Eighty-eight patients were analysed: 42 treated with indinavir and 46 with nelfinavir. RESULTS: The interquartile range (IQR) of the plasma trough concentration corrected for the sampling time (Ccalc) was 116-374 microg/L for indinavir alone and 163-508 microg/L for indinavir/ritonavir. Ritonavir significantly increased indinavir elimination half-life and plasma exposure. For nelfinavir, the IQR of Ccalc was 896-2059 microg/L for three-times-daily administration and 998-2124 microg/L for twice-daily administration. Variabilities were high for both PIs. Intrapatient variability for indinavir alone (and indinavir + ritonavir) was 76% (107%) and interpatient variability was 58% (10%) in adherent patients. Intrapatient variability for nelfinavir three times daily (and twice daily) was 41% (74%) and interpatient variability was 62% (50%). Intrapatient variability was lowered in patients with a high adherence level. CONCLUSION: Although performed in a homogeneous population, this study documented a high interpatient but also intrapatient variability of indinavir and nelfinavir pharmacokinetics, which should be taken into account when interpreting therapeutic drug monitoring. Once patients have reached a sustained virological response, plasma PI monitoring may have a limited impact.

Adult↗

PubMed2004

Pharmacokinetics and neutrophil toxicity of paclitaxel orally administered in mice with recombinant interleukin-2.

PURPOSE: Intrinsic P-glycoprotein (P-gp) expression in the gut limits paclitaxel uptake and, thus, its bioavailability when administered orally. Interleukin-2 has been reported to be a P-gp modulator in vitro and in vivo in mice. In the work described here, the effects of interleukin-2 pretreatment on pharmacokinetics and toxicity of paclitaxel orally administered were investigated. METHODS: For the pharmacokinetic study, 96 mice were allocated to two groups receiving either 10 mg/kg of paclitaxel by the oral route alone or 16.5 microg of human recombinant interleukin-2 (rIL2) by the intraperitoneal route twice daily for 3 days and then paclitaxel. Pharmacokinetic profiles were analysed first by the Bailer method, and then using a compartmental approach. For the toxicity study, 90 Swiss mice were allocated to three groups receiving paclitaxel (10 mg/kg orally), rIL2 alone (16.5 microg i.p. twice daily for 3 days, control group), or both treatments. Haematological parameters were measured and the three groups were compared using the Bailer method. A Bonferroni correction was applied to the test. RESULTS: A complex absorption of paclitaxel was revealed. The Bailer method showed that the mean area under the curve (AUC) values over 0-24 h were not significantly different in the two groups, despite a trend to reduced AUC in the pretreated group. The AUC over 0-0.5 h was significantly higher in the group pretreated with rIL2, but represented only a fraction of total exposure. These results were confirmed by the compartmental analysis. The elimination rate constant remained the same across both groups. rIL2 thus increased paclitaxel absorption for the 15 min following oral intake of the drug but did not enhance the overall exposure. CONCLUSION: We found that a 3-day pretreatment with rIL2 had some in vivo inhibitory effects on P-gp activity for a short period after oral dosing of paclitaxel. Those results encourage further investigation of the effect of rIL2 on the overall exposure of paclitaxel. On the other hand, it seems that the joint administration of the two drugs did not increase the risk of myelosuppression, which might be worth knowing to treat advanced cancers.

Administration, Oral↗

PubMed2004

Modelling and simulation in the development and use of anti-cancer agents: an underused tool?

To help identify the role of modelling and simulation in the development of anti-cancer agents, their main advantages and the obstacles to their rational use, an expert meeting was organized by COST B15. This manuscript presents a synthesis of views expressed at that meeting and indicates future directions. The manuscript also shows some examples where modelling and simulation have proven to be of relevant value in the drug development process for anti-cancer agents.

Antineoplastic Agents↗