Biomedical subjects

Jean-Louis Steimer

Publications and source records attributed to Jean-Louis Steimer.

5 recordsLinked to original sources

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↗

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↗

PubMed2004

A semimechanistic and mechanistic population PK-PD model for biomarker response to ibandronate, a new bisphosphonate for the treatment of osteoporosis.

AIMS: Ibandronate, a highly potent nitrogen-containing bisphosphonate, is the subject of an ongoing clinical development programme that aims to maximize the potential of simplified, less frequent oral and intravenous (i.v.) administration in osteoporosis. A modelling and simulation project was undertaken to characterize further the clinical pharmacology of ibandronate and identify convenient intermittent oral and i.v. regimens for clinical evaluation. METHODS AND RESULTS: Using selected data from clinical studies involving 174 women with postmenopausal osteoporosis (PMO), a classical multicompartmental pharmacokinetic-pharmacodynamic (PK-PD) model was developed that accurately described the PK of i.v. ibandronate in plasma and urine and urinary excretion of the C-telopeptide of the alpha chain of type I collagen (uCTX), a sensitive biomarker of PD response to ibandronate. To reduce processing times, the classical PK-PD model was simplified using a "kinetics of drug action" or kinetic (K)-PD model (i.e. a dose-response model as opposed to a dose-concentration-response model). The performance of the K-PD model was evaluated by fitting data simulated with the PK-PD model under various dosing regimens. The simplified model produced a virtually indistinguishable fit of the data from that of the PK-PD model. The K-PD model was extended to consider the influence of supplemental therapy (calcium with or without vitamin D) on the PD response and validated by retrospectively simulating the uCTX response in a prior Phase III and Phase II/III study of i.v. ibandronate, given once every 3 months, in 3380 women with PMO. The observed median uCTX responses at the scheduled assessment points in the completed studies were within the distribution of the simulated responses. The K-PD model for i.v. ibandronate was extended further to allow simultaneous fitting of uCTX responses after i.v. and oral administration in 676 postmenopausal women with osteoporosis, and validated by retrospectively simulating the data observed in a Phase I study of oral daily ibandronate in 180 women with PMO. The K-PD model adequately described the uCTX response after oral dosing. CONCLUSIONS: This validated K-PD model is currently being used to evaluate a range of novel intermittent oral and i.v. ibandronate regimens in an ongoing clinical development programme.

Administration, Oral↗

PubMed2003

Clinical pharmacokinetic/pharmacodynamic and physiologically based pharmacokinetic modeling in new drug development: the capecitabine experience.

Preclinical studies, along with Phase I, II, and III clinical trials demonstrate the pharmacokinetics, pharmacodynamics, safety and efficacy of a new drug under well controlled circumstances in relatively homogeneous populations. However, these types of studies generally do not answer important questions about variability in specific factors that predict pharmacokinetic and pharmacodynamic (PKPD) activity, in turn affecting safety and efficacy. Semi-physiological and clinical PKPD modeling and simulation offer the possibility of utilizing data obtained in the laboratory and the clinic to make accurate characterizations and predictions of PKPD activity in the target population, based on variability in predictive factors. Capecitabine is an orally administered pro-drug of 5-fluorouracil (5-FU), designed to exploit tissue-specific differences in metabolic enzyme activities in order to enhance efficacy and safety. It undergoes extensive metabolism in multiple physiologic compartments, and presents particular challenges for predicting pharmacokinetic and pharmacodynamic activity in humans. Clinical and physiologically based pharmacokinetic (PBPK) and pharmacodynamic models were developed to characterize the activity of capecitabine and its metabolites, and the clinical consequences under varying physiological conditions such as creatinine clearance or activity of key metabolic enzymes. The results of the modeling investigations were consistent with capecitabine's rational design as a triple pro-drug of 5-FU. This paper reviews and discusses the PKPD and PBPK modeling approaches used in capecitabine development to provide a more thorough understanding of what the key predictors of its PBPK activity are, and how variability in these predictors may affect its PKPD, and ultimately, clinical outcomes.

Animals↗

PubMed2003

Population pharmacokinetics and concentration-effect relationships of capecitabine metabolites in colorectal cancer patients.

AIMS: To assess the relationship between systemic exposure to capecitabine metabolites and parameters of efficacy and safety in patients with advanced or metastatic colorectal cancer from two phase III studies. METHODS: Concentration-effect analyses were based on data from 481 patients (248 males, 193 females; age range 27-86 years) in two phase III studies. Plasma concentration-time data for 5'-deoxy-5-fluorouridine (5'-DFUR), 5-fluorouracil (5-FU) and alpha-fluoro-beta-alanine (FBAL) were obtained from sparse blood samples collected within the time windows 0.5-1.5 h, 1.5-3.0 h, and 3.0-5.0 h after capecitabine administration (1250 mg m(-2)) on the first day of cycles 2 (day 22) and 4 (day 64), respectively. Systemic exposure based on plasma concentrations of capecitabine and its metabolites was determined using individual parameter estimates derived from a population pharmacokinetic model constructed for this purpose in NONMEM. Logistic regression analysis was conducted for selected safety parameters (all treatment-related grade 3-4 adverse events, treatment-related grade 3-4 diarrhoea, grade 3 hand-foot syndrome (HFS) and grade 3-4 hyperbilirubinaemia) and for tumour response. Cox regression analysis was used for the analysis of time-to-event data (time to disease progression and duration of survival). RESULTS: Statistically significant relationships between covariates and PK parameters were found as follows. A doubling of alkaline phosphatase activity was associated with a 11% decrease in 5-FU clearance and a 12% increase in its AUC. A 50% decrease in creatinine clearance was associated with a 35% decrease in FBAL clearance, a 53% increase in its AUC, a 24% decrease in its volume of distribution, and a 41% increase in its Cmax. A 30% increase in body surface was associated with a 24% increase in the volume of distribution of FBAL and a 19% decrease in its Cmax. There was a broad overlap in systemic drug exposure between patients regardless of the occurrence of treatment-related grade 3-4 adverse events or response to treatment, leading to weak relationships between systemic exposure to capecitabine metabolites and the safety and efficacy parameters. Of 42 concentration-effect relationships investigated, only five achieved statistical significance. Thus, we obtained a positive association between the AUC of FBAL and grade 3-4 diarrhoea (P = 0.035), a positive association between the AUC of 5-FU and grade 3-4 hyperbilirubinaemia (P = 0.025), a negative association between the Cmax of FBAL and grade 3-4 hyperbilirubinaemia (P = 0.014), a negative association between the AUC of 5-FU (in plasma) and time to disease progression (hazard ratio (HR) = 1.626, P = 0.0056), and a positive association between the Cmax of 5'-DFUR and survival (HR = 0.938, P = 0.0048). Additionally, there were inconsistencies when concentration-effect relationships were compared across the two studies. CONCLUSIONS: Systemic exposure to capecitabine and its metabolites in plasma is poorly predictive of safety and efficacy. The present results have no clinical implications for the use of capecitabine and argue against the value of therapeutic drug monitoring for dosage adjustment.

Administration, Oral↗