Jean-Louis Steimer

An Evaluation of the Integration of Pharmacokinetic and Pharmacodynamic Principles in Clinical Drug Development Experience within Hoffmann La Roche

SummaryThe integration of pharmacokinetic and pharmacodynamic principles into drug development has been proposed as a way of making it more rational and efficient. The use of these principles in drug development to make scientific and strategic decisions is defined as the ‘pharmacokinetic-pharmacodynamic guided approach to drug development’.The objectives of this survey were: (i) to assess the extent the pharmacokinetic-pharmacodynamic guided approach to drug development has been used in a large multinational pharmaceutical company: (ii) to evaluate the impact of pharmacokinetic and/or pharmacodynamic results on clinical drug development; and (iii) to identify factors which prevented the full application of the pharmacokinetic-pharmacodynamic guided approach.This was done by looking at 18 projects in the current development portfolio at Hoffman La Roche and evaluating the use of this approach by interviewing the responsible clinical pharmacologist using a standardised questionnaire.(i) Benefits from using the pharmacokinetic-pharmacodynamic guided approach were reported in every project, independent of development phase and therapeutic area. This approach was more extensively used in the recent projects. The selection of dosages in clinical studies was found to be the most important application of pharmacokinetic-pharmacodynamic results in terms of an impact on drug development, (ii) Time savings, up to several months, could be quantified in 8 projects during the entry-into-man studies and in 6 projects during the phase II or III studies. In 4 projects, 1 clinical study was avoided. (iii) The most important scientific factor preventing the full application of the approach was the lack of knowledge on the predictive value of the pharmacodynamic or surrogate marker for effect (6 projects).The results of the survey have shown that the use of the pharmacokinetic-pharmacodynamic guided approach has contributed to making clinical drug development more rational and more efficient. Opportunities to apply the pharmacokinetic-pharmacodynamic approach should be identified in each project and a project specific strategy for the pharmacokinetic-pharmacodynamic guided approach should be defined during phase 0 of drug development.

Relationships Between Exposure to Saquinavir Monotherapy and Antiviral Response in HIV-Positive Patients

ObjectiveThe aim of this study was to confirm the most appropriate dosage of a new soft gelatin capsule (SGC) formulation of the HIV protease inhibitor saquinavir by investigating the relationships between systemic (plasma) exposure to saquinavir and plasma HIV RNA and CD4+ cell counts using empirical mathematical modelling.Design and settingA randomised, non-blind, multicentre, dose-ranging 8-week study of monotherapy with 400, 800 or 1200mg of saquinavir-SGC or 600mg of the hard gelatin capsule (HGC) formulation, both administered 3 times daily, was carried out in protease inhibitor-naive, HIV-positive adults. Two surrogate markers of response, plasma HIV RNA level and CD4+ cell count, were fitted to 2 measures of systemic drug exposure, the area under the plasma concentration-time curve (AUC) and trough plasma concentration (Cmin), using 6 exposure-response models of progressively increasing complexity. Akaike and Schwarz model selection criteria were applied to determine the most effective pharmacokinetic-pharmacodynamic relationship.ResultsA total of 88 patients were randomised; pharmacokinetic and pharmacodynamic data were available for 84 patients. In terms of plasma HIV RNA, pharmacokinetic-pharmacodynamic relationships were best described by a 2-parameter maximum effect (Emax) model, which predicted a typical maximum reduction in viral load of 1.94 log10 copies/ml [coefficient of variation (CV) 12%], with a half-maximal antiviral response occurring at a Cmin of 50 μ g/L (CV 40%). Saquinavir-SGC 1200mg administered 3 times daily produced a median AUC to 24 hours (AUC24) of approximately 20 000 μg/L · h, corresponding to 85% of the maximum achievable antiviral effect as defined by the model. None of the models yielded a satisfactory fit for CD4+ cell count.ConclusionEmpirical mathematical modelling confirmed that, when administered 3 times daily, the optimum dose of saquinavir-SGC is 1200mg, corresponding to 3600 mg/day.

Role of modelling and simulation in Phase I drug development

Although the use of pharmacokinetic/pharmacodynamic modelling and simulation (M&S) in drug development has increased during the last decade, this has most notably occurred in patient studies using the population approach. The role of M&S in Phase I, although of longer history, does not presently have the same impact on drug development. However, trends such as the increased use of biomarkers and clinical trial simulation as well as adoption of the learn/confirm concept can be expected to increase the importance of modelling in Phase I. To help identify the role of M&S, its main advantages and the obstacles to its rational use, an expert meeting was organised by COST B15 in Brussels, January 10-11, 2000. This article presents the views expressed at that meeting. Although it is clear that M&S occurs in only a minority of Phase I clinical trials, it is used for a large number of different purposes. In particular, M&S is considered valuable in the following situations: censoring because of assay limitation, characterisation of non-linearity, estimating exposure-response relationship, combined analyses, sparse sampling studies, special population studies, integrating PK/PD knowledge for decision making, simulation of Phase II trials, predicting multiple dose profile from single dose, bridging studies and formulation development. One or more of the following characteristics of M&S activities are often present and severely impede its successful integration into clinical drug development: lack of trained personnel, lack of protocol and/or analysis plan, absence of pre-specified objectives, no timelines or budget, low priority, inadequate reporting, no quality assurance of the modelling process and no evaluation of cost-benefit. The early clinical drug development phase is changing and if these implementation aspects can be appropriately addressed, M&S can fulfill an important role in reshaping the early trials by more effective extraction of information from studies, better integration of knowledge across studies and more precise predictions of trial outcome, thereby allowing more informed decision making.

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 capecitabines 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.

New strategies in drug development and clinical evaluation: the population approach

Variation in the response of individual patients to drugs is of great concern to those involved in drug evaluation and therapy [1]. The magnitude of the variability and the factors or covariates which contribute to the variability are critical issues. Together with the therapeutic index, they define the range of dose strengths required and the patient groups at particular risk with standard dosages. In broad terms, variability in therapeutic outcome can be assigned to pharmacokinetics and pharmacodynamics. Common influential factors are genetics, age, and disease. Other determinants include co-medication, pharmaceutical formulation, diet, and evironmental factors. Drug development, and particularly clinical evaluation, is a lengthy process. Earliest information in humans generally comes from detailed, carefully monitored studies in relatively small groups. Pharmacokinetic data are often obtained in young healthy men who are sampled intensively, allowing the characterization of individual pharmacokinetics. Frequently, the desired therapeutic response can only be elicited in patients, and such initial studies also tend to involve small, intensively monitored, homogeneous groups. While providing invaluable baseline information on pharmacokinetics and efficacy, these early detailed studies provide limited insight into variability. To gain the pertinent information on variability, studies involving many patients are undertaken, often in many centres. In contrast to the early phase studies, large clinical studies generally provide very sparse individual data, so that it is not possible to characterize an individuals pharmacokinetics or pharmacodynamics.

Population approaches in drug development

An expert meeting to discuss population pharmacokinetic/pharmacodynamic software was held in Brussels in November 1993 under the auspices of the European Co-operation in Science and Technology (COST), Medicine (B1) programme.Recently developed statistical methods offer the possibility of gaining integrated information on pharmacokinetics and response from relatively sparse observational data obtained directly in patients who are being treated with the drug under development. These methods can minimize the need to exclude patient groups and also allow analysis of a variety of unbalanced designs that frequently arise in the evaluation of the relationships between dose or concentration on the one hand and efficacy or safety on the other relationships that do not readily lend themselves to other forms of statistical analysis.The purpose of the Brussels meeting was to evaluate the state of both existing software and software under development, and to specify the needs and wishes of potential users of such software. It was apparent from the meeting that software development for population data analysis is currently a very active area of investigation and that several very good packages are already available, with more in development.The general consensus of the meeting was that well validated, easy to use software was essential to the implementation of the population approach to drug development.

Population pharmacokinetics of levodopa in patients with Parkinson's disease treated with tolcapone

To use pharmacostatistical models to evaluate the overall exposure of patients with Parkinsons disease to levodopa in the presence and absence of tolcapone.