Expanding clinical applications of population pharmacodynamic modelling

被引:38
作者
Minto, C [1 ]
Schnider, T
机构
[1] Royal N Shore Hosp, Dept Anaesthesia & Pain Management, St Leonards, NSW 2065, Australia
[2] Univ Sydney, Sydney, NSW 2006, Australia
[3] Univ Bern, Inselspital, Inst Anasthesie & Intens Med, CH-3012 Bern, Switzerland
关键词
computer simulations; pharmacodynamics; population models;
D O I
10.1046/j.1365-2125.1998.00792.x
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Population pharmacokinetics or pharmacodynamics is the study of the variability in drug concentration or pharmacological effect between individuals when standard dosage regimens are administered. We provide an overview of pharmacokinetic models, pharmacodynamic models, population models and residual error models. We outline how population modelling approaches seek to explain interpatient variability with covariate analysis, and, in some approaches, to characterize the unexplained interindividual variability. The interpretation of the results of population modelling approaches is facilitated by shifting the emphasis from the perspective of the modeller to the perspective of the clinician. Both the explained and unexplained interpatient variability should be presented in terms of their impact on the dose-response relationship. Clinically relevant questions relating to the explained and unexplained variability in the population can be posed to the model, and confidence intervals can be obtained for the fraction of the population that is estimated to fall within a specific therapeutic range given a certain dosing regimen. Such forecasting can be used to develop optimal initial dosing guidelines. The development of population models (with random effects) permits the application of Bayes's formula to obtain improved estimates of an individual's pharmacokinetic and pharmacodynamic parameters in the light of observed responses. An important challenge to clinical pharmacology is to identify the drugs that might benefit from such adaptive-control-with-feedback dosing strategies. Drugs used for life threatening diseases with a proven pharmacokinetic-pharmacodynamic relationship, a small therapeutic range, large interindividual variability, small interoccasion variability and severe adverse effects are likely to be good candidates. Rapidly evolving changes in health care economics and consumer expectations make it unlikely that traditional drug development approaches will succeed in the future. A shift away from the narrow focus on rejecting the null hypothesis towards a broader focus on seeking to understand the factors that influence the dose-response relationship-together with the development of the next generation of software based on population models-should permit a more efficient and rational drug development programme.
引用
收藏
页码:321 / 333
页数:13
相关论文
共 90 条
[1]  
AARONS L, 1991, BRIT J CLIN PHARMACO, V32, P669
[2]   AN EVALUATION OF POPULATION PHARMACOKINETICS IN THERAPEUTIC TRIALS .3. PROSPECTIVE DATA-COLLECTION VERSUS RETROSPECTIVE DATA ASSEMBLY [J].
ANTAL, EJ ;
GRASELA, TH ;
SMITH, RB .
CLINICAL PHARMACOLOGY & THERAPEUTICS, 1989, 46 (05) :552-559
[3]   A technique for population pharmacodynamic analysis of concentration-binary response data [J].
Bailey, JM ;
Gregg, KM .
ANESTHESIOLOGY, 1997, 86 (04) :825-835
[4]   Concentration-effect relationship of the positive chronotropic and hypokalaemic effects of fenoterol in healthy women of childbearing age [J].
Bouillon, T ;
Meineke, I ;
Port, R ;
Hildebrandt, R ;
Gunther, K ;
GundertRemy, U .
EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY, 1996, 51 (02) :153-160
[5]  
CROWDER MJ, 1990, ANAL REPEATED MEASUR, P87
[6]   COMPARISON OF 4 BASIC MODELS OF INDIRECT PHARMACODYNAMIC RESPONSES [J].
DAYNEKA, NL ;
GARG, V ;
JUSKO, WJ .
JOURNAL OF PHARMACOKINETICS AND BIOPHARMACEUTICS, 1993, 21 (04) :457-478
[7]   COMPUTER-CONTROLLED INFUSION OF INTRAVENOUS DEXMEDETOMIDINE HYDROCHLORIDE IN ADULT HUMAN VOLUNTEERS [J].
DYCK, JB ;
MAZE, M ;
HAACK, C ;
AZARNOFF, DL ;
VUORILEHTO, L ;
SHAFER, SL .
ANESTHESIOLOGY, 1993, 78 (05) :821-828
[8]   THE PHARMACOKINETICS OF THE NEW SHORT-ACTING OPIOID REMIFENTANIL (GI87084B) IN HEALTHY ADULT MALE-VOLUNTEERS [J].
EGAN, TD ;
LEMMENS, HJM ;
FISET, P ;
HERMANN, DJ ;
MUIR, KT ;
STANSKI, DR ;
SHAFER, SL .
ANESTHESIOLOGY, 1993, 79 (05) :881-892
[9]   Population pharmacokinetic modeling: The importance of informative graphics [J].
Ette, EI ;
Ludden, TM .
PHARMACEUTICAL RESEARCH, 1995, 12 (12) :1845-1855
[10]   Modeling a bivariate control system: LH and testosterone response to the GnRH antagonist antide [J].
Fattinger, KE ;
Verotta, D ;
Porchet, HC ;
Munafo, A ;
leCotonnec, JY ;
Sheiner, LB .
AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM, 1996, 271 (04) :E775-E787