POPULATION PHARMACOKINETICS.docx

POPULATION PHARMACOKINETICS Define the term population pharmacokinetics “Population pharmacokinetics is the study of the sources and correlates of variability in drug concentrations among individuals who are the target patient population receiving clinically relevant doses of a drug of interest” -...

POPULATION PHARMACOKINETICS Define the term population pharmacokinetics “Population pharmacokinetics is the study of the sources and correlates of variability in drug concentrations among individuals who are the target patient population receiving clinically relevant doses of a drug of interest” - The US FDA Example CL (ml/min)= 19.3 x (Weight (kg)/75)2.55 (For males) CL (ml/min) = 12.1 x (Weight (kg)/65)2.75 (For females) Vd (L) = 12 + 0.5 x Weight (kg) (for both genders Factors affecting pharmacokinetics: Age Reduction in organ function in elderly requires lowering the doses of drugs Neonates have a higher proportion of body mass made up of water and neonatal dose may larger per kilogram of body weight than in an adult (for drugs that distribute into body water) Disease states Renal, cardiac, hepatic dysfunction Genetic factors Poor CYP2C19 metabolizers were found to have an increased incidence of fluoxetine adverse effects Other Concomitant drug administration and drug-drug interactions Pregnancy: altered volume of distribution Understand various methods to study population pharmacokinetics Standard Two Stage approach Widely used when extensive sampling is done in a study where individual pharmacokinetic parameters can be calculated Mean pharmacokinetic parameters are generally accurate but the variability parameters are biased due to improper handling of error in the data Nonlinear mixed effects approach Observed data and the Truth It is important to realize that the observed or measured concentration data contains various sources of errors Analytical error Dose time errors Sample collection time errors Personal differences in the technique Model fitting versus Noncompartmental analysis Fitting a nonlinear regression equation to data to estimate PK parameters will separate error: Computer programs Noncompartmental analysis uses observed data as is without separation of error Sparse samples per subject Therapeutic drug monitoring data Phase 2 or 3 trial data (population of interest) Pediatric population (you cannot collect too many samples) Many other places where only sparse samples can be collected Nonlinear Mixed Effects Modeling Approach (NLME or NONMEM) Population Pharmacokinetic Model Features of NLME/NONMEM Can handle sparse sampling No uniform sampling schedules are required Several factors can be studied in one large study Real time use of the product in target population can be studied Can be implemented in software such as NONMEM, Monolix and Phoenix Complex methodology requiring advanced skills in PK-PD and statistical modeling This technique is widely used in drug development and regulatory guidances are available from US FDA, EMA Discuss application of population pharmacokinetics FDA Suggested Approach Model Informed Drug Development: Applications and Future Directions The application of a wide range of quantitative models in drug development to facilitate the decision‐making process MIDD was formally recognized as an important enabler of efficient and effective drug development and included in the Prescription Drug User Fee Act (PDUFA) Precision Dosing using Bayesian Programs