In this section, a complete step-by step approach to population modeling is provided for beginners for three different case studies using NONMEM® or R®.
Case Studies
Case Study 1
Aim of analysis
To develop a Population Pharmacokinetic model and explore covariate relationships.
Study design and background
A Clinical trial was conducted for hypothetical test drug used in the treatment of atrial fibrillation. The study was a double blind, parallel, single dose intravenous bolus study. Patients were randomized to either of two doses namely, 100 mg or 250 mg. The trial was conducted in 100 patients. Blood samples were collected at 0.25, 0.5, 0.75,1,1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16, 20, 24 hours post-dose. Covariates measured were Age, Weight, Creatinine Clearance and Gender.
Preliminary data information
The drug was found to follow a one compartment model with an half life of about 7 hrs. The drug is known to be primarily renally eliminated, where creatinine clearance can be correlated to systemic clearance.
Data analysis
Case Study 2
Aim of analysis
To develop a population pharmacokinetic model after multiple dosing.
Study design and background
A clinical trial was conducted for hypothetical test drug used in the treatment of diabetes. The study was a double blind, multiple dose oral study. Patients were randomized to receive 500 mg three times in a day for 5 days. The trial was conducted in 100 patients. Blood samples were collected at regular time intervals.
Preliminary data information
The drug follows a two compartment disposition with dosing given every half-life. The absolute bioavailability is reported to be 50%.
Data analysis
Case Study 3
Aim of analysis
To develop a Population Pharmacokinetic-pharmacodynamic (PK-PD) model
Study design and background
A clinical trial was conducted for hypothetical test drug used in the treatment of immunosuppression and also used as an anti-inflammatory agent. Patients were randomized to receive 100mg infused over 6 hours. The trial was conducted in 20 patients. Blood samples were collected at 0.5, 1, 3, 5, 6, 8, 12, 15, 18, 24 & 30 hours post dose. The biomarker measured was blood histamine concentration.
Preliminary data information
The drug was found to follow a one compartment model with a half-life of about 3 hrs. The drug is an immunosuppressant, it causes changes in cellular trafficking pattern of leucocytes, such as basophils, T helper cells resulting in net movement of cells from blood to extravascular sites. It is assumed that the drug inhibits the return of the cells to the blood without affecting the egress of the cells. A indirect response model where there is an inhibition of production of response (movement of cells from extravascular sites to blood) is assumed here and modeled accordingly 1.
Data analysis
References
1. Jusko and Ko,HC, Physiologic indirect response models characterize diverse types of pharmacodynamic effects. Clin Pharmacol Ther. 1994 Oct;56(4):406-19.