Application of relative forgiveness using clinically observed adherence profiles

Background: The circumstance of how sensitive therapeutic success is under imperfect adherence is driven by the property known as forgiveness. We have previously developed a relative forgiveness (RF) criterion [1]. The relative forgiveness criterion can also be used to quantify an RF of each patient given their own drug taking behaviour.

Aim: To evaluate the RF for individual patients taking atorvastatin and omeprazole.

Methods: The developed RF criterion was used with atorvastatin (n=3) and omeprazole (n=5). For each drug, the methods are divided into four parts: (1) identification of a population PKPD model, (2) extraction of clinically observed adherence profiles from Medication Event Monitoring Systems (MEMS), (3) parametric simulation of PKPD profiles for each patient and (4) quantification of attainment of a treatment target and computation of relative forgiveness for each individual patient. All simulations in this study were conducted in MATLAB®.

Results: Atorvastatin: No atorvastatin population PKPD model was available. A population PKPD model was constructed that linked a PK of atorvastatin to a PD model for simvastatin. [2,3]. The observed random missed doses and drug holidays for patients 1, 2 and 3 were 12, 4 and 2; and 0, 0, and 1, respectively. The RF for patients 1, 2 and 3 were 0.88, 0.85 and 0.89, respectively.
Omeprazole: No population PKPD model was found for omeprazole and a model for lansoprazole was used instead [4]. The observed random missed doses and drug holidays for patients 4, 5, 6, 7 and 8 were 2, 25, 0, 0 and 10; and 0, 3, 0, 0 and 0, respectively. The RF for patients 4, 5, 6, 7 and 8 were 0.96, 0.07, 1.01, 0.90 and 0.97, respectively.

Discussion: The concept of RF appears to be generalisable to other drugs. It appears that atorvastatin is forgiving. Fewer patients taking omeprazole had drug holidays or had random missed doses. It is noted that omeprazole is not forgiving to missed doses.

1. Assawasuwannakit et al, CPT Pharmacometrics Syst Pharmacol 2014; accepted
2. Narwal et al, Clin Pharmacokinet 2010; 49: 693-702
3. Kim et al, Basic Clin Pharmacol Toxicol 2011; 109: 156-63
4. Puchalski et al, J Clin Pharmacol 2001; 41: 251-8

Piyanan Assawasuwannakit