Quantitative drug benefit-risk assessment: utility of modeling and simulation to optimize drug safety in older adults.
BACKGROUND
More than 50 % of individuals affected by adverse drug events (ADEs) are older adults. Establishing a drug dosing regimen that balances benefit and risk, and minimizes ADEs in older populations can be challenging.


OBJECTIVE
The aim of this study is to evaluate the use of modeling, simulation, and risk-benefit acceptability methods to establish a drug dosing regimen that balances benefit and risk.


METHODS
The study population comprised nondiabetic patients with schizophrenia from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) ≥50 years old, who had been on oral olanzapine for ≥2 weeks. We used mixed-effects modeling based on a preexisting pharmacokinetic model to derive clearance estimates, which were then used to determine the olanzapine area under the concentration-time curve (AUC). Subsequently, with multivariate regression and Monte Carlo simulation, we estimated the olanzapine dose corresponding to the benefit-risk AUC breakpoint.


RESULTS
The study population (n = 34) was predominantly male (82.3%) and white (67.6%), with a mean age of 54.4 years and treatment duration of 361.8 days. The mean AUC was 747.6 ng h/mL (95% CI = 524.5, 970.7) for the benefit group (n = 16) and 754.1 (95% CI = 505.9, 1002.4) for the risk group (n = 15). The benefit-risk AUC breakpoint was 524.5 ng h/mL and the corresponding oral olanzapine dose that optimizes benefit-risk balance was 17.8 mg/d.


CONCLUSIONS
Our study introduces a real-world approach for finding the safe drug dosing regimen without extensive exposure of a vulnerable and older population to drugs. Further studies into the use of modeling, simulation, and risk-benefit acceptability methods to enhance geriatric drug safety are needed.
Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA.
Victor
V
Crentsil
Jung
J
Lee
Andre
A
Jackson
D000328:Adult; D014150:Antipsychotic Agents / Q000009:adverse effects* / Q000493:pharmacokinetics; D001569:Benzodiazepines / Q000009:adverse effects* / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009010:Monte Carlo Method; D000077152:Olanzapine; D018570:Risk Assessment; D012559:Schizophrenia / Q000188:drug therapy*
D014150:Antipsychotic Agents; D001569:Benzodiazepines; D000077152:Olanzapine
drug dosing; geriatric; modeling; risk-benefit acceptability threshold; simulation