Olmesartan medoxomil dosing schedule justification in pediatric hypertensive patients

1. Olmesartan medoxomil dosing schedule justification in pediatric hypertensive patients Authors: SaeHeum Song*, Raymond Miller, Daniel Salazar Daiichi Sankyo Pharma Development, Edison, NJ, USA Objectives • To compare olmesartan pharmacokinetics between pediatric and adult hypertensive patients • To compare olmesartan exposure-response between pediatric and adult patients • To evaluate peak blood pressure lowering effects (PD effects) in comparison to when maximum drug exposures were achieved in pediatric patients. • To aid olmesartan dosage regimen decision for hypertensive pediatric population at ages above 1 year old. Pharmacodynamic Comparison(Pediatrics (p)/Adults (black dots)) Effect of olmesartan dose (top) and exposure (bottom) on diastolic blood pressure lowering effects in adult and pediatrics. in lower figures ‘p’ indicates diastolic blood pressure lowering effects in pediatric population. Corresponding olmesartan doses were normalized by their body weights. Dose (mg/Kg) –Response (BP lowering effects) Method Clinical Studies AUC (mg/Kg) –Response (BP lowering effects) *) POP-PK subjects . Peak exposure and Blood Pressure lowering effects Dose and Administration Summary of peak, baseline and predose blood pressure and their differences in pediatric patients in CS0866-A-U301 study Peak and Trough BP measurement (CS866-A-U301 Study) Blood Pressure Measurement with matching pharmacokinetic samples were collected after 1-8 hours post dose in visit 2, week 2 and predose, and 1-3 hours post dose in visit 2, week 3 • 2 BLQ measurements were observed as a postdose • 2 Week 3 Trough measurements as actual post dose samples by time recording • 28 Samples on Visit 2 week 2 in 1-3 hr post dose Analysis Olmesartan weight adjusted dose, Peak Concentration and Daily exposure 0effects on peak pd effects in comparison with baseline and predose blood pressure level • Pharmacokinetics comparison (pediatrics/adults): • Pediatric pharmacokinetics of olmesartan were simulated based on the population pharmacokinetic analysis utilizing CS866-102 and CS866-301 study based on the dosage regimen intended for the pediatric use CS866-301. • The simulated observations were compared to posthoc estimated adult pharmacokinetic exposures from previous research. • Pharmacodynamic comparison (pediatrics/adults): • Dose and pharmacokinetic exposures (AUC) and observed blood pressure • lowering effects in pediatrics and adults were compared graphically . • Evaluation of the Peak drug effects: • For the comparison of the peak drug effect in pediatrics population: • observed plasma concentration at the time of 1-3 hour post administration and posthoc estimated AUC were used to evaluate peak drug effects. • The blood pressures at the peak drug exposure (1-3 hr post dose) were compared to those at baseline and predose . Steady State Peak –Baseline Steady State Peak –Predose Dose Conc AUC Results Pediatric Pharmacokinetics of OM Exposure dependent Sys/Dia blood pressure lowering effects at week 2-3 compared to baseline No Exposure dependent Changes in Sys/Dia blood pressures at peak exposure at week 2-3 compared to those at predose exposure Pharmacokinetic Comparison(Pediatrics/Adults) QD dosing is not likely to cause dosing interval dependent fluctuations in blood pressure lowering effects Simulated and observed olmesartan exposure in pediatric subjects age >=6 years old (left) and below 6 years (right) old. >= 6years 1-5 years Conclusions: • PK, and PK/PD of olmesartan in pediatrics were similar to those of adults. • Recommended starting dose regimen based on the PKPD relationship is • Once Daily, • 10 mg in body weight 20-35 Kg, • 20 mg in body weight 35 Kg and above and • 0.3 mg/Kg below 20 Kg above one years old. 20 mg 10 mg *) Horizontal lines: Red: 20 mg, and green: 40 mg QD OM with mean(solid) and 90 % CI (Dotted) in adult population