Population PK/PD modeling of supine heart rate after oral administration of a new candidate antipsychotic drug

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Objectives: In the first clinical studies with a new candidate antipsychotic, supine heart rate (HR) increased, which is thought to be related to its noradrenaline reuptake inhibiting properties. In order to help with the selection of doses that could be safely administered in subsequent clinical trials, a population PK/PD analysis was performed.

Methods: Data both from phase 1 and phase 2 trials were included in the population PK/PD analysis using NONMEM, and model-predicted concentrations at the time of the (supine) ECG measurements were used as drivers of the response.

Results: The effect of the drug on the supine HR was best described by a sigmoidal E_max model, and was assumed to be direct (no time delay) and constant over time (no tolerance). Other parameters affecting the HR were the diurnal rhythm, implemented as the sum of 2 cosine functions. Baseline HR was found to be different between healthy volunteers and patients (52 versus 64 beats/min in males), and within the patient population, between males (65 beats/min) and females (69 beats/min). E_max was estimated at 43.7% and EC₅₀ at 31.5 ng/mL. Hill was lower than 1, indicative of the shallow relationship between plasma concentrations and increases in supine HR. Interindividual variabilities (IIV) were below 50%, except for E_max. With the exception of EC₅₀, and the IIV on Hill and on one of the amplitudes, all parameter estimates had relative standard errors below 50%.

Conclusion:  Predictions using the final population PK/PD model show that up to doses of 35-40 mg, less than half of the patients have increases in supine HR of 6 beats/min at peak. This range increases to 55-60 mg if average instead of peak steady-state concentrations are considered. Therefore, safety problems are to be anticipated only when doses higher than 40 mg/day are administered.