Prediction of Repeat-Dose Occupancy from Single-Dose Data: Characterisation of the Relationship between Plasma Pharmacokinetics and Brain Target Occupancy

Abstract

Positron emission tomography (PET) is used in drug development to assist dose selection and to establish the relationship between blood and tissue pharmacokinetics (PKs). We present a new biomathematical approach that allows prediction of repeat-dose (RD) brain target occupancy (TO) using occupancy data obtained after administration of a single dose (SD). A PET study incorporating a sequential adaptive design was conducted in 10 healthy male adults who underwent 4 PET scans with [(11)C]DASB ([(11)C]N,N-dimethyl-2-(2-amino-4-cyanophenylthio) benzylamine): 1 at baseline, 2 after 20 mg SD of the 5-hydroxytryptamine transporter (5-HTT) inhibitor duloxetine, and 1 after 4 days daily administration of 20 mg duloxetine. An adaptive design was used to select optimal times after SD for measurement of occupancy. Both direct and indirect PK/TO models were fitted to the SD data to characterise the model parameters and then applied to a predicted RD duloxetine plasma time course to predict the 5-HTT occupancy after RD. Repeat-dose prediction from the indirect model (OC(50)=2.62±0.93 ng/mL) was significantly better (P<0.05) than that from the direct model (OC(50)=2.29±1.11 ng/mL). This approach increases the value of SD occupancy studies that are performed as part of first time in human drug development programmes by providing an estimate of the dose required to achieve the desired TO at RD.

Predicting Brain Occupancy from Plasma Levels using PET: Superiority of Combining Pharmacokinetics with Pharmacodynamics while Modeling the Relationship

“…It demonstrates that the PK-PD modeling can bring more reliability and accuracy to the prediction of occupancy. Our finding is in agreement with the findings with duloxetine, where PK-PD modeling showed significantly better prediction of chronic dose occupancy from a single dose of duloxetine data than PD modeling alone (Abanades et al, 2011). Figure 5B shows that greater spread of data points in the concentration-occupancy plot may be due to the data being measured before the effect site reaches equilibrium with the central compartment.…”

Positron emission tomography molecular imaging for drug development

“…Repeat dose occupancy studies may induce changes in target expression, in which case application of single dose occupancy measures will be inaccurate. However, if the pharmacokinetic model appropriate to the drug can be estimated, repeat dose brain target occupancy can be estimated based on the basis of the combined occupancy data obtained after administration of a single dose and plasma pharmacokinetic data [19]. Theoretical arguments show that the models used in these analyses can predict repeat dose occupancy even when the relationship following single dose is not described by a simple direct model dependent on the instantaneous plasma concentration.…”

Imaging in Central Nervous System Drug Discovery

“…Whilst early studies used fixed designs with a pre-set range of doses, the latest studies benefit from adaptive designs that use data from the study as it proceeds to efficiently calculate the optimal doses and scan timings . This means that the information acquired from scans is maximised and that study size and duration can be minimized [25,27]. Typically, initial doses and timings are obtained from preclinical data and information on the drugs PK.…”

“…measured from a SD PET study will translate to an RD study and only RD PK is needed. However, if the relationship is Indirect then one either needs to measure the occupancy from a RD PET study or predict it from the SD PET study using an appropriate mathematical model [25,26]. Under such conditions, and assuming the administration of the drug does not change the target affinity for either the drug or the radioligand, the !"…”

“…can be readily estimated from such experiments. If these conditions are not met and the drug kinetics are "Indirect" then improved experimental designs are required which involve the measurement of occupancy at different time points post-administration and varying doses [25][26][27].…”