A pharmacokinetic-pharmacodynamic model for cardiovascular safety assessment of R1551

Pharmacokinetic-pharmacodynamic relationships are crucial in understanding a drug's arrhythmogenic potential. Models assist to quantitatively relate parent and metabolite concentrations to adverse electrocardiographic effects, including an apparent delay between effect and circulating parent species concentration. Here, we used an effect compartment model to investigate PR and QRS prolongation previously observed in preclinical studies with the NK1-NK3 antagonist R1551.

Using a cross-over design, beagle dogs received a single oral dose of R1551 (0-100mg/kg), and cynomolgus monkeys received oral doses of 0-30 mg/kg once daily for 5 days. PR and QRS intervals and heart rate were measured by telemetry, for ≥ 24h after each dose in dogs, and on treatment days 1, 3, and 5 in monkeys. Pharmacokinetic parameters were estimated by fitting a two-compartment model to the data. For each species, a linear effect compartment model was used to relate PR and QRS intervals to effect compartment concentrations.

The effect compartment model provided a good fit to the observed data for both ECG parameters in dogs, and for QRS interval in monkeys (PR(0)=95.1 ms ± 2.74 and 64.9 ms ± 1.46, QRS(0)=42.5 ms ± 1.24 and 46.5 ms ± 1.11 in dog and monkey, respectively). For PR interval in monkeys, the fit was improved by adding a placebo effect compartment to the linear model. R1551 effects on intervals in dogs suggested the presence of responder and non-responder sub-populations. In monkeys, only the highest R1551 dose prolonged PR intervals. Effect slope factors were similar between dog and monkey for both intervals (S(PR)=0.00930 ms mg(-1)kg(-1)l(-1) ± 0.00133 in dog and 0.00934 ms mg(-1)kg(-1)l(-1) ± 0.00141 in monkey; S(QRS)=0.00274 ms mg(-1)kg(-1)l(-1) ± 0.00101 in dog and 0.00200 ms mg(-1)kg(-1)l(-1) ± 0.000552 in monkey).

Our results indicate a non-linear relationship between R1551 plasma kinetics and electrophysiological effects and suggest that the parent was not responsible for the observed ECG effects. In addition, the population based approach allows exploitation of sparse PK data in dog and monkey, analysis throughout the complete effect time course, and assessment of inter-individual variability, all in a single comprehensive model.