A population pharmacokinetic-pharmacodynamic model evaluating efficacy of nalbuphine extended-release in patients with prurigo nodularis.

Aims: Population pharmacokinetic (PK) and pharmacokinetic-pharmacodynamic (PK-PD) models were used to describe the exposure-response (E-R) relationship between nalbuphine exposure and two widely used rating scales for itch: the Numerical Rating Scale for the subject's 'average'; itch experience (NRS-AV) and the Worst Itch (WI-NRS), with 24-h recall. Simulations based on the model E-R relationship were used to support dose selection for Phase 3 clinical trials and were evaluated with a target of reducing the 7-day average of the 24-h WI-NRS by at least 30% from baseline in most of the analysis population.

Methods: Data from two clinical trials (NCT02373215: 9 healthy subjects; NCT02174419: 62 subjects with PN), in patients with prurigo nodularis (PN) with moderate to severe itch who received treatment with either of two doses of nalbuphine extended release (ER) or placebo, were used for the analysis. A two-compartment PK model with serial zero and first-order oral absorption was used to describe drug exposure. A maximum effect ( ) model with a placebo effect was used to model the itch response endpoints (NRS-AV, WI-NRS).

Results: The PK-PD model predicted the exposure-related reduction in both NRS-AV and WI-NRS over time with approximately 63% and 27% of , respectively. Exposures associated with 80% of were achieved in about 78% of the patients at 162 mg, twice daily (BID), compared to 35% at 81 mg BID.

Conclusion: Simulated dose response indicated that 108 and 162 mg BID doses result in the highest proportion of patients achieving at least a 30% reduction in NRS-AV and WI-NRS, respectively.