A Population Pharmacokinetic-Pharmacodynamic Model Evaluating Efficacy
of Nalbuphine Extended-Release in Patients with Prurigo Nodularis
Abstract
Population pharmacokinetic (PK) and pharmacokinetic- pharmacodynamic
(PK-PD) models were used to quantify the exposure-response (E-R)
relationship between nalbuphine exposure and 2 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-hour recall.
Simulations based on the model E-R relationship were used to support
dose selection for future clinical investigations and were evaluated
with a target of reducing the 7-day average of the 24-hour WI-NRS by at
least 30% from baseline in the majority of the analysis population.
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
2 doses of Nalbuphine ER versus 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 sigmoidal maximum
effect (Emax) model with a placebo effect was used to model the itch
response endpoints (NRS-AV, WI-NRS). The PK/PD model adequately
predicted the exposure-related reduction in both NRS-AV and WI-NRS over
time with approximately 63% and 27% of Emax, respectively. Exposures
associated with 80% of Emax were achieved in about 78% of the patients
at 162 mg BID compared to 35% at 81 mg BID. 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.