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\begin{document}

\title{A Population Pharmacokinetic-Pharmacodynamic Model Evaluating Efficacy
of Nalbuphine Extended-Release in Patients with Prurigo Nodularis}



\author[1]{Rena Eudy-Byrne}%
\author[1]{Matthew Riggs}%
\author[2]{Amale Hawi}%
\author[3]{Thomas Sciascia}%
\author[3]{Shashank Rohatagi}%
\affil[1]{Metrum Research Group}%
\affil[2]{A. Hawi Consulting}%
\affil[3]{Trevi Therapeutics}%


\vspace{-1em}



  
  \date{May 21, 2024}


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\begin{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.%
\end{abstract}%



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