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A Population Pharmacokinetic-Pharmacodynamic Model Evaluating Efficacy of Nalbuphine Extended-Release in Patients with Prurigo Nodularis
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  • Rena Eudy-Byrne,
  • Matthew Riggs,
  • Amale Hawi,
  • Thomas Sciascia,
  • Shashank Rohatagi
Rena Eudy-Byrne
Metrum Research Group

Corresponding Author:[email protected]

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Matthew Riggs
Metrum Research Group
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Amale Hawi
A. Hawi Consulting
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Thomas Sciascia
Trevi Therapeutics
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Shashank Rohatagi
Trevi Therapeutics
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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.
26 Aug 2022Submitted to British Journal of Clinical Pharmacology
29 Aug 2022Submission Checks Completed
29 Aug 2022Assigned to Editor
31 Aug 2022Reviewer(s) Assigned
10 Oct 2022Review(s) Completed, Editorial Evaluation Pending
11 Oct 2022Editorial Decision: Revise Major
03 Dec 20221st Revision Received
05 Dec 2022Submission Checks Completed
05 Dec 2022Assigned to Editor
05 Dec 2022Review(s) Completed, Editorial Evaluation Pending
11 Dec 2022Editorial Decision: Accept