Assembling the evidence…
Hereditary angioedema (HAE) is a rare disorder linked to kallikrein-kinin system dysregulation, which leads to uncontrolled activation of plasma prekallikrein. Donidalorsen is an antisense oligonucleotide designed to selectively degrade prekallikrein messenger RNA and thereby reduce prekallikrein production. We aimed to develop population pharmacokinetic and pharmacokinetic/pharmacodynamic models of donidalorsen and evaluate the impact of potential intrinsic/extrinsic covariates on exposure and prekallikrein response. Plasma donidalorsen and prekallikrein data were obtained from phase 1 to 3 studies in healthy volunteers (NCT03263507, 721744-CS9) and adult and adolescent patients with HAE (NCT04030598, NCT05139810). The evaluated doses were 20, 40, 60, and 80 mg every 4 weeks (Q4W) and 80 mg every 8 weeks (Q8W), administered subcutaneously over 13-21 weeks. Donidalorsen pharmacokinetics were well described by a linear 2-compartment model with first-order absorption. The population terminal elimination half-life was 31.4 days. Prekallikrein was well described by an indirect response model with inhibition of prekallikrein production by donidalorsen. Covariate analysis identified body weight as the main factor affecting pharmacokinetic exposure; however, this effect was not considered clinically significant. The developed population pharmacokinetic/pharmacodynamic model well characterized the donidalorsen exposure-prekallikrein response relationship. Modeling analyses support that no dose adjustment is needed with respect to intrinsic/extrinsic factors in adults and adolescents with HAE. The nearly identical simulated pharmacokinetic or prekallikrein time courses for Q4W versus monthly dosing and for Q8W versus every-2-month dosing regimens support switching to more convenient regimens for patients.
The nearly identical simulated pharmacokinetic or prekallikrein time courses for Q4W versus monthly dosing and for Q8W versus every-2-month dosing regimens support switching to more convenient regimens for patients.
overlapping simulated PK and PKK profiles without direct clinical testing of the calendar schedules
Modeling analyses support that no dose adjustment is needed with respect to intrinsic/extrinsic factors in adults and adolescents with HAE.
covariate analyses support studied groups, but moderate and severe organ impairment were expressly unstudied
Covariate analysis identified body weight as the main factor affecting pharmacokinetic exposure; however, this effect was not considered clinically significant.
large exposure differences were accompanied by less than seven-percent variation in simulated PKK reduction
PKK reductions were similar between the lowest and highest weight groups, differing by less than 7%.
post hoc simulations directly support the bounded comparison, subject to the singleton-claim cap
The population terminal elimination half-life was 31.4 days.
directly estimated from the pooled concentration dataset, subject to the singleton-claim cap
Derived from the full evaluation — not a separate score.
Strengths
The two-compartment PK model and indirect-response model of inhibited PKK production match the drug's disposition and stated mechanism. Both are qualified using goodness-of-fit diagnostics and pcVPCs.
↳ Materials and Methods, Model Development; Results, Figures 1–2
The analysis evaluates body weight, disease status, administration factors, demographics, and renal and hepatic measures. Forest plots and post hoc simulations connect exposure changes to PKK response.
↳ Materials and Methods, Model Development and Simulations; Results, Figures 3–4 and Tables S3–S4
The simulations compare Q4W with Q1M and Q8W with Q2M in the target HAE population, creating a direct pathway to regulatory and clinical dosing decisions.
↳ Results, Simulations and Figure 5; Discussion, dosing-frequency paragraph
Limitations
No participant was directly treated under the simulated Q1M or Q2M schedules in the analyzed trials. The bridge therefore rests on overlapping PK and PKK profiles rather than attack outcomes observed under those schedules.
↳ Materials and Methods, Clinical Studies and Simulations; Results, Figure 5
The Discussion limits renal and hepatic support to mild impairment and excludes moderate or severe impairment, while the Conclusion states broadly that no adjustment is needed for intrinsic or extrinsic factors.
↳ Discussion, covariate paragraph; Conclusion
The software and analytical procedures are named, but no code, model control files, or raw data are provided in the supplied paper. This limits independent reproduction of the sponsor-developed analysis.
↳ Materials and Methods, Software; Funding and Conflicts of Interest
The pooled dataset and mechanistically grounded model structures support a competent pharmacometric analysis, with covariate testing, uncertainty propagation, and pcVPCs aligned to the study aims. The practical advance is the simulation-based bridge from Q4W/Q8W to calendar-equivalent Q1M/Q2M schedules, but those schedules were not directly tested for clinical attack prevention. The broad fixed-dose conclusion also fails to preserve the Discussion's explicit restriction to mild renal and hepatic impairment. These issues lower clarity and context while leaving the central PK/PD modeling results intact.
Nabu’s assessment, alongside the field’s view.
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Sound3.5
Confidence highThe paper adds a pooled phase 1–3 PK/PD characterization, covariate analysis, and calendar-schedule simulations with direct clinical-development utility. The contribution is incremental and specific to one therapeutic rather than a methodological advance.
The final population PK/PD model was also used to simulate concentration-time profiles of donidalorsen and PKK following various dose regimens.
The two-compartment PK and indirect-response PD structures are mechanistically aligned, with prespecified covariate selection, uncertainty propagation, and pcVPC qualification. Validation is internal, and the supplied paper does not provide code, model files, or direct clinical-outcome validation of the schedule bridge.
Model qualification was conducted using prediction-corrected visual predictive checks (pcVPCs) with 200 simulated replicates.
The PK-to-PD-to-simulation progression is followable and numerical findings are generally presented precisely. The Conclusion nevertheless conveys broader clinical and covariate certainty than the biomarker simulations and organ-impairment evidence establish.
Covariate analyses support that no dose adjustment is needed with respect to intrinsic or extrinsic factors.
The Discussion compares findings with related antisense oligonucleotides and competing HAE prophylactics and identifies relevant population limits. Its broad final dose-adjustment statement contradicts the express exclusion of moderate or severe renal and hepatic impairment, so the serious limitation-handling ceiling binds.
Donidalorsen has not been studied in patients with moderate or severe hepatic impairment or in patients with moderate or severe renal impairment.
Lower confidence on Reporting, Positioning — domain match limited.
Caveats4 of 4 checks
The reported data and model outputs are internally consistent, but the final dose-adjustment claim is broader than the organ-impairment evidence described in the Discussion.
The paper declares institutional review-board approval and written informed consent and discloses sponsor funding, employment, equity holdings, and consultancy relationships.
Flags: 2 declared / 5 total
33 of 33 checkable references verified
38 references in manuscript 3 are books, websites or datasets — counted, but not index-checkable 2 could not be checked — not the same as no match found
No retraction notice found in Retraction Watch.
Sources: Retraction Watch ✓
Where this paper’s evidence sits on the path from initial observation to real-world use.
The model draws on completed phase 1–3 trials in the target disease and therefore sits relatively close to regulatory and clinical application. The proposed Q1M/Q2M schedules remain supported by PK and PKK simulations rather than direct attack-outcome evaluation under those schedules.
Overall, the PK and PD profiles for Q4W vs. Q1M, as well as Q8W vs. Q2M, closely overlapped.
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