Dear Dr. Monchaud,

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FM, SAZ, HS, and YF declare no competing interests.

CM has received speaker honoraria and/or research funding from Chiesi, Astellas, Pfizer, and Gilead.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #1: Yes

Reviewer #2: Yes

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2. Has the statistical analysis been performed appropriately and rigorously? -->?>

Reviewer #1: Yes

Reviewer #2: Yes

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3. Have the authors made all data underlying the findings in their manuscript fully available??>

The PLOS Data policy

Reviewer #1: Yes

Reviewer #2: Yes

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4. Is the manuscript presented in an intelligible fashion and written in standard English??>

Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: Dear Author/s

Greetings

The incidence of drug-related rejection (overdose or missed medication) is significant in renal transplantation.

Calcineurin levels can be monitored at 0 and 2 hours during medication monitoring. However, mycophenolate mofetil levels did not check and are ignore.

The study also carefully monitored and analyzed the AUC levels and efficacy of missed medication.

The article is suitable for publication in its current form.

Reviewer #2: This manuscript investigates the pharmacokinetic consequences of missed or delayed doses of mycophenolate mofetil (MMF) in kidney transplant recipients, using simulations based on two previously published and validated population pharmacokinetic (PopPK) models. The authors explore a range of clinically relevant scenarios — including full dose omissions, delays of varying duration, and compensation strategies — across multiple dosing regimens. The study shows that a fully missed dose leads to a 40–60% reduction in MPA exposure (AUC₀–₁₂h) and a delayed return to steady state (up to 72–84 hours). Delays of less than 6 hours had only a limited impact on exposure (<15% reduction), while full-dose compensation frequently resulted in overexposure, particularly in higher-dose regimens. In contrast, a strategy of administering 50% of the missed dose at the next intake effectively restored therapeutic exposure without excessive rebound.

The topic is highly relevant for clinicians involved in transplantation. Missed or delayed immunosuppressive doses are common in clinical practice, yet current guidance remains vague and largely unsupported by pharmacokinetic evidence. This study fills an important gap by providing quantitative, model-based recommendations that can guide therapeutic decision-making in routine care. The modeling approach is methodologically appropriate, well described, and transparently reported. The clinical scenarios are realistic and aligned with the questions encountered by physicians and pharmacists in the field.

Some clarifications or additions, however, would improve the manuscript's clinical applicability and methodological transparency :

1/ Although the results are clearly presented, their practical implementation could be further supported. The key recommendations would benefit from being summarized in an accessible format, such as a decision table or clinical algorithm. A brief discussion of how these strategies could be integrated into patient education materials, discharge protocols, or therapeutic drug monitoring procedures would help reinforce their clinical utility.

2/ The authors fixed the residual error at a minimal value (σ = 0.001) to focus on inter-individual variability. While this is justifiable in the context of simulation, it likely underestimates the overall variability encountered in clinical settings, particularly among patients with fluctuating adherence or altered absorption. This limitation should be acknowledged explicitly, as it may affect the generalizability of the findings.

3/ AUC values below the 0.1st and above the 99.9th percentiles were excluded, with reference to general recommendations on outlier handling. Although this is methodologically reasonable, the implications of this decision should be briefly discussed. Patients with extreme pharmacokinetic profiles — such as those with low baseline exposure — may be at greater risk of adverse consequences following a missed dose. Excluding these individuals could potentially limit the applicability of the findings to high-risk subgroups.

4/ The study models isolated dosing deviations. In clinical practice, however, non-adherence is frequently recurrent or fluctuating. While such patterns are more complex to simulate, this should be noted as a limitation, and future work exploring the impact of repeated deviations could be proposed.

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Reviewer #1: Yes:  Yavuz Ayar

Reviewer #2: No

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Population Pharmacokinetic Modeling of Missed Mycophenolate Mofetil Doses: Impact on Exposure and Exploration of Mitigation Strategies

PONE-D-25-36180R1

Dear Dr. Caroline Monchaud,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

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Kind regards,

Paulo Caceres Guido

Academic Editor

PLOS ONE