N-acetylcysteine (NAC), a precursor of cysteine and, thereby, glutathione (GSH), acts as an antioxidant through a variety of mechanisms, including oxidant scavenging, GSH replenishment, antioxidant signaling, etc. Owing to the variety of proposed targets, NAC has a long history of use as a prescription product and in wide-ranging applications that are off-label as an over-the-counter (OTC) product. Despite its discovery in the early 1960s and its development for various indications, systematic clinical pharmacology explorations of NAC pharmacokinetics (PK), pharmacodynamic targets, drug interactions, and dose-ranging are sorely limited. Although there are anecdotal instances of NAC benefits in a variety of diseases, a comprehensive review of the use of NAC in rare diseases does not exist. In this review, we attempt to summarize the existing literature focused on NAC explorations in rare diseases targeting mitochondrial dysfunction along with the history of NAC usage, approved indications, mechanisms of action, safety, and PK characterization. Further, we introduce the research currently underway on other structural derivatives of NAC and acknowledge the continuum of efforts through pre-clinical and clinical research to facilitate further therapeutic development of NAC or its derivatives for rare diseases.

Eliglustat is a glucosylceramide synthase inhibitor indicated as a long‐term substrate reduction therapy for adults with type 1 Gaucher disease, a lysosomal rare disease. It is primarily metabolized by cytochrome P450 2D6 (CYP2D6), and variants in the gene encoding this enzyme are important determinants of eliglustat pharmacokinetics (PK) and drug–drug interactions (DDIs). The existing drug label addresses the DDIs to some extent but has omitted scenarios where both metabolizing CYPs (2D6 and 3A4) are mildly or moderately inhibited. The objectives of this study were (i) to develop and validate an eliglustat physiologically‐based pharmacokinetic (PBPK) model with and without drug interactions, (ii) to simulate untested DDI scenarios, and (iii) to explore potential dosing flexibility using lower dose strength of eliglustat (commercially not available). PK data from healthy adults receiving eliglustat with or without interacting drugs were obtained from literature and used for the PBPK model development and validation. The model‐predicted single‐dose and steady‐state maximum concentration (C_max) and area under the concentration‐time curve (AUC) of eliglustat were within 50–150% of the observed values when eliglustat was administered alone or coadministered with ketoconazole or paroxetine. Then as model‐based simulations, we illustrated eliglustat exposure as a victim of interaction when coadministered with fluvoxamine following the US Food and Drug Administration (FDA) dosing recommendations. Second, we showed that with lower eliglustat doses (21 mg, 42 mg once daily) the exposure in participants of intermediate and poor metabolizer phenotypes was within the outlined safety margin (C_max <250 ng/mL) when eliglustat was administered with ketoconazole, where the current recommendation is a contraindication of coadministration (84 mg). The present study demonstrated that patients with CYP2D6 deficiency may benefit from lower doses of eliglustat.

The lack of reliable biomarkers is a significant challenge impeding progress in orphan drug development. For appropriate interpretation of intervention-based results or for evaluating candidate biomarkers, other things being equal, lower variability in biomarker measurement would be helpful. However, variability in rare disease biomarkers is often poorly understood. Type 1 Gaucher disease (GD1) is one such rare lysosomal storage disorder. Oxidative stress and inflammation have been linked to the pathophysiology of GD1 and validated measures of these processes can provide predictive value for treatment success or disease progression. This study was undertaken to investigate and compare the extent of longitudinal biological variation over a three-month period for various blood-based oxidative stress and inflammation markers in participants with GD1 on stable standard-of-care therapy (N = 13), treatment-naïve participants with GD1 (N = 5), and in age- and gender-matched healthy volunteers (N = 18). We utilized Bland–Altman plots for visual comparison of the biological variability among the three measurements. We also report group-wise means and the percentage of coefficient of variation (%CV) for 15 biomarkers. Qualitatively, we show specific markers (IL-1Ra, IL-8, and MIP-1b) to be consistently altered in GD1, irrespective of therapy status, highlighting the need for adjunctive therapies that can target and modulate these biomarkers. This information can help guide the selection of candidate biomarkers for future intervention-based studies in GD1 patients.

COVID‐19 continues to be a threat to global health and a burden on healthcare systems. There is an ongoing need for COVID‐19 antiviral therapies that are safe and effective across broad patient populations. Ibuzatrelvir is a potent, selective inhibitor of the SARS‐CoV‐2 main protease and demonstrated favorable properties for clinical development. We report safety, tolerability, and pharmacokinetic data for ibuzatrelvir from a phase 1 first‐in‐human study in healthy adults. Study parts evaluated ibuzatrelvir as single or multiple ascending doses, including analysis of participants in fasted and fed states, pharmacokinetics in Chinese and Japanese participants, relative bioavailability of crystalline tablet formulations, and dose selection for patients with COVID‐19. Oral administration of ibuzatrelvir led to rapid absorption after all doses, and steady‐state plasma concentrations were achieved by Day 2 for all doses. High‐fat meals decreased maximum plasma concentration and area under the plasma concentration‐time curve from time 0 to the time of the last quantifiable concentration, but the concentration at 12 h postdose was comparable when administered without food. Exposures of ibuzatrelvir were similar between Chinese and non‐Chinese participants, as well as between Japanese and non‐Japanese participants. Ibuzatrelvir was safe and well‐tolerated, with no serious or severe adverse events reported and no participants discontinuing. In conclusion, pharmacokinetics and safety were established for single‐agent oral ibuzatrelvir, supporting the design and dose selection for further phase 2 trials and the continued development of ibuzatrelvir (NCT05580003).

There are currently no oral treatment options for infections caused by extended spectrum β‑lactamase‐producing Enterobacterales. Avibactam tomilopil, a novel oral prodrug of avibactam, is being developed in combination with the oral cephalosporin, ceftibuten, as a potential treatment for patients with complicated urinary tract infections (cUTIs). The safety, tolerability, and pharmacokinetic profiles of single and multiple doses of avibactam tomilopil (900 to 1350 mg) and ceftibuten (400 to 1600 mg), alone and/or in combination were evaluated in three Phase 1 trials in healthy participants. Avibactam tomilopil was rapidly metabolized to active avibactam and plasma avibactam exposure increased proportionately with dose. Both avibactam and cis‐ceftibuten had similar plasma half‐lives, and were predominantly renally excreted. While there was negligible food effect on ceftibuten exposures, plasma avibactam exposure in the fed state for a fixed‐dose combination ceftibuten‐avibactam tomilopil tablet was higher compared with the fasted state. Based on joint probability of target attainment simulations using a simultaneous oral ceftibuten‑avibactam tomilopil population pharmacokinetic model, a tablet formulation ceftibuten 400 mg + avibactam tomilopil 1200 mg dosed every 8 h without regard to food is proposed for Phase 3 evaluation in adult patients with cUTIs. Trial registration: NCT03931876; NCT05554237; NCT06593054.