Application of Clinical Pharmacology in Rare Diseases and Non-suicidal Self-injury

Abstract

The overall objectives of this dissertation are twofold (1) to develop N-acetylcysteine (NAC) as a repurposed adjunctive treatment for two rare diseases -childhood cerebral adrenoleukodystrophy (cALD), and Gaucher disease type 1 (GD1); and a psychiatric behavior called non-suicidal self-injury (NSSI) and (2) to explore in-silico approaches to improve dosing flexibility and safety associated with the use of eliglustat in the treatment of GD1. A rare disease is a condition that affects not more than 200,000 people in the US. The regulatory definition of rare diseases varies across the globe. Few regulatory agencies further classify rare diseases that affect an even smaller fraction of patients as ultrarare diseases, such a classification does not exist per the US-FDA. There are about 7,000 rare diseases of which for approximately 5,000 conditions there are no approved pharmacological treatments. In cALD, hematopoietic stem cell transplant (HSCT) is practiced as a standard of care regimen for pediatric patients with radiological evidence of cerebral disease when the symptoms are still mild, and the risk-to-benefit ratio is favorable. Only the individual components such as medications (e.g., cytotoxic drugs, antibiotics) and procedures (e.g., use of radiation) that encompass HSCT have been approved by the FDA, largely in reference to other diseases (e.g., cancer, infectious diseases)—thus, there is variability in HSCT practice across different clinics. Due to the oxidative stress and inflammation caused by the underlying disease and enhanced by the procedures such as radiation as part of HSCT, a supporting treatment that can alleviate post-transplant complications, and improve prognosis is desired. For treatment of GD1, there are 5 approved products in the US, however, the patients continue to suffer worsening and sporadic symptoms related to pain and fatigue—thought to emerge from unresolved inflammation. A safe and effective adjunctive treatment that can address the unabated underlying pathophysiology leading to symptom manifestation can be of immense importance to enhance patient care. There are no FDA-approved pharmacological treatments for NSSI, a common adolescent mental health problem manifested as self-inflicted harmful behavior. Owing to the shared underlying pathophysiology of oxidative stress and inflammation in these three diseases, this dissertation investigated the hypothesis that an antioxidant and anti-inflammatory agent N-acetylcysteine (NAC) would be of clinical benefit in patients with these diseases. This dissertation specifically studied clinical pharmacology aspects of NAC in patients with cALD, GD1, and NSSI including characterization of pharmacokinetics (PK), pharmacodynamics, variability in biomarkers at baseline, and implications for optimum NAC dose and the design of future clinical studies. The steady-state pharmacokinetics of IV NAC were studied following 70mg/kg doses on three occasions in pediatric patients with inherited metabolic disorders (IMDs, e.g., cALD). The objective was to identify if the NAC dose would need to be adjusted relative to the transplant day from a PK standpoint (chapter 3). The PK and pharmacodynamics following oral doses of NAC in patients with NSSI were assessed for dose optimization and to identify the biological signature of NAC in these patients (chapter 4). I also explored the longitudinal biological variability in fifteen oxidative stress and inflammation biomarkers to assess candidate biomarkers with a smaller extent of variability to aid the design of a prospective clinical trial of NAC in patients with GD1 (chapter 5). Finally, for eliglustat, a first-line oral substrate reduction therapy for adult patients with GD1 the drug-drug interactions (DDI) were simulated to identify situations where lower eliglustat doses would improve safety from a QT prolongation perspective (chapter 6) The objectives of chapter 3 were to (1) characterize NAC PK in patients with IMDs undergoing HSCT using population PK modeling and (2) evaluate the impact of the HSCT process on NAC PK parameters. Eighteen pediatric patients with IMDs who underwent HSCT were included in a population PK analysis using nonlinear mixed-effects modeling. NAC clearance (CL) and volume of distribution (V) were explored on 3 occasions: –7, +7, and +21 days relative to the transplant. Additionally, the effect of transplant procedure on NAC disposition was explored by accounting for between-occasion variability. We found that a 2-compartment model adequately described the PK of total NAC. Additionally, HSCT did not change CL and V1 significantly, and analysis across occasions did not reveal any trends. PK parameter estimates were in general comparable to those reported previously in different populations. These results suggest that the dosing of NAC does not need to be altered following HSCT. The study detailed in chapter 4 was a randomized, double-blind study comparing two doses of NAC against the placebo. The objectives of chapter 4 were (1) to assess the effect of 4-weeks-treatment with NAC on percent change observed in four candidate biomarkers of oxidative stress (total glutathione (GSH), redox ratio (GSH/GSSG), catalase, and heme oxygenase (HO-1)) and (2) to assess the differences in NAC exposure between the 5.4g/day (HIGH dose) and 3.6 g/day (LOW dose) group at the steady-state. The exposure was compared using steady-state trough concentration of NAC and the partial area under the curve (AUC0-2) following the last dose of either HIGH or LOW NAC. Our results suggest that there was no discernable relationship between NAC dose and response. In addition to the high prevalence of placebo response; there was large variability in response in all three groups dampening the statistical significance of differences across groups. In chapter 5 our objective was to estimate plausible baseline values of fifteen biomarkers of interest along with the extent of the inherent variability; both intra-subject and inter-subject, observed in their repeated measurements over three months 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 the 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. The objectives of chapter 6 were (1) to develop and validate the eliglustat physiologically based PK model (PBPK) with and without drug interactions, (2) to simulate untested DDI scenarios, and (3) to explore potential dosing flexibility using lower doses of eliglustat (commercially not available, compounding of eliglustat capsules is not recommended). Published physicochemical properties and PK information of eliglustat was utilized for the development and validation of the eliglustat PBPK model. Then, as model-based simulations, we illustrated eliglustat exposure as a victim of interaction when co-administered with an anti-depressant and exploratory COVID medication fluvoxamine. Second, we showed that lower eliglustat doses (21mg, 42mg QD) may benefit patients in a co-administration setting with ketoconazole, a strong metabolism inhibitor for eliglustat. NAC has been used for various indications since the 1960s, however systematic studies investigating NAC’s clinical pharmacology and biomarkers of response have been lacking. This dissertation attempts to bridge those knowledge gaps and makes the better design of future NAC clinical trials possible. Research presented in this dissertation can also serve as a prototype for ad-hoc studies that can be undertaken to answer new clinical questions. DDI simulations and possible mitigation strategies for eliglustat represent an example of the impact of clinical pharmacology techniques such as PBPK modeling and simulations.