Pharmacokinetic comparability between two populations using nonlinear mixed effect models: a Monte Carlo study.

'Are two populations the same or are they different' is a question that is often faced in clinical pharmacology trials e.g., a pharmacokinetic trial studying a particular drug in racially different groups. To address this question, concentration-time data were simulated from a reference and test population, where in the latter the clearance, sample size, and sampling design were systematically varied. It was of interest to determine whether the estimates of clearance from the two groups were the same or different. Two approaches were used to estimate the empirical Bayes estimates (EBEs) for clearance. One approach developed a population pharmacokinetic model for the reference population and the EBEs for the reference population were estimated from this model. The parameters of the reference population were fixed to their maximum likelihood estimates. The model was then applied to the test population dataset to estimate the EBEs of the test population using the MAXEVAL = 0 option in NONMEM. A second approach, the theta approach, combined the reference and test datasets into a single dataset and used population as a covariate in the model; the EBEs were estimated from this combined model. The power and type I error rate of each approach were calculated for each treatment combination using a variety of statistical tests to determine whether there was a difference in the distribution of the EBEs in the reference population compared to the test population. Our results suggest that either MAXEVAL or theta approaches can be used with informative sampling designs. In addition to reasonable power and type I error, both approaches gave almost identical results under a dense sampling design. To statistically compare the distribution of EBEs of pharmacokinetic parameters from a reference group to that of a test group, a T-test and DTS eCDF test are equally useful.

Translational and clinical pharmacology considerations in drug repurposing for X-linked adrenoleukodystrophy-A rare peroxisomal disorder.

X-linked adrenoleukodystrophy (X-ALD) is an inherited, neurodegenerative rare disease that can result in devastating symptoms of blindness, gait disturbances and spastic quadriparesis due to progressive demyelination. Typically, the disease progresses rapidly, causing death within the first decade of life. With limited treatments available, efforts to determine an effective therapy that can alter disease progression or mitigate symptoms have been undertaken for many years, particularly through drug repurposing. Repurposing has generally been guided through clinical experience and small trials. At this time, none of the drug candidates have been approved for use, which may be due, in part, to the lack of pharmacokinetic/pharmacodynamic information on the repurposed medications in the target patient population. Greater consideration for the disease pathophysiology, drug pharmacology and potential drug-target interactions, specifically at the site of action, would improve drug repurposing and facilitate drug development. Incorporating advanced translational and clinical pharmacological approaches in preclinical studies and early-stage clinical trials will improve the success of repurposed drugs for X-ALD as well as other rare diseases.

Biological Variation in Peripheral Inflammation and Oxidative Stress Biomarkers in Individuals with Gaucher Disease.

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.

N-acetylcysteine Pharmacology and Applications in Rare Diseases-Repurposing an Old Antioxidant.

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.

Nervonic Acid Attenuates Accumulation of Very Long-Chain Fatty Acids and is a Potential Therapy for Adrenoleukodystrophy.

Adrenoleukodystrophy (ALD) is an X-linked inherited peroxisomal disorder due to mutations in the ALD protein and characterized by accumulation of very long-chain fatty acids (VLCFA), specifically hexacosanoic acid (C26:0). This can trigger other pathological processes such as mitochondrial dysfunction, oxidative stress, and inflammation, which if involves the brain tissues can result in a lethal form of the disease called childhood cerebral ALD. With the recent addition of ALD to the Recommended Uniform Screening Panel, there is an increase in the number of individuals who are identified with ALD. However, currently, there is no approved treatment for pre-symptomatic individuals that can arrest or delay symptom development. Here, we report our observations investigating nervonic acid, a monounsaturated fatty acid as a potential therapy for ALD. Using ALD patient-derived fibroblasts, we examined whether nervonic acid can reverse VLCFA accumulation similar to erucic acid, the active ingredient in Lorenzo's oil, a dietary intervention believed to alter disease course. We have shown that nervonic acid can reverse total lipid C26:0 accumulation in a concentration-dependent manner in ALD cell lines. Further, we show that nervonic acid can protect ALD fibroblasts from oxidative insults, presumably by increasing intracellular ATP production. Thus, nervonic acid can be a potential therapeutic for individuals with ALD, which can alter cellular biochemistry and improve its function.

Physiologically-Based Pharmacokinetic Model Development, Validation, and Application for Prediction of Eliglustat Drug-Drug Interactions.

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 (Cmax ) 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 (Cmax <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.

Population Pharmacokinetic Analysis of N-Acetylcysteine in Pediatric Patients With Inherited Metabolic Disorders Undergoing Hematopoietic Stem Cell Transplant.

N-acetylcysteine (NAC) has been used in patients with cerebral adrenoleukodystrophy as an antioxidant agent in association with hematopoietic stem cell transplant (HSCT). However, an understanding of the pharmacokinetic characteristics of intravenous NAC dosing in these patients is limited. If and how NAC pharmacokinetics change following the transplant is unknown. Toward that end, a total of 260 blood samples obtained from 18 pediatric patients with inherited metabolic disorders who underwent HSCT were included in a population pharmacokinetic 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 transplant. Additionally, the effect of transplant procedure on NAC disposition was explored by accounting for between-occasion variability. The covariate OCC was modeled as a fixed-effect parameter on CL and/or V1. A 2-compartment model adequately described the pharmacokinetics of total NAC. Weight-based allometric scaling on pharmacokinetic parameters was assumed using standard coefficients. Estimates for CL, central (V1), and peripheral volume (V2), and intercompartment clearance were 14.7 L/h, 23.2 L, 17.1 L, 3.99 L/h, respectively, for a 70-kg person. The data only supported between-subject variability in CL (12%) and V1 (41%). Residual variability was estimated to be 16%. HSCT did not change CL and V1 significantly, and analysis across occasions did not reveal any trends. Pharmacokinetic parameter estimates were in general comparable to those reported previously in different populations. These results suggest that dosing of NAC does not need to be altered following HSCT.

Identifying Biological Signatures of N-Acetylcysteine for Non-Suicidal Self-Injury in Adolescents and Young Adults.

The prevalence of non-suicidal self-injury (NSSI) is high in adolescents and young adults. However, there is a paucity of evidence-based treatments to address this clinical problem. An open-label, pilot study in the target population showed that treatment with oral N-acetylcysteine (NAC), a widely available dietary supplement, was associated with reduction in NSSI frequency. In preparation for a biologically informed design of an efficacy trial, a critical preliminary step is to clarify NAC's biological signatures, or measures of the mechanisms underlying its clinical effects. Toward that end, we propose a 2-stage project to investigate NAC's biological signatures (changes in glutathione (GSH) and/or glutamate (Glu)) in women with NSSI. The first stage; a double-blind randomized placebo-controlled study will focus on identifying the optimal dose to achieve meaningful change in GSH and Glu during short-term (4 weeks) NAC treatment in 36 women aged 16-24 years with NSSI. Go/No-go criteria to determine if the study will progress to the second stage include pre-specified changes in brain and blood measures of GSH. Changes in the brain GSH are measured through magnetic resonance spectroscopy (MRS). The dose for the stage 2 will be selected based on the biological changes and the tolerability observed in the stage 1. The stage 2 will seek to replicate the biological signature findings in an 8-week trial in a new patient cohort, and examine the relationships among biological signatures, NAC pharmacokinetics and clinical response. This 2-stage project is unique as it unifies clinical psychiatric measurements, quantitative MRS and pharmacological approaches in the first placebo-controlled clinical trial of NAC in young women with NSSI. TRIAL REGISTRATION: The stage 1 trial protocol has been registered on https://clinicaltrials.gov/ with ClinicalTrials.gov ID "NCT04005053" (Registered on 02 July 2019. Available from: https://clinicaltrials.gov/ct2/show/NCT04005053).