Rare diseases affect an estimated 600–700 million people across the globe and are often chronic, progressive, degenerative, and life threatening. In United States, there are more than 7,000 known rare diseases, of which less than 5% are treatable with approximately 550 approved orphan drugs. Drug development for rare disease possesses several layers of challenges. Pharmacometrics represents an attractive tool during orphan drug development as it provides a way to integrate knowledge about the disease and its treatment in a quantitative framework. These models can be utilized to optimize clinical trial designs for evaluation of treatments under development. X-linked adrenoleukodystrophy (X-ALD) is a peroxisomal disorder, most commonly affecting boys, associated with increased very long chain fatty acids (C26:0) in all tissues, causing cerebral demyelination and adrenocortical insufficiency. Certain monounsaturated long-chain fatty acids including oleic and erucic acids, known as Lorenzo's oil (LO), lower plasma C26:0 levels. We characterized the effect of LO administration on plasma C26:0 concentrations and determined whether there is an association between plasma concentrations of erucic acid or C26:0 and the likelihood of developing brain MRI abnormalities in asymptomatic boys. Non-linear mixed effects modelling was performed on 2384 samples that were collected during an open label single arm trial. The subjects (n = 104) were administered LO daily at ~2–3 mg/ kg with a mean follow-up of 4.88 ± 2.76 years. The effect of erucic acid exposure on plasma C26:0 concentrations was characterized by an inhibitory fractional Emax model. A Weibull model was used to characterize the time-to-developing MRI abnormality. The population estimate for the fractional maximum reduction of C26:0 plasma concentrations was 0.76 (bootstrap 95% CI 0.73, 0.79). Our time-to-event analyses showed that every mg/L increase in time-weighted average of erucic acid and C26:0 plasma concentrations was, respectively, associated with a 3.7% reduction and a 753% increase in the hazard of developing MRI abnormality. However, the results were not significant (P = 0.5344, 0.1509, respectively). Congenital adrenal hyperplasia (CAH) is a form of adrenal insufficiency characterized by impaired cortisol synthesis. Replacement with oral hydrocortisone (HC) does somewhat correct the resulting over-production of adrenal androgens, but significant medical problems follow these children into adulthood. To better understand dosing requirements, population pharmacokinetics of cortisol was characterized in children with CAH. Children with CAH (n=48; median [range] age and weight were: 7.1 years [1.47-18.2 years] and 29.3 kg [10.8-80.6 kg], respectively) receiving oral HC, had 12 serum samples obtained over 6 hours starting at 0800 h. Nonlinear mixed-effect modeling assuming a one-compartment model and allometric scaling was used for data analysis. The model included information on circadian rhythm from historical data to allow simulation of 24-h profiles of cortisol. Effects of disease phenotype, formulation type, pubertal stage, and sex on cortisol disposition were examined. Clearance (CL/F) and volume of distribution (V/F) were: 21.7.(WT/70)3/4 L/h and 37.6.(WT/70) L, respectively, and a resulting half-life of 0.896 hr. The bioavailability of the suspension was comparable to tablet formulation (99.6% relative to the tablet formulation). Our model-based simulations suggest many children with CAH are exposed to prolonged periods of hypocortisolemia and hyperandrogenemia over 24 hours with current hydrocortisone dosage regimens.