Objective: The study was designed to determine (1) the pharmacokinetic (PK) profile of dexmethylphenidate (d-MPH) after oral administration of three dosage strengths of a new treatment containing d-MPH and a novel prodrug, serdexmethylphenidate (SDX); (2) the dose proportionality of the different SDX/d-MPH dosages; and (3) the steady-state PK profile of d-MPH and SDX after multiple dosing of SDX/d-MPH.Methods: Twenty-three healthy volunteers (aged 18-55 years) under fasted conditions received in a crossover design SDX/d-MPH 26.1/5.2 mg (Treatment A), 39.2/7.8 mg (Treatment B), and 52.3/10.4 mg (Treatment C) for a total d-MPH hydrochloride equivalent dose of 20, 30, and 40 mg, respectively. After a 96-hour washout period, all participants received four consecutive daily doses of SDX/d-MPH 52.3/10.4 mg. Blood samples were collected for measurement of plasma d-MPH and SDX and for PK analysis.Results: Administration of all three doses of SDX/d-MPH resulted in a rapid rise and slow decline in the plasma concentration of d-MPH. For Treatments A, B, and C, mean (+/- standard deviation) maximum concentrations (C-max) were 7.1 +/- 2.1, 9.8 +/- 2.8, and 13.8 +/- 3.8 ng/mL, and overall exposures (AUC(0-last)) were 97.2 +/- 28.8, 142.5 +/- 41.2, and 199.8 +/- 57.2 h*ng/mL, respectively. Dose-normalized C-max, AUC(0-last), and AUC(0-inf) for d-MPH were similar when comparing the high and low doses versus the middle dose. Power model regression analysis revealed that C-max and AUC(0-inf) proportionally increased with an increase in SDX/d-MPH dose. In the multiple-dose study, d-MPH reached steady state before the third dose, and SDX after the first dose.Conclusion: The PK profile of SDX/d-MPH is characterized by a rapid rise and a gradual decline in d-MPH concentration, with proportional C-max and AUC(0-inf) across doses. The PK attributes of SDX/d-MPH may optimize symptom control from early morning to early evening, while the demonstrated dose proportionality may facilitate initial dose titration and ongoing dose adjustment.

Introduction/Rationale: Patients with pulmonary arterial hypertension (PAH) experience multiple symptoms and decreased exercise capacity.Physical activity is decreased in PAH; however, we do not know the association of self-reported physical function and other PAH-symptoms or health-related quality of life (HRQOL).Methods: This was a cross-sectional study of 60 women with PAH.Participants completed a series of questionnaires: Patient-Reported Outcomes Measurement Information System (PROMIS ® ) Physical Function, Pulmonary Arterial Hypertension Symptom Scale (PAHSS), Multidimensional Dyspnea Profile (MDP), Patient Health Questionnaire (PHQ-8), Pittsburgh Sleep Quality Index (PSQI), PROMIS ® Sleep-Related Impairment, and emPHasis 10.They also underwent phlebotomy, wrist actigraphy and had a 6-minute walk test.The PROMIS ® Physical Function scores were used to define three functional groups: Within Normal Limits (>50); Mild Physical Impairment (40-49); Moderate/Severe Physical Impairment (<40).One-way analysis of variance was used to compare the physical function groups for normally distributed continuous variables and the Kruskal-Wallis test for those variables that were either not normality distributed or ordinal.Chi-square and Fisher's exact tests were used to compare physical function groups on categorical variables.If omnibus statistical results were P<0.05 then Bonferroni correction was used for post-hoc tests.Multiple regression determined predictors of physical function after adjusting for age, race/ethnicity, PAH etiology, World Health Organization (WHO) functional class, body mass index (BMI), 6-minute distance and N-terminal pro b-type natriuretic peptide (NTproBNP).Results: Sixty women were enrolled with a mean age of 50 years.Forty six percent were non-Hispanic white and 40% were diagnosed with idiopathic PAH.Eleven percent (n=7) were categorized as Within Normal Limits for physical function; 42% (n=25) Mild Physical Impairment and 47% (n=28) Moderate/Severe Physical Impairment.Those with Moderate/Severe Physical Impairment had significantly worse symptoms (PAHSS, MDP, PHQ-8), sleep quality (PSQI), sleep-related impairment (PROMIS SRI), HRQOL (emphasis 10), increased NTproBNP, right atrial pressures and sleep onset latency Table 1.There was no association between actigraphy and self-reported physical function.Predictors of physical function were shortness of breath on exertion and swelling of ankles/feet (F=16.9,P<0.001) (r 2 =.73) after adjusting for covariates.Conclusion: The majority of the sample reported worse physical impairment.Those in the mild and moderate/severe physical function groups experienced more severe symptoms and reduced HRQOL.Improving physical function may impact symptoms and HRQOL in PAH.Future research should test interventions to improve physical function.

Calquence® (crystalline acalabrutinib), a commercially marketed tyrosine kinase inhibitor (TKI), exhibits significantly reduced oral exposure when taken with acid-reducing agents (ARAs) due to the low solubility of the weakly basic drug at elevated gastric pH. These drug–drug interactions (DDIs) negatively impact patient treatment and quality of life due to the strict dosing regimens required. In this study, reduced plasma drug exposure at high gastric pH was overcome using a spray-dried amorphous solid dispersion (ASD) comprising 50% acalabrutinib and 50% hydroxypropyl methylcellulose acetate succinate (HPMCAS, H grade) formulated as an immediate-release (IR) tablet. ASD tablets achieved similar area under the plasma drug concentration–time curve (AUC) at low and high gastric pH and outperformed Calquence capsules 2.4-fold at high gastric pH in beagle dogs. In vitro multicompartment dissolution testing conducted a priori to the in vivo study successfully predicted the improved formulation performance. In addition, ASD tablets were 60% smaller than Calquence capsules and demonstrated good laboratory-scale manufacturability, physical stability, and chemical stability. ASD dosage forms are attractive for improving patient compliance and the efficacy of acalabrutinib and other weakly basic drugs that have pH-dependent absorption.

Serdexmethylphenidate (SDX)/d-methylphenidate (d-MPH) capsules are an approved ADHD product designed to provide rapid onset and extended duration of symptom improvement. SDX/d-MPH capsules contain 70% SDX, a prodrug of d-MPH that is gradually converted to d-MPH, and 30% d-MPH, which provides rapid exposure to d-MPH after administration. The objectives of these studies were to: 1) in study 1, examine the single-dose (SD) pharmacokinetics (PK) of SDX/d-MPH and determine the effect of body weight (BW) on the PK properties in children and adolescents with ADHD; and 2) in study 2, examine SD PK of SDX/d-MPH in healthy adults under fed conditions. Both studies were phase 1, open-label, SD oral administration of SDX/d-MPH capsules. After a standardized meal in study 1, subjects (aged 6-17 years, N = 30) received treatments stratified into 3 age and 2 dose groups: 6- to 8-year-olds (Cohort 1, n = 10) received 26.1/5.2 mg, 9- to 12-year-olds (Cohort 2, n = 10) received 52.3/10.4 mg, and 13- to 17-year-olds (Cohort 3) received either 26.1/5.2 mg (n = 5) or 52.3/10.4 mg (n = 5). Blood samples for PK were collected predose and at multiple time points postdose. In study 2, adults (N = 28) received SDX/d-MPH 52.3/10.4 mg after a high-fat meal. In study 1, dose-normalized (to the 52.3/10.4 mg dose) peak and overall exposure to d-MPH was highest in Cohort 1 (Cmax = 34.4 ng/mL; AUC0-24 = 362.0 h*ng/mL), followed by Cohort 2 (Cmax = 25.9 ng/mL; AUC0-24 = 294.1 h*ng/mL), and lowest in Cohort 3 (Cmax = 17.8 ng/mL and 14.0 ng/mL; AUC0-24 = 195.0 ng/mL and 171.1 h*ng/mL, for the low and high doses, respectively). When normalized for both dose and BW, mean Cmax and AUC0-24 values were similar across cohorts. Clearance (CL/F) values were lower in Cohorts 1 and 2 (96.85 and 97.44 L/h, respectively) than Cohort 3 (170.3 L/h for low dose and 172.3 L/h for high dose). When adjusted for BW differences, CL/F values were similar. A nonlinear regression model indicated a moderate correlation (R2 = 0.628) between d-MPH CL/F and BW. In adults (study 2), the shape of the PK curve was comparable to those obtained in children and adolescents when administered under the same conditions. BW is an appropriate scaling factor for d-MPH exposure after oral SDX/d-MPH dosing in children, adolescents, and adults.

Rationale: Patients with idiopathic pulmonary arterial hypertension (PAH) diagnosed in recent eras are older, more likely to be male, and more commonly overweight/obese with earlier disease recognition compared to previous eras.Over the past decade, screening for PAH associated with systemic sclerosis (SSc-PAH) has been recommended which might result in evolving patient characteristics at initial evaluation.The objective of this study was to examine changes in characteristics of patients with SSc-PAH over time.We hypothesized that SSc-PAH patients in a recent cohort would more likely be overweight/obese with less severe disease compared to patients from a historical cohort.Methods: We performed a retrospective cohort study of SSc-PAH patients at the time of their initial evaluation at the University of Pennsylvania.Patients were divided into an "early" cohort (presented between 2005 and 2008) and a "recent" cohort (presented between 2015 and 2018).Categorical variables are reported as percentages and continuous variables are reported as median with IQR.Fisher's exact tests and Wilcoxon rank sum tests were used, as appropriate.Logistic regression was used to estimate the odds ratio for survival at two years, adjusting for age and sex.Results: We identified 80 patients with SSc-PAH: 31 patients in the early cohort and 49 patients in the recent cohort (Table ).Patients in the recent cohort were somewhat older (p=0.16) and more likely to be overweight/obese (p=0.01).Patients in the early cohort were more likely to have right atrial dilatation (p=0.05),right ventricular dilatation (p=0.01),right ventricular dysfunction (p=0.03) and pericardial effusion (p=0.15) and had higher estimated right ventricular systolic pressures (p=0.01).Patients in the recent cohort were more likely to have lower pulmonary vascular resistance (p=0.06) and higher cardiac index (p=0.04).There were no significant differences in sex, race/ethnicity, WHO functional class, or spirometry between cohorts.Patients in the recent cohort had a lower risk of death at two years compared to patients from the early cohort (OR 0.34, 95% CI 0.13-0.89,p=0.03) even after adjusting for age and sex.Conclusions: Over the span of a decade at our center, recently diagnosed SSc-PAH patients were more commonly overweight/obese at the time of diagnosis and may have had reduced disease severity, perhaps as a result of increased awareness and more screening of patients with SSc.The difference in outcome could be explained by improved survival for our patients, lead-time and length-time bias, or an evolution of the phenotype of SSc-PAH over time.

Amorphous solid dispersions (ASDs) can increase the bioavailability of drugs with poor aqueous solubility. However, concentration-sustaining dispersion polymers (CSPs) incorporated in ASDs can result in low drug loading and, therefore, a large dosage-form size or multiple units to meet dose requirements, potentially decreasing patient compliance. To address this challenge, a high-loaded dosage-form (HLDF) architecture for ASDs was developed, in which a drug is first spray-dried with a high glass-transition temperature (Tg) dispersion polymer to facilitate high drug loading while maintaining physical stability. The ASD is then granulated with a CSP designed to extend supersaturation in solution. The HLDF differs from traditional ASD architectures in which the dispersion polymer inside the ASD acts as the CSP. By strategically combining two different polymers, one "inside" and one "outside" the ASD, solubilization performance, physical stability, and overall drug loading are maximized. This study demonstrates in vivo performance of the HLDF architecture using posaconazole as a model drug. Two sizes of HLDF tablets were tested in beagle dogs, along with traditional ASD architecture (benchmark) tablets, ASD tablets without a CSP, and a commercial crystalline oral suspension (Noxafil OS). HLDF tablets performed equivalently to the benchmark tablets, the smaller HLDF tablet being 40% smaller (by mass) than the benchmark tablet. The HLDF tablets doubled the blood plasma AUC relative to Noxafil OS. In line with the in vivo outcome, in vitro results in a multicompartment dissolution apparatus demonstrated similar area under the curve (AUC) values in the intestinal compartment for ASD tablets. However, the in vitro data underpredicted the relative in vivo AUC of Noxafil OS compared to the ASD tablets. This study demonstrated that the HLDF approach can increase drug loadings while achieving good performance for ASD drug products.

Although Amorphous Solid Dispersions (ASDs) effectively increase bioavailability, tablet mass can be high due to the large fraction of excipients needed to stabilize the amorphous drug in the solid state, extend drug supersaturation in solution and achieve robust manufacturability. The aim of this work was to reduce tablet mass of an ASD tablet comprising a low glass transition temperature (Tg), rapidly crystallizing drug without compromising these key attributes.In this approach, erlotinib (Tg = 42 °C, Tm/Tg = 1.4 K/K) was spray dried with the high Tg polymer poly(methyl methacrylate-co-methacrylic acid) (Eudragit® L100, Evonik) (Tg = 187 °C) to facilitate high drug loading while maintaining physical stability. Hydroxypropyl methylcellulose acetate succinate (HPMCAS) (AQOAT® HF, Shin-Etsu) was granulated with the ASD to extend supersaturation in solution. For comparison, a benchmark ASD was spray dried at a lower drug loading with HPMCAS-H (Tg = 119 °C).This High Loaded Dosage Form (HLDF) approach reduced tablet mass by 40%, demonstrated similar physical stability and in vitro performance as the benchmark and exhibited excellent downstream manufacturability. Strategically combining two different polymers in a tablet to maintain physical stability and sustain supersaturation in solution can decrease tablet mass of some low Tg, rapidly crystallizing amorphous drugs.