Population pharmacokinetic rationale for intravenous contezolid acefosamil followed by oral contezolid dosage regimens.

Contezolid is a novel oxazolidinone antibiotic with a promising safety profile. Oral contezolid and its intravenous (IV) prodrug contezolid acefosamil (CZA) are in development for treatment of diabetic foot and acute bacterial skin and skin structure infections (ABSSSI). The prodrug CZA is converted to active contezolid via intermediate MRX-1352. This study aimed to provide the pharmacokinetic rationale for safe, effective, and flexible dosage regimens with initial IV CZA followed by oral contezolid. We simultaneously modeled plasma concentrations from 110 healthy volunteers and 74 phase 2 patients with ABSSSI via population pharmacokinetics (using the importance sampling estimation algorithm), and optimized dosage regimens by Monte Carlo simulations. This included data on MRX-1352, contezolid, and its metabolite MRX-1320 from 66 healthy volunteers receiving intravenous CZA (150-2400 mg) for up to 28 days, and 74 patients receiving oral contezolid [800 mg every 12 h (q12h)] for 10 days. The apparent total clearance for 800 mg oral contezolid with food was 16.0 L/h (23.4% coefficient of variation) in healthy volunteers and 17.7 L/h (53.8%) in patients. CZA was rapidly converted to MRX-1352, which subsequently transformed to contezolid. The proposed dosage regimen used an IV CZA 2000 mg loading dose with 1000 mg IV CZA q12h as maintenance dose(s), followed by 800 mg oral contezolid q12h (with food). During each 24-h period, Monte Carlo simulations predicted this regimen to achieve consistent areas under the curve of 91.9 mg·h/L (range: 76.3-106 mg·h/L) under all scenarios. Thus, this regimen was predicted to reliably achieve efficacious contezolid exposures independent of timing of switch from IV CZA to oral contezolid.IMPORTANCEThis study provides the population pharmacokinetic rationale for the dosage regimen of the intravenous (IV) prodrug contezolid acefosamil (CZA) followed by oral contezolid. We developed the first integrated population model for the pharmacokinetics of the MRX-1352 intermediate prodrug, active contezolid, and its main metabolite MRX-1320 based on data from three clinical studies in healthy volunteers and phase 2 patients. The proposed regimen was predicted to reliably achieve efficacious contezolid exposures independent of timing of switch from IV CZA to oral contezolid.

Pharmacokinetics, Metabolism, and Excretion of Intravenous [14C]Difelikefalin in Healthy Subjects and Subjects on Hemodialysis.

BACKGROUND AND OBJECTIVE: Difelikefalin, a selective kappa-opioid receptor agonist, is the first approved treatment for moderate-to-severe pruritus in patients with end-stage renal disease (ESRD) on hemodialysis (HD) in the USA and Europe. The purpose of this open-label study was to investigate the pharmacokinetics and disposition of [14C]difelikefalin following a single intravenous dose in subjects with normal renal function and subjects on HD. METHODS: Twelve adult males (n = 6 healthy subjects; n = 6 subjects on HD) received single intravenous doses of [14C]difelikefalin containing 100 µCi (total doses of 1.7-3.0 µg/kg difelikefalin). Blood, urine, feces, and dialysate samples (when applicable) were collected after dosing. RESULTS: The median time to maximum concentration was similar for HD and healthy subjects, occurring at 5 min post-dose. The mean area under the concentration-time curve (AUC) was approximately 11-fold higher in HD versus healthy subjects; mean plasma half-life was 38.0 h and 2.6 h, respectively. In healthy subjects, 80.5% of the dose was recovered in urine, and 11.3% was recovered in feces. In subjects on HD, 58.8% of the dose was recovered in feces, and 19.5% was recovered in dialysate [for subjects on HD with residual kidney function (n = 3), 11.2% was recovered in urine]. Based on plasma AUClast, parent [14C]difelikefalin was the most abundant analyte in systemic circulation (> 99% of total exposure) for both cohorts. Metabolite profiles in urine and feces suggested minimal metabolism of the parent compound. CONCLUSION: In subjects on HD, difelikefalin total exposure was higher and plasma half-life was longer compared with subjects with intact renal function. Metabolism was low in both healthy subjects and subjects on HD, with unchanged drug representing > 99% of systemic circulation; however, the route of excretion was primarily into urine versus feces in healthy subjects, and feces versus dialysate in subjects on HD. REGISTRATION: ClinicalTrials.gov NCT03947970.

Phase I studies of the safety, tolerability, pharmacokinetics, and pharmacodynamics of DS-1211, a tissue-nonspecific alkaline phosphatase inhibitor.

Tissue-nonspecific alkaline phosphatase (TNAP) hydrolyzes and inactivates inorganic pyrophosphate (PPi), a potent inhibitor of calcification; therefore, TNAP inhibition is a potential target to treat ectopic calcification. These two first-in-human studies evaluated safety, tolerability, pharmacokinetics (PKs), and pharmacodynamics (PDs) of single (SAD) and multiple-ascending doses (MAD) of DS-1211, a TNAP inhibitor. Healthy adults were randomized 6:2 to DS-1211 or placebo, eight subjects per dose cohort. SAD study subjects received one dose of DS-1211 (range, 3-3000 mg) or placebo, whereas MAD study subjects received DS-1211 (range, 10-300 mg) once daily, 150 mg twice daily (b.i.d.), or placebo for 10 days. Primary end points were safety and tolerability. PK and PD assessments included plasma concentrations of DS-1211, alkaline phosphatase (ALP) activity, and TNAP substrates (PPi, pyridoxal 5'-phosphate [PLP], and phosphoethanolamine [PEA]). A total of 56 (DS-1211: n = 42; placebo: n = 14) and 40 (DS-1211: n = 30; placebo: n = 10) subjects enrolled in the SAD and MAD studies, respectively. In both studies, adverse events were mild or moderate and did not increase with dose. PKs of DS-1211 were linear up to 100 mg administered as a single dose and 150 mg b.i.d. administered as a multiple-dose regimen. In multiple dosing, there was minimal accumulation of DS-1211. Increased DS-1211 exposure correlated with dose-dependent ALP inhibition and concomitant increases in PPi, PLP, and PEA. In two phase I studies, DS-1211 appeared safe and well-tolerated. Post-treatment PD assessments were consistent with exposure-dependent TNAP inhibition. These data support further evaluation of DS-1211 for ectopic calcification diseases.

Phase 1 Clinical Trials of Small Molecules: Evolution and State of the Art.

BACKGROUND: Phase 1 studies comprise the first exposure of a promising new chemical entity in healthy volunteers or, when appropriate, in patients. To assure a solid foundation for subsequent drug development, this first step must carefully assess the safety and tolerance of a new compound and often provide some indication of potential effect, so that a safe dose or dose range can be confidently selected for the initial Phase 2 efficacy study in the target patient population. METHODS: This review was based on a literature search using both Google Scholar and PubMed, dated back to 1970, using search terms including "healthy volunteers", "Phase 1", and "normal volunteers", and also based on the authors' own experience conducting Phase 1 clinical trials. This paper reviews the history of Phase 1 studies of small molecules and their rapid evolution, focusing on the critical single and multiple dose studies, their designs, methodology, use of pharmacokinetic and pharmacodynamic modeling, application of potentially helpful biomarkers, study stopping criteria, and novel study designs. RESULTS: We advocate for determining the safe dose range of a new compound by conducting careful dose escalation in a well-staffed inpatient setting, defining the maximally tolerated dose (MTD) by reaching the minimally intolerated dose (MID). The dose immediately below the MID is then defined as the MTD. This is best accomplished by using appropriately screened patients for the target indication, as patients in many CNS indications often tolerate doses differently than healthy non-patients. Biomarkers for safety and pharmacodynamic measures can also assist in further defining a safe and potentially effective dose range for subsequent clinical trial phases. CONCLUSION: Phase 1 studies can yield critical insights into the pharmacology of a new compound in man and offer perhaps the only development period in which the dose range can be safely and thoroughly explored. Phase 1 studies often contain multiple endpoint objectives, the reconciliation of which can present a dilemma for drug developers and study investigators alike, but which can crucially determine whether a compound can survive to the next step in the drug development process.

A Single-Dose, Two-Way Crossover, Open-Label Bioequivalence Study of an Amphetamine Extended-Release Oral Suspension in Healthy Adults.

Objective: The purpose of this study was to compare the pharmacokinetics of a new extended-release amphetamine oral suspension (AMP XR-OS) with a standard extended-release mixed amphetamine salts product, Adderall XR®. Method: In this single-dose, open-label, randomized, two-period, two-treatment crossover study, 42 healthy adult volunteers received 15 mL of AMP XR-OS in one period and a 30 mg Adderall XR capsule in another period (both containing 18.8 mg of amphetamine base) under fasted conditions. Blood samples were analyzed for d- and l-amphetamine concentrations, and pharmacokinetic parameters Cmax, AUC0-5, AUC5-last, and AUCinf were calculated to determine bioequivalence. Safety was monitored throughout the study. Results: The 90% confidence intervals (CIs) for the log-transformed Cmax, AUC0-5, AUC5-last, and AUCinf fell within the accepted 80% to 125% range for establishing bioequivalence for d- and l-amphetamine. The most common adverse events were nausea and decreased appetite. Conclusion: AMP XR-OS is bioequivalent to Adderall XR in healthy adult participants.

Diagnosis and Treatment of Attention-Deficit/Hyperactivity Disorder in Preschool-Aged Children.

OBJECTIVES: Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder defined as a persistent pattern of inactivity and/or hyperactivity that interferes with behavioral function or development. Diagnosis and treatment of ADHD in the preschool-aged population (children 3-5 years old) is more complicated compared with older children because of developmental and physiological differences. This article reviews the available literature regarding the challenges associated with ADHD diagnosis and treatment in preschool-aged children, as well as the unmet needs of preschool-aged children with ADHD. METHODS: Key considerations for ADHD diagnosis and treatment patterns in preschool-aged children are summarized in this review, including the need for early intervention, the association with comorbidities, and the differences in pharmacokinetic profiles between preschool-aged children and older children. RESULTS: Efficacy and safety data are lacking, as clinical trial design and execution pose unique challenges in this population. Preschool-aged children often have difficulty with pill swallowing and tolerating phlebotomy necessary for the collection of pharmacokinetic and safety data. However, early diagnosis and treatment are essential to mitigate ADHD symptoms and comorbidities that may develop during childhood and adolescence in patients with persistent ADHD. CONCLUSION: This review describes the established diagnostic and treatment modalities, along with the unmet needs of preschool-aged children with ADHD.

Pharmacokinetics of a New Amphetamine Extended-Release Oral Suspension in Children with Attention-Deficit/Hyperactivity Disorder.

OBJECTIVE: An extended-release amphetamine (AMP) oral suspension has been developed to facilitate medication ingestion and dose titration. This study sought to determine the pharmacokinetic (PK) profile of this new formulation in children with attention-deficit/hyperactivity disorder (ADHD). METHODS: This was an open-label, single-period, PK study in 29 pediatric participants with ADHD. Participants were stratified into age groups 1 (6-7 years), 2 (8-9 years), and 3 (10-12 years), and dosed with 15 mL extended-release AMP liquid suspension (equivalent to 30 mg mixed AMP salts) after an overnight fast. Blood samples were collected at prespecified time points and analyzed for d- and l-AMP concentrations. Key PK parameters included maximum plasma concentration (Cmax), time to maximum plasma concentration, half-life (T1/2), area under the curve from time 0 to last quantifiable concentration (AUClast) and to infinity (AUCinf), oral clearance (CL/F), and volume of distribution (Vz/F). The 95% confidence intervals (CIs) about the geometric means of the weight-normalized CL/F, Vz/F, and AUClast were determined. Safety was also assessed. RESULTS: All participants completed the study. As age increased, mean maximum and total exposure to AMP decreased; weight-normalized CL/F slightly increased, resulting in decreasing T1/2 values with age. For d- and l-AMP, the 95% CIs for the geometric means of weight-normalized CL/F/kg and Vz/F/kg were within the 60%-140% range for groups 2 and 3, while those of weight-normalized AUClast were within range for all age groups. Adverse events were mild and consistent with the safety profile of AMP. CONCLUSIONS: Exposure (Cmax, AUCinf, and AUClast) to AMP decreased with age, possibly as a result of the 30-mg/15-mL fixed dose across a range of weights (20-57 kg) and the consequent lower dose per kilogram in older participants, as well as the slight increase in clearance with age.

Fed and Fasted Administration of a Novel Extended-Release Methylphenidate Orally Disintegrating Tablet Formulation for the Treatment of ADHD.

Extended-release methylphenidate is a first-line treatment for attention-deficit/hyperactivity disorder. A methylphenidate extended-release orally disintegrating tablet (MPH XR-ODT) has recently been developed. Here we report an open-label, randomized, 2-period, 2-treatment crossover study to determine the effect of food on the bioavailability of a single 60-mg dose of MPH XR-ODT in healthy adults. Blood samples were collected predose through 36 hours postdose. Maximum plasma concentration (Cmax ), time to maximum plasma concentration (Tmax ), terminal elimination half-life (T1/2 ), overall systemic exposure (AUClast and AUCinf ), and partial areas under the concentration curve (AUC0-3 , AUC3-7 , and AUC7-12 ) were calculated. In total, 48 participants completed the study. For total methylphenidate from MPH XR-ODT, the lower limit of the 90% confidence interval (CI) around the geometric mean ratio (GMR, fed/fasted) for Cmax was below 80%, indicating a slightly decreased rate of absorption with food, whereas the 90%CIs around the GMRs of AUClast and AUCinf were within the 80%-125% limits, suggesting no food effect on exposure. The most common adverse events (AEs) were palpitations and decreased appetite. No serious, unusual, or unexpected AEs were reported. Thus, food had no substantial effect on overall bioavailability of MPH XR-ODT, which may be an important factor for some patients.

A Comparison of the Pharmacokinetics of Methylphenidate Extended-Release Orally Disintegrating Tablets With a Reference Extended-Release Formulation of Methylphenidate in Healthy Adults.

Extended-release (ER) methylphenidate (MPH) is a first-line treatment for attention-deficit/hyperactivity disorder. A methylphenidate extended-release orally disintegrating tablet (MPH XR-ODT) has recently been developed. This was a randomized, open-label, 3-period, 3-treatment study comparing the bioavailability and absorption of 2 MPH XR-ODT formulations with an MPH ER reference medication. Here we report the 2 treatments comparing the commercial MPH XR-ODT formulation and reference medication. Following a ≥10-hour fast, 42 healthy adults received 60 mg of reference medication or MPH XR-ODT (2 × 30 mg). The following pharmacokinetic (PK) parameters were calculated for total methylphenidate (d + l): maximum plasma concentration (Cmax ), time to maximum plasma concentration (Tmax ), terminal half-life (T1/2 ), and areas under the concentration-time curve from time zero to the time of the last quantifiable concentration (AUClast ), and from time zero extrapolated to infinity (AUCinf ). Secondary PK end points included partial AUCs. Safety was also assessed. Overall systemic exposure to methylphenidate after MPH XR-ODT administration was similar to that of the reference product, and the concentration-time profiles for MPH XR-ODT and the reference drug were similar, although the Cmax was 25% higher for MPH XR-ODT. The most common treatment-emergent adverse events were nausea (6) and anxiety (4), which were similar across treatments.

Pharmacokinetics of a New Amphetamine Extended-release Oral Liquid Suspension Under Fasted and Fed Conditions in Healthy Adults: A Randomized, Open-label, Single-dose, 3-treatment Study.

PURPOSE: A new amphetamine extended-release liquid formulation (AMP XR-OS), intended for the treatment of attention-deficit/hyperactivity disorder, has been developed. This study was performed to determine if administration with food affected the rate of absorption or bioavailability of AMP XR-OS. The formulation was also compared with an equivalent dose of an extended-release mixed amphetamine salts reference product (30 mg) under fed conditions. METHODS: Thirty adult volunteers participated in this single-dose, open-label, randomized, 3-period, 3-treatment crossover study. Each participant received a single 15-mL dose of AMP XR-OS (equivalent to 30 mg of the reference drug) under fasted conditions, a single 15-mL dose of AMP XR-OS under fed conditions, and a single dose of the reference drug under fed conditions. A 7-day washout separated the 3 treatment periods. Blood samples were collected at predetermined time points and analyzed for d- and l-amphetamine. Pharmacokinetic parameters reported are AUC0-5, AUC0-last, AUC5-last, and AUC0-∞; Cmax; elimination t1/2; and Tmax. The geometric mean ratios and 90% CIs of Cmax, AUC0-last, and AUC0-∞were determined for the comparison of AMP XR-OS fed and fasted, and Cmax, AUC0-5, AUC5-last, and AUC0-∞ were calculated for AMP XR-OS compared with the reference drug under fed conditions. Safety was also assessed. FINDINGS: Twenty-nine subjects completed the study. Subjects were mostly male, white, and of Hispanic/Latino ethnicity with a mean age of 35.83 years and a mean BMI of 25.36kg/m2. The 90% CIs of Cmax, AUC0-last, and AUC0-∞ for AMP XR-OS fasted versus fed were within the accepted 80% to 125% range, indicating lack of a food effect. In the comparison of AMP XR-OS fed versus the reference product, Cmax, AUC5-last, and AUC0-∞ were within the range to establish bioequivalence; however, AUC0-5 was significantly higher for AMP XR-OS compared with that of the reference drug. This difference between products was likely due to the known delay of Tmax and decreased exposure when the extended-release mixed amphetamine salts reference product is administered with food. A total of 36 mild or moderate adverse events were reported; 1 subject withdrew due to an adverse event, and no deaths occurred. These adverse events were consistent with the known pharmacodynamic effects of amphetamine. IMPLICATIONS: The absence of a food effect may allow for AMP XR-OS to be administered with or without a meal.

A Randomized Phase I Study to Assess the Effect of Alcohol on the Pharmacokinetics of an Extended-release Orally Disintegrating Tablet Formulation of Amphetamine in Healthy Adults.

PURPOSE: There is a strong association between attention-deficit/hyperactivity disorder (ADHD) and alcohol abuse, yet no studies have systematically assessed the effect of alcohol on the pharmacokinetics of psychostimulants such as amphetamine (AMP) in vivo. This study evaluated the effects of alcohol on the rate and extent of absorption of Adzenys™ XR-ODT*, a new extended-release orally disintegrating AMP tablet (AMP XR-ODT) for ADHD. METHODS: A Phase I single-dose, open-label study was conducted in 32 healthy adults. Participants were split into 2 cohorts, allowing for close monitoring of safety profile and tolerability, and were randomized 1:1:1:1 to receive treatment in 1 of 4 sequences. Each treatment included the administration of a single 18.8-mg dose of AMP XR-ODT, followed by 240 mL of deionized water or 4%, 20%, or 40% ethanol. Blood samples were collected at prespecified time points. The pharmacokinetic profiles of d- and l-AMP were comparable across treatment groups. FINDINGS: There was no change in the extent of absorption for d- or l-AMP with alcohol coingestion and no dose dumping of the extended-release portion of the formulation. The 90% CIs for the geometric mean ratios (4%, 20%, and 40% ethanol versus water) for Cmax and systemic exposure (AUC0-5, AUClast, and AUC0-∞) were within 80% to 125%. Adverse events were mild to moderate and were consistent with the known adverse event profile for AMP XR-ODT or alcohol. IMPLICATIONS: Varying concentrations of alcohol (4%-40%) did not significantly alter the pharmacokinetic profile of AMP XR-ODT. These findings are relevant to clinicians who have concerns about alcohol use and/or abuse when treating ADHD.

Pharmacokinetics of a Novel Amphetamine Extended-Release Orally Disintegrating Tablet in Children with Attention-Deficit/Hyperactivity Disorder.

BACKGROUND: A novel formulation for treating attention-deficit/hyperactivity disorder (ADHD) has recently been developed-amphetamine extended-release orally disintegrating tablets (AMP XR-ODTs). In this study, we assessed the rate of absorption and exposure of AMP XR-ODT under fasted conditions in children with ADHD. METHODS: Children (6-12 years) with ADHD were enrolled in a single-dose, open-label, single-period pharmacokinetic (PK) study. Patients were stratified by age (6-7, 8-9, and 10-12 year olds) and were dosed with 18.8-mg AMP XR-ODT under fasted conditions. Plasma samples were analyzed for d-and l-amphetamine. Maximum plasma concentration (Cmax), time to maximum plasma concentration (Tmax), area under the concentration-time curve from time zero-infinity (AUCinf), weight-normalized clearance (CL/F), and weight-normalized volume of distribution (Vz/F) were assessed. The geometric mean and 95% confidence intervals (CIs) were calculated for weight-normalized CL/F and Vz/F in each age group to determine if the 95% CIs were within the target range of 60%-140%. RESULTS: A total of 28 children completed the study. The 95% CIs for the geometric mean CL/F/kg and Vz/F/kg for both d- and l-amphetamine fell within the target range of 60%-140% for each age group, thus meeting the primary end point. Four participants experienced treatment-related adverse events, including vomiting (n = 3), abdominal pain (n = 2), dry mouth (n = 1), and insomnia (n = 1). CONCLUSIONS: AMP XR-ODT, a novel formulation that does not require swallowing an intact tablet or capsule, was well tolerated and demonstrated a PK profile consistent with once-daily dosing in children with ADHD.

A randomized crossover study to assess the pharmacokinetics of a novel amphetamine extended-release orally disintegrating tablet in healthy adults.

OBJECTIVES: In this pharmacokinetic (PK) study in healthy adults, we sought to: (1) compare the PK properties of a novel amphetamine extended-release orally disintegrating tablet formulation (Adzenys XR-ODT™ [AMP XR-ODT]) to a reference extended-release mixed amphetamine salts (MAS ER) formulation and (2) assess the effect of food on AMP XR-ODT. METHODS: Forty-two adults were enrolled in a single-dose, open-label, 3-period, 3-treatment, randomized crossover study and received an 18.8-mg dose of AMP XR-ODT (fasted or fed) or equivalent dose (30 mg) of MAS ER (fasted). Plasma samples were analyzed for d-and l-amphetamine. Maximum plasma concentration (Cmax), time to maximum plasma concentration (Tmax), elimination half-life (T1/2), area under the concentration-time curve from time zero to last quantifiable concentration (AUClast), from time zero to infinity (AUCinf), relevant partial AUCs, and weight-normalized clearance (CL/F/kg) were assessed. The PK parameters were compared across treatments using an ANOVA. Safety was also assessed. RESULTS: A total of 39 adults completed this study. The geometric mean ratios (90% confidence interval [CI]) for AMP XR-ODT/MAS ER Cmax, AUC5-last, AUClast, and AUCinf were within 80%-125% for both d-and l-amphetamine. The 90% CIs for AUC0-5 were slightly below the 80%-125% range. When AMP XR-ODT was administered with food, there was a slight decrease in the d-and l-amphetamine Cmax and approximately a 2-hour delay in Tmax. The most common adverse events reported (>5% of participants) were dry mouth, palpitations, nausea, dizziness, headache, anxiety, and nasal congestion. CONCLUSIONS: AMP XR-ODT displayed a PK profile similar to MAS ER, and no clinically relevant food effect was observed.

Safety and efficacy considerations due to misuse of extended-release formulations of stimulant medications.

Amphetamine or methylphenidate are first-line options for treating attention-deficit/hyperactivity disorder (ADHD). Deviations from suggested routes of administration such as crushing, chewing, intravenous administration, or snorting stimulant medication may alter the release rate, absorption, and bioavailability of the active drug. Additionally, the pharmacokinetic (PK) profiles of extended-release formulations of certain medications (e.g., some opioids) are known to be dangerously altered when consumed with alcohol; specifically, there is an unintended, rapid release of a significant portion of the drug (dose dumping). In vitro data suggest some extended-release stimulants dose dump in the presence of alcohol, which is of concern because the ADHD patient population is at risk for alcohol abuse. This article reviews the available scientific literature concerning modifications to routes of administration that may alter PK properties of stimulant-based medication for treating ADHD. These modifications are of clinical interest because they may pose safety hazards and affect efficacy. Electronic databases were searched for appropriate studies using relevant search terms. The misuse and abuse potential for stimulants and the efforts to prevent misuse are also discussed. Future research should be focused on determining the PK ramifications of stimulant misuse, along with developing new formulations with abuse-deterrent properties.

A Single-Dose, Single-Period Pharmacokinetic Assessment of an Extended-Release Orally Disintegrating Tablet of Methylphenidate in Children and Adolescents with Attention-Deficit/Hyperactivity Disorder.

OBJECTIVE: To determine the pharmacokinetic (PK) profile of a proprietary formulation of methylphenidate (MPH) in children and adolescents with attention-deficit/hyperactivity disorder (ADHD) in a phase 1 study. Methylphenidate extended-release orally disintegrating tablets (MPH XR-ODTs) combine two technologies in a single-tablet formulation-an extended-release profile that was designed for once-daily dosing in an ODT that does not require water or chewing for ingestion. METHODS: This was a single-dose, open-label, single-period, single-treatment study, in which 32 children with ADHD who were receiving MPH in doses of 40 or 60 mg before beginning the study each received a 60-mg dose (2 × 30 mg) of MPH XR-ODT. The following plasma PK parameters of MPH were determined for participants grouped by age (6-7, 8-9, 10-12, and 13-17 years old): maximum concentration (Cmax), time to maximum concentration (Tmax), elimination half-life (T½), area under the curve from 0 hours to infinity (AUCinf), oral clearance (CL/F), and volume of distribution in the terminal phase (Vz/F). Safety and tolerability were also assessed. RESULTS: A total of 32 participants received the study drug. For all participants, plasma concentration-time profiles of MPH exhibited a broad peak after administration of MPH XR-ODT through ∼8 hours, indicating extended release from the formulation, followed by an apparent first-order elimination phase. As age increased, MPH exposure decreased and mean estimates of CL/F increased; however, weight-normalized CL/F values were comparable across age groups. Similarly, mean estimates of Vz/F increased with age, but weight-normalization decreased differences across age groups, with the exception of the youngest age group, which had higher values. All adverse events (AEs) were mild. CONCLUSION: This XR-ODT formulation of MPH demonstrated weight-normalized clearance rates that were consistent across all age groups, a PK profile consistent with once-daily dosing, and an AE profile consistent with this class of medication in children and adolescents with ADHD.

Similar eicosapentaenoic acid and docosahexaenoic acid plasma levels achieved with fish oil or krill oil in a randomized double-blind four-week bioavailability study.

BACKGROUND: Long-chain n-3 polyunsaturated fatty acids (LC n-3-PUFA), docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) provide multiple health benefits for heart, brain and eyes. However, consumption of fatty fish, the main source of LC n-3-PUFAs is low in Western countries. Intakes of LC n-3-PUFA can be increased by taking dietary supplements, such as fish oil, algal oil, or krill oil. Recently, conflicting information was published on the relative bioavailability of these omega-3 supplements. A few studies suggested that the phospholipid form (krill) is better absorbed than the fish oil ethyl ester (EE) or triglyceride (TG) forms. Yet studies did not match the doses administered nor the concentrations of DHA and EPA per supplement across such comparisons, leading to questionable conclusions. This study was designed to compare the oral bioavailability of the same dose of both EPA and DHA in fish oil-EE vs. fish oil-TG vs. krill oil in plasma at the end of a four-week supplementation. METHODS: Sixty-six healthy adults (n = 22/arm) were enrolled in a double blind, randomized, three-treatment, multi-dose, parallel study. Subjects were supplemented with a 1.3 g/d dose of EPA + DHA (approximately 816 mg/d EPA + 522 mg/d DHA, regardless of formulation) for 28 consecutive days, as either fish oil-EE, fish oil-TG or krill oil capsules (6 caps/day). Plasma and red blood cell (RBC) samples were collected at baseline (pre-dose on Day 1) and at 4, 8, 12, 48, 72, 336, and 672 h. Total plasma EPA + DHA levels at Week 4 (Hour 672) were measured as the primary endpoint. RESULTS: No significant differences in total plasma EPA + DHA at 672 h were observed between fish oil-EE (mean = 90.9 ± 41 ug/mL), fish oil-TG (mean = 108 ± 40 ug/mL), and krill oil (mean = 118.5 ± 48 ug/mL), p = 0.052 and bioavailability differed by < 24 % between the groups. Additionally, DHA + EPA levels were not significantly different in RBCs among the 3 formulations, p = 0.19, providing comparable omega-3 indexes. CONCLUSIONS: Similar plasma and RBC levels of EPA + DHA were achieved across fish oil and krill oil products when matched for dose, EPA, and DHA concentrations in this four week study, indicating comparable oral bioavailability irrespective of formulation. TRIAL REGISTRATION: Clinicaltrials.gov identifier NCT02427373.

A single-dose, 3-way crossover pharmacokinetic comparison between immediate-release oxycodone hydrochloride with aversion technology (IRO-A, Oxecta), IRO-a with Niacin, and Oxycodone Hydrochloride (Roxicodone) in healthy adults under fasting conditions.

Snorting and intravenous use are common routes of administration for advanced opioid abusers. A tablet form of immediate-release oxycodone (IRO) developed using Aversion Technology combines immediate release (IR) oxycodone HCl with inactive functional excipients that are intended to discourage tampering associated with intranasal and intravenous abuse (IRO-A; Oxecta, Pfizer). The purpose of this single-dose, open-label, randomized, 3-period, 3-treatment crossover study was to evaluate the bioequivalence of IRO-A to the marketed immediate-release oxycodone HCl (IRO; Roxicodone, Xanodyne Pharmaceuticals Inc., Newport, KY). IRO-A was also compared with IRO-A with niacin, a product previously developed containing the same functional excipients plus niacin as an aversive agent to discourage oral overconsumption. Healthy adults (N = 40) aged 18-55 years received single 15-mg doses of IRO-A, IRO-A with niacin (60 mg), or IRO after fasting overnight. Naltrexone was administered to diminish opioid effects. Doses were separated by a ≥7-day washout. Plasma samples taken at designated time points were analyzed using liquid chromatography with tandem mass spectrometry. Geometric mean ratios for ln-transformed parameters for IRO-A and IRO were 92%, 104%, and 104% for Cmax, AUClast (AUC is area under the concentration-time curve), and AUCinf; 90% confidence intervals were within the accepted 80%-125% range. IRO-A was also bioequivalent to IRO-A with niacin. Adverse events were mild to moderate in intensity and typical of opioid therapy (nausea, headache, vomiting). Flushing only occurred when the subjects received the IRO-A with niacin treatment (9/37 subjects). The results demonstrated that IRO-A is bioequivalent to IRO and IRO-A with niacin. With features designed to discourage tampering associated with common forms of abuse, IRO-A may provide an alternative to conventional immediate-release oxycodone formulations.

The advent of a new pseudoephedrine product to combat methamphetamine abuse.

BACKGROUND: The personal and societal effects of methamphetamine abuse are well documented. The ease of accessibility to methamphetamine and the quality of the "high" it produces makes the drug highly desired by its abusers. Over time, many methamphetamine users will also become methamphetamine cooks, where pseudoephedrine in over-the-counter cold products is converted to methamphetamine through a simple, albeit extremely dangerous, process. New laws limiting access to these products have had limited success. No existing commercial pseudoephedrine products offer significant impediments to slow or limit the extraction and conversion of pseudoephedrine in clandestine methamphetamine laboratories. OBJECTIVE AND METHODS: A new pseudoephedrine 30 mg tablet product using Impede technology (Nexafed®) to deter methamphetamine production has recently been introduced into the marketplace. Using methods designed to mimic clandestine laboratory processes, the ability of this product to disrupt extraction and conversion of pseudoephedrine to methamphetamine yet provide therapeutic effectiveness was evaluated. RESULTS: Impede™ technology tablets limited the extraction and/or conversion of pseudoephedrine to methamphetamine when compared to a commercially marketed pseudoephedrine product (Sudafed®). Nexafed® tablets were also shown to be bioequivalent to the same control product, thus ensuring therapeutic equivalence. CONCLUSIONS: With the advent of new pseudoephedrine products in the marketplace with features to limit the extraction and conversion of pseudoephedrine to methamphetamine, new tools are now available to minimize the clandestine manufacture of the drug and potentially limit its social impact.

Dose proportionality and the effects of food on bioavailability of an immediate-release oxycodone hydrochloride tablet designed to discourage tampering and its relative bioavailability compared with a marketed oxycodone tablet under fed conditions: a single-dose, randomized, open-label, 5-way crossover study in healthy volunteers.

BACKGROUND: An immediate-release oxycodone hydrochloride formulation (IRO-A) indicated for moderate to severe pain was designed (by adding functional excipients) to discourage tampering associated with intranasal and intravenous abuse of prescription opioids. OBJECTIVES: The primary objective of this study was to determine the dose proportionality of oxycodone in IRO-A tablets under fasted conditions. Secondary objectives were to assess food effects on the pharmacokinetics of IRO-A tablets, to compare the relative bioavailability of oxycodone in IRO-A tablets versus marketed oxycodone hydrochloride (IRO) tablets under fed conditions and to evaluate the single-dose safety profile of the IRO-A tablets in healthy volunteers pretreated with naltrexone. METHODS: This open-label, single-dose, randomized, 5-way crossover study was conducted in healthy adults who received each of the following treatments, separated by a washout period of ≥7 days: IRO-A 1 × 5 mg, 2 × 5 mg, and 2 × 7.5 mg under fasted conditions, and IRO-A 2 × 7.5 mg and IRO 1 × 15 mg after a high-fat, high-calorie breakfast. Naltrexone was administered to minimize untoward pharmacologic effects of oxycodone. Dose proportionality (IRO-A), food effects (IRO-A), and relative bioavailability in a fed state (IRO-A and IRO) were assessed by using bioequivalence criteria (90% CIs between 80% and 125% for C(max) and AUC). RESULTS: Of the 35 adults enrolled in the study, 33 completed at least 1 dosing period. Most participants were male (54%) and white (69%), with a mean (SD) age of 32.6 (11.1) years and mean weight of 75.5 (12.3) kg. Plasma levels of oxycodone in IRO-A suggested dose-proportional pharmacokinetics; 90% CIs for dose-normalized C(max), AUC(0-last), and AUC(0-∞) fell within the 80% to 125% range. Concomitant food intake with IRO-A resulted in an ~14% reduction in oxycodone C(max) and an ~21% increase in AUC(0-last). The bioavailability of oxycodone from IRO-A tablets in the fed state was comparable with IRO tablets based on AUC parameters, although C(max) was ~16.5% lower. Reported or observed treatment-emergent adverse events were monitored throughout the study and were similar for IRO-A and IRO tablets. Nausea, headache, abdominal pain, and dizziness were the most common and are consistent with known effects of oxycodone after naltrexone blockade. CONCLUSIONS: Plasma levels of oxycodone in IRO-A tablets were compatible with proportional single-dose pharmacokinetics from 5 to 15 mg under fasted conditions. Administration of IRO-A with food suggested increased overall bioavailability relative to fasting conditions and a reduction in peak systemic exposure of oxycodone that is not expected to be clinically significant. When comparing IRO-A tablets with IRO tablets in the fed state, the overall systemic exposure of oxycodone was comparable, and peak systemic exposure was lower.

Dose proportionality and pharmacokinetics of fentanyl buccal soluble film in healthy subjects: a phase I, open-label, three-period, crossover study.

BACKGROUND AND OBJECTIVES: Fentanyl buccal soluble film (FBSF) is a small, bilayered, water-soluble polymer film (BioErodible MucoAdhesive; BEMA™) that adheres to the buccal mucosa and rapidly delivers fentanyl into the systemic circulation. It is approved for the treatment of cancer breakthrough pain in adult opioid-tolerant patients. The objective of this study was to evaluate the dose proportionality of the pharmacokinetics of FBSF in healthy subjects across a range of doses. METHODS: This was a phase I, open-label, single-dose, three-period, Latin-square crossover study in which 12 healthy subjects received single FBSF doses of 200, 600 and 1200 µg with 72 hours between doses. Oral naltrexone was administered to each subject prior to and after each study dose. Serial venous blood samples were collected for 48 hours after study drug administration. Adverse events were recorded throughout the study. Dose linearity was examined using a power model (P = a × Doseb), where P represents the dependent variable (maximum plasma drug concentration [C(max)], area under the plasma concentration-time curve [AUC] from time zero to time of the last measurable concentration [AUC(last)], or AUC from time zero to infinity [AUC(∞)]), and a and b are constants. A value of b≈1 indicated linearity. RESULTS: Following administration of FBSF doses of 200-1200 µg, mean C(max) values increased in a linear manner with values ranging from 0.383 ng/mL to 2.19 ng/mL, respectively. Mean AUC(last) values increased from 3.001 ng·h/mL to 19.17 ng·h/mL and mean AUC(∞) increased in a linear manner from 3.456 ng·h/mL to 20.43 ng·h/mL. All reported adverse events were considered to be mild to moderate in severity. CONCLUSIONS: This study demonstrates that peak fentanyl plasma concentrations and overall exposure increase in a dose-proportional manner following administration of FBSF.