Population Pharmacokinetic-Pharmacodynamic Modeling of a Novel Methylphenidate Extended-Release Orally Disintegrating Tablet in Pediatric Patients With Attention-Deficit/Hyperactivity Disorder.

PURPOSE/BACKGROUND: A methylphenidate (MPH) extended-release orally disintegrating tablet (MPH XR-ODT) formulation was recently approved for attention-deficit/hyperactivity disorder treatment in children 6 to 17 years of age. This analysis sought to develop a population pharmacokinetic (PK)/pharmacodynamic (PD) model to describe MPH XR-ODT PD-response data in a classroom study and use the model to simulate PD responses for a range of body weights and doses. METHODS/PROCEDURES: The MPH XR-ODT PK/PD model was developed with pediatric and adult PK data from prior studies and efficacy data from a laboratory classroom study in children with attention-deficit/hyperactivity disorder. In these studies, the safety profile of MPH XR-ODT was consistent with other extended-release MPH formulations. The PK/PD model efficacy end point was the Swanson, Kotkin, Agler, M-Flynn, and Pelham Scale Combined score. Body weight effects on MPH clearance and volume of distribution were included in the resulting model. Simulations using the PK/PD model were performed for patients with body weights between 7 and 100 kg and MPH XR-ODT doses of 10 to 60 mg MPH hydrochloride equivalents. FINDINGS/RESULTS: In the PK/PD model, the maximal reduction in the Swanson, Kotkin, Agler, M-Flynn, and Pelham Scale Combined score was approximately 38 units, and the MPH concentration required to achieve 50% of the maximal reduction was 14.24 ng/mL, suggesting favorable efficacy for MPH XR-ODT. Simulations showed a direct correlation between the effective MPH XR-ODT dose and body weight, with heavier participants requiring higher doses for symptom control. IMPLICATIONS/CONCLUSION: This model may help facilitate the dose-titration process by identifying an effective MPH XR-ODT target dose.

Population pharmacokinetics of methylphenidate hydrochloride extended-release multiple-layer beads in pediatric subjects with attention deficit hyperactivity disorder.

A new multilayer-bead formulation of extended-release methylphenidate hydrochloride (MPH-MLR) has been evaluated in pharmacokinetic studies in healthy adults and in Phase III efficacy/safety studies in children and adolescents with attention deficit hyperactivity disorder (ADHD). Using available data in healthy adults, a two-input, one-compartment, first-order elimination population pharmacokinetic model was developed using nonlinear mixed-effect modeling. The model was then extended to pediatric subjects, and was found to adequately describe plasma concentration-time data for this population. A pharmacokinetic/pharmacodynamic model was also developed using change from baseline in the ADHD Rating Scale (ADHD-RS)-IV total scores from a pediatric Phase III trial and simulated plasma concentration-time data. During simulations for each MPH-MLR dose level (10-80 mg), increased body weight resulted in decreased maximum concentration. Additionally, as maximum concentration increased, ADHD-RS-IV total score improved (decreased). Knowledge of the relationship between dose, body weight, and clinical response following the administration of MPH-MLR in children and adolescents may be useful for clinicians selecting initial dosing of MPH-MLR. Additional study is needed to confirm these results.

Steady-state bioavailability of extended-release methylphenidate (MPH-MLR) capsule vs. immediate-release methylphenidate tablets in healthy adult volunteers.

OBJECTIVES: The objective of the study was to determine the relative bioavailability of an extended-release multilayer bead formulation of methylphenidate hydrochloride (MPH-MLR) 80 mg vs. methylphenidate immediate-release (IR; Ritalin(®)) tablets as single and multiple doses in the fed state. METHODS: A single-center, multiple-dose, randomized, open-label, two-period crossover study conducted in 26 healthy adults assigned to 4 days of once-daily MPH-MLR 80 mg or IR methylphenidate 25 mg three times daily. RESULTS: MPH-MLR 80 mg produced reproducible biphasic profiles of plasma methylphenidate concentrations characterized by a rapid initial peak, followed by a moderate decline reaching a plateau ~5 h post dose, then a gradual increase culminating in an attenuated second peak ~7 h post dose. Maximum concentration was lower for MPH-MLR 80 mg than IR methylphenidate 25 mg three times daily on day 1 (23.70 vs. 31.47 ng/mL); exposure was similar. The geometric mean ratios (MPH-MLR/IR methylphenidate [90 % CI]) of log-transformed area under the plasma drug concentration-time curve to the last measurable observation (day 1: 0.88 [84.75-91.80]; day 4: 0.84 [81.16-86.94]), and area under the plasma drug concentration extrapolated to infinity (day 1: 0.93 [88.57-97.28]; day 4: 0.88 [84.48-91.17]) were within the 80-125 % bioequivalence range. The mean ± SD MPH-MLR 80-mg capsule day 4 area under the plasma drug concentration vs. time curve from 0 to 4 h (74.5 ± 15.2 ng·h/mL) was greater than IR methylphenidate 25 mg three times daily (66.0 ± 17.4 ng·h/mL), confirming steady-state levels during the study period. All treatment regimens were safe and well tolerated. CONCLUSION: MPH-MLR 80-mg capsule once daily or IR methylphenidate 25 mg three times daily provides comparable maximum methylphenidate concentrations and systemic exposure in the fed state.

Single-dose pharmacokinetics of methylphenidate extended-release multiple layer beads administered as intact capsule or sprinkles versus methylphenidate immediate-release tablets (Ritalin(®)) in healthy adult volunteers.

OBJECTIVES: The purpose of this study was to evaluate the relative bioavailability and safety of a multilayer extended-release bead methylphenidate (MPH) hydrochloride 80 mg (MPH-MLR) capsule or sprinkles (37% immediate-release [IR]) versus MPH hydrochloride IR(Ritalin(®)) tablets, and to develop a pharmacokinetic (PK) model simulating MPH concentration-time data for different MPH-MLR dosage strengths. METHODS: This was a single-center, randomized, open-label, three-period crossover study conducted in 26 fasted healthy adults (mean weight±standard deviation, 70.4±11.7 kg) assigned to single-dose oral MPH-MLR 80 mg capsule or sprinkles with applesauce, or Ritalin IR 25 mg (1×5 mg and 1×20 mg tablet) administered at 0, 4, and 8 hours. RESULTS: MPH-MLR 80 mg capsule and sprinkles were bioequivalent; ratios for maximum concentration (Cmax), area under plasma drug concentration versus time curve (AUC)0-t, and AUC0-inf were 1.04 (95% confidence interval [CI], 96.3-112.4), 0.99 (95% CI, 95.3-102.8), and 0.99 (95% CI, 95.4-103.0), respectively. MPH-MLR capsule/sprinkles produced highly comparable, biphasic profiles of plasma MPH concentrations characterized by rapid initial peak, followed by moderate decline until 5 hours postdose, and gradual increase until 7 hours postdose, culminating in an attenuated second peak. Based on 90% CIs, total systemic exposure to MPH-MLR 80 mg capsule/sprinkles was similar to that for Ritalin IR 25 mg three times daily, but marked differences in Cmax values indicated that MPH-MLR regimens were not bioequivalent to Ritalin. MPH Cmax and total systemic exposure over the first 4 hours postdose with MPH-MLR capsule/sprinkles was markedly higher than that associated with the first dose of Ritalin. All study drugs were safe and well tolerated. The PK modeling in adults suggested that differences in MPH pharmacokinetics between MPH-MLR and Ritalin are the result of dosage form design attributes and the associated absorption profiles of MPH. CONCLUSIONS: MPH-MLR 80 mg provides a long-acting biphasic pattern of plasma MPH concentrations with one less peak and trough than Ritalin IR.

A food effect study and dose proportionality study to assess the pharmacokinetics and safety of bardoxolone methyl in healthy volunteers.

This study investigated the effect of food on the plasma pharmacokinetics of bardoxolone methyl, an antioxidant inflammation modulator, at a 20 mg dose, and the dose proportionality of bardoxolone methyl pharmacokinetics from 20 to 80 mg. It was a single-dose study conducted at a single center in 32 healthy volunteers aged 18-45 years using an amorphous spray-dried dispersion formulation of bardoxolone methyl. In Part A, 16 subjects received single 20 mg doses of bardoxolone methyl under fasting and non-fasting conditions. In Part B, 16 subjects received a single 60 or 80 mg dose of bardoxolone methyl and a matching placebo dose under fasting conditions. Blood samples for pharmacokinetic analysis were taken over 120 hours following dose administration. Single dose administration of 20, 60, and 80 mg bardoxolone methyl was safe and well-tolerated in healthy volunteers. Total bardoxolone methyl exposure was unchanged in the presence of food. However, doses of bardoxolone methyl above 20 mg appear to have a saturated dissolution or absorption process and are associated with less than proportional increases in drug exposure.

A Novel Study Using Accelerated Mass Spectrometry to Evaluate the Pharmacokinetics of Total (14)C AL-8309 (Tandospirone) Following Topical Ocular Administration in Healthy Male Subjects.

The primary objective of this study is to characterize the pharmacokinetics of total (14)C concentrations following bilateral, topical ocular drops of (14)C-AL-8309B labeled either at the pyrimidyl ring (cohort A) position or at the imido-carbonyl ring (cohort B) position twice daily from day 1 through day 6 and once in the morning of day 7 in 16 healthy male subjects (8 per cohort). Each drop (approximately 24 µL) of (14)C-AL-8309B 1.75% ophthalmic solution (equivalent to 420 µg-equiv AL-8309) contained approximately 500 nCi of (14)C-AL-8309. AL-8309 systemic absorption was relatively slow; the time of maximum observed plasma concentrations ranged from 0.25 to 3 hours. Moderate accumulation (1.48- to 1.86-fold) was observed in the mean systemic total (14)C plasma concentrations at steady state (day 7) compared with single dose (day 1). The mean total (14)C eliminated was 3.5-fold and 3.7-fold greater in the urine than the feces for cohort A and cohort B, indicating that (14)C-AL-8309 is primarily excreted through renal elimination. Single and multiple topical doses of AL-8309B were found to be safe and well-tolerated in healthy subjects. This is the first reported use of accelerator mass spectrometry technology with a topically applied ophthalmic product.

Role of PEPT2 in peptide/mimetic trafficking at the blood-cerebrospinal fluid barrier: studies in rat choroid plexus epithelial cells in primary culture.

Recent studies have established the functional and molecular presence of a high-affinity peptide transporter, PEPT2, in whole tissue rat choroid plexus. However, the precise membrane location and directionality of PEPT2-mediated transport is uncertain at present. In this study, we examined the transport kinetics of a model dipeptide, glycylsarcosine (GlySar), along with the protein expression of PEPT2 using primary cell cultures of choroidal epithelium from neonatal rats. GlySar accumulation and transepithelial transport were 3 to 4 times higher when introduced from the apical as opposed to the basal side of the monolayers. GlySar apical uptake was also stimulated by an inwardly directed proton gradient. The uptake of GlySar was inhibited by di/tripeptides, carnosine, and alpha-amino cephalosporins but was unaffected by amino acids, cephalosporins lacking an alpha-amino group, and organic anions and cations. The Michaelis constant (K(m)) of GlySar was 59.6 microM for apical uptake and 1.4 mM for basal uptake; this is consistent with the high-affinity properties of PEPT2 at the apical membrane. Immunoblot analyses and immunofluorescent confocal microscopy demonstrated the presence of PEPT2, but not PEPT1, in rat choroid plexus epithelial cells. Moreover, PEPT2 was present in the apical and subapical regions of the cell but was absent in the basolateral membrane. These findings demonstrate, for the first time, that PEPT2 protein is present at the apical membrane of choroidal epithelial cells and that it is functionally active at this membrane surface. The results suggest that PEPT2 may have a role in the efflux of peptides and/or mimetics from cerebrospinal fluid to the blood.

Carnosine uptake in rat choroid plexus primary cell cultures and choroid plexus whole tissue from PEPT2 null mice.

PEPT2 is functionally active and localized to the apical membrane of rat choroid plexus epithelial cells. However, little is known about the transport mechanisms of endogenous neuropeptides in choroid plexus, and the role of PEPT2 in this process. In the present study, we examined the uptake kinetics of carnosine in rat choroid plexus primary cell cultures and choroid plexus whole tissue from wild-type (PEPT2(+/+)) and null (PEPT2(-/-)) mice. Our results indicate that carnosine is preferentially taken up from the apical as opposed to basolateral membrane of cell monolayers, and that basolateral efflux in limited. Transepithelial flux of carnosine was not distinguishable from that of paracellular diffusion. The apical uptake of carnosine was characterized by a high affinity (K(m) = 34 microM), low capacity (V(max) = 73 pmol/mg protein/min) process, consistent with that of PEPT2. The non-saturable component was small (K(d) = 0.063 microL/mg protein/min) and, under linear conditions, was only 3% of the total uptake. Studies in transgenic mice clearly demonstrated that PEPT2 was responsible for over 90% of carnosine's uptake in choroid plexus whole tissue. These findings elucidate the unique role of PEPT2 in regulating neuropeptide homeostasis at the blood-cerebrospinal fluid interface.