In Vitro Evaluation of Poly(lactide-co-glycolide) In Situ Forming Gels for Bedaquiline Fumarate Salt and Pharmacokinetics Following Subcutaneous Injection in Rats.

This study evaluated in vitro and in vivo drug release of bedaquiline from in situ forming gels (ISGs) containing 200 mg eq./g bedaquiline fumarate salt prepared with four different grades of poly(d,l-lactide) (PDLLA) or poly(d,l-lactide-co-glycolide) (PLGA) with a lactide/glycolide ratio of 50/50 or 75/25 and acid (A) or ester (E) end-capping in N-methyl-2-pyrrolidone at a polymer/solvent ratio of 20/80% (w/w). Mean in vitro drug release in 0.05 M phosphate buffer pH 7.4 with 1% (w/v) sodium lauryl sulphate was 37.3, 47.1, 53.3, and 62.3% within 28 days for ISGs containing PLGA5050A, PDLLA, PLGA7525A, and PLGA7525E, respectively. The data suggested that drug release was primarily controlled by precipitated drug redissolving, rather than polymer erosion. In vivo pharmacokinetic profiles after subcutaneous injections in rats were comparable for all ISGs (mean half-lives (t1/2) ranged from 1411 to 1695 h) and indicated a sustained drug release when compared to a solution of bedaquiline fumarate salt in polyethylene glycol 400/water 50/50% (v/v) (mean t1/2 of 895 h). In conclusion, PLGA or PDLLA-based ISGs have shown potential for parenteral sustained delivery of bedaquiline, suggesting further preclinical and clinical studies. From a formulation point of view, this case example highlights the importance of the interplay between drug solubility in biological media and dissolution of drug precipitates, which, in addition to the incorporation of diffusion controlling polymers, governs the release of the active drug.

Data driven evaluation of healthy volunteer characteristics at screening for phase I clinical trials to inform on study design and optimize screening processes.

Protocols for clinical trials describe inclusion and exclusion criteria based on general and compound-specific considerations to ensure subject safety and data quality. In phase I clinical trials, healthy volunteers (HVs) are screened against these criteria that often specify predefined eligibility ranges for vital signs, electrocardiogram, and laboratory tests. HVs are excluded if baseline parameters deviate from these ranges even though this may not indicate underlying pathology, which could delay trial execution. Data from 3365 HVs participating in 9670 screening visits for 94 phase I HV trials, conducted between December 2008 and May 2019 at the Janssen Clinical Pharmacology Unit, were retrospectively analyzed. Commonly predefined protocol ranges were overlaid with HV data to estimate predicted screen failure rates (SFRs). Of the overall population, 91% was White and 64% were men with mean age of 42.8 ± 12.5 years. High predicted SFRs are related to cardiovascular/metabolic (body mass index, heart rate [HR], blood pressure [BP], and corrected QT Fridericia's formula [QTcF]), renal (estimated glomerular filtration rate [eGFR]), liver (alanine aminotransferase [ALT], and total bilirubin), and coagulation (prothrombin time [PT]) parameters. Predicted SFRs increased with age for high systolic and diastolic BP, QTcF interval, and eGFR. In contrast, lower SFRs in the older age groups were seen for low diastolic BP, liver function test, ALT, PT, and total bilirubin. This analysis can be used to inform on study design, protocol inclusion and exclusion criteria, and to optimize the screening process. Data-driven critical appraisal of proposed inclusion and exclusion criteria using a risk-based approach may significantly reduce screen failure rates without compromising subjects' safety.

In vitro evaluation of poloxamer in situ forming gels for bedaquiline fumarate salt and pharmacokinetics following intramuscular injection in rats.

The objective of this study was to evaluate in vitro and in vivo drug release from in situ forming gels prepared with poloxamer 338 (P338) and/or 407 (P407) in N-methyl-2-pyrrolidone (NMP)/water mixtures for the model compound bedaquiline fumarate salt. The impact of total poloxamer concentration (20%-25% (w/w)), P338/P407 ratio (100/0%-0/100% (w/w)) and NMP/water ratio (0/100%-25/75% (v/v)) on gel point temperature (GPT) was investigated via a design of experiments (DoE), showing that GPT decreased mainly with increasing poloxamer concentration and decreasing P338/P407 ratio, while the relation with NMP/water ratio was more complex resulting in a flexion. Based on the DoE, four formulations with 10 mg/g bedaquiline fumarate salt, a fixed NMP/water ratio of 25/75% (v/v) and varying total poloxamer concentration and P338/P407 ratio were selected for evaluation of gel erosion in vitro. The fastest eroding formulation had the lowest total poloxamer concentration (20% (w/w)) and the lowest P338/P407 ratio (20.4/79.6% (w/w)), while the formulation with the highest total poloxamer concentration (23.5% (w/w)) and highest P338/P407 ratio (100/0% (w/w)) showed the lowest gel erosion rate. These fast and slow eroding formulations showed a similar trend for in vitro drug release and in vivo pharmacokinetics after intramuscular (IM) injection in rats. In vivo tmax of the IM administered poloxamer in situ forming gels was about 6 h and a short-term sustained drug release was observed in vivo in rats up to 24 h after dosing, similar to a solution of bedaquiline fumarate salt in polyethylene glycol (PEG400)/water. In conclusion, IM administration of the evaluated poloxamer in situ forming gels may be useful for drugs that require a short-term sustained release, but is not able to extend drug release rates up to weeks or months.

Preclinical Bioavailability Strategy for Decisions on Clinical Drug Formulation Development: An In Depth Analysis.

The aim of the presented retrospective analysis was to verify whether a previously proposed Janssen Biopharmaceutical Classification System (BCS)-like decision tree, based on preclinical bioavailability data of a solution and suspension formulation, would facilitate informed decision making on the clinical formulation development strategy. In addition, the predictive value of (in vitro) selection criteria, such as solubility, human permeability, and/or a clinical dose number (Do), were evaluated, potentially reducing additional supporting formulation bioavailability studies in animals. The absolute ( Fabs,sol) and relative ( Frel, susp/sol) bioavailability of an oral solution and suspension, respectively, in rat or dog and the anticipated BCS classification were analyzed for 89 Janssen compounds with 28 of these having Frel,susp/sol and Fabs,sol in both rat and dog at doses around 10 and 5 mg/kg, respectively. The bioavailability outcomes in the dog aligned well with a BCS-like classification based upon the solubility of the active pharmaceutical ingredient (API) in biorelevant media, while the alignment was less clear for the bioavailability data in the rat. A retrospective analysis on the clinically tested formulations for a set of 12 Janssen compounds confirmed that the previously proposed animal bioavailability-based decision tree facilitated decisions on the oral formulation type, with the dog as the most discriminative species. Furthermore, the analysis showed that based on a Do for a standard human dose of 100 mg in aqueous and/or biorelevant media, a similar formulation type would have been selected compared to the one suggested by the animal data. However, the concept of a Do did not distinguish between solubility enhancing or enabling formulations and does not consider the API permeability, and hence, it produces the risk of slow and potentially incomplete oral absorption of an API with poor intestinal permeability. In cases where clinical dose estimations are available early in development, the preclinical bioavailability studies and dose number calculations, used to guide formulation selection, may be performed at more relevant doses instead of the proposed standard human dose. It should be noted, however, that unlike in late development, there is uncertainty on the clinical dose estimated in the early clinical phases because that dose is usually only based on in vitro and/or in vivo animal pharmacology models, or early clinical biomarker information. Therefore, formulation strategies may be adjusted based on emerging data supporting clinical doses. In summary, combined early information on in vitro-assessed API solubility and permeability, preclinical suspension/solution bioavailability data in relation to the intravenous clearance, and metabolic pathways of the API can strengthen formulation decisions. However, these data may not always fully distinguish between conventional (e.g., to be taken with food), enhancing, and enabling formulations. Therefore, to avoid overinvestment in complex and expensive enabling technologies, it is useful to evaluate a conventional and solubility (and/or permeability) enhancing formulation under fasted and fed conditions, as part of a first-in-human study or in a subsequent early human bioavailability study, for compounds with high Do, a low animal Frel,susp/sol, or low Fabs,sol caused by precipitation of the solubilized API.

Single-dose pharmacokinetics of ibrutinib in subjects with varying degrees of hepatic impairment.

This open-label, single-dose study was designed to characterize pharmacokinetics and safety profile of ibrutinib in hepatically impaired subjects. Each subject received single oral dose of ibrutinib (140 mg) following an overnight fast (hepatic impairment-mild [n = 6], moderate [n = 10], and severe [n = 8]; healthy control [n = 6]). Subjects with hepatic impairment showed significant increase in ibrutinib plasma exposures and fraction unbound ibrutinib. Compared to control group, mean exposure (AUClast; unbound) in mild, moderate, and severe cohorts was 4.1-, 9.8-, 13.4-fold higher, respectively. Terminal half-life trended slightly longer in moderately and severely impaired subjects, but risk of accumulation on repeated dosing appears negligible as half-life did not exceed 10 h. Based on observed effects on exposure, reduced doses are recommended for patients with mild and moderate liver impairment (Child-Pugh Class A and B), whereas 140 mg is considered too high for severely impaired patients (Class-C). A single dose of 140 mg was well tolerated in this study (NCT01767948).

Stable isotope-labelled intravenous microdose for absolute bioavailability and effect of grapefruit juice on ibrutinib in healthy adults.

AIMS: Ibrutinib, an inhibitor of Bruton's tyrosine kinase, is used in the treatment of mantle cell lymphoma or chronic lymphocytic leukaemia. Ibrutinib undergoes extensive rapid oxidative metabolism mediated by cytochrome P450 3A both at the level of first pass and clearance, which might result in low oral bioavailability. The present study was designed to investigate the absolute bioavailability (F) of ibrutinib in the fasting and fed state and assess the effect of grapefruit juice (GFJ) on the systemic exposure of ibrutinib in order to determine the fraction escaping the gut (Fg ) and the fraction escaping hepatic extraction (Fh ) in the fed state. METHODS: All participants received treatment A [560 mg oral ibrutinib, under fasting conditions], B (560 mg PO ibrutinib, fed, administered after drinking glucose drink) and C (140 mg oral ibrutinib, fed, with intake of GFJ before dosing). A single intravenous (i.v.) dose of 100 µg (13) C6 -ibrutinib was administered 2 h after each oral dose. RESULTS: The estimated 'F' for treatments A, B and C was 3.9%, 8.4% and 15.9%, respectively. Fg and Fh in the fed state were 47.0% and 15.9%, respectively. Adverse events were mild to moderate in severity (Grade 1-2) and resolved without sequelae by the end of the study. CONCLUSION: The absolute oral bioavailability of ibrutinib was low, ranging from 3.9% in the fasting state to 8.4% when administered 30 min before a standard breakfast without GFJ and 15.9% with GFJ. Ibrutinib was well tolerated following a single oral and i.v. dose, under both fasted and fed conditions and regardless of GFJ intake status.

Effect of CYP3A perpetrators on ibrutinib exposure in healthy participants.

Ibrutinib (PCI-32765), a potent covalent inhibitor of Bruton's tyrosine kinase, has shown efficacy against a variety of B-cell malignancies. Given the prominent role of CYP3A in ibrutinib metabolism, effect of coadministration of CYP3A perpetrators with ibrutinib was evaluated in healthy adults. Ibrutinib (120 mg [Study 1, fasted], 560 mg [studies 2 (fasted), and 3 (nonfasted)]) was given alone and with ketoconazole [Study 1; 400 mg q.d.], rifampin [Study 2; 600 mg q.d.], and grapefruit juice [GFJ, Study 3]. Lower doses of ibrutinib were used together with CYP3A inhibitors [Study 1: 40 mg; Study 3: 140 mg], as safety precaution. Under fasted condition, ketoconazole increased ibrutinib dose-normalized (DN) exposure [DN-AUClast: 24-fold; DN-C max: 29-fold], rifampin decreased ibrutinib exposure [C max: 13-fold; AUClast: 10-fold]. Under nonfasted condition, GFJ caused a moderate increase [DN-C max: 3.5-fold; DN-AUC: 2.2-fold], most likely through inhibition of intestinal CYP3A. Half-life was not affected by CYP perpetrators indicating the interaction was mainly on first-pass extraction. All treatments were well-tolerated.

The effect of food on the pharmacokinetics of oral ibrutinib in healthy participants and patients with chronic lymphocytic leukemia.

PURPOSE: To assess ibrutinib pharmacokinetics under fasted and fed conditions, impact of food-intake timing, and the safety and tolerability. METHODS: Three studies were analyzed. Study 1 was a randomized, open-label, single-dose, four-way crossover study in 44 healthy participants. Study 2 was a randomized, repeat-dose crossover study in 16 patients with previously treated chronic lymphocytic leukemia (CLL). Ibrutinib dose was 420 mg in both studies. Study 3 was an open-label, sequential study to assess the effect of a standard breakfast on ibrutinib 560 mg in eight healthy participants. RESULTS: Administration of single-dose ibrutinib under fasting conditions (study 1) resulted in approximately 60 % of exposure compared with drug intake either 30 min before, 30 min after (fed), or 2 h after a high-fat meal. Similar food effect was observed (study 3) when ibrutinib was given 30 min before meal. In CLL patients (study 2), the C max and AUC under fasting conditions were 43 and 61 %, respectively, relative to fed conditions. When administered once-daily in uncontrolled food-intake conditions (≥30 min before or 2 h after), exposures were slightly (≈30 %) lower than in fed condition. When corrected for repeated dosing, pharmacokinetic parameters in healthy participants and patients were comparable. Ibrutinib was generally well tolerated in all settings studied. CONCLUSIONS: Ibrutinib administered in fasted condition reduces exposure to approximately 60 % as compared with dosing in proximity to food-intake, regardless of timing/type of meal. Because repeated drug intake in fasted condition is unlikely, no food restrictions may be needed to administer ibrutinib.

Helicobacter pylori treatment in children: defining a dose for rabeprazole as a part of a triple therapy regimen.

The proton pump inhibitor, rabeprazole, has been studied in children for the treatment of gastroesophageal reflux disease (GERD). In adults, rabeprazole is indicated for Helicobacter pylori eradication in combination with amoxicillin and clarithromycin. Nonlinear mixed effects modeling was conducted to estimate pharmacokinetic (PK) parameters for rabeprazole and its thioether metabolite from 336 subjects, 35% of whom were children 1-11 years with GERD from phase I and III studies. A 2-compartment disposition model with a transit absorption model provided the best fit for rabeprazole PK. The steady-state area under the concentration-time curves given several candidate doses were simulated to identify a dose per each body weight group that is comparable to a 20 mg twice-daily dose in adults, which is the recommended dose for treatment of H. pylori in adults. Simulations provided the following recommended twice-daily weight-based doses for children ≥1 year and <16 years: 10 mg for 6-10 kg, 15 mg for 10-30 kg, and 20 mg for ≥30 kg.

Population pharmacokinetics of rabeprazole and dosing recommendations for the treatment of gastroesophageal reflux disease in children aged 1-11 years.

BACKGROUND AND OBJECTIVE: Rabeprazole sodium is a proton pump inhibitor used for the treatment of gastroesophageal reflux disease (GERD). The objective of this study was to develop a population pharmacokinetic model for rabeprazole that describes concentration-time data arising from phase I and phase III studies in adult and pediatric subjects, including neonates and preterm infants, and propose dosing recommendations for pediatric subjects aged 1-11 years. METHODS: A total of 4,417 pharmacokinetic observations from 597 subjects aged 6 days to 55.7 years with body weights of 1.15-100 kg were used to develop the population pharmacokinetic model using non-linear mixed-effects modeling techniques. Weight and age were included in the structural model to describe clearance (CL) and central volume of distribution (V c). Other covariates considered during model development included sex, race, creatinine clearance, hepatic function, formulation, feeding status, and route of administration. The final model was used to determine doses for pediatric subjects aged 1-11 years to achieve a steady-state area under the plasma concentration-time curve across the dose interval of 24 h (AUC24) within the target adult AUC24 range obtained following a rabeprazole 10 mg dose. RESULTS: The best model was a two-compartment disposition model with a sequential zero-order duration of input (Dur), first-order absorption (k a) following a lag time (T lag), with weight and age effects on CL and V c. Formulation type and feeding status described some of the variability in bioavailability and the absorption parameters T lag, Dur, and k a. A dosage regimen of 5 mg once daily for children <15 kg, and 10 mg for children ≥15 kg is recommended for 1- to 11-year-old pediatric patients with GERD. CONCLUSIONS: The pharmacokinetics of rabeprazole were described with good precision following administration of rabeprazole across a range of doses and in a range of formulations.

Pharmacokinetics of rabeprazole granules versus tablets, and the effect of food on the pharmacokinetics of rabeprazole granules in healthy adults-cross-study comparison.

The primary objective was to compare the pharmacokinetics (PK) of rabeprazole granules versus rabeprazole tablets, and assess the effect of food on the PK of rabeprazole granules. Data from three phase 1, open-label, single-dose, randomized, crossover studies in healthy adult participants are presented separately and as a cross-study comparison; study 1: PK of phase 1 rabeprazole granules versus rabeprazole tablets under fasting conditions; study 2: PK of phase 3 rabeprazole granules versus phase 1 rabeprazole granules; study 3: bioequivalence of to-be-marketed rabeprazole granules (sprinkle capsules) versus phase 3 rabeprazole granules; and assessment of the food effect for the to-be-marketed rabeprazole granules. Overall, 123 of 130 participants enrolled completed the studies. The overall plasma exposure as measured by area under the plasma concentration-time curve (AUC) was comparable between rabeprazole granules and tablets; mean peak plasma concentration (Cmax ) was lower for the granules compared with tablets. The plasma elimination half-life was short and independent of formulation. Food intake prior to administration of the to-be-marketed granules delayed the absorption and reduced the estimated parameters for bioavailability by 55% (Cmax ) and 28% (AUCinf ). Rabeprazole was well-tolerated.

Population pharmacokinetics of JNJ-37822681, a selective fast-dissociating dopamine D2-receptor antagonist, in healthy subjects and subjects with schizophrenia and dose selection based on simulated D2-receptor occupancy.

BACKGROUND AND OBJECTIVES: JNJ-37822681 is a selective, fast-dissociating dopamine D2-receptor antagonist currently in development as a candidate antipsychotic. The aim of the analyses was to develop a population pharmacokinetic model to describe the pharmacokinetics of JNJ-37822681 in healthy subjects and patients with schizophrenia and to identify covariates of interest. The model was then used to simulate D2-receptor occupancy in support of dose selection for subsequent studies. METHODS: Data were obtained from 378 subjects enrolled in three phase I and two phase II studies. Nonlinear mixed effects modeling of pooled data was conducted using NONMEM(®) to estimate population pharmacokinetic parameters and the effect of covariates on these parameters. The model was evaluated on a subset of data that was not used for model building and was subsequently used to simulate steady-state exposure for each subject in the phase IIb study. Striatal D2-receptor occupancy was predicted using simulated exposure combined with pharmacodynamic parameters from a sigmoid maximum effect model established from previous [(11)C]raclopride positron emission tomography studies. RESULTS: A two-compartment disposition model with zero-order input in a depot compartment followed by first-order absorption into and first-order elimination from the central compartment combined with a transit compartment provided the best fit to the data. Significant covariates were sex and bioavailability on apparent clearance and food intake on the absorption rate constant. Clearance was 11 % higher in females compared with males. The model passed external evaluation. The estimated pharmacokinetic parameters for the phase IIb study were similar to those observed in the phase IIa study. D2-receptor occupancy was predicted to be in the 65-80 % range at 10 mg twice daily and partially or fully reaching the 80 % threshold at doses of 20 and 30 mg twice daily. CONCLUSION: The population pharmacokinetic model of JNJ-37822681 successfully described the pharmacokinetics of JNJ-37822681 and allowed the reliable determination of individual exposure parameters in a phase IIb study. It was concluded that 5 or 7.5 mg twice daily would likely be minimal- or no-effect doses, whereas 10 mg twice daily was expected to provide an optimal balance of efficacy and tolerability.

Effect of renal impairment on the pharmacokinetics of prucalopride: a single- dose open-label Phase I study.

OBJECTIVE: To evaluate the pharmacokinetics of prucalopride in individuals with renal impairment (RI). METHODS: This open-label Phase I study (ClinicalTrials.gov identifier: NCT01674192) enrolled men and women aged 18-75 years who were classified by renal function: normal renal function (creatinine clearance ≥ 80 mL/min/1.73 m²), mild RI (50-79 mL/min/1.73 m²), moderate RI (25-49 mL/min/1.73 m²), and severe RI (≤ 24 mL/min/1.73 m²). All received a single oral dose of prucalopride 2 mg. RESULTS: Thirty-four individuals (normal renal function: 10; mild RI: 8; moderate RI: 7; severe RI: 9) received prucalopride. In all groups, maximum plasma concentration was reached within 2-4 hours. There was no significant difference in exposure (area under the plasma concentration-time curve from time zero to infinity) between participants with mild RI and those with normal renal function. However, area under the plasma concentration-time curve from time zero to infinity values were 1.5- and 2.3-fold higher (P = 0.002 and P < 0.001) in patients with moderate RI and severe RI, respectively, than in those with normal renal function. The proportion of total body clearance accounted for by renal clearance was significantly reduced in those with RI. CONCLUSION: Clinically meaningful reductions in renal clearance were seen in participants with severe RI, which supports a decrease from the standard dose of prucalopride 2 mg daily to 1 mg daily in these individuals.

D2-receptor occupancy measurement of JNJ-37822681, a novel fast off-rate D2-receptor antagonist, in healthy subjects using positron emission tomography: single dose versus steady state and dose selection.

RATIONALE: JNJ-37822681 is a highly selective, fast dissociating dopamine D2-receptor antagonist being developed for the treatment of schizophrenia. A single dose [¹¹C]raclopride positron emission tomography (PET) imaging study had yielded an estimated clinical dose range. Receptor occupancy at steady state was explored to test the validity of the single-dose estimates during chronic treatment. OBJECTIVES: The aims of this study are to characterize single and multiple dose pharmacokinetics and obtain striatal D2-receptor occupancies to predict doses for efficacy studies and assess the safety and tolerability of JNJ-37822681. METHODS: An open-label single- and multiple-dose study with 10 mg JNJ-37822681 (twice daily for 13 doses) was performed in 12 healthy men. Twenty [¹¹C]raclopride PET scans (up to 60 h after the last dose) from 11 subjects were used to estimate D2-receptor occupancy. A direct effect O (max) model was applied to explore the relationship between JNJ-37822681 plasma concentration and striatal D2-receptor occupancy. RESULTS: Steady state was reached after 4-5 days of twice daily dosing. JNJ-37822681 plasma concentrations of 3.17 to 63.0 ng/mL resulted in D2 occupancies of 0 % to 62 %. The concentration leading to 50 % occupancy was 18.5 ng/mL (coefficient of variation 3.9 %) after single dose and 26.0 ng/mL (8.2 %) at steady state. JNJ-37822681 was well tolerated. CONCLUSIONS: Receptor occupancy after single dose and at steady state differed for JNJ-37822681 and the robustness of the estimates at steady state will be tested in phase 2 studies. Dose predictions indicated that 10, 20, and 30 mg JNJ-37822681 twice daily could be suitable for these studies.

Population pharmacokinetics of oral risperidone in children, adolescents and adults with psychiatric disorders.

BACKGROUND AND OBJECTIVES: Oral risperidone is licensed globally for the treatment of several psychiatric disorders in children, adolescents and adults. The pharmacokinetic profile of risperidone is well documented in adults. In this study, the pharmacokinetics of oral risperidone in children and adolescents were investigated along with population pharmacokinetics in paediatric and adult subjects. METHODS: The pharmacokinetics of oral risperidone in children and adolescents were investigated through non-compartmental analysis (paediatric phase I study; n = 24) and population pharmacokinetic analysis using nonlinear mixed-effects modelling software (NONMEM) on a pooled database including both paediatric (n = 304) and adult (n = 476) data. Monte Carlo simulations were performed to evaluate the relevance of the effects of covariates on the plasma exposure of the active antipsychotic fraction. RESULTS: Non-compartmental pharmacokinetic analysis showed that, after correcting doses for bodyweight, plasma exposure was comparable between children and adolescents and in line with historical adult data. Pooled population pharmacokinetic analysis, using a priori allometric scaling of the clearance and volume of distribution, showed that apparent renal clearance of the active antipsychotic fraction was 0.96 L/h and apparent metabolic clearance was 4.26 L/h for a typical patient weighing 62 kg, aged 18.1 years, with a median creatinine clearance of 117.6 mL/min. For a typical child (11 years, 39 kg), adolescent (15 years, 60 kg) and adult (33 years, 70 kg), the apparent total oral clearance values were 4.35, 5.30 and 5.04 L/h, respectively. None of the tested demographic or biochemical characteristics were found to have a relevant effect on any of the pharmacokinetic parameters of risperidone and the active antipsychotic fraction. CONCLUSION: Population pharmacokinetics and Monte Carlo simulations demonstrated similar pharmacokinetics of risperidone in children, adolescents and adults.

Risperidone long-acting injection: pharmacokinetics following administration in deltoid versus gluteal muscle in schizophrenic patients.

Long-acting injectable (LAI) risperidone for intramuscular injection into the gluteal muscle every 2 weeks is approved for schizophrenia. The deltoid muscle provides a more accessible injection site and could therefore facilitate patient acceptance of an injectable medication. Two studies in chronic schizophrenic subjects evaluated the pharmacokinetics and tolerability of LAI risperidone administered into the deltoid muscle. The pharmacokinetics following deltoid injection and bioequivalence between deltoid and gluteal administration were assessed in an open-label, single-dose, crossover, fully powered bioavailability study. Tolerability and safety of deltoid LAI risperidone were investigated in an open-label multiple-dose study in subjects who were previously being treated with gluteal injections of LAI risperidone. Patients received 4 sequential intramuscular injections of LAI risperidone, administered every 2 weeks into the deltoid muscle. Deltoid and gluteal injections of LAI risperidone were shown to be bioequivalent at equal doses with respect to peak and total plasma exposure and exhibited dose-proportional pharmacokinetics, independent of injection site. In addition, deltoid injection was safe and well tolerated. Injection of LAI risperidone into the deltoid muscle can be considered an alternative route of administration, because deltoid and gluteal injections are interchangeable in terms of drug exposure, with no additional safety or tolerability issues.

Dose-dependent effects of the CRF(1) receptor antagonist R317573 on regional brain activity in healthy male subjects.

BACKGROUND: Corticotropin-releasing factor receptor type 1 (CRF(1)) antagonists have been proposed as therapeutic agents in the treatment of mood and anxiety disorders although clinical evidence supporting their development and understanding of a dose-response relationship has been lacking. METHODS: We tested two doses of the CRF(1) antagonist R317573 for effects on regional cerebral glucose metabolism (rCMglu) using [(18)F] fluoro-2-deoxy-D: -glucose (FDG) positron emission tomography (PET) following single-dose challenges in a double-blind, placebo-controlled, cross-over design, in 12 healthy male volunteers. RESULTS: Single 30- and 200-mg doses of R317573 resulted in dose-related changes in rCMglu. Relative increases in rCMglu were observed in frontal cortical regions while relative decreases occurred in the putamen and right amygdala after both doses. Relative decreases occurred in cerebellum and right parahippocampal gyrus following the higher dose. CONCLUSIONS: R317573 appears to produce acute dose-dependent changes in rCMglu. Effects occurred in regions that may be behaviorally relevant to mood and anxiety disorders. In some regions, these effects may be related to the receptor (target) density. Measuring acute effects on rCMglu with FDG-PET may offer a method for defining pharmacologically active doses for central nervous system targets for which selective radiotracers are lacking.

Monthly administration of long-acting injectable risperidone and striatal dopamine D2 receptor occupancy for the management of schizophrenia.

OBJECTIVE: Long-acting risperidone administered intramuscularly biweekly is approved for the management of schizophrenia. However, dosing of long-acting antipsychotics is frequently extended in clinical practice, and a recent clinical trial has lent support to monthly dosing of long-acting risperidone. The objective of this positron emission tomography (PET) study was to examine the striatal dopamine D(2) binding of long-acting risperidone administered intramuscularly once a month. METHOD: Following at least 3 maintenance monthly injections of 50 mg long-acting risper-idone, 7 patients with a DSM-IV diagnosis of schizophrenia or schizoaffective disorder under-went PET using [(11)C]raclopride to measure D(2) binding potential within 4 days of the next scheduled injection. Data were collected from May to October 2003. This PET study was part of a larger 52-week clinical study wherein individuals received long-acting risperidone once monthly over a 1-year interval. One-year follow-up data were obtained from the 52-week parent investigation. RESULTS: The mean +/- SD D(2) receptor occupancy was 56% +/- 24% (range, 29%-82%). Of note, there were 4 subjects with less than 60% D(2) occupancy, none of whom relapsed over the course of the 1-year follow-up. The mean +/- SD total plasma level of risperidone plus 9-hydroxyrisperidone was 16.6 +/- 12.3 ng/mL (range, 5.7-40.8). CONCLUSION: As with plasma levels, there was considerable variability in D(2) occupancy levels for individuals receiving long-acting risperidone. This work suggests a possibility that sustained D(2) occupancy at or above the accepted threshold with acute clinical response may not be necessary to maintain response, a hypothesis with important clinical implications as we consider antipsychotic dosing and future antipsychotic development. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00236353.

Plasma pharmacokinetic characteristics of risperidone and their relationship to saliva concentrations in children with psychiatric or neurodevelopmental disorders.

BACKGROUND: Risperidone is a second-generation antipsychotic agent widely used in the treatment of schizophrenia and other psychotic disorders in adults. Risperidone is probably the most frequently used atypical antipsychotic in the pediatric population. OBJECTIVES: The goals of this study were to estimate the pharmacokinetic parameters of risperidone and its enantiomers in a pediatric population and explore relationships between saliva and plasma concentrations. METHODS: Eligible patients, between 4 and 15 years of age, included those taking a stable dose of oral risperidone ranging from 0.01 to 0.07 mg/kg BID for > or =4 weeks to treat psychiatric or neurodevelopmental conditions. A trough blood level and predose saliva sample were collected at study initiation; the regular risperidone dose was administered; and paired samples of blood and saliva were collected at 1, 2, 4, and 7 hours postdose. Plasma/saliva concentrations of risperidone and enantiomers of its principal active metabolite, 9-hydroxyrisperidone (9-OH-risperidone), were measured using a chiral liquid chromatography-tandem mass spectrometry assay. Standard pharmacokinetic parameters were calculated. Cytochrome P450 2D6 genotypes of *3,*4,*5 deletion and duplication were determined. RESULTS: The study included 19 patients (age range, 4 years 2 months to 15 years 11 months). Mean (SD) values for C(max), t(1/2), and AUC 0 to 12 hours for risperidone in plasma were 15.9 (22.2) ng/mL, 3.0 (2.3) h, and 92.1 (200.6) ng x h/mL, respectively. Corresponding values in saliva were 12.0 (21.0) ng/mL, 3.4 (3.2) h, and 27.8 (38.7) ng x h/mL, respectively. Mean (SD) plasma enantiomer values for C(max) and AUC calculated up to the last observation were: (+)-9-OH-risperidone, 13.6 (10.0) ng/mL and 73.6 (52.3) ng x h/mL; (-)-9-OH-risperidone, 4.9 (3.1) ng/mL and 29.3 (19.1) ng x h/mL. Corresponding enantiomer values in saliva were: (+)-9-OH-risperidone, 5.2 (8.8) ng/mL and 15.6 (8.9) ng x h/mL; (-)-9-OH-risperidone, 5.0 (7.9) ng/mL and 15.6 (9.1) ng x h/mL, respectively. Large interindividual variability in risperidone and enantiomer concentrations was noted. A highly significant relationship between predose plasma and predose saliva risperidone concentrations was observed. The logarithmic regression model indicated that the log risperidone saliva concentration = -0.100 + 0.594 x log plasma concentration (R(2) = 0.93 [Spearman]). CONCLUSIONS: In this preliminary pharmacokinetic study of parameters for risperidone and the enantiomers of 9-OH-risperidone in a pediatric population, mean C(max) and t(1/2) of risperidone were generally similar to those previously described in adults. The highly significant relationship between predose plasma and predose saliva risperidone concentrations suggests that saliva measurements may be a viable alternative to plasma sampling in children.

Rapidly disintegrating risperidone in subjects with schizophrenia or schizoaffective disorder: a summary of ten phase I clinical trials assessing taste, tablet disintegration time, bioequivalence, and tolerability.

BACKGROUND: Schizophrenia and schizoaffective disorder are severe and chronic psychiatric illnesses for which treatment compliance is important in the prevention of relapse. Atypical antipsychotic drugs, such as risperidone, have been found to be effective in the treatment of a range of psychiatric disorders. Although the oral route of administration is generally preferable to injection, some patients (eg, elderly patients or children) find swallowing physically difficult and thus refuse oral treatments. Rapidly disintegrating (RD) oral formulations of these drugs have been developed to improve their acceptability to patients and thus improve compliance. OBJECTIVE: The aim of this report was to describe the results from clinical studies that have assessed the taste, time to disintegration, and tolerability of RD risperidone tablets, and bioequivalence of RD risperidone tablets (2 x 0.5 mg, 2 mg, and reduced-size 4 mg) versus conventional (CV) risperidone tablets. METHODS: This study used data from 10 clinical trials conducted between 1996 and 2003. Eight trials were open-label, crossover trials; 2 were pilot trials, and all of the trials were short-term. The results from 2 trials were published previously; the remainder are unpublished trials. Taste, time to dissolution, and tolerability of RD risperidone tablets were assessed, and bioequivalence (based on the guidelines from the European and US health care evaluation agencies) of RD versus CV risperidone tablets were determined for risperidone, the active metabolite (9-hydroxy-risperidone), and the total antipsychotic fraction (sum of risperidone and the active moiety, 9-hydroxy-risperidone). RESULTS: In total, these trials included 264 subjects(160 patients with schizophrenia or schizoaffective disorder, 104 healthy volunteers; 173 men, 91 women; age range, 20-61 years). The taste of the RD risperidone tablets was rated as "nice" in 54.2% of subjects compared with 18.3% of subjects who rated CV risperidone as "nice." Totals of 28.8% and 49.2% of subjects described the RD risperidone tablets as "sweet" or "other taste" (commonly mint), respectively. A total of 66.7% of subjects rated the 4-mg RD risperidone tablets as "acceptable, but could be improved," while 85.7% rated the lower-dose RD risperidone tablets as "good." The median time to complete disintegration of the RD risperidone tablet was 38.0 seconds. The mean plasma concentration-time profiles of risperidone and the active moiety of RD or CV risperidone tablets were similar, and these 2 risperidone formulations were found to be bioequivalent. The RD and CV risperidone tablets were well tolerated; there were no serious adverse events reported. CONCLUSIONS: In the 10 studies analyzed, the taste of RD risperidone tablets was found to be acceptable in the majority of healthy subjects and patients with schizophrenia or schizoaffective disorder. In addition, RD risperidone tablets were found to be bioequivalent to CV risperidone tablets.