ABSTRACT
Multidrug-resistant tuberculosis (MDR-TB) patients not cured at the time of stopping treatment are exposed to Minimum Inhibitory Concentration (MIC) and sub-MIC levels for many months after discontinuing bedaquiline (BDQ) or clofazimine (CFZ) treatment. In vitro cultures treated with BDQ and CFZ sub-MIC concentrations clearly showed enrichment in the Rv0678 mutant population, demonstrating that pre-existing Rv0678 mutants can be selected by sub-MIC concentrations of BDQ and CFZ if not protected by an alternative MDR-TB treatment.
Subject(s)
Mycobacterium tuberculosis , Tuberculosis, Multidrug-Resistant , Humans , Mycobacterium tuberculosis/genetics , Clofazimine/pharmacology , Antitubercular Agents/pharmacology , Antitubercular Agents/therapeutic use , Diarylquinolines/pharmacology , Tuberculosis, Multidrug-Resistant/drug therapy , Tuberculosis, Multidrug-Resistant/microbiology , Microbial Sensitivity TestsABSTRACT
AIMS: Postpartum haemorrhage (PPH) is the leading cause of maternal mortality worldwide. To prevent PPH, the WHO recommends administration of oxytocin (OT) immediately after birth, i.e. during the third stage of labour (TSL). Previous studies demonstrate that methods to quantify OT in biological matrices, e.g. enzyme-linked immunosorbent assays (ELISA), radioimmunoassays (RIA) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) lack the specificity and/or sensitivity to accurately quantify OT in plasma from women administered OT during TSL. This is due to increased metabolic clearance of OT in late-stage pregnancy and at the time of childbirth, resulting in extremely low OT plasma concentrations. This study describes the development of an ultra-sensitive bioanalytical method that overcomes the issues previously reported and enables accurate pharmacokinetic analyses of exogenously administered OT in TSL. METHODS: A selective and sensitive assay to quantify OT in TSL plasma was developed. Immunoprecipitation (IP) was applied to selectively extract OT from the TSL plasma, thereby generating clean extracts compatible with nanoflow LC (nLC). nLC-MS/MS was chosen for its high sensitivity and ability to differentiate between OT and potentially co-captured OT-like immunoreactive products. RESULTS: The presented methodology is accurate and precise, with a good linear fit between 100-10 000 fg mL-1 OT. TSL plasma samples from a clinical phase 1 study (NCT02999100) were analysed successfully, enabling OT quantification down to 100 fg mL-1. CONCLUSIONS: The presented IP-nLC-MS/MS method succeeded in overcoming the sensitivity challenge related to the assay of OT in TSL plasma and thereby revealing the PK profiles of OT in TSL plasma clinical study samples.
ABSTRACT
BACKGROUND: This phase 1b study evaluated the pharmacokinetics, safety, and antiviral effects of the respiratory syncytial virus (RSV)-specific fusion inhibitor JNJ-53718678 (JNJ-8678) in hospitalized RSV-infected patients aged > 1 to ≤24 months. METHODS: Patients categorized by age (cohort 1: ≥6 to ≤24 months; cohort 2: ≥3 to < 6 months; cohort 3: > 1 to < 3 months) were randomized to oral JNJ-8678 or placebo once daily for 7 days. Dose increases followed data review committee recommendations (cohort 1: 2/6/8/9 mg/kg; cohort 2: 1.5/4.5/6 mg/kg; cohort 3: 1/3/5 mg/kg). Cohort 1 included a 9 mg/kg dose, as target exposures were not reached at lower doses. Sparse pharmacokinetic samples were assessed using population pharmacokinetics modeling. Safety was assessed by adverse events (AEs), laboratory tests, and electrocardiograms. To assess antiviral effects, RSV RNA viral load from nasal swabs was quantified over time using reverse-transcription quantitative polymerase chain reaction. RESULTS: Patients received JNJ-8678 (n = 37) or placebo (n = 7). Pharmacokinetic parameters were similar at the highest doses for cohorts 1-3 (area under the plasma concentration-time curve from time of administration up to 24 hours postdosing at day 7: 35 840, 34 980, and 39 627 ng × hour/mL, respectively). Two grade 3 AEs were reported (both bronchiolitis; 1 JNJ-8678, 1 placebo), reported as serious AEs; all other AEs were grade 1 or 2. Two additional serious AEs were reported (rhinitis [JNJ-8678]; pneumonia [placebo]). No deaths, grade 4 AEs, or AEs leading to discontinuation were reported. Median RSV viral load change from baseline in JNJ-8678 vs placebo by day 3 was -1.98 vs -0.32 log10 copies/mL. CONCLUSIONS: In RSV-infected infants, JNJ-8678 was well tolerated. Target exposures were reached and antiviral activity was observed. CLINICAL TRIALS REGISTRATION: NCT02593851.
Subject(s)
Imidazolidines , Respiratory Syncytial Virus Infections , Aged , Antiviral Agents/therapeutic use , Double-Blind Method , Humans , Imidazolidines/therapeutic use , Indoles/therapeutic use , Infant , Respiratory Syncytial Virus Infections/drug therapyABSTRACT
Background: Respiratory syncytial virus (RSV) disease has no effective treatment. JNJ-53718678 is a fusion inhibitor with selective activity against RSV. Methods: After confirmation of RSV infection or 5 days after inoculation with RSV, participants (n = 69) were randomized to JNJ-53718678 75 mg (n = 15), 200 mg (n = 17), 500 mg (n = 18), or placebo (n = 17) orally once daily for 7 days. Antiviral effects were evaluated by assessing RSV RNA viral load (VL) area under the curve (AUC) from baseline (before the first dose) until discharge, time-to-peak VL, duration of viral shedding, clinical symptoms, and quantity of nasal secretions. Results: Mean VL AUC was lower for individuals treated with different doses of JNJ-53718678 versus placebo (203.8-253.8 vs 432.8 log10 PFUe.hour/mL). Also, mean peak VL, time to peak VL, duration of viral shedding, mean overall symptom score, and nasal secretion weight were lower in each JNJ-53718678-treated group versus placebo. No clear exposure-response relationship was observed. Three participants discontinued due to treatment-emergent adverse events of grade 2 and 1 electrocardiogram change (JNJ-53718678 75 mg and 200 mg, respectively) and grade 2 urticaria (placebo). Conclusions: JNJ-53718678 at all 3 doses substantially reduced VL and clinical disease severity, thus establishing clinical proof of concept and the compound's potential as a novel RSV treatment. Clinical trials registration: ClinicalTrials.gov: NCT02387606; EudraCT number: 2014-005041-41.
Subject(s)
Antiviral Agents/administration & dosage , Imidazolidines/administration & dosage , Indoles/administration & dosage , Respiratory Syncytial Virus Infections/drug therapy , Respiratory Syncytial Virus, Human/drug effects , Administration, Oral , Adolescent , Adult , Antiviral Agents/pharmacology , Drug-Related Side Effects and Adverse Reactions/epidemiology , Drug-Related Side Effects and Adverse Reactions/pathology , Female , Healthy Volunteers , Humans , Imidazolidines/pharmacology , Indoles/pharmacology , Male , Middle Aged , Placebos/administration & dosage , Respiratory Syncytial Virus Infections/pathology , Respiratory Syncytial Virus Infections/prevention & control , Respiratory Syncytial Virus, Human/isolation & purification , Treatment Outcome , Viral Load , Virus Shedding , Young AdultABSTRACT
BACKGROUND: Schizophrenia is a common disease which is commonly managed using antipsychotic medications (APS). Inadequate response and lack of adherence often prevent optimal therapeutic effectiveness. Monitoring APS concentrations can be useful to help improve outcomes for the patient. AIMS: The aim of this study was to develop "reference ranges" for oral aripiprazole, olanzapine, and quetiapine to allow clinicians to understand expected variability in patients treated with APS. The reference ranges were constructed to account for different oral doses, sampling times, and variability both between, and within, subjects. METHODS: Population pharmacokinetic models were used to simulate plasma concentrations over time under different doses and population demographics. The references were validated against external data both numerically and graphically. RESULTS: Reference ranges for oral aripiprazole, olanzapine, and quetiapine were derived and successfully validated against the external data. The 80% reference range for aripiprazole following a 2-mg oral dose was 14.7-41.6 ng/mL 0-4 h post dose and 10.6-37.1 ng/mL 20-24 h post dose. These ranges increased to 221-624 ng/mL 0-4 h post dose following administration of a 30-mg dose, and 159-557 ng/mL 20-24 h post dose. The 80% reference range 0-4 h post dose was 22.5-67.1 ng/mL following a 15-mg dose once daily of oral olanzapine, and 179-768 ng/mL following a 150-mg dose once daily of oral quetiapine. CONCLUSIONS: Comparing individual patients' APS levels with reference ranges, along with a full clinical assessment, could provide important insights to help a clinician optimize APS therapy.
Subject(s)
Antipsychotic Agents/blood , Aripiprazole/blood , Benzodiazepines/blood , Models, Biological , Quetiapine Fumarate/blood , Administration, Oral , Adolescent , Adult , Aged , Aged, 80 and over , Antipsychotic Agents/pharmacokinetics , Aripiprazole/pharmacokinetics , Benzodiazepines/pharmacokinetics , Child , Child, Preschool , Female , Humans , Male , Middle Aged , Olanzapine , Quetiapine Fumarate/pharmacokinetics , Reference Values , Young AdultABSTRACT
AIMS: To prospectively select the dose of the paliperidone palmitate 3-month (PP3M) formulation, using a pharmacometric bridging strategy based on the paliperidone palmitate 1-month (PP1M) formulation previously approved for schizophrenia treatment. METHODS: Pharmacokinetic (PK) data from a 6-month interim analysis of a single dose PP3M Phase I clinical trial was integrated with a previously developed PP1M population-PK model. The model was updated to incorporate formulation as a covariate on absorption parameters and to explore the most critical design element of the Phase III study: the PP1M-to-PP3M dose multiplier for patients switching formulations. Plasma paliperidone concentrations were measured at predetermined intervals during Phase III, enabling comparison of the multiple-dose PK between PP1M and PP3M. Exposure matching was assessed graphically to determine whether paliperidone plasma concentrations from the two formulations overlapped. RESULTS: Prospective steady-state PK simulations revealed that a 3.5 multiple of the PP1M dose would yield a corresponding PP3M dose with comparable exposure. The prospective pharmacometric simulation and observed Phase III PK data agreed closely. Phase III results confirmed the hypothesis that efficacy of PP3M was noninferior to that of PP1M. The similarity in exposures between the two formulations was likely a key determinant of the equivalent efficacy between the two products observed in the Phase III study. CONCLUSIONS: Successful prospective PP3M Phase III clinical trial dose selection was achieved through the use of pharmacometric bridging, without conducting a Phase II study and using only limited Phase I data for PP3M. We estimate that this strategy reduced development time by 3-5 years and may be applicable to other drug development projects.
Subject(s)
Drug Administration Schedule , Drug Compounding , Paliperidone Palmitate/administration & dosage , Paliperidone Palmitate/pharmacokinetics , Adolescent , Adult , Aged , Delayed-Action Preparations/administration & dosage , Delayed-Action Preparations/pharmacokinetics , Drug Dosage Calculations , Female , Humans , Male , Middle Aged , Models, Biological , Paliperidone Palmitate/blood , Prospective Studies , Schizophrenia/blood , Young AdultABSTRACT
Paliperidone palmitate (PP) is a recently (USA) approved injectable new-generation antipsychotic. This 53-wk, Phase-III double-blind study was designed to assess the non-inferiority of PP to risperidone long-acting injectable (RIS-LAI) in schizophrenia treatment. Acutely symptomatic patients (n=749), with a Positive and Negative Syndrome Scale (PANSS) total score between 60 and 120 were randomly allocated to gluteal injections of either (a) PP: 50 mg eq. on days 1 and 8, and flexible dosing [25-100 mg eq. (i.e. 39-156 mg USA dosing)] once-monthly; or (b) RIS-LAI: bi-weekly injections of 25 mg on days 8 and 22, and flexible dosing (25-50 mg) starting from day 36, with allowed oral supplementation. Patients (n=747) were 59% men, 92% white, mean (s.d.) age of 41 (11.95) yr and 45% (n=339) completed the study. Mean (s.d.) change from baseline to endpoint in PANSS total score was: -11.6 (21.22) PP; and -14.4 (19.76) RIS-LAI (per-protocol analysis set, primary measure); least-squares means difference was -2.6 (95% CI -5.84 to 0.61), with a prespecified 5-point non-inferiority margin. PP's suboptimal dosing regimen (<150 mg eq. initial dose) resulted in lower median plasma levels of the active moiety in PP-treated vs. RIS-LAI-treated patients. Insomnia was the most common treatment-emergent adverse event, with a similar incidence in both groups (15%). PP did not demonstrate comparable efficacy to RIS-LAI, which may be attributable to the initiation dosing strategy employed. Tolerability of both treatments was comparable to previous studies, with no new safety signals detected.
Subject(s)
Antipsychotic Agents/administration & dosage , Isoxazoles/administration & dosage , Palmitates/administration & dosage , Risperidone/administration & dosage , Schizophrenia/drug therapy , Administration, Oral , Adult , Antipsychotic Agents/adverse effects , Buttocks , Delayed-Action Preparations/administration & dosage , Delayed-Action Preparations/adverse effects , Double-Blind Method , Female , Humans , Injections, Intramuscular , Isoxazoles/adverse effects , Male , Paliperidone Palmitate , Palmitates/adverse effects , Psychiatric Status Rating Scales , Risperidone/adverse effects , Schizophrenia/physiopathology , Sleep Initiation and Maintenance Disorders/chemically induced , Treatment Outcome , White PeopleABSTRACT
BACKGROUND: There are no previous reports of paliperidone palmitate's (PP) long term tolerability or pharmacokinetics of the highest dose in patients with schizophrenia. This study evaluates safety and tolerability, as well as pharmacokinetics, of the highest marketed dose of PP (150 mg eq. [234 mg]) in stable patients with schizophrenia over a 1-year period. METHODS: In this 1-year prospective study, eligible patients (aged 18-65 years; Positive and Negative Syndrome Scale's total score ≤ 70) received an initial deltoid injection of PP 150 mg eq. The second injection one week later and subsequent once-monthly injections were deltoid or gluteal. All injections were to be PP 150 mg eq. Patients willing to participate in intensive pharmacokinetic sampling were classified as Treatment A. Patients unwilling to undergo intensive pharmacokinetic sampling or unable to tolerate the 150 mg eq. dose (consequently receiving flexible doses of 50, 100 or 150 mg eq.) were classified as Treatment B. RESULTS: Of the 212 patients (safety analysis set), 73% were men; 45% white; 20% black; 34% Asians; mean (SD) age 41 (10.2) years, and mean (SD) baseline Positive and Negative Syndrome Scale total score 54.9 (9.03). A total of 53% (n = 113) patients completed the study and 104 received PP 150 mg eq. throughout. Mean (SD) mode dose of PP was 144.8 (19.58) mg eq. The dosing initiation regimen resulted in rapidly achieved and maintained therapeutic paliperidone levels over the study (average concentrations during the dosing interval were 34.7, 40.0, and 47.8 ng/mL after the 2nd, 8th, and 14th injection respectively). Most frequent (≥ 10%) treatment-emergent adverse events were nasopharyngitis (n = 37), insomnia (n = 32), injection-site pain (n = 32), headache (n = 28), and tachycardia (n = 27). Akathisia (n = 19) and tremor (n = 11) were the most common extrapyramidal adverse events. 33 patients had an SAE and 27 discontinued due to treatment-emergent adverse events. No deaths were reported. Mean (SD) weight change from baseline was 2.5 (5.41) kg at endpoint. Patients' psychoses remained stable. CONCLUSIONS: Safety results after one-year therapy with the highest available dose of once-monthly paliperidone palmitate were consistent with results from previous studies, with no new concerns noted. Plasma concentrations were within the expected range. TRIAL REGISTRATION NO: ClinicalTrials.gov: NCT01150448.
Subject(s)
Antipsychotic Agents/therapeutic use , Isoxazoles/therapeutic use , Palmitates/therapeutic use , Schizophrenia/drug therapy , Schizophrenic Psychology , Adolescent , Adult , Aged , Antipsychotic Agents/administration & dosage , Antipsychotic Agents/adverse effects , Antipsychotic Agents/pharmacokinetics , Dose-Response Relationship, Drug , Drug Administration Schedule , Female , Humans , Injections, Intramuscular/adverse effects , Injections, Intramuscular/statistics & numerical data , Isoxazoles/administration & dosage , Isoxazoles/adverse effects , Isoxazoles/pharmacokinetics , Male , Middle Aged , Paliperidone Palmitate , Palmitates/administration & dosage , Palmitates/adverse effects , Palmitates/pharmacokinetics , Prospective Studies , Psychiatric Status Rating Scales/statistics & numerical data , Schizophrenia/blood , Treatment FailureABSTRACT
INTRODUCTION: The study objective was to characterize the excretion and metabolic profile of the respiratory syncytial virus fusion protein inhibitor, JNJ-53718678. Prior animal and in vitro studies suggested three main elimination pathways: N-glucuronidation to M8; CYP(3A4) metabolism leading to circulating metabolites M5, M12, M19 and M37; and JNJ-53718678 biliary excretion. To gain insight into the relative contribution of JNJ-53718678 and M8 biliary excretion, duodenal fluid sampling was incorporated into this mass balance study. METHODS: A single oral dose of 500 mg 14C-JNJ-53718678 was administered to six healthy male subjects. Four hours after study drug intake, gallbladder contraction was stimulated and duodenal fluid samples were collected. JNJ-53718678, its key circulating metabolites and total radioactivity (TR) were quantified in plasma, feces, urine and duodenal fluid. Safety was monitored throughout. RESULTS: JNJ-53718678 and M12 represented 47.4% and 17.8%, respectively, of TR area under the curve (AUC)∞ in plasma. M37 (9.6%), M19 (5.2%), M5 (4.3%) and M8 (1.4%) were minor metabolites; 70.6% of TR was recovered in feces and 19.9% in urine. Duodenal fluid concentrations (% of TR) were highest for JNJ-53718678 (11.6%) followed by M8 (10.4%), M5 (5.9%) and M12 (1.1%). In feces, 10-16% of TR was JNJ-53718678, 5-8% M5, < 1% M12 and < 1% M8. N-glucuronidation to M8 and direct biliary excretion of JNJ-53718678 represented 7% and 8% of drug clearance, respectively. JNJ-53718678 was safe and well tolerated. CONCLUSIONS: JNJ-53718678 is primarily eliminated through CYP3A4-mediated metabolism. By integrating duodenal sampling, N-glucuronidation was confirmed as another metabolic pathway despite the low amount of M8 excreted in urine and feces. TRIAL REGISTRATION: Eudract no. 2016-002664-14.
Subject(s)
Imidazolidines/metabolism , Indoles/metabolism , Respiratory Syncytial Viruses/metabolism , Adult , Animals , Area Under Curve , Cytochrome P-450 CYP3A/metabolism , Humans , Male , Metabolic Clearance Rate , Metabolic Networks and PathwaysABSTRACT
The paliperidone pharmacokinetics after intramuscular administration of once-monthly paliperidone palmitate in Japanese patients were studied in 3 phase 1 studies and in 2 phase 3 studies performed in Japan, Korea, and Taiwan. These data (Japanese, n = 509; Korean, n = 31; Taiwanese, n = 47) were used to describe the paliperidone palmitate pharmacokinetics in Japanese, to compare with non-Japanese, and to validate the historical population pharmacokinetic (Pop-PK) model for paliperidone palmitate, developed using data from studies in patients with schizophrenia outside Japan. The final historical Pop-PK model, including all significant patient covariates of Japanese studies, was used to simulate paliperidone plasma concentration-time data using nonlinear mixed effects, followed by comparison with actual data. Visual predictive checks displayed considerable overlap between predicted and actual plasma concentrations; the majority of observations were within the 90% prediction interval. Japanese, Korean, and Taiwanese patients had comparable plasma concentrations. Covariate distributions demonstrated comparatively lower median body mass index in Japanese, Korean, and Taiwanese patients versus rest-of-world population. Prediction errors for the data set used for external validation were within cutoff values, confirming accuracy/precision of the model. Paliperidone pharmacokinetics were adequately predicted for Japanese studies using the historical Pop-PK model, confirming its robustness. Pharmacokinetics in Japanese, Korean, and Taiwanese patients with schizophrenia were comparable with rest-of-world population.
Subject(s)
Antipsychotic Agents/pharmacokinetics , Paliperidone Palmitate/pharmacokinetics , Schizophrenia/drug therapy , Adult , Aged , Antipsychotic Agents/administration & dosage , Antipsychotic Agents/blood , Antipsychotic Agents/therapeutic use , Body Mass Index , Case-Control Studies , Dopamine D2 Receptor Antagonists , Female , Half-Life , Humans , Injections, Intramuscular , Japan/epidemiology , Male , Middle Aged , Paliperidone Palmitate/administration & dosage , Paliperidone Palmitate/blood , Paliperidone Palmitate/therapeutic use , Predictive Value of Tests , Republic of Korea/epidemiology , Serotonin 5-HT2 Receptor Antagonists , Taiwan/epidemiology , Treatment OutcomeABSTRACT
Orexin neurons originating in the perifornical and lateral hypothalamic area project to anxiety- and panic-associated neural circuitry, and are highly reactive to anxiogenic stimuli. Preclinical evidence suggests that the orexin system, and particularly the orexin-1 receptor (OX1R), may be involved in the pathophysiology of panic and anxiety. Selective OX1R antagonists thus may constitute a potential new treatment strategy for panic- and anxiety-related disorders. Here, we characterized a novel selective OX1R antagonist, JNJ-61393215, and determined its affinity and potency for human and rat OX1R in vitro. We also evaluated the safety, pharmacokinetic, and pharmacodynamic properties of JNJ-61393215 in first-in-human single- and multiple-ascending dose studies conducted. Finally, the potential anxiolytic effects of JNJ-61393215 were evaluated both in rats and in healthy men using 35% CO2 inhalation challenge to induce panic symptoms. In the rat CO2 model of panic anxiety, JNJ-61393215 demonstrated dose-dependent attenuation of CO2-induced panic-like behavior without altering baseline locomotor or autonomic activity, and had minimal effect on spontaneous sleep. In phase-1 human studies, JNJ-61393215 at 90 mg demonstrated significant reduction (P < 0.02) in CO2-induced fear and anxiety symptoms that were comparable to those obtained using alprazolam. The most frequently reported adverse events were somnolence and headache, and all events were mild in severity. These results support the safety, tolerability, and anxiolytic effects of JNJ-61393215, and validate CO2 exposure as a translational cross-species experimental model to evaluate the therapeutic potential of novel anxiolytic drugs.
Subject(s)
Orexin Receptor Antagonists , Panic , Rodentia , Animals , Humans , Models, Theoretical , Orexin Receptors , RatsABSTRACT
Non-adherence to antipsychotic medication is a primary factor in disease relapse in schizophrenic patients. We sought to evaluate if plasma concentrations of the antipsychotic risperidone can be used as a predictor of treatment adherence and to identify the optimal plasma concentration threshold to reliably distinguish between adherent and non-adherent patients. A population pharmacokinetic model was used to simulate plasma risperidone steady-state trough concentrations in 1000 virtual patients, where 60% of the patients were 100% adherent to their medication, while 40% of the patients were non-adherent to their medication. The probability of adherence was assessed by receiver operating characteristic (ROC) analysis on Ctrough. The area under the ROC curve (AUCROC) was used to identify the optimal Ctrough threshold. Single vs multiple Ctrough at steady state was also evaluated. After a single risperidone Ctrough measurement, the AUCROC (95% CI) was estimated to be 0.71 (0.69-0.72) and the optimal Ctrough threshold accounting for the lowest number of adherent and non-adherent misclassifications was estimated to be 11.9 ng/mL. After multiple Ctrough measurements, the AUCROC (95% CI) increased up to 0.85 (0.84-0.87) for three Ctrough measurements. The optimal probability threshold to reliably discriminate between adherent and non-adherent patients was estimated to be 0.51. Using this model which is reflective of typical adherence to antipsychotic medication, we found that three consecutive steady-state Ctrough measurements are needed for an accurate and precise diagnostic test to discriminate between patients who are adherent or non-adherent to treatment.
Subject(s)
Antipsychotic Agents/pharmacokinetics , Drug Monitoring/methods , Medication Adherence , Risperidone/pharmacokinetics , Schizophrenia/drug therapy , Antipsychotic Agents/blood , Antipsychotic Agents/therapeutic use , False Negative Reactions , False Positive Reactions , Humans , Models, Biological , Predictive Value of Tests , ROC Curve , Risperidone/blood , Risperidone/therapeutic use , Schizophrenia/bloodABSTRACT
Absorption, metabolism, and excretion of paliperidone, an atypical antipsychotic, was studied in five healthy male subjects after a single dose of 1 mg of [(14)C]paliperidone oral solution ( approximately 16 microCi/subject). One week after dosing, 88.4 to 93.8% (mean 91.1%) of the administered radioactivity was excreted: 77.1 to 87.1% (mean 79.6%) in urine and 6.8 to 14.4% (mean 11.4%) in the feces. Paliperidone was the major circulating compound (97% of the area under the plasma concentration-time curve at 24 h). No metabolites could be detected in plasma. Renal excretion was the major route of elimination with 59% of the dose excreted unchanged in urine. About half of the renal excretion occurred by active secretion. Unchanged drug was not detected in feces. Four metabolic pathways were identified as being involved in the elimination of paliperidone, each of which accounted for up to a maximum of 6.5% of the biotransformation of the total dose. Biotransformation of the drug occurred through oxidative N-dealkylation (formation of the acid metabolite M1), monohydroxylation of the alicyclic ring (M9), alcohol dehydrogenation (formation of the ketone metabolite M12), and benzisoxazole scission (formation of M11), the latter in combination with glucuronidation (M16) or alicyclic hydroxylation (M10). Unchanged drug, M1, M9, M12, and M16 were detected in urine; M10 and M11 were detected in feces. The monohydroxylated metabolite M9 was solely present in urine samples of extensive CYP2D6 metabolizers, whereas M10, another metabolite monohydroxylated at the alicyclic ring system, was present in feces of poor metabolizers as well. In conclusion, paliperidone is not metabolized extensively and is primarily renally excreted.
Subject(s)
Biogenic Monoamines/antagonists & inhibitors , Intestinal Absorption/physiology , Isoxazoles/metabolism , Pyrimidines/metabolism , Adult , Biogenic Monoamines/metabolism , Feces/chemistry , Humans , Intestinal Absorption/drug effects , Isoxazoles/chemistry , Isoxazoles/pharmacology , Kidney/drug effects , Kidney/metabolism , Liver/drug effects , Liver/metabolism , Male , Metabolic Networks and Pathways/drug effects , Metabolic Networks and Pathways/physiology , Middle Aged , Paliperidone Palmitate , Pyrimidines/chemistry , Pyrimidines/pharmacology , Time FactorsABSTRACT
Two liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) methods are described, one for the quantitative determination of risperidone and the enantiomers of its active metabolite 9-hydroxyrisperidone (paliperidone) in human plasma and the other for the determination of the enantiomers of 9-hydroxyrisperidone in human urine. The plasma method is based on solid-phase extraction of 200 microl of sample on a mixed-mode sorbent, followed by separation on a cellulose-based LC column with a 13.5-min mobile phase gradient of hexane, isopropanol and ethanol. After post-column addition of 10 mM ammonium acetate in ethanol/water, detection takes place by ion-spray tandem mass spectrometry in the positive ion mode. Method validation results show that the method is sufficiently selective towards the enantiomers of 7-hydroxyrisperidone and capable of quantifying the analytes with good precision and accuracy in the concentration range of 0.2-100 ng/ml. An accelerated (run time of 4.3 min) and equally valid method for the enantiomers of 9-hydroxyrisperidone alone in plasma is obtained by increasing the mobile phase flow-rate from 1.0 to 2.0 ml/min and slightly adapting the gradient conditions. The urine method is based on the same solid-phase extraction and chromatographic approach as the accelerated plasma method. Using 100 microl of sample, (+)- and (-)-9-hydroxyrisperidone can be quantified in the concentration range 1-2000 ng/ml. The accelerated method for plasma and the method for urine can be used only when paliperidone is administered instead of risperidone, as there is insufficient separation of the 9-hydroxy enantiomers from the 7-hydroxy enantiomers, the latter ones being present only after risperidone administration.
Subject(s)
Chromatography, Liquid/methods , Isoxazoles/chemistry , Pyrimidines/chemistry , Risperidone/chemistry , Tandem Mass Spectrometry/methods , Humans , Isoxazoles/blood , Isoxazoles/pharmacokinetics , Isoxazoles/urine , Paliperidone Palmitate , Pyrimidines/blood , Pyrimidines/pharmacokinetics , Pyrimidines/urine , Risperidone/blood , Risperidone/pharmacokinetics , Risperidone/urine , Sensitivity and SpecificityABSTRACT
OBJECTIVE: Antipsychotic blood levels (ABLs) may help identify patients at risk for treatment failure. Reference ranges (RR) for plasma concentrations of ABLs that account for between-patient variability were developed for risperidone and olanzapine based on population pharmacokinetic models. The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) collected clinical outcomes and ABLs, allowing testing of the relationship of ABLs with outcomes. METHODS: ABLs from 694 patients who were randomized to olanzapine or risperidone were compared to the 80% RRs and were assessed as below or within/above the RR. Treatment failure was defined per any of these criteria: (1) emergency room visit for psychiatric reasons, (2) hospitalization for psychiatric reasons, (3) adverse event of completed suicide, suicidal ideation, or suicide attempt, (4) assaultive behavior, (5) arrested or jailed, (6) 2-point increase from baseline in Clinical Global Impression-Severity score, (7) 25% increase in Positive and Negative Syndrome Scale total score. Patients assessed with treatment failure within 100â¯days of drug concentration measurement were analyzed. RESULTS: Treatment failure occurred in 126 of 323 patients. The proportion of patients with ABLs below RR was 18.3% (59/323) compared to 10% expected in a fully adherent population. Among the 59 with ABLs below RR, 50.8% had treatment failure (compared to 36.4% for the 264 with ABLs within/above RR). The difference between groups was significant (odds ratioâ¯=â¯1.810; 95% CIâ¯=â¯1.025, 3.197; pâ¯=â¯0.0408). CONCLUSIONS: Analysis of CATIE data showed that ABLs within the context of RRs may identify patients with higher risk of relapse.
Subject(s)
Antipsychotic Agents/blood , Antipsychotic Agents/therapeutic use , Schizophrenia/blood , Schizophrenia/drug therapy , Adolescent , Adult , Aged , Antipsychotic Agents/adverse effects , Female , Humans , Male , Medication Adherence , Middle Aged , Olanzapine/adverse effects , Olanzapine/blood , Olanzapine/therapeutic use , Recurrence , Risperidone/adverse effects , Risperidone/blood , Risperidone/therapeutic use , Treatment Failure , Young AdultABSTRACT
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.
Subject(s)
Antipsychotic Agents/administration & dosage , Psychotic Disorders/drug therapy , Risperidone/administration & dosage , Schizophrenia/drug therapy , Administration, Oral , Adult , Antipsychotic Agents/adverse effects , Antipsychotic Agents/chemistry , Antipsychotic Agents/pharmacokinetics , Chemistry, Pharmaceutical , Clinical Trials, Phase I as Topic , Female , Humans , Isoxazoles/pharmacokinetics , Male , Middle Aged , Paliperidone Palmitate , Patient Compliance , Patient Satisfaction , Pyrimidines/pharmacokinetics , Risperidone/adverse effects , Risperidone/chemistry , Risperidone/pharmacokinetics , Solubility , Tablets , Taste , Therapeutic EquivalencyABSTRACT
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.
Subject(s)
Antipsychotic Agents/pharmacokinetics , Mental Disorders/drug therapy , Risperidone/pharmacokinetics , Saliva/chemistry , Adolescent , Antipsychotic Agents/blood , Antipsychotic Agents/therapeutic use , Area Under Curve , Child , Child, Preschool , Cytochrome P-450 CYP2D6/genetics , Cytochrome P-450 CYP2D6/metabolism , Developmental Disabilities/drug therapy , Female , Genotype , Half-Life , Humans , Isoxazoles/chemistry , Isoxazoles/metabolism , Male , Paliperidone Palmitate , Pyrimidines/chemistry , Pyrimidines/metabolism , Risperidone/blood , Risperidone/therapeutic useSubject(s)
Antipsychotic Agents/adverse effects , Isoxazoles/adverse effects , Long QT Syndrome/chemically induced , Pyrimidines/adverse effects , Animals , Antipsychotic Agents/administration & dosage , Clinical Trials as Topic/methods , Drug Evaluation, Preclinical/methods , Ether-A-Go-Go Potassium Channels/antagonists & inhibitors , Humans , Isoxazoles/administration & dosage , Paliperidone Palmitate , Pyrimidines/administration & dosage , Risk FactorsABSTRACT
Quantification of blood levels of antipsychotic drugs may be useful for managing medication therapy. This open-label, parallel-group study was performed to compare finger-stick-based capillary with corresponding venous plasma concentrations for risperidone, paliperidone, quetiapine, olanzapine, and aripiprazole and their major metabolites after repeated dosing in patients with schizophrenia or related illnesses. Finger-stick-based capillary and venous blood samples were collected at various times within a dosing interval. All drug concentration measurements in the derived plasma samples were performed with validated liquid chromatography-tandem mass spectrometry methods. Finger-stick-based capillary and venous plasma drug concentrations after repeated dosing were generally similar. Olanzapine capillary plasma concentrations, however, were on average approximately 20% higher than venous concentrations, with a trend for a relatively greater difference occurring shortly after dosing. In addition, smaller capillary-venous differences were observed for extended-release and long-acting intramuscular formulations and for aripiprazole, a drug with a long half-life, compared with drugs administered as an immediate-release formulation (risperidone, olanzapine). After repeated dosing, plasma derived from finger-stick-based blood was observed to be predictive of the venous concentrations. Capillary sampling may be an appropriate alternative to venous sampling to readily evaluate systemic drug concentrations.
Subject(s)
Antipsychotic Agents/blood , Capillaries/metabolism , Veins/metabolism , Adolescent , Adult , Antipsychotic Agents/adverse effects , Aripiprazole/pharmacokinetics , Benzodiazepines/pharmacokinetics , Blood Specimen Collection/methods , Female , Fingers , Half-Life , Humans , Male , Middle Aged , Olanzapine , Paliperidone Palmitate/pharmacokinetics , Quetiapine Fumarate/pharmacokinetics , Risperidone/pharmacokinetics , Schizophrenia/drug therapy , Schizophrenia/metabolism , Young AdultABSTRACT
Risperidone, paliperidone, quetiapine, olanzapine, and aripiprazole are antipsychotic drugs approved for treating various psychiatric disorders, including schizophrenia. The objective of this randomized, parallel-group, open-label study was to compare finger-stick-based capillary with corresponding venous whole-blood and plasma concentrations for these drugs after administration of a single dose to healthy volunteers. All whole-blood and plasma drug concentrations were measured with validated liquid chromatography-tandem mass spectrometry methods. Capillary and venous concentrations (both in plasma and whole blood) were in close agreement, although a time-dependent difference was observed, most obviously for olanzapine and paliperidone, with slightly higher capillary versus venous drug concentrations during the first hours after administering a single dose. The observed difference between capillary and venous plasma drug concentrations is expected not to be relevant in clinical practice, considering the wide window of therapeutic concentrations and the wide range of drug concentrations in the patient population for a given dose. Based on these results, finger-stick-based capillary drug concentrations have been shown to approximate venous drug concentrations.