A Phase 2 Study of Pimodivir (JNJ-63623872) in Combination With Oseltamivir in Elderly and Nonelderly Adults Hospitalized With Influenza A Infection: OPAL Study.

BACKGROUND: Both the elderly and individuals with comorbidities are at increased risk of developing influenza-related complications. Novel influenza antivirals are required, given limitations of current drugs (eg, resistance emergence and poor efficacy). Pimodivir is a first-in-class antiviral for influenza A under development for these patients. METHODS: Hospitalized patients with influenza A infection were randomized 2:1 to receive pimodivir 600 mg plus oseltamivir 75 mg or placebo plus oseltamivir 75 mg twice daily for 7 days in this phase 2b study. The primary objective was to compare pimodivir pharmacokinetics in elderly (aged 65-85 years) versus nonelderly adults (aged 18-64 years). Secondary end points included time to patient-reported symptom resolution. RESULTS: Pimodivir pharmacokinetic parameters in nonelderly and elderly patients were similar. Time to influenza symptom resolution was numerically shorter with pimodivir (72.45 hours) than placebo (94.15 hours). There was a lower incidence of influenza-related complications in the pimodivir group (7.9%) versus placebo group (15.6%). Treatment was generally well tolerated. CONCLUSIONS: No apparent relationship was observed between pimodivir pharmacokinetics and age. Our data demonstrate the need for a larger study of pimodivir in addition to oseltamivir to test whether it results in a clinically significant decrease in time-to-influenza-symptom alleviation and/or the frequency of influenza complications. CLINICAL TRIALS REGISTRATION: NCT02532283.

Exposure-safety analysis of QTc interval and transaminase levels following bedaquiline administration in patients with drug-resistant tuberculosis.

Bedaquiline (BDQ) has shown great value in the treatment of multidrug-resistant tuberculosis (MDR-TB) in recent years. However, exposure-safety relationships must be explored to extend the use of BDQ. Two reported safety findings for BDQ are prolongation of the QTc interval and elevation of transaminase levels. In this study, we investigated the potential relationships between BDQ and/or its main metabolite (M2) pharmacokinetic (PK) metrics and QTcF interval or transaminase levels in patients with MDR-TB using the approved dose regimen. Data from 429 patients with MDR-TB from two phase IIb studies were analyzed via nonlinear mixed-effects modeling. Individual model-predicted concentrations and summary PK metrics were evaluated, respectively, in the QTcF interval and transaminase level exposure-response models. Investigation of further covariate effects was performed in both models. M2 concentrations were found to be responsible for the drug-related QTcF increase in a model accounting for circadian rhythm patterns, time on study, effect of concomitant medication with QT liability, and patient demographics. Simulations with the final model suggested that doses higher than the approved dose (leading to increased M2 concentrations) are not expected to lead to a critical QTcF interval increase. No exposure-safety relationship could be described with transaminase levels despite previous reports of higher levels in patients treated with BDQ. The developed longitudinal models characterized the role of M2 concentrations in QTc interval prolongation and found no concentration dependency for transaminase level elevation, together suggesting that BDQ exposure at the high end of the observed range may not be associated with a higher risk of safety events.

Population Pharmacokinetic Analysis of Bedaquiline-Clarithromycin for Dose Selection Against Pulmonary Nontuberculous Mycobacteria Based on a Phase 1, Randomized, Pharmacokinetic Study.

Based on the in vitro profile of bedaquiline against mycobacterial species, it is being investigated for clinical efficacy against pulmonary nontuberculous mycobacteria (PNTM). Being a cytochrome P450 3A substrate, pharmacokinetic interactions of bedaquiline are anticipated with clarithromycin (a cytochrome P450 3A inhibitor), which is routinely used in pulmonary nontuberculous mycobacteria treatment. This phase 1, randomized, crossover study assessed the impact of steady-state clarithromycin (500 mg every 12 hours for 14 days) on the pharmacokinetics of bedaquiline and its metabolite (M2) after single-dose bedaquiline (100 mg; n = 16). Using these data, population pharmacokinetic modeling and simulation analyses were performed to determine the effect of clarithromycin on steady-state bedaquiline exposure. Although no effect was observed on maximum plasma concentration of bedaquiline and time to achieve maximum plasma concentration, its mean plasma exposure increased by 14% after 10 days of clarithromycin coadministration, with slower formation of M2. Simulations showed that bedaquiline plasma trough concentration at steady state was higher (up to 41% until week 48) with clarithromycin coadministration as compared to its monotherapy (400 mg once daily for 2 weeks, followed by 200 mg 3 times a week for 46 weeks; reference regimen). The overall exposure of a simulated bedaquiline regimen (400 mg once dialy for 2 weeks, followed by 200 mg twice a week for 46 weeks) with clarithromycin was comparable (<15% difference) to the monotherapy. Overall, combination of bedaquiline (400 mg once daily for 2 weeks, followed by 200 mg twice a week for 46 weeks) with clarithromycin seems a suitable regimen to be explored for efficacy and safety against pulmonary nontuberculous mycobacteria.

Linking In Vitro Intrinsic Dissolution Rate and Thermodynamic Solubility with Pharmacokinetic Profiles of Bedaquiline Long-Acting Aqueous Microsuspensions in Rats.

Pharmacokinetic (PK) profiles of a range of bedaquiline (BDQ) long-acting injectable (LAI) microsuspensions in rats after parenteral (i.e., intramuscular and subcutaneous) administration were correlated with the in vitro intrinsic dissolution rate (IDR) and thermodynamic solubility of BDQ in media varying in surfactant type and concentration to better understand the impact of different nonionic surfactants on the in vivo performance of BDQ LAI microsuspensions. All LAI formulations had a similar particle size distribution. The investigated surfactants were d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS), poloxamer 338, and poloxamer 188. Furthermore, the relevance of medium complexity by using a biorelevant setup to perform in vitro measurements was assessed by comparing IDR and thermodynamic solubility results obtained in biorelevant media and formulation vehicle containing different surfactants in varying concentrations. In the presence of a surfactant, both media could be applied to obtain in vivo representative dissolution and solubility data because the difference between the biorelevant medium and formulation vehicle was predominantly nonsignificant. Therefore, a more simplistic medium in the presence of a surfactant was preferred to obtain in vitro measurements to predict the in vivo PK performance of LAI aqueous suspensions. The type of surfactant influenced the PK profiles of BDQ microsuspensions in rats, which could be the result of a surfactant effect on the IDR and/or thermodynamic solubility of BDQ. Overall, two surfactant groups could be differentiated: TPGS and poloxamers. Most differences between the PK profiles (i.e., maximum concentration observed, time of maximum concentration observed, and area under the curve) were observed during the first 21 days postdose, the time period during which particles in the aqueous suspension are expected to dissolve.

Population Pharmacokinetics of Esketamine Nasal Spray and its Metabolite Noresketamine in Healthy Subjects and Patients with Treatment-Resistant Depression.

BACKGROUND: Esketamine nasal spray is approved for treatment-resistant depression. OBJECTIVE: The objective of this study was to characterize the pharmacokinetics of esketamine and noresketamine in healthy subjects and patients with treatment-resistant depression. METHODS: Esketamine and noresketamine were measured in > 9000 plasma samples collected from 820 individuals who received esketamine by the intranasal, intravenous, and oral routes. An open linear model for esketamine (three compartments) and noresketamine (two compartments) that included a hepato-portal compartment was developed using NONMEM® VII. The effects of covariates on esketamine pharmacokinetics and a model evaluation were performed using conventional methods. RESULTS: The fraction of a 28-mg intranasal dose absorbed through the nasal cavity (FRn) is 54% (100% of this fraction is completely absorbed); the remaining 46% is swallowed and undergoes intestinal and first-pass metabolism and 18.6% of the swallowed dose reaches the systemic circulation. The absolute bioavailability of 56 and 84 mg of intranasal esketamine is 54 and 51%, respectively. Esketamine volume at steady state and clearance were 752 L and 114 L/h, respectively. Noresketamine volume at steady state and apparent clearance were 185 L and 38 L/h, respectively. Relative to non-Asian subjects, Asian subjects showed a 64.0 and 19.4% decrease in the esketamine elimination rate constant and noresketamine apparent clearance, respectively. Japanese subjects exhibited a 34% increase in FRn vs other races. Hepatic blood flow decreased by 21.9 L/h for each decade in age in subjects aged > 60 years. These changes resulted in esketamine and noresketamine maximum concentration and area under the concentration-time curve after 24 h post-dose values that were up to 36% higher than those observed in other races or in younger adult subjects. CONCLUSIONS: Esketamine and noresketamine pharmacokinetics was successfully characterized in healthy subjects and patients with treatment-resistant depression. The model quantified esketamine absolute nasal and oral bioavailability, its hepatic flow-limited clearance and biotransformation to the major metabolite noresketamine, and the influence of intrinsic and extrinsic factors on esketamine pharmacokinetics. Clinical trials registration numbers of the studies included in the analysis: ESKETINTRD1001 (NCT01780259), ESKETINTRD1002 (NCT01980303), ESKETINTRD1003 (NCT02129088), ESKETINTRD1008 (NCT02846519), ESKETINTRD1009 (NCT02343289), ESKETINTRD1010 (NCT02568176), ESKETINTRD1012 (NCT02345148), 54135419TRD1015 (NCT02682225), ESKETINTRD2003 (NCT01998958), ESKETINSUI2001 (NCT02133001), ESKETINTRD3001 (NCT02417064), ESKETINTRD3002 (NCT02418585), and ESKETINTRD3005 (NCT02422186).

A Population Pharmacokinetic Model for a Solid Oral Tablet Formulation of Posaconazole.

A delayed-release solid tablet formulation that releases posaconazole in the small intestine was developed to maximize systemic absorption. This study aimed to characterize the pharmacokinetics of the posaconazole solid tablet formulation in adult subjects and to investigate the potential impact of demographic and clinical factors on posaconazole exposure through a population pharmacokinetic approach. Nonlinear mixed-effects modeling was performed using data from several studies conducted in healthy volunteers and patients. The influence of demographic and clinical factors on pharmacokinetic parameters was evaluated using a stepwise forward inclusion/backward exclusion procedure. The final pharmacokinetic model was used to simulate posaconazole exposure in patients at high risk for invasive fungal diseases treated with the proposed posaconazole dose of 300 mg twice daily on day 1, followed by 300 mg daily for 27 days. A one-compartment pharmacokinetic model with sequential zero-order and first-order absorption and a first-order disposition from the central compartment adequately described the pharmacokinetic profile of the posaconazole solid tablet formulation. Significant covariates included disease state (acute myeloid leukemia/myelodysplasia versus allogeneic hematopoietic stem cell transplantation), body weight, and formulation on bioavailability; food status on first-order absorption rate; and dosing regimen (a single dose versus multiple doses) on clearance. Except for body weight, the impact of these covariates on posaconazole exposure was considered clinically irrelevant. This population pharmacokinetic analysis confirmed that the proposed dose of the posaconazole solid tablet formulation provides adequate target therapeutic exposure (>0.5 mg/liter) to a broad range of patients at high risk for invasive fungal disease.

Dosing and Switching Strategies for Paliperidone Palmitate 3-Month Formulation in Patients with Schizophrenia Based on Population Pharmacokinetic Modeling and Simulation, and Clinical Trial Data.

Paliperidone palmitate 3-month formulation (PP3M), a long-acting injectable atypical antipsychotic, was recently approved in the US and Europe for the treatment of schizophrenia in adult patients who have already been treated with paliperidone palmitate 1-month formulation (PP1M) for ≥4 months. This article reviews the pharmacokinetic rationale for the approved dosing regimens for PP3M, dosing windows, management of missed doses and treatment discontinuation, switching to other formulations, and dosing in special populations. Approved PP3M dosing regimens are based on the comparisons of simulations with predefined dosing regimens using paliperidone palmitate and oral paliperidone extended release (ER) population pharmacokinetic models (one-compartment model with two saturable absorption processes for PP3M; one-compartment model with parallel zero- and first-order absorption for PP1M; two-compartment model with sequential zero- and first-order absorption for ER) versus clinical trial data. Covariates were obtained by resampling subject covariates from the pharmacokinetics database for PP1M and PP3M. Simulation scenarios with varying doses and covariate values were generated. The population median and 90% prediction interval of the simulated concentration-time profiles were plotted for simulation outcomes evaluation. Simulations described in this paper provide (a) simulated plasma exposures for switching from PP1M to PP3M, (b) support for a once-every-3-months injection cycle, (c) information on dosing windows and managing missed doses of PP3M, (d) important guidance on PP3M dosing in special patient populations, and (e) key PP3M pharmacokinetic exposure metrics based on the population pharmacokinetic PP3M model. Population pharmacokinetics provided practical guidance to establish dosing regimens for PP3M.

Population Pharmacokinetics of a Novel Once-Every 3 Months Intramuscular Formulation of Paliperidone Palmitate in Patients with Schizophrenia.

OBJECTIVES: Our objective was to characterize the population pharmacokinetics of paliperidone after intramuscular administration of its long-acting 3-month formulation palmitate ester at various doses and at different injection sites (deltoid and gluteal muscles). METHODS: This retrospective analysis included pooled data from 651 subjects from one phase I study (single injection of the 3-month formulation) and one phase III study (multiple injections of both 1- and 3-month formulations). A total of 8990 pharmacokinetic samples with valid concentration time points were available for this analysis. Nonlinear mixed-effects modelling of the pooled data was conducted using NONMEM software. Knowledge from a previously developed 1-month formulation model was used as a starting point to build the 3-month formulation model. RESULTS: The final model describing the plasma concentrations after administration of the 3-month formulation was a one-compartment model with first-order elimination and two saturable absorption processes (rapid and slow). The apparent volume of distribution estimated for the 3-month formulation was not the same as for the previously modelled 1-month formulation. Apparent clearance (CL), apparent volume of distribution (V), and fraction of the absorbed dose (F3) were estimated to be 3.84 l/h, 1960 L, and 20.9 %. For slow absorption, the maximum absorption rate constant (k a1 max), amount of paliperidone at the absorption site when half of the maximum absorption rate was achieved (k amt1 50), and Hill factor (γ) were estimated to be 90.4 µg/h, 120 mg, and 1.44, respectively. For rapid absorption, the maximum absorption rate constant (k a3 max) and amount of paliperidone at the absorption site when half of the maximum absorption rate was achieved (k amt3 50) were estimated to be 164 µg/h and 21.4 mg, respectively. CONCLUSION: The final model with two saturable absorption processes provided a good description of the pharmacokinetic characteristics of paliperidone after intramuscular administration of its long-acting 3-month formulation palmitate ester. In addition to the structural covariates (creatinine clearance on CL, body mass index on V, and injection volume on both absorption rates), injection site and sex were identified as covariates on k a max of the slow absorption process (k a1 max). Clinical trial registration numbers: NCT01559272, NCT01529515, and NCT01515423.

The Absolute Bioavailability and Effect of Food on the Pharmacokinetics of Odanacatib: A Stable-Label i.v./Oral Study in Healthy Postmenopausal Women.

A stable-label i.v./oral study design was conducted to investigate the pharmacokinetics (PK) of odanacatib. Healthy, postmenopausal women received oral doses of unlabeled odanacatib administered simultaneously with a reference of 1 mg i.v. stable (13)C-labeled odanacatib. The absolute bioavailability of odanacatib was 30% at 50 mg (the phase 3 dose) and 70% at 10 mg, which is consistent with solubility-limited absorption. Odanacatib exposure (area under the curve from zero to infinity) increased by 15% and 63% when 50 mg was administered with low-fat and high-fat meals, respectively. This magnitude of the food effect is unlikely to be clinically important. The volume of distribution was ∼100 liters. The clearance was ∼0.8 l/h (13 ml/min), supporting that odanacatib is a low-extraction ratio drug. Population PK modeling indicated that 88% of individuals had completed absorption of >80% bioavailable drug within 24 hours, with modest additional absorption after 24 hours and periodic fluctuations in plasma concentrations contributing to late values for time to Cmax in some subjects.

The effect of macrophage and angiogenesis inhibition on the drug release and absorption from an intramuscular sustained-release paliperidone palmitate suspension.

The intramuscular (IM) administration of long-acting injectable (LAI) aqueous nano-/microsuspensions elicits a chronic granulomatous injection site reaction, which recently has been hypothesized to drive the (pro)drug dissolution and systemic absorption resulting in flip-flop pharmacokinetics. The goal of this mechanistic study was to investigate the effects of the local macrophage infiltration and angiogenesis on the systemic drug exposure following a single IM administration of a paliperidone palmitate (PP) LAI nano-/microsuspension in the rat. Liposomal clodronate (CLO) and sunitinib (SNT) were co-administered to inhibit the depot infiltration and nano-/microparticle phagocytosis by macrophages, and the neovascularization of the depot, respectively. Semi-quantitative histopathology of the IM administration sites at day 1, 3, 7, 14, 21 and 28 after dosing with PP-LAI illustrated that CLO significantly decreased the rate and extent of the granulomatous inflammatory reaction. The macrophage infiltration was slowed down, but only partially suppressed by CLO and this translated in paliperidone (PAL) plasma concentration-time profiles that resembled those observed upon injection of PP-LAI only, albeit with a lower PAL input rate and delayed maximum plasma concentration (CMAX). Conversely, SNT treatment completely suppressed the granulomatous reaction, besides effectively inhibiting the neovascularization of the PP-LAI depot. This resulted in an even slower systemic PAL input with delayed and lower maximum PAL CMAX. The reduced PP-LAI lymph node retention after CLO and SNT treatment, as well as pharmacokinetic drug-drug interactions were rejected as possible sources of the observed pharmacokinetic differences. The biphasic PAL plasma concentration-time profiles could best be described by an open first-order disposition model with parallel fast (first-order) and slow (sequential zero-first-order) absorption. The correlation of the pharmacokinetic data with the histopathological findings indicated that the macrophage infiltration, with subsequent phagocytosis of an important fraction of the PP-LAI dose, actively contributed to the observed PAL plasma exposures by promoting the prodrug dissolution and conversion to the active. An initial fast PP dissolution of individual nano-/microcrystals present in the interstitium was followed by a second, slower, but dominating input process that was driven by the PAL formation rate in the infiltrated portions of the LAI depot. The present work provides new fundamental insights into the influence of the local tissue response to IM LAI (pro)drug suspensions on the systemic drug exposure. This knowledge might support the future development of predictive in vitro and in silico models, which could help guide the LAI formulation design.

Pharmacokinetic profile after multiple deltoid or gluteal intramuscular injections of paliperidone palmitate in patients with schizophrenia.

Paliperidone palmitate (PP) is a once-monthly long-acting injectable antipsychotic approved for the treatment of schizophrenia in many countries. To evaluate the different injection-site options, we compared the pharmacokinetic profile of paliperidone after multiple injections of PP 100 mg eq. (156 mg of PP, equivalent to 100 mg of paliperidone) on days 1, 8, 36, and 64 into the deltoid (n = 24) or gluteal muscle (n = 25) in patients with schizophrenia. After four injections in the deltoid muscle, paliperidone exposure was higher for AUCτ and Cmax , compared with the gluteal muscle (geometric mean AUCτ -based ratio: 120% [90% CI: 93.1-154.7%], and geometric mean Cmax -based ratio: 130% [90% CI: 100.6-168.9%]). The mean [SD] fluctuation index was higher, with a larger interpatient variability, after deltoid-injections (75.9% [30.9%]) than gluteal-injections (58.5% [14.3%]). The median tmax was similar for both sites. PP was generally tolerable in patients, with more favorable local-site tolerability for gluteal-injection. In conclusion, to achieve therapeutic-concentrations quickly, the first-two injections of PP are best administered into the deltoid muscle, whereas thereafter maintenance-injections can be administered either in the deltoid or gluteal muscle.

Development of in vitro-in vivo correlation for extended-release niacin after administration of hypromellose-based matrix formulations to healthy volunteers.

Development of in vitro-in vivo correlations (IVIVCs) for extended-release (ER) products is commonly pursued during pharmaceutical development to increase product understanding, set release specifications, and support biowaivers. This manuscript details the development of Level C and Level A IVIVCs for ER formulations of niacin, a highly variable and extensively metabolized compound. Three ER formulations were screened in a cross-over study against immediate-release niacin. A Multiple Level C IVIVC was established for both niacin and its primary metabolite nicotinuric acid (NUA) as well as total niacin metabolites urinary excretion. For NUA, but not for niacin, Level A IVIVC models with acceptable prediction errors were achievable via a modified IVIVC rather than a traditional deconvolution/convolution approach. Hence, this is in contradiction with current regulatory guidelines that suggest that when a Multiple Level C IVIVC is established, Level A models should also be readily achievable. We demonstrate that for a highly variable, highly metabolized compound such as niacin, development of a Level A IVIVC model fully validated according to agency guidelines may be challenging. However, Multiple Level C models are achievable and could be used to guide release specifications and formulation/manufacturing changes.

A single-dose, open-label, parallel, randomized, dose-proportionality study of paliperidone after intramuscular injections of paliperidone palmitate in the deltoid or gluteal muscle in patients with schizophrenia.

Paliperidone palmitate (PP) is a long-acting injectable (LAI) antipsychotic, developed for monthly intramuscular (i.m.) administration into deltoid/gluteal muscle, approved for the treatment of schizophrenia in many countries. To assess the options for i.m. injection sites, dose-proportionality of PP was investigated after injection of a single dose (25-150 mg eq.) of PP in either gluteal (n = 106) or deltoid (n = 95) muscle of schizophrenic patients. Overall, mean (geometric) area under plasma concentration-time curve from time zero to infinity (AUC∞ ) of paliperidone increased proportionally with increasing PP doses, regardless of injection site. Mean maximum plasma concentration (Cmax ) was slightly less than dose-proportional for both injection sites at PP doses >50 mg eq. Mean Cmax was higher after injection in the deltoid compared with the gluteal muscle, except for the 100 mg eq. dose, while AUC∞ for both injection sites was comparable at all doses. Median time to reach Cmax (tmax ) ranged from 13-14 days after deltoid and 13-17 days after gluteal injection across all doses. Single PP injections in deltoid and gluteal muscles in the dose range of 25-150 mg eq. were generally tolerable both locally and systemically.

Evaluation of efficacy and safety of the anti-VWF Nanobody ALX-0681 in a preclinical baboon model of acquired thrombotic thrombocytopenic purpura.

ALX-0681 is a therapeutic Nanobody targeting the A1-domain of VWF. It inhibits the interaction between ultra-large VWF and platelet GpIb-IX-V, which plays a crucial role in the pathogenesis of thrombotic thrombocytopenic purpura (TTP). In the present study, we report the efficacy and safety profile of ALX-0681 in a baboon model of acquired TTP. In this model, acute episodes of TTP are induced by administration of an ADAMTS13-inhibiting mAb. ALX-0681 completely prevented the rapid onset of severe thrombocytopenia and schistocytic hemolytic anemia. After induction of TTP, platelet counts also rapidly recovered on administration of ALX-0681. This effect was corroborated by the full neutralization of VWF activity. The schistocytic hemolytic anemia was also halted and partially reversed by ALX-0681 treatment. Brain CT scans and post mortem analysis did not reveal any sign of bleeding, suggesting that complete neutralization of VWF by ALX-0681 under conditions of thrombocytopenia was not linked with an excessive bleeding risk. The results obtained in this study demonstrate that ALX-0681 can successfully treat and prevent the most important hallmarks of acquired TTP without evidence of a severe bleeding risk. Therefore, ALX-0681 offers an attractive new therapeutic option for acquired TTP in the clinical setting.

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 and pharmacodynamics of rivaroxaban in patients with acute coronary syndromes.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: • Population pharmacokinetics and pharmacodynamics of rivaroxaban have been characterized in healthy subjects and in patients with total venous thromboembolism, deep vein thrombosis or atrial fibrillation. WHAT THIS STUDY ADDS: • This article is the first description of the population pharmacokinetics (PK) and pharmacodynamics (PD) of rivaroxaban in patients with acute coronary syndrome (ACS). It is the largest population pharmacokinetic and pharmacodynamic study on rivaroxaban conducted to date (n= 2290). The PK and PK-PD relationship of rivaroxaban in patients with ACS were similar to those in other patient populations. In addition, model-based simulations showed that the influence of renal function and age on the exposure to rivaroxaban in the ACS population were similar to the findings from Phase 1 special population studies. These findings suggest that rivaroxaban has highly predictable PK-PD and may provide a consistent anticoagulant effect across the studied patient populations, which allows an accurate prediction of the dose to control anticoagulation optimally. AIMS: The aim of this analysis was to use a population approach to facilitate the understanding of the pharmacokinetics and pharmacodynamics of rivaroxaban in patients with acute coronary syndrome (ACS) and to evaluate the influence of patient covariates on the exposure of rivaroxaban in patients with ACS. METHODS A population pharmacokinetic model was developed using pharmacokinetic samples from 2290 patients in Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome Thrombolysis in Myocardial Infarction 46. The relationship between pharmacokinetics and the primary pharmacodynamic end point, prothrombin time, was evaluated. RESULTS: The pharmacokinetics of rivaroxaban in patients with ACS was adequately described by an oral one-compartment model. The estimated absorption rate, apparent clearance and volume of distribution were 1.24 h(-1) (interindividual variability, 139%), 6.48 l h(-1) (31%) and 57.9 l (10%), respectively. Simulations indicate that the influences of renal function, age and bodyweight on exposure in ACS patients are consistent with the findings in previous Phase 1 studies. Rivaroxaban plasma concentrations exhibit a close-to-linear relationship with prothrombin time in the ACS population, with little interindividual variability. The estimated pharmacokinetic and pharmacodynamic parameters for the ACS patients were comparable to those for venous thromboembolism prevention, deep vein thrombosis and atrial fibrillation patients. CONCLUSIONS: The similarity in pharmacokinetics/pharmacodynamics of rivaroxaban among different patient populations and the low interindividual variability in the exposure-prothrombin time relationship indicate that the anticoagulant effect of rivaroxaban is highly predictable and consistent across all the patient populations studied.

A time scaling approach to develop an in vitro-in vivo correlation (IVIVC) model using a convolution-based technique.

In vitro-in vivo correlation (IVIVC) models prove very useful during drug formulation development, the setting of dissolution specifications and bio-waiver applications following post approval changes. A convolution-based population approach for developing an IVIVC has recently been proposed as an alternative to traditional deconvolution based methods, which pose some statistical concerns. Our aim in this study was to use a time-scaling approach using a convolution-based technique to successfully develop an IVIVC model for a drug with quite different in vitro and in vivo time scales. The in vitro and the in vivo data were longitudinal in nature with considerable between subject variation in the in vivo data. The model was successfully developed and fitted to the data using the NONMEM package. Model utility was assessed by comparing model-predicted plasma concentration-time profiles with the observed in vivo profiles. This comparison met validation criteria for both internal and external predictability as set out by the regulatory authorities. This study demonstrates that a time-scaling approach may prove useful when attempting to develop an IVIVC for data with the aforementioned properties. It also demonstrates that the convolution-based population approach is quite versatile and that it is capable of producing an IVIVC model with a big difference between the in vitro and in vivo time scales.

Antithrombotic drug candidate ALX-0081 shows superior preclinical efficacy and safety compared with currently marketed antiplatelet drugs.

Neutralizing the interaction of the platelet receptor gpIb with VWF is an attractive strategy to treat and prevent thrombotic complications. ALX-0081 is a bivalent Nanobody which specifically targets the gpIb-binding site of VWF and interacts avidly with VWF. Nanobodies are therapeutic proteins derived from naturally occurring heavy-chain-only Abs and combine a small molecular size with a high inherent stability. ALX-0081 exerts potent activity in vitro and in vivo. Perfusion experiments with blood from patients with acute coronary syndrome on standard antithrombotics demonstrated complete inhibition of platelet adhesion after addition of ALX-0081, while in the absence of ALX-0081 residual adhesion was observed. In a baboon efficacy and safety model measuring acute thrombosis and surgical bleeding, ALX-0081 showed a superior therapeutic window compared with marketed antithrombotics. Pharmacokinetic and biodistribution experiments demonstrated target-mediated clearance of ALX-0081, which leads to a self-regulating disposition behavior. In conclusion, these preclinical data demonstrate that ALX-0081 combines a high efficacy with an improved safety profile compared with currently marketed antithrombotics. ALX-0081 has entered clinical development.

A comparison of serum prolactin concentrations after administration of paliperidone extended-release and risperidone tablets in patients with schizophrenia.

Increases in serum prolactin concentrations after administration of risperidone have been attributed, by some, to the availability of paliperidone in plasma. This double-blind, randomized, parallel-group study in patients with schizophrenia compared serum prolactin concentrations following the administration of paliperidone extended-release and risperidone immediate-release tablets. At steady state, the doses administered resulted in a similar exposure to paliperidone and the pharmacologically active fraction of risperidone (i.e. risperidone + paliperidone), respectively. Eligible patients were randomized to either paliperidone extended-release 12 mg on days 1-6 or risperidone immediate-release 2 mg on day 1 and 4 mg on days 2-6. Mean serum prolactin concentrations increased on day 1 (C(max): 71.8 ng/ml and 89.7 ng/ml reached at 6.5 hours and 2.6 hours for paliperidone extended-release and risperidone immediate-release, respectively). On day 6, serum prolactin concentration-time profiles were similar for both treatments, with overall higher serum prolactin concentrations than on day 1 (AUC(0-24 h): 1389 and 842 ng h/ml, and 1306 and 741 ng.h/ml on day 6 and day 1 for paliperidone extended-release and risperidone immediate-release, respectively). These results indicate that paliperidone extended-release 12 mg and risperidone immediate-release 4 mg, administered over a period of 6 days, lead to similar elevations in serum prolactin concentrations.

Single- and multiple-dose pharmacokinetics and dose proportionality of the psychotropic agent paliperidone extended release.

Paliperidone extended-release tablet (paliperidone ER) is a centrally active dopamine D(2)- and serotonergic 5-HT(2A)-receptor antagonist that is registered for the treatment of schizophrenia. The controlled rate of release of paliperidone from the ER formulation is designed to have a slower absorption rate, which results in gradual ascending plasma concentrations with observed maximum plasma concentrations occurring at 24 hours after dosing on the first dosing day. On subsequent treatment days, the ER formulation provides minimal fluctuations in plasma concentrations. Paliperidone is eliminated with a terminal half-life of approximately 24 hours. Steady state is achieved after 4 daily doses. Paliperidone ER exhibits time-invariant pharmacokinetics. It shows a 3.5-fold accumulation upon steady state, mainly caused by the controlled release characteristics of the formulation. Paliperidone ER displays dose proportionality over the dose range of 3 to 15 mg; the 90% confidence intervals of the pairwise dose comparisons are all included in the 80% to 125% bioequivalence limits.