Pharmacokinetics, Safety, and Tolerability of Brivaracetam in Healthy Elderly Participants.

The pharmacokinetics, metabolism, safety, and tolerability of the antiseizure medication brivaracetam (BRV) were characterized in 16 healthy elderly participants (8 men/8 women) aged 65-78 years who received a single 200-mg oral dose of BRV on day 1, followed by 200 mg twice daily from day 3 until day 12. BRV and three metabolites were determined in plasma and urine. Adverse events, vital signs, electrocardiograms, laboratory tests, general and neurological examinations, and psychometric rating scales were recorded at regular intervals. No clinically relevant changes or abnormalities were detected. The adverse events were similar to those observed in pivotal trials. Rating scales indicated transiently increased sedation and decreased alertness. BRV pharmacokinetics and metabolism were unchanged relative to younger populations. Based on our observations in this healthy elderly population receiving oral BRV 200 mg twice daily (twice the maximum recommended dose), dose reductions are not warranted relative to other, younger populations. Further investigations may be necessary in frail elderly populations aged >80 years.

Development of C1q Affinity Chromatography for the Study of C1q-IgG Interactions.

The classical complement system represents a central effector mechanism of Abs initiated by the binding of C1q to target bound IgG. Human C1q contains six heterotrimeric globular head groups that mediate IgG interaction, resulting in an avidity-driven binding event involving multiple IgG molecules binding a single C1q. Accordingly, surface bound IgG molecules are thought to assemble into noncovalent hexameric rings for optimal binding to the six-headed C1q. To study the C1q-Fc interaction of various Abs and screen for altered C1q binding mutants, we developed, to our knowledge, a novel HPLC-based method. Employing a single-chain form of C1q representing one C1q head group, our HPLC methodology was able to detect the interaction between the single-chain monomeric form of C1q and various ligands. We show that, despite a narrow window of specific binding owing to the low affinity of the monomeric C1q-IgG interaction, this approach clearly distinguished between IgG subclasses with established C1q binding properties. IgG3 displayed the strongest binding, followed by IgG1, with IgG2 and IgG4 showing the weakest binding. Fc mutants known to have increased C1q binding through oligomerization or enhanced C1q interaction showed greatly increased column retention, and IgG glycovariants displayed a consistent trend of increasing retention upon increasing galactosylation and sialylation. Furthermore, the column retention of IgG isotypes and glycovariants matches both the cell surface recruitment of C1q and complement-mediated cytotoxicity induced by each variant on an anti-CD20 Ab backbone. This methodology therefore provides a valuable tool for testing IgG Ab (glyco)variants for C1q binding, with clear relevance for therapeutic Ab development.

Mechanistic incorporation of FcRn binding in plasma and endosomes in a whole body PBPK model for large molecules.

Monoclonal antibodies, endogenous IgG, and serum albumin bind to FcRn in the endosome for salvaging and recycling after pinocytotic uptake, which prolongs their half-life. This mechanism has been broadly recognized and is incorporated in currently available PBPK models. Newer types of large molecules have been designed and developed, which also bind to FcRn in the plasma space for various mechanistic reasons. To incorporate FcRn binding affinity in PBPK models, binding in the plasma space and subsequent internalisation into the endosome needs to be explicitly represented. This study investigates the large molecules model in PK-Sim® and its applicability to molecules with FcRn binding affinity in plasma. With this purpose, simulations of biologicals with and without plasma binding to FcRn were performed with the large molecule model in PK-Sim®. Subsequently, this model was extended to ensure a more mechanistic description of the internalisation of FcRn and the FcRn-drug complexes. Finally, the newly developed model was used in simulations to explore the sensitivity for FcRn binding in the plasma space, and it was fitted to an in vivo dataset of wild-type IgG and FcRn inhibitor plasma concentrations in Tg32 mice. The extended model demonstrated a strongly increased sensitivity of the terminal half-life towards the plasma FcRn binding affinity and could successfully fit the in vivo dataset in Tg32 mice with meaningful parameter estimates.

Not just what you did, but how: Children see distributors that count as more fair than distributors who don't.

To distribute resources in a fair way, identifying an appropriate outcome is not enough: We must also find a way to produce it. To solve this problem, young children spontaneously use number words and counting in fairness tasks. We hypothesized that children are also sensitive to other people's use of counting, as it reveals that the distributor was motivated to produce the outcome they believed was fair. Across four experiments, we show that U.S. children (N = 184 from the New Haven area; ages four to six; Approximately 58% White, 16% Black, 18% Hispanic, 4% Asian, and 4% other) believe that agents who count when distributing resources are more fair than agents who produce the same outcome without counting, even when both agents invest the same amount of effort. And vice versa, when the same two agents produce an unfair outcome, children now condemn the agent who counted. Our findings suggest that, from childhood, people understand that counting reflects a motivation to be precise and use this to evaluate other people's behavior in fairness contexts.

Caplacizumab Model-Based Dosing Recommendations in Pediatric Patients With Acquired Thrombotic Thrombocytopenic Purpura.

Acquired thrombotic thrombocytopenic purpura (aTTP) is a rare and life-threatening autoimmune thrombotic microangiopathy. Caplacizumab, evaluated in phase II and III studies in adults, shortens the time to platelet count response and reduces aTTP exacerbations, has a favorable safety profile, and can potentially reduce refractoriness and mortality associated with aTTP. Since no children with aTTP were enrolled in these clinical trials, caplacizumab has been initially approved for use only in adult patients with aTTP (10 mg). Pediatric dosing recommendations were developed using model-based simulations. A semimechanistic pharmacokinetic/pharmacodynamic population model has been developed describing the interaction between caplacizumab and von Willebrand factor antigen (vWF:Ag) following intravenous and subcutaneous administration of caplacizumab in different adult populations, at various dose levels, using nonlinear mixed-effects modeling. Based on the allometrically scaled pharmacokinetic/pharmacodynamic model, different dosing regimens were simulated in 8000 children (aged 2-18 years). Simulated caplacizumab exposures and vWF:Ag levels across different age categories were compared to an adult reference group. A simulated daily dose of 5 mg in children weighing <40 kg and of 10 mg in children weighing ≥40 kg resulted in similar exposures and vWF:Ag suppression across age and weight groups. Despite the lack of pediatric clinical data, the results of this modeling and simulation analysis constituted the basis for the European extension of indication for caplacizumab (10 mg) to adolescents aged >12 years and with a body weight ≥40 kg. This represents a rare case in which regulatory authorities have deemed a modeling and simulation study robust enough to approve a variation of indication.

Giant left atrial myxoma - literature review and case presentation.

Primary cardiac tumors are an extremely rare pathology, representing only 5-10% of cardiac neoplasms, but among them, the most common are cardiac myxomas, that appear to originate from multipotent mesenchymal cells of the subendocardial and endocardial stroma. The incidence of cardiac myxomas is higher in females and they are usually diagnosed between the fourth and sixth decade of life. Most often, they are located in the left atrium, having the site of attachment at the level of the interatrial septum, especially at the level of the fossa ovalis and the adjacent limbus. Due to the increased risk of systemic embolization and intracardiac obstruction, cardiac myxomas have a definite indication for emergency surgical treatment. Cardiac myxomas are a very rare cause of transient ischemic attacks and stroke. We present the case of a 38-year-old patient who experienced four recurrent transient ischemic attacks and strokes. At the fourth cerebrovascular event, echocardiography was performed and it revealed a giant tumor located in the left atrium that was surgically removed. Pathological examination confirmed the diagnosis of cardiac myxoma. The postoperative evolution was favorable, both from a neurological and cardiac point of view. Although cardiac myxomas represent a rare cause of transient ischemic attacks and stroke, they must be considered as part of the assessment protocol for cerebrovascular events.

Multi-Attribute Monitoring of Complex Erythropoetin Beta Glycosylation by GluC Liquid Chromatography-Mass Spectrometry Peptide Mapping.

Recombinant human erythropoetin (EPO) is an important biopharmaceutical mainly used for the treatment of anemia. It is highly heterogeneous because of common amino acid chemical degradations known to occur in protein therapeutics (e.g., oxidation and deamidation) and its complex glycosylation profile. Recently, multi-attribute monitoring (MAM), i.e., the quantification of multiple post-translational and chemical modifications in a single peptide mapping liquid chromatography-mass spectrometry (LC-MS)-based method, has received increased attention for the analysis of antibody-like biotherapeutic proteins. In this study, an MAM method for examination of residue-specific glycan profiles of EPO was established. The MAM method, by virtue of the increased sensitivity and selectivity provided with LC-MS, yielded additional site-specific information not afforded by the conventional quality control (QC) methods. Low abundant glycans as well as additional post-translational and chemical modifications could also be simultaneously detected by the MAM method. Our results demonstrate that desialylated N-oligosaccharides (DeNO) and N-acetylneuraminic acids (Neu5Ac) could be monitored by the developed MAM approach with data readout highly comparable to QC methods, while differences were observed for charge isoform distribution. In summary, the comparative data obtained demonstrate that MAM by LC-MS peptide mapping can, in principle, adequately replace selected QC methods and would add value to the in-process control and release testing strategy of EPO.

Clinical pharmacology of caplacizumab for the treatment of patients with acquired thrombotic thrombocytopenic purpura.

Introduction: Caplacizumab is a humanized anti-von Willebrand Factor (vWF) Nanobody® for the treatment of acquired Thrombotic Thrombocytopenic Purpura (aTTP). Caplacizumab targets the A1-domain of vWF, inhibiting the interaction between vWF and platelets. Clinical studies conducted in aTTP patients confirmed the rapid and sustained complete suppression of the vWF activity using an initial intravenous dose of 10 mg, and a maintenance subcutaneous 10 mg daily dosing regimen, with corresponding favorable efficacy and safety profiles. Areas covered: The pharmacokinetics of caplacizumab are non-linear, characterized by a target-mediated disposition and the exposure is dependent upon drug and target concentration over time. The pharmacokinetics of caplacizumab are predictable when considering the turn-over of the circulating vWF and its modulation by the drug over time. Renal and hepatic impairment are not expected to influence the exposure to the drug, and no direct or indirect drug-drug pharmacokinetic interactions are anticipated based on the mechanism of action and the specificity of the pharmacodynamic effect of caplacizumab. Expert opinion: Caplacizumab prevents the interaction between vWF and platelets, offering a direct and rapid therapeutic intervention to stop microthrombosis. The combination of caplacizumab with plasma exchange and immunosuppression represents an important, potentially life-saving advance in the treatment of aTTP patients.

Malignant melanoma - the most severe skin cancer and neurological pathology.

OBJECTIVE: We report our clinical experience with malignant melanoma (MM) patients associated with neurological involvement. PATIENTS, MATERIALS AND METHODS: A database of patients admitted from 2014-2019 in the Ist Clinic of Neurology, Emergency County Hospital of Târgu Mures, Romania, was reviewed to identify patients with MM and neurological involvement. We assessed the demographic and clinical data regarding the neurological disorders and the primary tumor characteristics from the patient registries. Both histopathological and immunohistochemical analysis of the neoplasm was available for the entire cohort. RESULTS: We analyzed 13 982 patient files and 21 met all the inclusion and exclusion criteria. Brain metastases were found in 38.09% of the patients, spinal metastases in 9.52% of the patients, ischemic stroke by cancer-associated thrombosis in 42.85% of the patients and peripheral nervous system involvement in 19.04% of the patients. No statistically significant differences between the four categories of neurological disorders according to socio-demographic parameters, location of the primary tumor, existence of primary tumor ulceration, invasion of the lymph nodes or the presence and location of distant metastasis was found (p>0.05). Our presented patient is the first case of uveal melanoma with hemorrhagic brain metastasis before hepatic involvement. CONCLUSIONS: Neurological involvement in MM encompasses a myriad of variants and while the clinical setting varies from one patient to another, an underlining neoplasia should be evaluated in suspected patients.

Pharmacokinetic interaction of brivaracetam on carbamazepine in adult patients with epilepsy, with and without valproate co-administration.

OBJECTIVE: This Phase I, open-label, dose-escalation study investigated the effects of steady-state brivaracetam on the pharmacokinetics of carbamazepine in patients with epilepsy, with and without valproate co-administration. Valproate and brivaracetam inhibit epoxide hydrolase and increase carbamazepine epoxide levels. METHODS: Adult patients with epilepsy being chronically treated with carbamazepine alone (n=9) or with carbamazepine and valproate (n=9) received brivaracetam during successive 1-week periods at doses of 50mg, 100mg, 200mg, and 100mg twice daily (bid). Doses of carbamazepine and valproate must have been stable for at least 3 months. Trough plasma concentrations of carbamazepine, carbamazepine epoxide, and diol metabolites were determined on Days 1, 8, 15, 22, and 29, and at the end of study visit (ESV, 2-3weeks later). RESULTS: Eighteen patients with median (range) age of 45 (20-62) years and body weight of 74 (59-124) kg were enrolled and completed the study. In patients treated with carbamazepine alone, brivaracetam dose-dependently increased mean trough levels of carbamazepine epoxide from 1.38µg/mL on Day 1 pre-dose to 2.16µg/mL (+57%) on Day 8 (50mg bid), 2.72µg/mL (+97%) on Day 15 (100mg bid), 3.02µg/mL (+119%) on Day 22 (200mg bid), 2.67µg/mL (+94%) on Day 29 (100mg bid), and 1.22µg/mL (-12%) at ESV, respectively. In patients on carbamazepine and valproate, carbamazepine epoxide increased from 1.98µg/mL at baseline to 2.72µg/mL (+37%), 3.70µg/mL (+87%), 4.43µg/mL (+124%), 3.11µg/mL (+57%), and 1.94µg/mL (-2%), respectively. There was no trend for change in carbamazepine, carbamazepine diol or valproate levels. Brivaracetam levels increased linearly with dose. Brivaracetam was well tolerated. CONCLUSIONS: Carbamazepine epoxide plasma concentrations were approximately doubled by brivaracetam 100 or 200mg bid. Data are consistent with a dose-dependent and reversible inhibition of epoxide hydrolase by brivaracetam. Carbamazepine epoxide was approximately 0.7µg/mL higher in presence of valproate. There is no need to limit brivaracetam dosing when used concomitantly with carbamazepine.

Applying mini-bore HPAEC-MS/MS for the characterization and quantification of Fc N-glycans from heterogeneously glycosylated IgGs.

High-performance anion-exchange chromatography (HPAEC) coupled to pulsed amperometric detection (PAD) is a highly sensitive method for the analysis of oligosaccharides without the need for prior derivatization. However, the method suffers from the lack of chemical information with peak assignments based on the retention times of authentic standards or known peaks of reference materials. Here we applied HPAEC coupled on-line with electrospray ion trap mass spectrometry (HPAEC-MS) using a prototype mini-bore (1mm I.D.) CarboPac PA200 column and challenged the analytical separation based method for the structural assignment of heterogeneous mixtures of N-glycans derived from immunoglobulin G from human plasma, glyco-engineered CHO cells, and Sp2/0 mouse myeloma cells. Compared to an analytical scale 3mm I.D. column, the mini-bore column demonstrated a superior performance with up to 8-fold improved limit of detection for specific N-glycans determined by PAD. Quantitative evaluation by extracted ion current chromatograms revealed detection limits in the 50-100 femtomole range using ion trap MS operated in positive ionization mode. In our hands HPAEC-MS/MS allowed the detection and quantification of even low abundant glycan species including biantennary complex-type, high mannose, hybrid and hybrid bisected structures. In comparison to the detection of N-glycans as lithiated or sodiated adducts, we obtained a 65-fold improved signal-to-noise ratio with protonated ions only. Relative quantitative evaluation by single ion current chromatograms was successfully applied and demonstrated an excellent performance with respect to selectivity in the relative quantification of heterogeneous samples of N-glycans compared to HPAEC-PAD and HILIC-UPLC of 2-AB labelled N-glycans.

Comparison of methods for the analysis of therapeutic immunoglobulin G Fc-glycosylation profiles--part 1: separation-based methods.

Immunoglobulin G (IgG) crystallizable fragment (Fc) glycosylation is crucial for antibody effector functions, such as antibody-dependent cell-mediated cytotoxicity, and for their pharmacokinetic and pharmacodynamics behavior. To monitor the Fc-glycosylation in bioprocess development, as well as product characterization and release analytics, reliable techniques for glycosylation analysis are needed. A wide range of analytical methods has found its way into these applications. In this study, a comprehensive comparison was performed of separation-based methods for Fc-glycosylation profiling of an IgG biopharmaceutical. A therapeutic antibody reference material was analyzed 6-fold on 2 different days, and the methods were compared for precision, accuracy, throughput and other features; special emphasis was placed on the detection of sialic acid-containing glycans. Seven, non-mass spectrometric methods were compared; the methods utilized liquid chromatography-based separation of fluorescent-labeled glycans, capillary electrophoresis-based separation of fluorescent-labeled glycans, or high-performance anion exchange chromatography with pulsed amperometric detection. Hydrophilic interaction liquid chromatography-ultra high performance liquid chromatography of 2-aminobenzamide (2-AB)-labeled glycans was used as a reference method. All of the methods showed excellent precision and accuracy; some differences were observed, particularly with regard to the detection and quantitation of minor glycan species, such as sialylated glycans.

The vibrational and configurational entropy of α-brass.

The heat capacities of two samples of a fcc Cu-Zn alloy with the composition CuZn15 and CuZn34 were measured from T = 5 K to 573 K using relaxation and differential scanning calorimetry. Below ∼90 K, they are characterised by negative excess heat capacities deviating from ideal mixing by up to -0.20 and -0.44 J · mol-1 · K-1 for CuZn15 and CuZn34, respectively. The excess heat capacities produce excess vibrational entropies, which are less negative compared to the excess entropy available from the literature. Since the literature entropy data contain both, the configurational and the vibrational part of the entropy, the difference is attributed to the excess configurational entropy. The thermodynamics of different short-range ordered samples was also investigated. The extent of the short-range order had no influence on the heat capacity below T = 300 K. Above T = 300 K, where the ordering changed during the measurement, the heat capacity depended strongly on the thermal history of the samples. From these data, the heat and entropy of ordering was calculated. The results on the vibrational entropy of this study were also used to test a relationship for estimating the excess vibrational entropy of mixing.

Brivaracetam disposition in mild to severe hepatic impairment.

Brivaracetam is a high-affinity synaptic vesicle protein 2A (SV2A) ligand in clinical development for epilepsy. This open-label, single-dose study evaluated brivaracetam disposition in participants with different degrees of hepatic impairment versus matched healthy controls. Twenty-six participants (38-72 years; 19 males and 7 females) with hepatic impairment classified by Child-Pugh score (mild, n = 6; moderate, n = 7; severe, n = 7) or normal hepatic function (n = 6) received a single oral dose of 100 mg brivaracetam. The pharmacokinetics of brivaracetam and its three main metabolites (acid, hydroxy, hydroxyacid) were determined and correlated with impairment severity. Dynamic liver function tests correlated with hepatic impairment severity. The plasma half-life of brivaracetam was 9.8, 14.2, 16.4, and 17.4 hours and the area under the plasma concentration-time curve was 29.7, 44.6, 46.7, and 47.1 µg h/mL in healthy controls and participants with mild, moderate, and severe liver impairment, respectively. Production of the acid metabolite was increased and the hydroxylated metabolites were decreased in participants with hepatic impairment versus healthy controls. Exposure to brivaracetam increased by 50-60% in patients with hepatic impairment, irrespective of severity. The relative importance of biotransformation pathways was altered; cytochrome P450 (CYP)-dependent hydroxylation decreased; CYP-independent acid metabolite formation increased concomitantly.

Brivaracetam disposition in renal impairment.

Brivaracetam is a novel high-affinity SV2A ligand currently in clinical development for epilepsy. The objective was to characterize its disposition in patients with renal impairment. A single oral dose of 200 mg brivaracetam was administered to 9 patients with severe renal impairment not requiring dialysis (creatinine clearance <15 mL/min, n = 6; 15-29 mL/min, n = 3) and 9 matched healthy controls. Plasma and urinary concentrations of brivaracetam and 3 pharmacologically inactive metabolites (acid, hydroxy, and hydroxyacid) were determined up to 72 hours postdose, and noncompartmental pharmacokinetic parameters were derived. The C(max) of brivaracetam was unchanged relative to healthy controls, whereas AUC was slightly increased (mean ratio, 1.21; 90% confidence interval, 1.01-1.45). Nonrenal and renal clearances of brivaracetam decreased from 47 and 4.5 to 41 and 1.7 mL/min/1.73 m(2). Exposure to the acid, hydroxy, and hydroxyacid metabolites was markedly increased: C(max) by 2.4-, 2.0-, and 11.7-fold and AUC by 3.2-, 4.1-, and 21.5-fold. Renal clearance of these rapidly cleared metabolites was decreased 10-fold in patients with severe renal impairment. Nonclinical toxicology studies concluded to the absence of safety issues related to the increased levels of metabolites. These observations suggest that dose adjustment of brivaracetam should not be required at any stage of renal dysfunction.

Assessment of levetiracetam bioavailability from targeted sites in the human intestine using remotely activated capsules and gamma scintigraphy: Open-label, single-dose, randomized, four-way crossover study in healthy male volunteers.

BACKGROUND: Levetiracetam is a broad-spectrum antiepileptic drug that binds to synaptic vesicle protein SV2A. Levetiracetam is indicated in the adjunctive treatment of partial-onset seizures, myoclonic seizures, and generalized tonic-clonic seizures. It is also approved in Europe as monotherapy for newly diagnosed partial-onset seizures. A Phase I clinical pharmacology trial was conducted during preregistration clinical development to better understand the regional gastrointestinal (GI) absorption of levetiracetam. OBJECTIVE: This study evaluated the relative bioavailability of levetiracetam in various regions of the GI tract using a noninvasive, remote-controlled capsule device providing targeted drug delivery, relative to that after oral administration, and explored the drug's absorption characteristics in healthy volunteers. METHODS: Pharmacokinetic data were obtained from healthy men aged 18 to 65 years in an open-label, single-dose, randomized, 4-way crossover study. Treatments included levetiracetam 250 mg administered as an immediate-release tablet and capsule delivery of 250 mg drug substance (levetiracetam powder without excipients) to the proximal small bowel, distal small bowel, and ascending colon. The location of the capsule in the GI tract was monitored using γ-scintigraphic imaging. Blood samples for plasma levetiracetam concentration were collected before dosing; at 10, 20, 30, and 45 minutes; and at 1, 1.5, 2, 3, 6, 9, 12, 16, 20, and 24 hours after tablet intake or after capsule activation. Pharmacokinetic parameters C(max), T(max), AUC0₋(last), AUC0₋(∞) and t(½) were calculated using noncompartmental methods. Tolerability was determined using clinical assessment, monitoring of vital signs, laboratory analysis, and interviews with the volunteers regarding adverse events. RESULTS: Nine healthy men, 7 whites and 2 Asians, were enrolled (mean [SD] age, 31 [14] years; weight, 77 [5] kg; height, 176 [6] cm). Six volunteers completed all 4 treatments. Seven adverse events (headache [3], lethargy [2], tachycardia [1], and contusion [1]) were reported in 5 volunteers, but only 2 (headache and lethargy) were judged by the investigator to be possibly drug related. The geometric mean (%CV) AUC(0-last) values of levetiracetam delivered in the proximal small bowel, distal small bowel, ascending colon, and stomach (oral tablet) were 58.2 (9.3%), 59.6 (8.9%), 51.5 (12.0%), and 59.0 (7.4%) µg · h/mL, respectively. Values for bioavailability in the proximal small bowel, distal small bowel, and ascending colon relative to the tablet were 98.5% (95% CI, 89.7%-108.2%), 100.8% (95% CI, 91.4%-111.1%), and 87.1% (95% CI, 77.9%-97.5%). CONCLUSION: After delivery in the proximal small bowel, distal small bowel, or ascending colon, the systemic bioavailability of levetiracetam (AUC), but not C(max) and T(max), appeared comparable to that after oral administration and thus appeared site independent in this small group of healthy fasting men.

Physiologically based pharmacokinetics (PBPK).

Allometric scaling is widely used to predict human pharmacokinetic parameters from preclinical species, and many different approaches have been proposed over the years to improve its predictive performance. Nevertheless, prediction errors are commonly observed in the practical application of simple allometry, for example, in cases where the hepatic metabolic clearance is mainly determined by enzyme activities, which do not scale allometrically across species. Therefore, if good correlation was noted for some drugs, poor correlation was observed for others, highlighting the need for other conceptual approaches. Physiologically based pharmacokinetic (PBPK) models are now a well-established approach to conduct extrapolations across species and to generate simulations of pharmacokinetic profiles under various physiological conditions. While conventional pharmacokinetic models are defined by drug-related data themselves, PBPK models have richer information content and integrate information from various sources, including drug-dependent, physiological, and biological parameters as they vary in between species, subjects, or with age and disease state. Therefore, the biological and mechanistic bases of PBPK models allow the extrapolation of the kinetic behavior of drugs with regard to dose, route, and species. In addition, by providing a link between tissue concentrations and toxicological or pharmacological effects, PBPK modeling represents a framework for mechanistic pharmacokinetic-pharmacodynamic models.

From pharmacokinetics to therapeutics.

Whilst pharmacokinetics describe the relationship between dose levels and concentration-time profiles of a drug in the body and pharmacodynamics describe the concentration-response relationships, pharmacokinectics-pharmacodynamics(PK-PD) models link these two items providing a framework for modelling the time course of drug response. In this chapter, PK-PD models, describing the therapeutic effects of drugs used for the therapy of allergic diseases have been reviewed. Emphasis was given also to the description of the receptor occupancy, which is tightly related to the downstream clinical response. PK - PD models describing unwanted effects were also commented. An integrated use of these models allows choosing appropriate dosing regimens and providing an objective evaluation of the benefit/risk balance.

Population pharmacokinetic and pharmacodynamic analysis in allergic diseases.

In this chapter, we introduce the concepts and methodologies of population analysis as applied to analyzing pharmacokinetic and pharmacodynamic data. One of the key determining characteristics of the population approach is that through it, one seeks not only to characterize deterministic trends in the data, but also to identify and estimate the magnitudes of the important sources of variability within the data. The first section of this chapter provides an introduction to the primary concepts of, and motivation for, population modeling by way of a hypothetical case study. Then, the various methodologies that have been employed throughout the history of population analysis are described in further detail. Of these, the most commonly employed today is nonlinear mixed-effects (NLME) modeling. Finally, notable examples of the application of population PK and PK/PD modeling to treatments for allergies and asthma are discussed. Population PK models have frequently been used to extrapolate exposures to special populations, such as pediatrics, as well as to optimize treatment regimens and trial designs for these populations. Population PK/PD models have most frequently been applied to analyzing and interpreting data from wheal and flare trials, but are also becoming increasingly important in the analysis of PD data from monoclonal antibodies.

Pharmacokinetics of levetiracetam XR 500mg tablets.

PURPOSE: To compare the relative bioavailability of levetiracetam extended-release tablets (XR) with immediate release tablets (IR) following single and multiple dosing; to assess the food effect and the dose-proportionality of XR from 1000 to 3000mg. METHODS: Two panels of 24 healthy subjects were enrolled. Study N01160 was a three-way crossover between IR fasted (single and repeated 500mg b.i.d.), XR fasted (single and repeated 1000mg o.d.) and XR with food (1000mg single dose). Study N01260 was a three-way crossover single dose-proportionality between XR 1000, 2000 and 3000mg. RESULTS: After single dose, levetiracetam XR and IR were bioequivalent with respect to AUC((0-t)), AUC(infinity) and C(max). The median t(max) was delayed from 0.9 to 4h. For the fed/fasted comparison, the confidence intervals around the C(max) and AUC ratios were within the 80-125% limits. At steady-state, the AUC(24h) were also bioequivalent. In the dose-proportionality trial, the AUC and C(max) increased linearly with the dose. Levetiracetam XR was well tolerated. CONCLUSIONS: Levetiracetam XR 1000mg o.d. is bioequivalent to levetiracetam IR 500mg b.i.d. There is no food effect, and the absorption of XR is dose-proportional from 1000 to 3000mg.