Pharmacokinetics, safety, and tolerability of intravenous brivaracetam in pediatric patients with epilepsy: An open-label trial.

OBJECTIVE: To evaluate the pharmacokinetics, safety, and tolerability of brivaracetam (BRV) as 15-min intravenous (IV) infusion and bolus (≤2-min injection). METHODS: EP0065 (ClinicalTrials.gov: NCT03405714) was a Phase 2, multicenter, open-label trial in patients ≥1 month to <16 years of age with epilepsy. Patients received up to 5 mg/kg/day BRV (not exceeding 200 mg/day). Enrollment was sequential by descending age, depending on safety review. Outcomes included BRV plasma concentrations before and after IV administration, treatment-emergent adverse events (TEAEs), and discontinuations due to TEAEs. RESULTS: Fifty patients were enrolled, received BRV, and completed the trial. Twenty-six patients (52.0%) received 15-min infusions and 24 (48.0%) received bolus injections. Most patients (80.0%) received one IV dose. In the 15-min infusion group, geometric mean (GeoMean) BRV concentrations 15 (±2) min (n = 21) and 3 h (±15 min) (n = 21) post dose were 1903.0 ng/mL (geometric coefficient of variation [GeoCV]: 60.7%) and 1130.3 ng/mL (58.8%), respectively. In the bolus group, GeoMean BRV concentrations 15 (±2) min (n = 19) and 3 h (±15 min) (n = 21) post dose were 1704.8 ng/mL (GeoCV: 74.5%) and 1383.9 ng/mL (85.0%), respectively. Overall, 14 patients (28.0%) had TEAEs (15-min infusion: 8 [30.8%]; bolus: 6 [25.0%]), most commonly (≥5% of patients) somnolence (3 [6.0%]). Ten patients (20.0%) had drug-related TEAEs (15-min infusion: 6 [23.1%]; bolus: 4 [16.7%]). No patients discontinued due to TEAEs, and no deaths occurred. SIGNIFICANCE: IV BRV (up to 200 mg/day) was well tolerated in patients ≥1 month to <16 years of age, regardless of whether BRV was administered as 15-min infusion or bolus. No unexpected safety or pharmacokinetic differences were observed between patients receiving 15-min infusions or bolus, and plasma concentrations were in the expected range. Safety results were consistent with the known safety profile of oral BRV, with no new safety concerns identified.

The variability in beta-cell function in placebo-treated subjects with type 2 diabetes: application of the weight-HbA1c-insulin-glucose (WHIG) model.

AIM: The weight-glycosylated haemoglobin (HbA1C)-insulin-glucose (WHIG) model describes the effects of changes in weight on insulin sensitivity (IS) in newly diagnosed, obese subjects receiving placebo treatment. This model was applied to a wider population of placebo-treated subjects, to investigate factors influencing the variability in IS and ß-cell function. METHODS: The WHIG model was applied to the WHIG dataset (Study 1) and two other placebo datasets (Studies 2 and 3). Studies 2 and 3 consisted of nonobese subjects and subjects with advanced type 2 diabetes mellitus (T2DM). Body weight, fasting serum insulin (FSI), fasting plasma glucose (FPG) and HbA1c were used for nonlinear mixed-effects modelling (using NONMEM v7.2 software). Sources of interstudy variability (ISV) and potential covariates (age, gender, diabetes duration, ethnicity, compliance) were investigated. RESULTS: An ISV for baseline parameters (body weight and ß-cell function) was required. The baseline ß-cell function was significantly lower in subjects with advanced T2DM (median difference: Study 2: 15.6%, P < 0.001; Study 3: 22.7%, P < 0.001) than in subjects with newly diagnosed T2DM (Study 1). A reduction in the estimated insulin secretory response in subjects with advanced T2DM was observed but diabetes duration was not a significant covariate. CONCLUSION: The WHIG model can be used to describe the changes in weight, IS and ß-cell function in the diabetic population. IS remained relatively stable between subjects but a large ISV in ß-cell function was observed. There was a trend towards decreasing ß-cell responsiveness with diabetes duration, and further studies, incorporating subjects with a longer history of diabetes, are required.

A Generic Multi-Compartmental CNS Distribution Model Structure for 9 Drugs Allows Prediction of Human Brain Target Site Concentrations.

PURPOSE: Predicting target site drug concentration in the brain is of key importance for the successful development of drugs acting on the central nervous system. We propose a generic mathematical model to describe the pharmacokinetics in brain compartments, and apply this model to predict human brain disposition. METHODS: A mathematical model consisting of several physiological brain compartments in the rat was developed using rich concentration-time profiles from nine structurally diverse drugs in plasma, brain extracellular fluid, and two cerebrospinal fluid compartments. The effect of active drug transporters was also accounted for. Subsequently, the model was translated to predict human concentration-time profiles for acetaminophen and morphine, by scaling or replacing system- and drug-specific parameters in the model. RESULTS: A common model structure was identified that adequately described the rat pharmacokinetic profiles for each of the nine drugs across brain compartments, with good precision of structural model parameters (relative standard error <37.5%). The model predicted the human concentration-time profiles in different brain compartments well (symmetric mean absolute percentage error <90%). CONCLUSIONS: A multi-compartmental brain pharmacokinetic model was developed and its structure could adequately describe data across nine different drugs. The model could be successfully translated to predict human brain concentrations.

Absence of clinically relevant cardiovascular interaction upon add-on of mirabegron or tamsulosin to an established tamsulosin or mirabegron treatment in healthy middle-aged to elderly men.

OBJECTIVE: Tamsulosin and mirabegron may be used concomitantly in patients with lower urinary tract symptoms. Since alpha1-adrenoceptor antagonists are associated with cardiovascular side effects, potential pharmacokinetic and cardiovascular interactions were evaluated. MATERIALS AND METHODS: This was an open-label, randomized, 2-arm, 2-sequence study in 48 healthy men (24/arm) aged 44 - 72 years. In arm 1, subjects received single-dose tamsulosin hydrochloride modified release capsules (0.4 mg) alone and with steady-state mirabegron oral controlled absorption system tablets (100 mg once daily) in random sequence. In arm 2, subjects received single-dose mirabegron alone and with steady-state tamsulosin. Samples for mirabegron and tamsulosin plasma concentrations were collected. Blood pressure (BP) and pulse rate (PR) were measured and orthostatic stress tests were performed. RESULTS: Mirabegron increased tamsulosin C(max) to 159% (90% confidence interval (CI) 143 - 177%), AUC(∞) to 161% (90% CI 149 - 173%), and t(1/2) to 116%. Tamsulosin reduced mirabegron C(max) to 85% (90% CI 71 - 103%) and AUC(∞) to 84% (90% CI 74 - 95%) without effect on t1/2. Mirabegron and tamsulosin co-treatment caused no statistically significant changes (p > 0.05) in PR or systolic BP versus mono-treatment up to 12 hours post-dose. Mean diastolic BP decreases of -2.1 (95% CI -4.1, -0.1) to -4.2 (-7.5, -0.9) mmHg in arm 1 and -3.0 (-5.7, -0.3) to -4.2 (-7.4, -1.0) mmHg in arm 2 were observed, statistically significant (p < 0.05) at several time points, not accompanied by orthostatic symptoms or increases in positive orthostatic stress tests. Adverse and orthostatic events were balanced across treatments. CONCLUSIONS: The observed pharmacokinetic interactions upon add-on of mirabegron or tamsulosin to existing tamsulosin or mirabegron therapy did not cause clinically relevant changes in cardiovascular safety or safety profiles.

The effect of mirabegron, a potent and selective ß3-adrenoceptor agonist, on the pharmacokinetics of CYP2D6 substrates desipramine and metoprolol.

Mirabegron is a potent and selective ß3-adrenoceptor agonist developed for the treatment of overactive bladder. In vitro studies demonstrated that mirabegron partly acts as a (quasi-) irreversible, metabolism-dependent inhibitor of CYP2D6. The effect of steady-state mirabegron on single doses of the sensitive CYP2D6 substrates metoprolol (100 mg) and desipramine (50 mg) was assessed in two open-label, one-sequence crossover studies in healthy subjects (CYP2D6 extensive metabolizers). Mirabegron 160 mg/day increased metoprolol maximum plasma concentration (C max) 1.90-fold (90 % confidence interval [CI] 1.54; 2.33) and total exposure (AUC0-∞) 3.29-fold (90 % CI 2.70; 4.00) in 12 males (study 1). Mean metoprolol half-life increased from 2.96 to 4.11 h. α-Hydroxymetoprolol C max and AUC to last measurable concentration decreased 2.6-fold and 2.2-fold, respectively. In study 2, mirabegron 100 mg/day increased desipramine C max 1.79-fold (90 % CI 1.69; 1.90) and AUC0-∞ 3.41-fold (90 % CI 3.07; 3.80) in 14 males and 14 females. Mean desipramine half-life increased from 19.5 to 35.8 h. C max of 2-hydroxydesipramine decreased ~twofold, while AUC increased ~1.3-fold. Desipramine was administered again 2 weeks after the last mirabegron dose. Desipramine C max and AUC0-∞ were still ~1.13-fold increased; the 90 % CIs fell within the 0.80-1.25 interval. All treatments were well tolerated. In conclusion, mirabegron is a moderate CYP2D6 inhibitor (ratio and 90 % CI <5.0).

Brivaracetam exposure-response predictions in pediatric patients from age 1 month: Extrapolation of levetiracetam adult-pediatric scaling to brivaracetam.

BACKGROUND: An adult population pharmacokinetic/pharmacodynamic (PK/PD) model for the antiseizure medication (ASM) brivaracetam (BRV) was previously extended to children aged 4-16 years by using a pediatric BRV population PK model. Effects were scaled using information from a combined adult-pediatric PK/PD model of a related ASM, levetiracetam (LEV). OBJECTIVE: To scale an existing adult population PK/PD model for BRV to children aged 1 month to < 4 years using information from a combined adult-pediatric PK/PD model for LEV, and to predict the effective dose of BRV in children aged 1 month to < 4 years using the adult BRV PK/PD model modified for the basal seizure rate in children. MATERIAL AND METHODS: An existing adult population PK/PD model for BRV was scaled to children aged from 1 month to < 4 years using information from a combined adult-pediatric PK/PD model for LEV, an ASM binding to the same target protein as BRV. An existing adult-pediatric PK/PD model for LEV was extended using data from UCB study N01009 (NCT00175890) to include children as young as 1 month of age. The BRV population PK model was updated with data up to 180 days after first administration from BRV pediatric studies N01263 (NCT00422422) and N01266 (NCT01364597). PK and PD simulations for BRV were performed for a range of mg/kg doses to predict BRV effect in pediatric participants, and to provide dosing recommendations. RESULTS: The extended adult-pediatric LEV PK/PD model was able to describe the adult and pediatric data using the same PD model parameters in adults and children and supported the extension of the adult BRV PK/PD model to pediatric patients aged 1 month to < 4 years. Simulations predicted exposures similar to adults receiving BRV 100 mg twice daily (b.i.d.), when using 3 mg/kg b.i.d. for weight < 10 kg, 2.5 mg/kg b.i.d. for weight ≥ 10 kg and < 20 kg, and 2 mg/kg b.i.d. for weight ≥ 20 kg in children aged 1 month to < 4 years. PK/PD simulations show that maximum BRV response is expected to occur with 2-3 mg/kg b.i.d. dosing of BRV in children aged 1 month to < 4 years, with an effective dose of 1 mg/kg b.i.d. for some participants. CONCLUSION: Development of an adult-pediatric BRV PK/PD model allowed characterization of the exposure-response relationship of BRV in children aged 1 to < 4 years, providing a maximal dose allowance based on weight.

Pharmacokinetics and safety of brivaracetam in neonates with repeated electroencephalographic seizures: A multicenter, open-label, single-arm study.

OBJECTIVE: To evaluate the pharmacokinetics (PK), safety, and tolerability of brivaracetam (BRV) in neonates with repeated electroencephalographic seizures not controlled with previous antiseizure medications (ASMs). METHODS: Phase 2/3, multicenter, open-label, single-arm study (N01349/NCT03325439) in neonates with repeated electroencephalographic seizures (lasting ≥10 s) confirmed by video-electroencephalography, and inadequate seizure control with at least one ASM. A screening period (up to 36 h) was followed by a 48-h evaluation period during which patients received 0.5 mg/kg BRV twice daily (b.i.d) intravenously (IV). Patients who benefitted from BRV (investigator's opinion) could continue 0.5 mg/kg b.i.d (IV or oral solution) in an extension period. Outcomes included plasma concentrations of BRV following the first dose (primary), and incidence of treatment-emergent adverse events (TEAEs). RESULTS: Six patients (median [range] postnatal age: 1.5 [1.0, 6.0] days) received ≥1 dose of BRV. All six patients completed the evaluation period; two entered and completed the extension period. Overall (evaluation and extension periods), three patients received one dose of 0.5 mg/kg BRV and three received more than one dose. The median (range) duration of exposure to BRV (IV and oral solution) was 1.5 (1.0, 29.0) days (n = 6). At 0.5-1, 2-4, and 8-12 h following IV BRV administration, the GeoMean (GeoCV) plasma concentrations of BRV were 0.53 mg/L (15.40% [n = 5]), 0.50 mg/L (28.20% [n = 6]), and 0.34 mg/L (13.20% [n = 5]), respectively. Individual and population BRV PK profiles were estimated, and individual PK parameters were calculated using Bayesian feedback. The observed concentrations were consistent with the predicted PK. Three patients experienced four TEAEs, none of which were considered related to BRV. SIGNIFICANCE: BRV plasma concentrations in neonates were consistent with data in older children receiving BRV oral solution, and with data from adults receiving a nominal IV dose of 25 mg b.i.d. BRV was well tolerated, with no drug-related TEAEs reported. PLAIN LANGUAGE SUMMARY: Few drugs are available to treat seizures in newborn babies. Brivaracetam is approved to treat focal-onset seizures in children and adults in Europe (patients 2 years of age and older) and the United States (patients 1 month of age or older). In this study, six newborns with repeated seizures were treated with intravenous brivaracetam. The study doctors took samples of blood from the newborns and measured the levels of brivaracetam. The concentrations of brivaracetam in the newborns' blood plasma were consistent with data from studies in older children and in adults. No brivaracetam-related medical problems were reported.

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.

Absorption, metabolism and excretion of [(14)C]mirabegron (YM178), a potent and selective ß(3)-adrenoceptor agonist, after oral administration to healthy male volunteers.

The mass balance and metabolite profiles of 2-(2-amino-1,3-thiazol-4-yl)-N-[4-(2-{[(2R)-2-hydroxy-2-phenylethyl]amino}ethyl)[U-(14)C]phenyl]acetamide ([(14)C]mirabegron, YM178), a ß(3)-adrenoceptor agonist for the treatment of overactive bladder, were characterized in four young, healthy, fasted male subjects after a single oral dose of [(14)C]mirabegron (160 mg, 1.85 MBq) in a solution. [(14)C]Mirabegron was rapidly absorbed with a plasma t(max) for mirabegron and total radioactivity of 1.0 and 2.3 h postdose, respectively. Unchanged mirabegron was the most abundant component of radioactivity, accounting for approximately 22% of circulating radioactivity in plasma. Mean recovery in urine and feces amounted to 55 and 34%, respectively. No radioactivity was detected in expired air. The main component of radioactivity in urine was unchanged mirabegron, which accounted for 45% of the excreted radioactivity. A total of 10 metabolites were found in urine. On the basis of the metabolites found in urine, major primary metabolic reactions of mirabegron were estimated to be amide hydrolysis (M5, M16, and M17), accounting for 48% of the identified metabolites in urine, followed by glucuronidation (M11, M12, M13, and M14) and N-dealkylation or oxidation of the secondary amine (M8, M9, and M15), accounting for 34 and 18% of the identified metabolites, respectively. In feces, the radioactivity was recovered almost entirely as the unchanged form. Eight of the metabolites characterized in urine were also observed in plasma. These findings indicate that mirabegron, administered as a solution, is rapidly absorbed after oral administration, circulates in plasma as the unchanged form and metabolites, and is recovered in urine and feces mainly as the unchanged form.

A semiphysiological population model for prediction of the pharmacokinetics of drugs under liver and renal disease conditions.

The application of model-based drug development in special populations becomes increasingly important for clinical trial optimization, mostly by providing a rationale for dose selection and thereby aiding risk-benefit assessment. In this article, a semiphysiological approach is presented, enabling the extrapolation of the pharmacokinetics from healthy subjects to patients with different disease conditions. This semiphysiological approach was applied to solifenacin, using clinical data on total and free plasma and urine concentrations in healthy subjects. The analysis was performed using nonlinear mixed-effects modeling and relied on the use of a general partitioning framework to account for binding to plasma proteins and to nonplasma tissues together with principles from physiology that apply to the main pharmacokinetic process, i.e., bioavailability, distribution, and elimination. Application of these physiology principles allowed quantification of the impact of key physiological parameters (i.e., body composition, glomerular function, liver enzyme capacity, and liver blood flow) on the pharmacokinetics of solifenacin. The prediction of the time course of the drug concentration in liver- and renal-impaired patients only required adjustment of the physiological parameters that are known to change upon liver and renal dysfunction without modifying the pharmacokinetic model structure and/or its respective parameter estimates. Visual predictive checks showed that the approach applied was able to adequately predict the pharmacokinetics of solifenacin in liver- and renal-impaired patients. In addition, better insight into the pharmacokinetic properties of solifenacin was obtained. In conclusion, the proposed semiphysiological approach is attractive for prediction of altered pharmacokinetics of compounds influenced by liver and renal disease conditions.

Tamsulosin shows a higher unbound drug fraction in human prostate than in plasma: a basis for uroselectivity?

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: The efficacy-tolerability profile of tamsulosin in patients with benign prostatic hyperplasia (BPH) is assumed to be associated both with the α1-adrenoceptor selectivity profile of the drug and a small peak : trough ratio in the plasma pharmacokinetic (PK) profile. Tamsulosin is highly bound to plasma proteins, notably α1-acid glycoprotein (AGP). This protein is a high-affinity binding protein and AGP plasma concentration was found to influence the therapeutic (unbound) plasma concentrations for high-AGP-binding drugs. WHAT THIS STUDY ADDS: The study actually assessed unbound tamsulosin concentrations in both blood plasma and prostate tissue and reported that the unbound tamsulosin concentrations after multiple dosing in men with BPH, were much higher in prostate than in blood plasma. The assumption is put forward that differential free drug concentrations in prostate and blood plasma may contribute to the relative 'uroselectivity' of tamsulosin. AIM: The aim of this small patient study was to investigate tamsulosin concentrations in prostate and plasma samples in order to identify potential differences in the pharmacokinetics (PK) in plasma and prostate contributing to its pharmacodynamic activity profile in patients. METHODS: Forty-one patients with benign prostatic hyperplasia (BPH) scheduled for open prostatectomy were given tamsulosin 0.4 mg for 6-21 days in order to reach steady-state PK. Patients were randomized over four groups to allow collection of plasma and tissue samples at different time points after last dose administration. Samples were collected during surgery and assayed for tamsulosin HCl. The free fraction (f(u)) of tamsulosin was determined by ultracentrifugation of plasma and prostate tissue spiked with (14)C-tamsulosin. RESULTS: C(max) in plasma at 4.4 h for total tamsulosin was 15.2 ng ml(-1) and AUC(0,24 h) was 282 ng ml(-1) h, while for prostate C(max) at 11.4 h post-dose was 5.4 ng ml(-1) and AUC(0,24 h) was 120 ng ml(-1) h. AUC(0,24 h) for total tamsulosin in prostate was 43% of the plasma AUC(0,24 h). f(u) was 0.4 % for plasma and 59.1% for prostate. Therefore calculated on unbound tamsulosin, a ratio of 63 resulted for prostate vs. plasma C(max) concentrations. CONCLUSIONS: These data indicate that in patients with confirmed BPH the amount of tamsulosin freely available in the target tissue (prostate) is much higher than in plasma.

Specific pharmacokinetic aspects of the urinary tract.

This chapter reviews the evidence for "specific" pharmacokinetics playing a role in currently marketed drugs intended to treat lower urinary tract (LUT) symptoms. Principles of drug targeting include intrinsic properties of drugs or organs as well as drug formulations to modify drug release or to create confinement of drug presence. Prodrugs and specific formulations to deliver high drug concentrations at the site(s) of action as well as other ways to manipulate drug distribution to achieve enrichment in target tissues are considered. In overactive bladder (OAB), specific formulations for oxybutynin have been introduced to reduce the level of side effects of the active drug. Extended release tablet formulations and a topical gel formulation have been introduced, with efficacy similar to immediate release (IR) tablets, but with a reduction in anticholinergic adverse effects. However, these modifications have not led to outstanding performance parameters compared to other anticholinergic drugs marketed as IR formulations. Urinary excretion is discussed as potential mechanism for targeting LUT symptoms, but no strong indications appear to exist that this mechanism would contribute for currently available drugs. Intravesical administration of drugs is not a preferred option and only considered for drugs like botulinum toxin, where the inconvenient application compensates for a reasonable degree of long-term efficacy in severe refractory OAB. Alpha acid glycoprotein binding is discussed as a potential factor to influence drug tissue distribution, and it is concluded that there is reasonable evidence that for tamsulosin this mechanism is responsible for the difference in free fraction of the drug observed in plasma and prostate, which could contribute to its relative absence of blood pressure effects in patients with LUT symptoms related to benign prostate hyperplasia (LUTS-BPH). The principle of irreversible inhibition of type II 5α-reductase as a tool to develop drugs to reduce prostatic levels of dihydrotestosterone is employed by both dutasteride and finasteride for treatment of LUTS-BPH. Of the mechanisms discussed, the principles employed for the 5α-reductase blockers and tamsulosin in this respect can be considered relatively specific for its urological indication.

An example of optimal phase II design for exposure response modelling.

This paper presents an example of how optimal design methodology was used to help design a phase II clinical study. The planned analysis would relate the clinical endpoint to exposure (measured via the area under the curve (AUC)), rather than dose. Optimal design methodology was used to compare a number of candidate phase II designs, and an algorithm for finding optimal designs was employed. The sigmoidal E(max) with baseline (E0) model was used to relate the clinical endpoint to individual subject AUCs, and the primary metrics were D optimality and the standard error (SE) of the AUC required to yield a clinically relevant change in the clinical endpoint. The performance of the candidate designs were compared across four different 'true' exposure response relationships (determined from the analysis of an earlier proof of concept (PoC) study). The results suggested the total sample size should be increased from the planned 540 individuals, and that the optimal design with 700 individuals would be equivalent to 812 individuals with the reference design (a 16% gain). The performance with this design was considered acceptable, although all designs performed poorly if the true exposure response relationship was very flat. This work allowed a prospective assessment of the likely performance and precision from the exposure response modelling prior to the start of the phase II study, and hence allowed the design to be revised to ensure the subsequent analysis would be of most value.

Pharmacokinetics of solifenacin in pediatric populations with overactive bladder or neurogenic detrusor overactivity.

The aim of this investigation was to characterize and compare the pharmacokinetics (PK) of the antimuscarinic drug solifenacin in pediatric patients with overactive bladder (OAB) or neurogenic detrusor overactivity (NDO) utilizing data from three phase III trials. LION was a placebo-controlled, 12-week trial in children (5-<12 years) and adolescents (12-<18 years) with OAB. MONKEY and MARMOSET were open-label, 52-week trials in children and adolescents or younger children (6 months-<5 years), respectively, with NDO. During the trials, solifenacin doses could be titrated to weight-adjusted pediatric equivalent doses (PEDs) of 2.5, 5, 7.5, or 10 mg day-1 . Nonlinear mixed effects modeling was used to develop population PK models to characterize the PK in patients with either OAB or NDO. Overall, 194 children and adolescents received solifenacin. At the time of PK sampling, the majority (119/164 [72.6%] patients) were receiving PED10 once daily. All population models included first-order oral absorption, a lag time, and interindividual variability. PK analysis showed that apparent clearance was similar in both patient populations. Mean apparent oral plasma clearance (CL/F), apparent volume of distribution during the terminal phase (Vz /F), and terminal half-life (t1/2 ) were higher in adolescents than in children, but median time to maximum plasma concentration (tmax ) was similar. Dose-normalized exposure results were similar for both younger and older patients with OAB or NDO. In conclusion, population PK modeling was used to successfully characterize solifenacin PK in pediatric patients with OAB or NDO. Similar solifenacin PK characteristics were observed in both populations.

Safety, Pharmacokinetics, and Pharmacodynamics of ASP3662, a Novel 11ß-Hydroxysteroid Dehydrogenase Type 1 Inhibitor, in Healthy Young and Elderly Subjects.

Inhibition of the enzyme 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) represents a potential mechanism for improving pain conditions. ASP3662 is a potent and selective inhibitor of 11ß-HSD1. Two phase I clinical studies were conducted to assess the safety, tolerability, pharmacokinetics (PKs), and pharmacodynamics (PDs) of single and multiple ascending doses of ASP3662 in healthy young and elderly non-Japanese and young Japanese subjects. Nonlinear, more than dose-proportional PKs were observed for ASP3662 after single-dose administration, particularly at lower doses (≤ 6 mg); the PKs at steady state were dose proportional, although the time to ASP3662 steady state was dose dependent at lower doses (≤ 2 mg). Similar PKs were observed among young Japanese, young non-Japanese, and elderly non-Japanese subjects. Specific inhibition of 11ß-HSD1 occurred after both single and multiple doses of ASP3662. A marked dissociation between PKs and PDs was observed after single but not multiple doses of ASP3662. ASP3662 was generally safe and well tolerated.

Validation of LC-MS/MS methods for the determination of mirabegron and eight metabolites in human plasma in a paediatric population.

Mirabegron is the first registered ß3-adrenoceptor agonist for treatment of overactive bladder as an alternative to antimuscarinics. Previously four liquid chromatography-tandem mass spectrometry assays were published to determine mirabegron and eight metabolites (M5, M8, M11-M16) in human plasma. In order to support paediatric development, the assays were further optimized to reduce the required blood volume and increase the sensitivity. The assays were miniaturized by using 96-well supported liquid extraction plates (mirabegron, M5, M16) or 96-well mixed-mode cation exchange solid phase extraction plates (M8, M11-M15) and a more sensitive MS-system was used. For the analytes, up to fivefold increase in assay sensitivity was achieved. The required blood sample volume was reduced from 10 to 2 mL for each timepoint. Validation demonstrated that the assays were accurate, precise and selective in the determination of mirabegron and metabolites. The assays were successfully applied to evaluate the pharmacokinetics of mirabegron in a paediatric population.

The effect of fluvoxamine on the pharmacokinetics, safety, and tolerability of ramosetron in healthy subjects.

OBJECTIVE: To investigate the effects of multiple doses of fluvoxamine on the pharmacokinetics, safety, and tolerability of a single oral 10-mug dose of ramosetron. METHODS: This was a single-center, open, one-sequence cross-over study. On Day 1, healthy male and female subjects were administered a single dose of 10 mug ramosetron. Dosing of fluvoxamine started with an initial morning dose of 50 mg on Day 3, followed by a twice daily (12-h interval) dosing of 50 mg on Days 4-12. The morning dose on Day 11 was administered in combination with a single dose of 10 mug ramosetron. RESULTS: Co-administration of fluvoxamine with ramosetron resulted in an increase in the C(max) and AUC(0-inf) of ramosetron by 1.42-fold (90% CI 1.35-1.49) and 2.78-fold (90% CI 2.53-3.05), respectively. CONCLUSION: Co-administration of the CYP1A2 inhibitor fluvoxamine with ramosetron resulted in an interaction. However, the safety data collected during the study do not indicate that this interaction will cause any major safety concerns.

Prediction of human CNS pharmacokinetics using a physiologically-based pharmacokinetic modeling approach.

Knowledge of drug concentration-time profiles at the central nervous system (CNS) target-site is critically important for rational development of CNS targeted drugs. Our aim was to translate a recently published comprehensive CNS physiologically-based pharmacokinetic (PBPK) model from rat to human, and to predict drug concentration-time profiles in multiple CNS compartments on available human data of four drugs (acetaminophen, oxycodone, morphine and phenytoin). Values of the system-specific parameters in the rat CNS PBPK model were replaced by corresponding human values. The contribution of active transporters for the four selected drugs was scaled based on differences in expression of the pertinent transporters in both species. Model predictions were evaluated with available pharmacokinetic (PK) data in human brain extracellular fluid and/or cerebrospinal fluid, obtained under physiologically healthy CNS conditions (acetaminophen, oxycodone, and morphine) and under pathophysiological CNS conditions where CNS physiology could be affected (acetaminophen, morphine and phenytoin). The human CNS PBPK model could successfully predict their concentration-time profiles in multiple human CNS compartments in physiological CNS conditions within a 1.6-fold error. Furthermore, the model allowed investigation of the potential underlying mechanisms that can explain differences in CNS PK associated with pathophysiological changes. This analysis supports the relevance of the developed model to allow more effective selection of CNS drug candidates since it enables the prediction of CNS target-site concentrations in humans, which are essential for drug development and patient treatment.

Pharmacokinetic Interactions Between Mirabegron and Metformin, Warfarin, Digoxin or Combined Oral Contraceptives.

BACKGROUND AND OBJECTIVES: Mirabeg ron is a selective ß3-adrenoceptor agonist approved for the treatment of overactive bladder (OAB). Four phase 1 studies were conducted in healthy subjects to evaluate the potential for pharmacokinetic interactions between mirabegron and metformin, warfarin, digoxin, or a combination oral contraceptive (COC). METHODS: Thirty-two male subjects received metformin (500 mg twice daily) or mirabegron (160 mg once daily) alone, in combination or with placebo. Twenty-four male and female subjects received single doses of warfarin (25 mg) alone and in combination with mirabegron (100 mg once daily). Twenty-five male and female subjects were administered digoxin (0.25 mg) alone and in combination with mirabegron (100 mg once daily). Thirty female subjects received low-dose COC containing ethinylestradiol (EE)/levonorgestrel (LNG) (30/150 µg once daily) in combination with mirabegron (100 mg once daily) or placebo. Pharmacokinetic parameters were determined by non-compartmental methods. Absence of a Pharmacokinetic interaction was concluded if the 90 % confidence intervals (CI) of geometric least-squares means ratio of area under the curve (AUC) and maximum concentration (C max) were contained within the standard 80-125 % no-effect boundaries. The effect of mirabegron on warfarin International Normalized Ratio (INR) was also assessed. RESULTS: Mirabegron increased digoxin AUC and Cmax by 27 and 29 %, respectively, indicating that mirabegron is a weak inhibitor of P-glycoprotein (P-gp) in vivo. Co-administration of mirabegron did not affect the pharmacokinetics of metformin, warfarin, EE and LNG, or warfarin INR, except for a slight extension of the 90 % CI for the C max ratio for metformin (lower limit 79 %). Metformin decreased mirabegron AUC and C max by 21 %. Most treatment-emergent adverse events were mild, and all resolved by study end. CONCLUSIONS: No dose adjustment of either drug is required when mirabegron is administered concomitantly with metformin, warfarin or COC. Patients receiving mirabegron with digoxin may require additional monitoring of digoxin concentrations with dose adjustments where necessary, due to its narrow therapeutic index.

Predicting Drug Concentration-Time Profiles in Multiple CNS Compartments Using a Comprehensive Physiologically-Based Pharmacokinetic Model.

Drug development targeting the central nervous system (CNS) is challenging due to poor predictability of drug concentrations in various CNS compartments. We developed a generic physiologically based pharmacokinetic (PBPK) model for prediction of drug concentrations in physiologically relevant CNS compartments. System-specific and drug-specific model parameters were derived from literature and in silico predictions. The model was validated using detailed concentration-time profiles from 10 drugs in rat plasma, brain extracellular fluid, 2 cerebrospinal fluid sites, and total brain tissue. These drugs, all small molecules, were selected to cover a wide range of physicochemical properties. The concentration-time profiles for these drugs were adequately predicted across the CNS compartments (symmetric mean absolute percentage error for the model prediction was <91%). In conclusion, the developed PBPK model can be used to predict temporal concentration profiles of drugs in multiple relevant CNS compartments, which we consider valuable information for efficient CNS drug development.