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Background: Eslicarbazepine acetate (Zebenix®) is a voltage-gated sodium channel blocker approved in 2009 by the European Medicines Agency as adjunctive therapy in adults with partial-onset seizures, with or without secondary generalization.Objectives: The objectives of the current population pharmacokinetic (PK) and PK/pharmacodynamic analyses were to characterize the population PK of eslicarbazepine (the main active metabolite of eslicarbazepine acetate), to evaluate the influence of patient factors and concomitant antiepileptic drugs (AEDs) on the PK variability of eslicarbazepine, to assess the effect of eslicarbazepine acetate on the PK of concomitant AEDs and to investigate the relationship between eslicarbazepine systemic exposure and eslicarbazepine acetate antiepileptic activity in patients with partial-onset seizures uncontrolled with one to three AEDs.Methods: Sparse plasma concentrations of eslicarbazepine and concomitant AEDs, along with efficacy data, were obtained from 641 patients enrolled in eslicarbazepine acetate phase III studies. Data were analysed using nonlinear mixed-effect modelling methods. Most analyses used a model using log-transformed data from trough concentration (minimum steady-state plasma concentration during a dosage interval [C(min,ss)]). The model estimated the apparent total body clearance from plasma (CL/F), which is sufficient to predict average plasma concentrations at steady state (C(av,ss)). After the final model was validated, individual concentrations at steady state were predicted, and exposure parameters (area under the plasma concentration-time curve over 24 hours, C(min,ss) and C(av,ss)) for a one-compartmental model with first-order elimination were calculated.Results: Eslicarbazepine CL/F was affected by bodyweight, dose of carbamazepine (D(CAR)) and co-administration of barbiturates or phenytoin (AED(PB)), as predicted by the equation CL/F = (2.36 + 0.00149 • D(CAR) + 1.41 • AED(PB)) • (weight/70)0.75, which means that CL/F is 2.36 L/h for a subject with a bodyweight of 70 kg and without concomitant carbamazepine and barbiturates/phenytoin. Concomitant use of lamotrigine, valproic acid, topiramate, gabapentin, clobazam and levetiracetam showed no effect on the exposure to eslicarbazepine. Inter-individual variability of eslicarbazepine CL/F was 44% and the residual error (intra-subject variability) was proportional to the log of concentrations, with a coefficient of variation of 6%. Age, ethnicity, sex and creatinine clearance did not affect eslicarbazepine CL/F. Eslicarbazepine acetate did not affect the CL/F of clobazam, gabapentin, phenytoin, phenobarbital, levetiracetam and valproic acid. Eslicarbazepine acetate slightly increased the CL/F of carbamazepine (up to 14%), lamotrigine (up to 12%) and topiramate (up to 16%). The antiepileptic effect of eslicarbazepine acetate, as assessed by a decrease in seizure frequency, increased with the increase of eslicarbazepine acetate dose and eslicarbazepine concentrations. The concomitant administration of other AEDs did not affect the eslicarbazepine acetate exposure-response relationship.Conclusions: The magnitude of the effect of eslicarbazepine acetate on the CL/F of the concomitant AEDs assessed appears to be not clinically relevant and does not justify the need for dose adjustment in most patients. A continuous dose-response relationship was observed between eslicarbazepine concentrations and seizure frequency reduction, which was not affected by concomitant AEDs. [ABSTRACT FROM AUTHOR]

The authors studied the pharmacokinetics of sumatriptan nasal spray after a single dose in children migraineurs outside of migraine attack. Seventeen subjects (9 females) ages 6 to 11 years were given one dose of sumatriptan nasal spray based on age and weight; children 6 to 8 years of age weighing 25 kg and children ages 9 to 11 years of age weighing 40 kg received 20 mg (n = 4). Plasma sumatriptan concentrations were determined in serial blood samples obtained over 8 hours. Pharmacokinetic analysis included both noncompartmental and population modeling methods. The pharmacokinetic parameter estimates (geometric mean [95% confidence interval]) following 5, 10, and 20 mg sumatriptan were, respectively, as follows: maximum concentration = 8.1 ng/mL (3.6-18.4), 10.8 ng/mL (7.7-15.4), and 12.3 ng/mL (7.6-19.9); half-life = 1.4 hours (1.2-1.8), 1.7 hours (1.4-2.0), and 1.7 hours (1.3-2.3); and AUC = 27.8 ng*h/mL (9.7-79.8), 42.4 ng*h/mL (30.6-58.8), and 49.2 ng*h/mL (32.9-73.7). The median time to maximum concentration for all groups was 2 hours. Population pharmacokinetic modeling included pooled data from this study and from an adolescent study (n = 16). Clearance (CL/F) was 197 L/h for a 30-kg child with between-subject variability of 28%, and the volume of distribution was 751 L, normalized for an 11-year-old child with variability of 43%. The covariate analysis showed that volume increases with age and clearance increases with body size. The absorption was complex, often displaying double-peak plasma concentrations, with a rapid absorption phase and a delayed and rate-limited absorption phase. The dosing scheme based on age and weight resulted in maximal concentrations (C(max)) and systemic exposure (AUC) that were comparable to those observed in adolescents and adults treated with 20 mg. The age- and weight-adjusted dosing scheme appears to an appropriate initial dosing regimen for children with migraine headache. Appropriate safety and efficacy trials will need to be completed in children prior to recommending its use in children. [ABSTRACT FROM AUTHOR]

Sumatriptan is a potent and selective vascular 5-HT1 receptor agonist effective for the treatment of migraine. In adults, intranasal sumatriptan is well absorbed and tolerated. The authors evaluated the pharmacokinetics and tolerability of a single dose of 20 mg intranasal sumatriptan in healthy adolescent migraineurs ages 12 to 17 years, administered outside of migraine attack. Serum sumatriptan levels were measured by high-performance liquid chromatography (HPLC) with electrochemical detection in serial samples collected over 8 hours. Physical exam, vital signs, clinical laboratory tests, and electrocardiogram measurements were monitored to assess safety and tolerability. A total of 16 subjects (10 males and 6 females) had pharmacokinetic data that could be analyzed, 2 withdrew from the study 30 and 60 minutes after dosing following the loss of venous access for blood sampling, and a bioanalysis failure resulted in loss of data from 3 subjects. Noncompartmental pharmacokinetic parameters (geometric mean and 95% confidence interval) for the remaining 16 subjects were as follows: Cmax was 13.9 (11.0, 17.6) ng/mL, AUC infinity was 57.3 (47.6, 69.0) ng/mL.h, and t1/2 was 2.0 (1.8, 2.3) hours. Population pharmacokinetic analysis for all subjects (n = 21) showed that clearance and volume of distribution increase slightly with age and body size, but the changes were minimal and would not warrant dose adjustment: CL/F was 316 L (coefficient of variance [CV] = 25%) and Vd/F was 1070 L (CV = 46%). Sumatriptan was well tolerated with only minor adverse events reported, which all resolved spontaneously. The pharmacokinetic parameters in these adolescent subjects were similar to those previously reported in adults, suggesting that adolescents should be dosed similar to adults. [ABSTRACT FROM AUTHOR]

A substantial proportion of migraine patients have gastric stasis and suffer severe nausea and/or vomiting during their migraine attack. This may lead to erratic absorption from the gastrointestinal tract and make oral treatment unsatisfactory. For such patients, an intranasal formulation may be advantageous. Sumatriptan is a potent serotonin 5HT(1B/1D) agonist widely used in the treatment of migraine; the effectiveness of the intranasal formulation (20mg) has been well established in several clinical studies. This article reviews the pharmacokinetics of intranasal sumatriptan and includes comparisons with oral and subcutaneous administration. After intranasal administration, sumatriptan is directly and rapidly absorbed, with 60% of the maximum plasma concentration (C(max)) occurring at 30 minutes after administration of a single 20mg dose. Following intranasal administration, approximately 10% more sumatriptan is absorbed probably via the nasal mucosa when compared with oral administration. Mean C(max) after a 20mg intranasal dose is approximately 13.1 to 14.4 ng/mL, with median time to C(max) approximately 1 to 1.75 hours. When given as a single dose, intranasal sumatriptan displays dose proportionality in its extent of absorption and C(max) over the dose range 5 to 10mg, but not between 5 and 20mg for C(max). The elimination phase half-life is approximately 2 hours, consistent with administration by other routes. Sumatriptan is metabolised by monoamine oxidase (MAO; predominantly the A isozyme, MAO-A) to an inactive metabolite. Coadministration with a MAO-A inhibitor, moclobemide, leads to a significant increase in sumatriptan plasma concentrations and is contraindicated. Single-dose pharmacokinetics in paediatric and adolescent patients following intranasal sumatriptan were studied to determine the effect of changes in nasal morphology during growth, and of body size, on pharmacokinetic parameters. The pharmacokinetic profile observed in adults was maintained in the adolescent population; generally, factors such as age, bodyweight or height did not significantly affect the pharmacokinetics. In children below 12 years, C(max) is comparable to that seen in adolescents and adults, but total exposure (area under the concentration-time curve from zero to infinity) was lower in children compared with older patients, especially in younger children treated with 5mg. Clinical experience suggests that intranasal sumatriptan has some advantages over the tablet (more rapid onset of effect and use in patients with gastrointestinal complaints) or subcutaneous (noninvasive and fewer adverse events) formulations. [ABSTRACT FROM AUTHOR]

Naratriptan is a novel 5-HT1 agonist developed to treat acute migraine. The study objective was to characterize the pharmacokinetics of oral naratriptan in adolescent migraine patients outside a migraine attack. Subjects received a single 2.5 mg naratriptan tablet. Serial serum samples for naratriptan concentrations were collected over 24 hours. Blood pressure, pulse rate, and 12-lead ECG were recorded at baseline and at regular intervals after dosing. Seven patients--3 males and 4 females, 12 to 16 years of age--received drug and completed the study. The geometric mean and 95% confidence interval maximum concentration (Cmax) was 8.0 ng/mL (5.9-10.7), elimination half-life (t1/2) was 4.9 hours (4.5-5.4), area under the concentration-time curve (AUC) was 74.6 ng.h/mL (56.6-98.2), and apparent total clearance (Cl/F) was 558.8 mL/min (424.3-735.9). The median time to maximal concentration (tmax) was 4 hours, with a range of 1.5 to 4. Blood pressure, pulse rate, and ECG parameters did not change significantly from baseline. No serious adverse events or subject withdrawal after drug administration occurred. Oral naratriptan pharmacokinetic parameters in adolescents were similar to values reported in adults. Naratriptan doses for adolescents older than 12 years of age would be expected to be similar to adult doses. [ABSTRACT FROM AUTHOR]

Aims: The pharmacokinetics (PK) of a triple-secured fibrinogen concentrate (FC) was assessed in patients ≥40 kg by noncompartmental analysis over a period of 14 days with multiple blood samples. Limited PK time point assessments in children lead to consideration of using Bayesian estimation for paediatric data. The objectives were (i) to define the population PK of FC in patients with afibrinogenaemia; (ii) to detect age- and body weight-related differences and consequences for dose adjustment., Methods: A population PK model was built using plasma fibrinogen activity data collected in 31 patients aged 1 to 48 years who had participated in a single-dose PK study with FC 0.06 g kg -1 ., Results: A 1-compartment model with allometric scaling accounting for body weight was found to best describe the kinetics of FC. Addition of age and sex as covariates did not improve the model. Incremental in vivo recovery assessed at the end of infusion with the predicted maximal concentrations was lower, weight-adjusted clearance was higher, and fibrinogen elimination half-life was shorter in patients <40 kg than patients ≥40 kg. Interpatient variability was similar in both groups., Conclusion: Dosing in patients ≥40 kg based on the previous empirical finding using noncompartmental analysis where FC 1 g kg -1 raises the plasma fibrinogen activity by 23 g L -1 was confirmed. In patients <40 kg, (covering the age range from birth up to about 12 years old) FC 1 g kg -1 raises the plasma fibrinogen by 19 g L -1 . Dosing should be adapted accordingly unless therapy is individualized., (© 2019 LFB Biotechnologies. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Purpose: This paper describes the pharmacokinetic/pharmacodynamic modelling of clazosentan in patients with aneurysmal subarachnoid haemorrhage (aSAH), and the impact of collecting data in an intensive care unit (ICU) setting. Factors influencing data quality, analysis, and interpretation are provided with recommendations for future clinical studies in ICU settings., Methods: CONSCIOUS-2 was a phase III study involving 1,157 patients with aSAH. Secured by surgical clipping, patients were infused with clazosentan or placebo for up to 14 days post-aSAH. Clazosentan exposure relationships with vital signs, QT intervals, and AST/ALT values as well as efficacy and safety endpoints were characterised using population PK/PD and logistic regression models., Results: Clazosentan clearance was influenced by age, sex, Asian origin, and disease status at baseline, and increased with time. Volume of distribution showed a sex difference. Exposure had no relationship with any efficacy endpoint or ALT/AST values, but was related to the increasing probability of lung complications. Blood pressure decreased proportionally to clazosentan concentrations, and the presence of clazosentan was associated with QT interval increases. Implausible values in the concentration data reflect the specific ICU challenges, possibly arising from PK sampling from the infusion arm or haemodilution., Conclusions: Population PK/PD modelling of CONCIOUS-2 data provided clinically relevant knowledge about various effects of clazosentan in the aSAH patient population in a real clinical setting. The quality of data and analyses could be improved by the collection of additional data and stricter training of study personnel. Differences in clinical practice between sites and geographical regions are more challenging to overcome.

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

Rufinamide is a new, orally active antiepileptic drug (AED), which has been found to be effective in the treatment of partial seizures and drop attacks associated with the Lennox-Gastaut syndrome. When taken with food, rufinamide is relatively well absorbed in the lower dose range, with approximately dose-proportional plasma concentrations up to 1,600 mg/day, but less than dose-proportional plasma concentrations at higher doses due to reduced oral bioavailability. Rufinamide is not extensively bound to plasma proteins. During repeated dosing, steady state is reached within 2 days, consistent with its elimination half-life of 6-10 h. The apparent volume of distribution (V(d)/F) and apparent oral clearance (CL/F) are related to body size, the best predictor being body surface area. Rufinamide is not a substrate of cytochrome P450 (CYP450) enzymes and is extensively metabolized via hydrolysis by carboxylesterases to a pharmacologically inactive carboxylic acid derivative, which is excreted in the urine. Rufinamide pharmacokinetics are not affected by impaired renal function. Potential differences in rufinamide pharmacokinetics between children and adults have not been investigated systematically in formal studies. Although population pharmacokinetic modeling suggests that in the absence of interacting comedication rufinamide CL/F may be higher in children than in adults, a meaningful comparison of data across age groups is complicated by age-related differences in doses and in proportion of patients receiving drugs known to increase or to decrease rufinamide CL/F. A study investigating the effect of rufinamide on the pharmacokinetics of the CYP3A4 substrate triazolam and an oral contraceptive interaction study showed that rufinamide has some enzyme-inducing potential in man. Findings from population pharmacokinetic modeling indicate that rufinamide does not modify the CL/F of topiramate or valproic acid, but may slightly increase the CL/F of carbamazepine and lamotrigine and slightly decrease the CL/F of phenobarbital and phenytoin (all predicted changes were <20%). These changes in the pharmacokinetics of associated AEDs are unlikely to make it necessary to change the dosages of these AEDs given concomitantly with rufinamide, with the exception that consideration should be given to reducing the dose of phenytoin. Based on population pharmacokinetic modeling, lamotrigine, topiramate, or benzodiazepines do not affect the pharmacokinetics of rufinamide, but valproic acid may increase plasma rufinamide concentrations, especially in children in whom plasma rufinamide concentrations could be increased substantially. Conversely, comedication with carbamazepine, vigabatrin, phenytoin, phenobarbital, and primidone was associated with a slight-to-moderate decrease in plasma rufinamide concentrations, ranging from a minimum of -13.7% in female children comedicated with vigabatrin to a maximum of -46.3% in female adults comedicated with phenytoin, phenobarbital, or primidone. In population modeling using data from placebo-controlled trials, a positive correlation has been identified between reduction in seizure frequency and steady-state plasma rufinamide concentrations. The probability of adverse effects also appears to be concentration-related.

WST11, a novel generation of photo sensitizers to be used for vascular-targeted phototherapy (VTP), is effective at short interval between injection and illumination and it is expected to enable selective destruction of neovasculature with minimal side effects or skin photo toxicity. This study was conducted to evaluate the clinical and laboratory safety, tolerability and pharmacokinetic profile of WST11 given as a single intravenous administration (1.25, 2.5, 5, 7.5, 10, or 15 mg/kg) during an escalating dose study in healthy male subjects. This article describes WST11 population pharmacokinetic modeling and simulations performed to optimize the IV infusion-dosing regimen in combination with illumination, the target PK profile being plateau concentrations during approximately 30 min. The study included 42 healthy male subjects, administered 1.25, 2.5, 5, 7.5, 10, or 15 mg/kg as a 10-min IV infusion. A population pharmacokinetic model was developed using nonlinear mixed effects modeling (NONMEM). Monte Carlo simulations of the population PK dataset (NONMEM) were performed to select series of dosing regimen which would result in a plateau of concentration lasting at least 30 min and allow laser illumination. A two-compartment model with nonlinear elimination best described the data. No demographic factor was shown to affect the WST11 pharmacokinetics. The clearance was shown to decreases with the dose administered, ranging from 6 L/h (dose of 79 mg) to 2 L/h (dose of 1110 mg). The duration of the infusion was estimated at 12 min. The volume of distribution of the central compartment was 3 L and the volume of the peripheral compartment was 1.15 L. The apparent inter-compartmental clearance was 0.137 L/h. The between subjects variability on clearance and on volume was low. Residual variability was moderate with a CV of 21%. Due to the dose effect on clearance and the rapid elimination, simulations showed that different dosing inputs are necessary: for 5 and 10 mg/kg BW, a sufficiently good dosing scenario is to administer 80% of the dose over 5 min, 15% over 10 min and the remaining 5% over 10 min. For lower doses, the sequence 70% in 5 min/20% in 10 min/10% in 10 min is preferable. The pharmacokinetic profile of WST11 by IV administration would allow a treatment by laser illumination in good clinical conditions using controlled infusions. The study results do not indicate that the dose should be adjusted for body size. The only factor that determines the drug input profile is the dose level, since the elimination half-life decreases when the dose administered increases. The use of the population PK model for simulations has shown that, at dose level of 5 mg/kg or more, a loading dose of 80% dose given over 5 min followed by 15% of dose during 10 min and remained dose to give over 10 min would result in a favorable PK profile., ((c) 2007 Wiley-Liss, Inc.)

Objective: To develop a population pharmacokinetic model and to determine the covariates affecting the pharmacokinetics of onercept (recombinant human tumour necrosis factor [TNF] receptor-1) in healthy subjects., Subjects and Methods: Onercept pharmacokinetics data were obtained from 48 healthy male and female subjects (four phase I studies). In study A, 12 subjects received increasing single intravenous doses of onercept either 5 and 50mg or 15 and 150mg. In study B, 12 subjects received single intravenous, subcutaneous and intramuscular doses of onercept 50mg. Study C investigated the pharmacokinetics of onercept following repeat subcutaneous administration of six doses of 50mg every 48 hours in 12 subjects. Study D investigated the pharmacokinetics of onercept following repeat subcutaneous administration of six doses of 100mg and 150mg over 2 weeks in 12 subjects. Nonlinear mixed-effects modelling software NONMEM was used to build a base model, while the final model was determined after selection of the covariates., Results: The disposition of onercept was described using a two-compartment model with two absorption processes (a first-order followed by a zero-order) and included a constant baseline, accounting for the endogenous TNF receptor-1 levels. Slow absorption of onercept following subcutaneous and intramuscular administration was observed and suggested that absorption was the rate-limiting process. The population mean (coefficient of variation %) values for clearance, absorption rate constant, volume of distribution of the central compartment, bioavailability of onercept and baseline TNF receptor-1 levels were 4.03 L/h (13.3%), 0.04 h-1 (29.1%), 4.42L (6.2%), 0.90 (23.8%) and 1.68 microg/L (20.4%), respectively. The only significant covariates were found to be dose (which affected clearance), and day (which affected absorption rate constant); however, the effects were small (10-15%) and are unlikely to be of any clinical relevance., Conclusion: The proposed population pharmacokinetic model characterises well the overall pharmacokinetic profile of onercept after intramuscular, subcutaneous and intravenous administration in healthy subjects. The pharmacokinetics of onercept showed modest intersubject variability.

Objective: This paper describes a developed pharmacokinetic model for the estimation of valproic acid (VPA) clearance (CL) calculated from routine clinical data taken from Egyptian epileptic patients., Methods: Retrospective clinical data from 81 adult and paediatric epileptic patients with one trough VPA serum concentration per patient were analysed using NONMEM to estimate drug CL and determine the influence of different covariates. A qualification group of 20 epileptic children (3-13 years old) was used to evaluate the final model., Results: The population CL as estimated by base model (no covariates) was 0.581 l h(-1) with inter-individual variability (C.V. %) of 17.4% and SD of residual error was 6.82 mg l(-1). Univariate selection and backward deletion of different covariates led to the development of the final regression model of CL as follows: CL(Lh-1) = 0.101 + 0.151 * CBZ + 0.000248 * VPADD + 0.0968 * age/20 + 0.0803 * INDI, in which CBZ indicates co-administration of carbamazepine, VPADD the daily dose of VPA and INDI uncontrolled epilepsy. The between-subject variability in CL was 23.6% while the standard deviation of the residual error was 5.24 mg l(-1). The model predictions in the qualification group were found to have no bias and satisfactory precision., Conclusion: The population pharmacokinetic model for VPA could be used for a priori recommendation and dose optimisation of that drug in the Egyptian population of epileptic patients.

Purpose: The overall aim of the present study was to investigate retrospectively the feasibility and utility of model-based clinical trial simulation as applied to the clinical development of naratriptan with effect measured on a categorical scale., Methods: A PK-PD model for naratriptan was developed by using information gathered from previous naratriptan and sumatriptan preclinical and clinical trials. The phase IIa naratriptan data were used to check the PK-PD model in its ability to describe future data. A further PK-PD model was developed by using the phase IIa naratriptan data, and a phase IIb trial was designed by simulation with the use of Matlab. The design resulting from clinical trial simulation was compared with that derived by using D-optimal design., Results: The PK-PD model showed reasonable agreement with the data observed in the phase IIa naratriptan clinical trial. Clinical trial simulation resulted in a design with four or five arms at 0 mg, 2.5 and/or 5 mg, 10 mg, and 20 mg, PD measurements to be taken at 0, 2, and 4 or 6 h and at least 150 patients per arm. A sub-D-optimal design resulted in two dosing arms at 0 and 10 mg and PD measurements to be taken at 1 and 2 h., Conclusions: Clinical trial simulation is a useful tool for the quantitative assessment of the influence of the controllable factors and is the only tool for the quantitative assessment of the uncontrollable factors on the power of a clinical trial.

This paper presents and illustrates methodology for specifying, estimating, and evaluating a predictive model for repeated measures time-to-event responses. The illustrative example specifies a model of the antiemetic effect vs. concentration relationship for the 5-HT3 antagonist ondansetron in the human ipecac model for emesis. A key part of this model is a time-dependent log hazard function for emesis that is increased by ipecac administration and decreased by ondansetron concentration. The model is fit using an approximate maximum likelihood method. The data consist of the time free of emeses and, for those individuals with emetic episodes, the time(s) of the episode(s). Model evaluation is accomplished using residual plots adapted to time-to-event data and a "posterior predictive check" wherein observed data statistics are compared to those obtained from data simulated from the fitted model. The ondansetron concentration required to obtain a 50% reduction in the hazard of emesis is estimated to be 1.4 +/- 0.2 ng/ml, and the rate constant for elimination of ipecac-induced hazard is 1.5 +/- 0.2 hr-1.

Sumatriptan is indicated for the treatment of migraine attack and cluster headache; it is currently marketed as a subcutaneous injection, nasal spray, and oral tablet. New formulations are under consideration. The knowledge of sumatriptan absorption, combined with PK/PD information would help the design of more efficient formulations. In this perspective, we attempted to model the absorption of sumatriptan by population PK analysis. Data following administration by the intravenous (i.v.), the subcutaneous (s.c.), and the oral (po) route in healthy subjects were analyzed. A large database with full kinetic profiles was constituted. Sumatriptan was administered to 215 healthy subjects (i.v., s.c., and po) and to 143 migraine sufferers (po). The mean age was 31 years (18-86 years) in healthy subject population and was 38 years (18-65 years) in migraine patients. The mean weights were 74 kg (54-104 kg) and 66 kg (38-136 kg) in healthy subjects and migraine patients, respectively, and the mean heights were 176 cm (157-193 cm) and 164 cm (152-183 cm) in healthy subjects and migraine patients, respectively. A NONMEN analysis was performed using a two-compartment disposition model. Oral absorption was modeled with a first-order input followed by a zero-order input. Less biased results were obtained using the FOCE method. The total clearance and the distribution volume at steady state were 71.2 L/hr and 94.5 L after i.v. dosing and 68.7 L/hr and 109 L after inclusion of the s.c. and po data. The absorption phase appeared to last for about 5 hr. The interindividual variability of the main PK parameters was low: It was around 20% for the total clearance and around 30% for the distribution volume at steady state. Although significant, the combination of age and height on clearance did not decrease considerably the interindividual variability of this parameter (decrease of 2.2%); nor was it possible to establish clearly if a migraine attack has an effect on drug absorption because of the sampling scheme during absorption. Simulations have shown that it would have been possible to estimate all the PK parameters with a data set reduced to one quarter of its actual number of samples.

Naratriptan is a novel, potent agonist at the 5HT1B/1D receptor. A total of 335 migraine patients were treated in this randomized, double-blind, placebo-controlled, dose-ranging, in-clinic study, to evaluate the efficacy, safety and tolerability of five doses of subcutaneous (sc) naratriptan (0.5, 1, 2.5, 5 or 10 mg) in comparison with sc sumatriptan (6 mg) and placebo in the acute treatment of a moderate/severe migraine attack. Headache relief [reduction of headache severity from moderate or severe (grade 2/3) to mild or none (grade 1/0)] at 1 and 2 h after each dose, was reported by a statistically significantly higher proportion of patients for all doses of sc naratriptan and sc sumatriptan (6 mg) than for placebo. The percentages of patients with headache relief at 2 h post-dose were: naratriptan (0.5 mg) 65%, (1 mg) 75%, (2.5 mg) 83%, (5 mg) 94% and (10 mg) 91%; sumatriptan (6 mg) 89%; placebo 41%, (P < 0.005). The earliest report of a statistically significant difference compared with placebo for the times assessed was with sc naratriptan (10 mg) at 10 min post-dose (P = 0.023). The percentages of patients reporting adverse events were dose-related; sc naratriptan (0.5 mg) 33%, (1 mg) 29%, (2.5 mg) 43%, (5 mg) 59% and (10 mg) 71%; sc sumatriptan 53%; placebo 22%. There were no clinically significant changes in electrocardiogram (ECG), vital signs or laboratory parameters. Systemic exposure increased proportionally to the dose, the absorption of sc naratriptan was rapid (tmax = 10 min) and the half-life was 5 h. In conclusion, sc naratriptan was an effective and well-tolerated acute treatment for migraine. Copyright 1998 Lippincott Williams & Wilkins

Allometric scaling is an empirical examination of the relationships between the pharmacokinetic parameters and size (usually body weight), but it can also involve brain weight for metabolized drug. Through all species, the protein binding of sumatriptan is similar (14-16%), and its metabolic pathway undergoes extensive oxidative deamination involving the monoamine oxidase A isoenzyme. These similarities across species suggested the possible relevance of an allometric analysis. Toxicokinetic data were collected from rats, pregnant rabbits, and dogs in animal pharmacokinetic studies where sumatriptan was administered intravenously to the animals at doses of 5 mg/kg. 0.25 mg/kg, and 1 mg/kg, respectively. Animal data were pooled and analyzed in one step using a mixed effect modeling (population) approach. The kinetic parameters predicted in any species were close to the observed values by species: 77 L/hr vs. 80 L/hr in man for total clearance, 137 L vs. 119 L for distribution volume at steady state. The value of the mixed effect modeling approach compared to the two-step method was demonstrated especially with the possibility of including covariates to describe the status of animal (e.g., pregnancy) in the model. Knowledge of the animal kinetics, dynamics, and metabolism of a drug contributes to optimal and expeditious development. Valuable information for the design of the first-dose-in-man study may emerge from more creative data analysis based on all the information collected during the preclinical and ongoing nonclinical evaluation of a new drug.

Objective: To assess the antihyperglycemic activity of a new peripherally acting alpha 2-adrenergic receptor antagonist, SL 84.0418 in healthy volunteers, Methods: This was a randomized, double-blind crossover study. The effects of 10, 50, and 100 mg SL 84.0418 on blood glucose, plasma insulin, C-peptide, glucagon, epinephrine, and norepinephrine were investigated in comparison with placebo and 5 mg glipizide before and after an oral glucose challenge (75 gm)., Results: Peak blood glucose and area under the blood-glucose curve were dose-dependently reduced by SL 84.0418; the extent of this reduction was similar with 100 mg SL 84.0418 and glipizide. Glipizide but not SL 84.0418 decreased nadir blood glucose. Plasma insulin and C-peptide were increased by glipizide but not by SL 84.0418. Treatments did not modify plasma glucagon. Plasma epinephrine increased during glipizide treatment and plasma norepinephrine increased during treatment with 50 and 100 mg SL 84.0418. Systolic and diastolic blood pressure were moderately enhanced by 50 and 100 mg SL 84.0418. Adverse effects reflecting alpha 2-adrenergic receptor blockade occurred more frequently with 100 mg SL 84.0418. The adverse effect profile of 50 mg SL 84.0418 was not different from that observed with glipizide., Conclusion: The alpha 2-adrenergic receptor antagonist SL 84.0418 dose dependently reduced the increase in blood glucose after glucose load without modification of plasma insulin. It may represent an alternative to sulfonylureas in the treatment of non-insulin-dependent diabetes mellitus. Further studies are needed to assess its efficacy and tolerability in non-insulin-dependent patients.

The antihistaminic activity, clinical safety, and pharmacokinetics of mizolastine (SL 85.0324) were studied in a 5-way, double-blind crossover study of ten healthy volunteers with doses of 1 to 75 mg. Inhibition of the histamine-induced wheal and flare showed clear dose-dependent antihistaminic activity beginning from the 2-mg dose with a maximum attained between 10 and 20 mg. The onset of action was rapid (one hour) and the effect persisted for more than 24 hours after a 10-mg dose or more. Mizolastine was well tolerated at doses up to 75 mg; subjective and objective signs of transient sedative activity were not observed at doses below 30 mg. The pharmacokinetic profile (rapid absorption with Tmax congruent to 1 h and elimination T1/2 of about eight hours) parallels the pharmacodynamic activity. Within the considered dose range, the pharmacokinetics was linear with no saturation phenomena.

The following study explores the possibility that zolpidem, a new hypnotic agent derived from imidopyridine, may induce changes in ventilatory function in normal subjects. The study, conducted double-blind on 16 subjects (eight men and eight women, aged 21 to 33 years) was undertaken in two successive phases: phase A with a cross-over, intended to compare the ventilatory effects of 10 mg oral dose of diazepam with a placebo, and then phase B, with a Latin square design, intended to compare the effects of 10 and 20 mg oral doses of zolpidem with 10 mg oral doses of diazepam and a placebo. Central inspiratory drive was assessed by occlusion pressure (P0.1) and breathing pattern in air and during carbon dioxide rebreathing. Measurements were performed one and three hours after each drug or placebo administration. Zolpidem did not affect tidal volume (Vt), slopes S1, S2 or P0.1, but decreased the duration of the phases of the respiratory cycle ti by 14% (p less than 0.01) and ttot by 15% (p = 0.03) after three hours post dosing without any change in ventilation, Vt/ti or ti/ttot. Nevertheless, these timing changes, although statistically significant, seem to have no clinical relevance to overall ventilation regulation in normal subjects. On the other hand, diazepam slightly changed S2 at three hours post dosing (0.14 +/- 0.07 versus 0.17 +/- 0.10 after the placebo; p = 0.06) without modifying the other parameters.