Population pharmacokinetic characterization of BAY 81-8973, a full-length recombinant factor VIII: lessons learned - importance of including samples with factor VIII levels below the quantitation limit.

INTRODUCTION: The pharmacokinetics (PK), safety and efficacy of BAY 81-8973, a full-length, unmodified, recombinant human factor VIII (FVIII), were evaluated in the LEOPOLD trials. AIM: The aim of this study was to develop a population PK model based on pooled data from the LEOPOLD trials and to investigate the importance of including samples with FVIII levels below the limit of quantitation (BLQ) to estimate half-life. METHODS: The analysis included 1535 PK observations (measured by the chromogenic assay) from 183 male patients with haemophilia A aged 1-61 years from the 3 LEOPOLD trials. The limit of quantitation was 1.5 IU dL-1 for the majority of samples. Population PK models that included or excluded BLQ samples were used for FVIII half-life estimations, and simulations were performed using both estimates to explore the influence on the time below a determined FVIII threshold. RESULTS: In the data set used, approximately 16.5% of samples were BLQ, which is not uncommon for FVIII PK data sets. The structural model to describe the PK of BAY 81-8973 was a two-compartment model similar to that seen for other FVIII products. If BLQ samples were excluded from the model, FVIII half-life estimations were longer compared with a model that included BLQ samples. CONCLUSIONS: It is essential to assess the importance of BLQ samples when performing population PK estimates of half-life for any FVIII product. Exclusion of BLQ data from half-life estimations based on population PK models may result in an overestimation of half-life and underestimation of time under a predetermined FVIII threshold, resulting in potential underdosing of patients.

Neuroprotection after cardiac arrest with 2-iminobiotin: a single center phase IIa study on safety, tolerability, and pharmacokinetics.

Background: Brain injury is a serious problem in patients who survive out-of-hospital cardiac arrest (OHCA). Neuroprotective drugs could reduce hypoxic-ischemic reperfusion injury. The aim of this study was to investigate the safety, tolerability, and pharmacokinetics (PK) of 2-iminobiotin (2-IB), a selective inhibitor of neuronal nitric oxide synthase. Methods: Single-center, open-label dose-escalation study in adult OHCA patients, investigating three 2-IB dosing schedules (targeting an AUC0-24h of 600-1,200 ng*h/m in cohort A, of 2,100-3,300 ng*h/mL in cohort B, and 7,200-8,400 of ng*h/mL in cohort C). Safety was investigated by monitoring vital signs until 15 min after study drug administration and adverse events up to 30 days after admission. Blood sampling for PK analysis was performed. Brain biomarkers and patient outcomes were collected 30 days after OHCA. Results: A total of 21 patients was included, eight in cohort A and B and five in cohort C. No changes in vital signs were observed, and no adverse events related to 2-IB were reported. A two-compartment PK model described data the best. Exposure in group A (dosed on bodyweight) was three times higher than targeted (median AUC0-24h 2,398 ng*h/mL). Renal function was an important covariate; therefore, in cohort B, dosing was performed on eGFR on admission. In cohort B and C, the targeted exposure was met (median AUC0-24h 2,917 and 7,323 ng*h/mL, respectively). Conclusion: The administration of 2-IB to adults after OHCA is feasible and safe. PK can be well predicted with correction for renal function on admission. Efficacy studies with 2-IB after OHCA are needed.

Cost effectiveness of duloxetine compared with venlafaxine-XR in the treatment of major depressive disorder.

PURPOSE: To determine the cost effectiveness of duloxetine, a new serotonin norepinephrine reuptake inhibitor, when compared with venlafaxine-XR in treating major depressive disorder. METHODS: A cost effectiveness analysis, using a decision tree modelled outpatient treatment over 6 months. Analytic perspectives were those of society (all direct and indirect costs) and the Ministry of Health of Ontario (MoH) as payer for all direct costs. Rates of success and dropouts were obtained from a meta-analysis of randomized placebo-controlled trials. Costs were taken from standard lists, adjusted to 2005 Canadian dollars; discounting was not applied. One-way sensitivity analyses were performed on monthly acquisition costs and success rates; Monte-Carlo analysis examined all parameters over 10000 iterations. RESULTS: From both perspectives, outcomes all numerically favoured venlafaxine-XR (Expected success = 53% and 57%; symptom-free days [SFDs] = 52.72 and 57.03 for duloxetine and venlafaxine-XR, respectively). Total expected costs/patient treated were, Can dollar 7081 and Can dollar 6551 (MoH), Can dollar 20987 and Can dollar 19 997 (societal perspective), for duloxetine and venlafaxine-XR, respectively. Expected costs/SFD were Can dollar134 and Can dollar 115 (MoH) and Can dollar 398 and Can dollar 351 (societal viewpoint) for duloxetine and venlafaxine-XR, respectively. Although results were sensitive to changes in success rate within the 95% CI, Monte-Carlo analyses using the ICER (incremental cost effectiveness ratio) as outcome found venlafaxine-XR was dominant in approximately 78% of scenarios in both perspectives. CONCLUSIONS: Differences in pharmacoeconomic outcomes found were modest, but in all cases, favoured venlafaxine-XR over duloxetine. Therefore, a possible advantage may exist at the population level in the treatment of major depressive disorder in Canada. Ultimately, a head to head study of the two drugs would be needed to confirm these findings.

Model-Based Once-Daily Darunavir/Ritonavir Dosing Recommendations in Pediatric HIV-1-Infected Patients Aged ≥3 to <12 Years.

An existing population pharmacokinetic model of darunavir in adults was updated using pediatric data from two studies evaluating weight-based, once-daily dosing of darunavir/ritonavir (ARIEL, NCT00919854 and DIONE, NCT00915655). The model was then used to provide once-daily dosing recommendations for darunavir/ritonavir in pediatric patients aged ≥3 to <12 years. The final model comprised two compartments with first-order absorption and apparent clearance dependent on the concentration of α1-acid glycoprotein. The recommended darunavir/ritonavir once-daily dosing regimens in children aged ≥3 to <12 years are: 35/7 mg/kg from 10 to <15 kg, 600/100 mg from 15 to <30 kg, 675/100 mg from 30 to <40 kg, and 800/100 mg for ≥40 kg. These doses should result in exposures similar to the adult exposure after treatment with darunavir/ritonavir 800/100 mg once daily, while minimizing pill burden and allowing a switch from suspension to tablet(s) as early as possible.

Population pharmacokinetic-pharmacodynamic modelling of S 15535, a 5-HT(1A) receptor agonist, using a behavioural model in rats.

The pharmacokinetic-pharmacodynamic relationship of S 15535 (1-(benzodioxan-5-yl) 4-(indan-2-yl)piperazine) and its active 5-hydroxy metabolite S 32784 (1-(benzodioxan-5-yl) 4-(5-hydroxyindan-2-yl)piperazine), and buspirone as a reference, were studied in male Wistar rats using a behavioural model of anxiety by determining the reduction in the number of fear-induced ultrasonic vocalisations. S 15535 and buspirone were administered p.o. and i.v. S 32784, present in man but not in rat, was administered i.v. The pharmacokinetics and pharmacokinetic-pharmacodynamic relationships were described using non-linear mixed effects modelling. The no-drug effect was constant and all compounds were active in the model, reducing ultrasonic vocalisations immediately after administration. The sigmoid E(max) model was used to describe the pharmacokinetic-pharmacodynamic relationships, with E(max) values of a 90% decrease in baseline ultrasonic vocalisations. Corrected for plasma protein binding, all compounds showed similar potency. The study shows that ultrasonic vocalisations can be considered a suitable endpoint for the anxiolytic effect when used in conjunction with non-linear mixed effects modelling to overcome the limited sampling and effect measurements.

The pathophysiological basis of pharmacological interventions in CAVD.

Calcific aortic valve disease (CAVD) results in aortic valve stenosis and is one of the most common cardiac diseases in both Western and developing countries. The burden of this disease is expected to increase rapidly in the future, but there are still no relevant pharmacological therapies available and aortic valve replacement remains the sole definite therapy. This review presents an overview of the most common causes of CAVD, followed by current debates and trials related to the onset and progression of this disease. Several differences and similarities between the different causes of CAVD are presented. Additionally, stages of CAVD are compared with stages in atherosclerosis. Finally, future directions for research on CAVD will be discussed.

Pharmacokinetics and pharmacodynamics of the non-nucleoside reverse-transcriptase inhibitor etravirine in treatment-experienced HIV-1-infected patients.

The pharmacokinetics and pharmacodynamics of the antiretroviral agent etravirine were evaluated in two phase III clinical trials. Pharmacokinetic data were available in 577 patients randomized to receive etravirine. The mean (SD) population-pharmacokinetics-derived area under the concentration-time curve at 12 h (AUC(12 h)) and concentration at 0 h (C(0 h)) were 5,501 (4,544) ng·h/ml and 393 (378) ng/ml, respectively. Hepatitis C coinfection raised etravarine exposure, and concomitant use of tenofovir disoproxil fumarate lowered etravirine exposure, but these changes were not considered clinically relevant. Etravirine apparent oral clearance was not affected by age, weight, sex, race, hepatitis B coinfection status, creatinine clearance, or concomitant use of enfuvirtide. Virologic response (<50 copies/ml) at week 24 was 59% in patients randomized to etravirine vs. 41% in those receiving placebo (P < 0.0001). There was no apparent relationship between etravirine pharmacokinetics and either efficacy or safety. Factors other than the pharmacokinetics of etravirine such as the characteristics of the patients and the disease, as well as characteristics of the treatment regimen, predict virologic response.

Characterization of the pharmacodynamics of several antiepileptic drugs in a direct cortical stimulation model of anticonvulsant effect in the rat.

In this investigation a newly developed direct cortical stimulation technique was evaluated for measurement of anticonvulsant efficacy in rats. The kinetics of drug action for carbamazepine, phenytoin, valproate, phenobarbital, ethosuximide and oxazepam were studied in conjunction with their pharmacokinetics. Motor cortex stimulation with a ramp-shaped pulse train allowed successive determination of a threshold for localized seizure activity (TLS) and for generalized seizure activity (TGS). For each drug the time course of effect was followed in individual animals. Differential effects on the pharmacodynamic parameters were seen. Phenytoin and carbamazepine clearly elevated the TGS. However, phenytoin did not affect TLS and carbamazepine only marginally. Valproate increased both TLS and TGS to the same extent. Phenobarbital and oxazepam elevated both thresholds, but the effect on TGS was more pronounced. Ethosuximide had little effect on both thresholds. Comparison with other animal models suggested that elevation of TLS reflects an effect on seizure initiation, whereas elevation of TGS above TLS reflects an effect on seizure propagation. All drugs exhibited a nonlinear relationship between plasma concentration and anticonvulsant efficacy, without ceiling of anticonvulsant intensity at the highest concentrations. The effective concentration range of most compounds coincided with the "therapeutic" range in humans. The direct cortical stimulation technique is useful for preclinical monitoring of anticonvulsant efficacy with most antiepileptic drugs because it allows detection of both qualitative and quantitative differences. In addition the model is particularly useful for time course studies.

Defibrination essential in the assay of ionized magnesium in mononuclear cells.

Intracellular free (ionized) magnesium concentration was measured in mononuclear cells isolated from healthy volunteers by use of dual wavelength fluorescence (indicator: mag-fura-2). We found a free Mg2+ concentration of 1.28 +/- 0.08 mmol/l in mononuclear cells isolated from heparinized blood. When we defibrinated blood samples prior to the isolation step we measured 0.78 +/- 0.05 mmol/l of free Mg2+ in these cells. We conclude that this difference is caused by the platelets present in the heparinized specimens.

Roles of phospholipase C and Ca(2+)-ATPase in calcium responses of single, fibrinogen-bound platelets.

Fura-2-loaded platelets were immobilized on fibrinogen, and cytosolic free calcium concentration ([Ca2+]i) was measured by video imaging of the fluorescence signal. In the immobilized, single platelets, ADP and low doses of thrombin evoked repetitive spikes of [Ca2+]i, whereas higher thrombin concentrations gave elevated plateaus in [Ca2+]i. Stimulation of the cells with thrombin after the addition of ADP changed the frequency of spiking, but not the maximal levels of [Ca2+]i reached. In suspensions of platelets, ADP and low doses of thrombin evoked transient elevation of myo-inositol phosphates, suggesting that the initiation of spiking was due to stimulation of phospholipase C. In platelet suspensions, the Ca(2+)-ATPase inhibitor thapsigargin (TG) evoked a gradual rise in [Ca2+]i, which was potentiated by preactivation of the platelets and inhibited by prostaglandin E1 and nitroprusside. In single platelets, TG induced a sudden increase in [Ca2+]i after a long but variable delay, followed by a phase of slow oscillations. The effects of preactivation with ADP were 2-fold: the delay time before the response to TG was shortened and the maximal level of [Ca2+]i reached with TG was higher than the level of the preceding Ca2+ spikes. Apparently, Ca2+ responses induced by the inhibition of Ca(2+)-ATPases are potentiated by prior elevation of [Ca2+]i and reduced by substances that inhibit agonist-evoked increases in [Ca2+]i. The data point to a mechanism of Ca(2+)-induced Ca2+ release and the presence of TG-sensitive and TG-insensitive Ca2+ stores in platelets. Rapid spiking may involve both pools, whereas the latter alone may account for the slow TG-evoked oscillations.