AimOmalizumab, a humanized IgG monoclonal antibody that binds to human immunoglobulin E (IgE), interrupts the allergic cascade in asthmatic patients. The aim was to compare simultaneously drug exposure and IgE biomarker responses in Japanese and White patient populations. MethodsAn instantaneous equilibrium drug-ligand binding and turnover population model was built from 202 Japanese patients. A posterior predictive evaluation for the steady-state distributions of omalizumab and IgE was then carried out against 531 White patients. ResultsThe mean parameters estimated from the Japanese patients were as follows: omalizumab clearance 7.32 Ϯ 0.153 ml h -1 , IgE clearance 71.0 Ϯ 4.68 ml h -1 and the difference between that for omalizumab and the complex 5.86 Ϯ 0.920 ml h -1 , the volume of distribution for omalizumab and IgE 5900 Ϯ 107 ml, and that for the complex 3630 Ϯ 223 ml, the rate of IgE production 30.3 Ϯ 2.04 mg h -1 . Half-lives of IgG (23 days) and IgE (2.4 days) were close to previous reports. The dissociation constant for binding, 1.07 nM, was similar to in vitro values. Clearance and volume of distribution for omalizumab varied with bodyweight, whereas the clearance and rate of production of IgE were predicted accurately by baseline IgE. Overall, these covariates explained much of the interindividual variability. ConclusionsThe predictiveness of the Japanese model was confirmed by Monte-Carlo simulations for a White population, also providing evidence that the pharmacokinetics of omalizumab and IgE were similar in these two populations. Furthermore, the model enabled the estimation of not only omalizumab disposition parameters, but also the binding with and the rate of production, distribution and elimination of its target, IgE. IntroductionOmalizumab is a recombinant DNA-derived humanized monoclonal antibody that selectively binds human immunoglobulin E (IgE). The antibody is an immunoglobulin (Ig) G 1 k with a human framework and complementarity determining regions (CDRs) from a humanized anti-IgE murine antibody [1]. The causal role of IgE in allergic disease is well established [1-3]. The British Journal of Clinical Pharmacology DOI:10.1111DOI:10. /j.1365DOI:10. -2125DOI:10. .2006 Administration of omalizumab significantly decreases serum free IgE concentrations, resulting in improved control of atopic asthma and, most probably, other atopic conditions. As a result of omalizumab binding to IgE, lowering its free concentration, total serum IgE concentrations rise. Such an increase could occur by two mechanisms: (i) omalizumab-IgE complexes could be eliminated more slowly than free IgE due to the ability of the IgG portion of complexes to access the Brambell receptor, sparing them from lysosomal degradation [13], and (ii) the complexes, being of higher molecular mass (at least 340 kDa for the dimer but up to 1000 kDa for the hexamer [14]), filter less effectively through the vascular endothelium and are therefore retained within the smaller plasma volume of distribution [15][16][17][18].However, these ...
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT Pulmonary arterial hypertension (PAH) is a rare syndrome of dyspnoea and fatigue due to an increase in pulmonary vascular resistance. Although the disease remains incurable, targeted therapies have been shown to be beneficial to patients. Oral sildenafil (20 mg three times daily) is a phosphodiesterase type 5 inhibitor with proven efficacy on exercise capacity, symptoms and pulmonary haemodynamics in patients with PAH. WHAT THIS STUDY ADDS It is advisable that chronic therapies for PAH, including oral sildenafil, not be interrupted. However, patients may not be able to take their medication because of an intervening illness or a requirement to undergo general anaesthesia, preventing oral drug administration. This study demonstrates that an intravenous bolus of 10 mg sildenafil in stable patients with PAH is safe, well tolerated and maintains plasma levels to preserve drug exposure. AIMS To assess pharmacokinetics and pharmacodynamics of a 10 mg intravenous sildenafil bolus in pulmonary arterial hypertension (PAH) patients stabilized on 20 mg sildenafil orally three times daily. METHODS Pharmacokinetic parameters were calculated using noncompartmental analysis. RESULTS After an acute increase, plasma concentrations stabilized within the range reported previously for a 20 mg oral tablet. At 0.5 h, mean ± SD changes from baseline were −8.4 ± 11.7 mmHg (systolic pressure), −2.6 ± 7.3 mmHg (diastolic pressure) and −3.5 ± 10.4 beats min−1 (heart rate). There was no symptomatic hypotension. CONCLUSIONS Although further research is warranted, a 10 mg sildenafil intravenous bolus appears to provide similar exposure, tolerability and safety to the 20 mg tablet.
A total of 72 adult healthy volunteers were administered 1 microgram/kg of rhG-CSF. There was no correlation between Cmax and an increase in peripheral neutrophil count, and there was a negative correlation between AUC and this increase. The mechanism of this is probably based on the correlation between the elimination rate constant (ke) and neutrophil increase. The ke probably has a close relationship with uptake by neutrophil and its progenitor via the G-CSF receptor. An individual with higher ke should therefore show a greater increase in neutrophil count. Therefore, AUC is proportional to the rhG-CSF remainder, that is, the proportion that is not consumed in the course of increasing the neutrophil count. In such a situation, the bioavailability calculated from the AUC is unlikely to indicate the absorbed amount. The authors also analyzed the pharmacokinetics using a two-compartment model with zero-order absorption and first-order elimination. This model was sufficient to obtain a good curve fit, and this demonstrates that the absorption process is not a first-order but a zero-order process. Therefore, there might be an upper limit to the rhG-CSF transfer rate from subcutaneous tissue to blood.
Aims Erythropoietin, a glycoprotein hormone is produced by the kidney and targeted to erythrocyte precursors. Recombinant human erythropoietin (Epoetin b) has been utilized for therapeutic purposes in renal anaemia or anaemia occurring after auto blood donation or chemotherapy. The administration routes for erythropoietin are normally subcutaneous or intravenous. No population pharmacokinetic analysis, however, has been performed following subcutaneous administration with consideration given for endogenous production. Methods In the present study, we have attempted to analyze the pharmacokinetics of erythropoietin after subcutaneous administration in healthy adult male volunteers by using the Nonlinear Mixed Effect Model program (NONMEM) with a model including endogenous erythropoietin production. Results It has been established that the final estimation of the population mean values of the absorption rate constant (k a ), the elimination rate constant (k e ), the distribution volume ( V ) and the endogenous production are 0.0430 h −1 , 0.206 h −1 , 3.14 l and 15.7IU h −1 , respectively. For the circadian rhythm of endogenous production, the amplitude was calculated as 9.86% and the peak appeared around 24.00 h.Conclusions The values for k e and V are very similar to those previously reported for intravenous administration. The circadian rhythm of endogenous production are also able to be substantiated. The factors influencing k e were found to be serum creatinine and age.
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