Aims To assess the absolute bioavailability, pharmacokinetics and metabolism of beclomethasone dipropionate (BDP) in man following intravenous, oral, intranasal and inhaled administration. Methods Twelve healthy subjects participated in this seven-way cross-over study where BDP was administered via the following routes: intravenous infusion (1000 mg), oral (4000 mg, aqueous suspension), intranasal (1344 mg, aqueous nasal spray) and inhaled (1000 mg ex-valve, metered dose inhaler). The contribution of the lung, nose and gut to the systemic exposure was assessed by repeating the inhaled, intranasal and oral dosing arms together with activated charcoal, to block oral absorption. Blood samples were collected for 24 h postdose for the measurement of BDP, beclomethasone-17-monopropionate (B-17-MP) and beclomethasone (BOH) in plasma by liquid chromatography tandem mass spectrometry. Results Intravenous administration of BDP (mean CL 150 l h x1 , V ss 20 l, t K 0.5 h) was associated with rapid conversion to B-17-MP which was eliminated more slowly (t 1/2 2.7 h). In estimating the parameters for B-17-MP (mean CL 120 l h x1 , V ss 424 l) complete conversion of BDP to B-17-MP was assumed. The resultant plasma concentrations of BOH were low and transient. BDP was not detected in plasma following oral or intranasal dosing. The mean absolute bioavailability (%F, 90% CI; nominal doses) of inhaled BDP was 2% (1±4%) and not reduced by coadministration of charcoal. The mean percentage F of the active metabolite B-17-MP was 41% (31±54%), 44% (34±58%) and 62% (47±82%) for oral, intranasal and inhaled dosing without charcoal, respectively. The corresponding estimates of nasal and lung absorption, based on the coadministration of charcoal, were <1% and 36% (27±47%), respectively. Conclusions Unchanged BDP has negligible oral and intranasal bioavailability with limited absorption following inhaled dosing due to extensive (95%) presystemic conversion of BDP to B-17-MP in the lung. The oral and intranasal bioavailabilities of the active metabolite B-17-MP were high and similar, but direct absorption in the nose was insigni®cant. The total inhaled bioavailability of B-17-MP (lung + oral) was also high (62%) and approximately 36% of this was due to pulmonary absorption. Estimates of oral bioavailability and pulmonary deposition based on total BOH were approximately half those found for B-17-MP.

With the continued increase in the use of Bayesian methods in drug development, there is a need for statisticians to have tools to develop robust and defensible informative prior distributions. Whilst relevant empirical data should, where possible, provide the basis for such priors, it is often the case that limitations in data and/or our understanding may preclude direct construction of a data-based prior. Formal expert elicitation methods are a key technique that can be used to determine priors in these situations. Within GlaxoSmithKline, we have adopted a structured approach to prior elicitation on the basis of the SHELF elicitation framework and routinely use this in conjunction with calculation of probability of success (assurance) of the next study(s) to inform internal decision making at key project milestones. The aim of this paper is to share our experiences of embedding the use of prior elicitation within a large pharmaceutical company, highlighting both the benefits and challenges of prior elicitation through a series of case studies. We have found that putting team beliefs into the shape of a quantitative probability distribution provides a firm anchor for all internal decision making, enabling teams to provide investment boards with formally appropriate estimates of the probability of trial success as well as robust plans for interim decision rules where appropriate. As an added benefit, the elicitation process provides transparency about the beliefs and risks of the potential medicine, ultimately enabling better portfolio and company-wide decision making.

Aims To establish whether enantioselective metabolism of racemic (rac)-salbutamol occurs in the lungs by determining its enantiomeric disposition following inhalation, in the absence and presence of oral charcoal, compared with that following the oral and intravenous routes. Methods Fifteen healthy subjects (eight male) were randomized into an open design, crossover study. Plasma and urine salbutamol enantiomer concentrations were measured for 24 h following oral (2 mg ) with or without oral charcoal (to block oral absorption), inhaled (MDI; 1200 mg ) with or without oral charcoal and intravenous (500 mg) rac-salbutamol. Systemic exposure ( plasma AUC(0,2) and urinary excretion (Au 24h ) of both enantiomers were calculated, and relative exposure to (R)-salbutamol both in plasma (AUC (R)-/AUC (S)-) and urine (Au (R)-/Au (S)-) was derived for each route. Relative exposure after the inhaled with charcoal and oral routes were compared with the intravenous route. Similar results were found when relative exposure was analysed using Au 24h . Conclusions These results show no evidence of significant enantioselective presystemic metabolism in the lungs, whilst confirming it in the gut and systemic circulation, indicating that the (R)-and (S)-enantiomers are present in similar quantities in the airways following inhaled rac-salbutamol.

Fifty-three patients with chronic hepatitis B and active viral replication were studied for 4 weeks while on treatment and for 12 weeks after treatment with the oral nucleoside analogue lamivudine. Children aged 2 to 12 years were randomized to receive twice-daily doses of 0.35, 1.5, or 4 mg of lamivudine solution per kg of body weight or once-daily doses of 3 mg of lamivudine solution per kg. Adolescents aged 13 to 17 years received lamivudine at 100 mg (as tablets). Blood samples for pharmacokinetic assay were taken on days 1 and 28. Lamivudine was rapidly absorbed following oral administration, with the maximum concentration in serum being reached 0.5 to 1 h postdosing. Apparent oral clearance (CL/F) was higher in younger children and decreased with age, with CL/F values for adolescents reaching those seen for adults by the age of 12. All doses produced a dramatic fall in serum hepatitis B virus (HBV) DNA levels, with a median reduction of >/=99.5% after 4 weeks of treatment and with the levels returning to the baseline levels posttreatment. The correlation of dose, area under the concentration-time curve (AUC), and changes in HBV DNA levels, as measured by the Chiron Quantiplex assay, showed maximal antiviral effects (99.9% inhibition and a reduction of the amount of HBV DNA of approximately 3 log(10)) at 3 mg/kg/day, with no discernible increase in effect seen whether the drug was given at 4 mg/kg twice daily or whether it was given once daily or twice daily. The limit of detection of the assay (2.5 pg/ml) was reached for some but not all patients across the dose ranges, with the smallest number (n = 2) of those having values negative by the Chiron Quantiplex assay being in the lowest-dose group. The 13- to 17-year-olds showed a similar overall response in terms of the HBV DNA level reduction compared to that for patients younger than age 13. Analysis of the same samples by PCR, which has a lower limit of sensitivity than the Chiron Quantiplex assay, also showed average drops in HBV DNA levels of about 3 log(10) at 4 weeks for patients for which the AUC was >/=4,000 ng. h/ml, confirming the conclusions given above. Lamivudine treatment was well tolerated at all doses, with no significant adverse events or laboratory data changes. On the basis of pharmacokinetic and pharmacodynamic data, a 3-mg/kg/day dose in children (ages 2 to 12 years) with chronic hepatitis B provides levels of exposure and trough concentrations similar to those seen in adults following the receipt of doses of 100 mg. The 100-mg dose is being evaluated in a large phase III study with HBV-infected pediatric patients.

In conclusion, this study calls into question the role of CCR3 in airway eosinophilia in asthma and suggests that other cellular mechanisms mediated by the CCR3 receptor may contribute to airway hyperresponsiveness.