AIMS To evaluate the effect of lansoprazole, a proton-pump inhibitor, on the absorption, pharmacokinetics, and safety of neratinib, a pan-HER tyrosine kinase inhibitor, in healthy subjects. METHODS This was an open-label, two-period, fixed-sequence study. Fifteen healthy adult subjects received a single oral dose of neratinib 240 mg (Period 1), followed by a washout period, then oral lansoprazole 30 mg once daily for 7 days and a single dose of neratinib 240 mg on Day 5 (Period 2). Pharmacokinetic sampling was performed for 72 h following each neratinib dose. Plasma neratinib concentration-time data were analysed using noncompartmental methods. Geometric mean ratios for AUC0-t , AUC0-inf , and peak plasma concentrations (Cmax ) for neratinib plus lansoprazole vs. neratinib were used to assess the magnitude of the drug-drug interaction if the 90% confidence intervals were outside 80.00-125.00%. RESULTS Neratinib geometric least-squares mean (LSM) Cmax was reduced from 84.5 ng ml-1 with neratinib alone to 24.5 ng ml-1 with neratinib plus lansoprazole. The extent of exposure to neratinib was also decreased: geometric LSM AUC0-t was 1478 ng ml-1  h with neratinib vs. 426 ng ml-1  h with neratinib plus lansoprazole, and geometric LSM AUC0-inf was 1557 ng ml-1  h vs. 542 ng ml-1  h, respectively. Mean t½ was similar with both treatments (approximately 14 h). Geometric mean ratios 90% confidence intervals for AUC0-t , AUC0-inf and Cmax fell outside the prespecified equivalence range (80.0-125.0%). Treatment-emergent adverse events, all mild, were reported by five (33%) subjects. CONCLUSIONS Coadministration of lansoprazole with neratinib reduced the rate and extent of neratinib exposure in healthy subjects.

EDS have been shown to deliver drug more broadly in the nasal cavity (particularly superiorly/posteriorly) with less loss to drip-out and swallowing than conventional nasal sprays. Significantly improved delivery should produce greater deposition on respiratory epithelium (vs intranasal squamous/transitional epithelium anterior to the nasal valve or loss of drug) and therefore increase blood levels. Though fluticasone is trivially absorbed, new super-sensitive techniques enable detecting low picogram levels. This study assessed pharmacokinetics of fluticasone propionate administered as FLU-EDS, Flonase®, and Flovent®. Part 1 (3-way, 3-treatment, 3-sequence randomized crossover in healthy subjects, n=90) assessed and compared systemic exposure of single doses of 186μg and 372μg FLU-EDS versus 400μg Flonase®. Part 2 (2-way, 2-treatment, 2-sequence randomized crossover in mild-moderate asthmatics, n=30) assessed and compared systemic exposure of 372μg FLU-EDS and 440μg Flovent®. FLU-EDS 186μg produced higher Cmax than Flonase® 400μg (16.0 vs11.7pg/mL, respectively, 137.4% geometric mean ratio [GMR]) and similar AUC0-∞ (97.3 vs 99.6pg/mL, 97.7% GMR). FLU-EDS 372μg produced a higher Cmax (23.5 vs11.7pg/mL, 201.5% GMR) and AUC0-∞ (146.6 vs 99.6pg/mL, 147.2% GMR) than Flonase® 400μg. In part 2, FLU-EDS 372μg produced substantially lower Cmax (25.3 vs 40pg/mL, 63.2% GMR) and lower AUC0-∞ than Flovent® 440μg (205.8 vs 415.2pg/mL, 49.6% GMR). Similar intranasal doses of FLU-EDS (372μg) and Flonase® (400μg) are clearly not bioequivalent. Though very low, FLU-EDS produces higher systemic exposure than Flonase® and substantially lower exposure than 440μg Flovent®. This is consistent with greatly improved (especially posterior/superior nasal cavity) drug deposition with EDS than with conventional nasal spray.

Objectives.—The purpose of this study was to directly compare the pharmacokinetic (PK) profile of 22‐mg sumatriptan powder delivered intranasally with a novel Breath Powered™ device (11 mg in each nostril) vs a 20‐mg sumatriptan liquid nasal spray, a 100‐mg oral tablet, and a 6‐mg subcutaneous injection.Background.—A prior PK study found that low doses of sumatriptan powder delivered intranasally with a Breath Powered device were efficiently and rapidly absorbed. An early phase clinical trial with the same device and doses found excellent tolerability with high response rates and rapid onset of pain relief, approaching the benefits of injection despite significantly lower predicted drug levels.Methods.—An open‐label, cross‐over, comparative bioavailability study was conducted in 20 healthy subjects at a single center in the USA. Following randomization, fasted subjects received a single dose of each of the 4 treatments separated by a 7‐day washout. Blood samples were taken pre‐dose and serially over 14 hours post‐dose for PK analysis.Results.—Quantitative measurement of residuals in used Breath Powered devices demonstrated that the devices delivered 8 ± 0.9 mg (mean ± standard deviation) of sumatriptan powder in each nostril (total dose 16 mg). Although the extent of systemic exposure over 14 hours was similar following Breath Powered delivery of 16‐mg sumatriptan powder and 20‐mg liquid nasal spray (area under the curve [AUC]0‐∞ 64.9 ng*hour/mL vs 61.1 ng*hour/mL), sumatriptan powder, despite a 20% lower dose, produced 27% higher peak exposure (Cmax 20.8 ng/mL vs 16.4 ng/mL) and 61% higher exposure in the first 30 minutes compared with the nasal spray (AUC0‐30 minutes 5.8 ng*hour/mL vs 3.6 ng*hour/mL). The magnitude of difference is larger on a per‐milligram basis. The absorption profile following standard nasal spray demonstrated bimodal peaks, consistent with lower early followed by higher later absorptions. In contrast, the profile following Breath Powered delivery showed higher early and lower late absorptions. Relative to the 100‐mg oral tablet (Cmax 70.2 ng/mL, AUC0‐∞, 308.8 ng*hour/mL) and 6‐mg injection (Cmax 111.6 ng/mL, AUC0‐∞ 128.2 ng*hour/mL), the peak and overall exposure following Breath Powered intranasal delivery of sumatriptan powder was substantially lower.Conclusions.—Breath Powered intranasal delivery of sumatriptan powder is a more efficient form of drug delivery, producing a higher peak and earlier exposure with a lower delivered dose than nasal spray and faster absorption than either nasal spray or oral administration. It also produces a significantly lower peak and total systemic exposure than oral tablet or subcutaneous injection.

AIMS:Mizoribine is an oral immunosuppressive agent approved in several countries for prevention of rejection in renal transplantation. Its therapeutic window is based on trough concentrations staying at > or =0.5 but <3 microg ml(-1). It has been postulated that as renal function returns to normal, higher doses may be needed to maintain efficacy than the current clinical dosage of 2-5 mg kg(-1) day(-1). The safety, tolerability and pharmacokinetics from two clinical trials of higher-dose mizoribine treatments in healthy male volunteers are presented.METHODS:Forty-eight healthy White male nonsmokers participated in two randomized, double-blind, placebo-controlled trials: 32 in a single-dose study (3, 6, 9 and 12 mg kg(-1)) and 16 in a multiple-dose study [6 mg kg(-1) day(-1) once daily for 5 days or twice daily (12 mg kg(-1) day(-1)) for 7 days]. Standard assessments of safety, tolerability and pharmacokinetics were performed.RESULTS:The safety profiles of both studies were generally unremarkable, except for elevated serum uric acid concentrations at the highest dose (12 mg kg(-1) day(-1)) in the multiple-dose study. Orally administered mizoribine reached peak concentrations within 2-3 h and was eliminated mostly via the kidney (65-100% of dose) with a 3-h half-life. Only the 12 mg kg(-1) day(-1) group achieved trough concentrations that were within the therapeutic window. Conclusions Based on the favourable safety profile and current pharmacokinetic information, a new starting dose in the 6-12 mg kg(-1) day(-1) range is recommended in the up to 3 months acute phase following transplantation, with dose reduction recommended only if the function of the transplanted kidney is impaired.