The relative bioavailability of 2 prototype fixed-dose combination formulations for amlodipine and rosuvastatin in healthy white and Chinese subjects.

A fixed-dose combination (FDC) may improve patient compliance and clinical outcomes in the management of cardiovascular risk in hypertensive and dyslipidemic patients. The study (NCT02075619) evaluated the bioavailability of 2 prototype FDC tablet formulations (FDC1 and FDC2) of amlodipine/rosuvastatin (10 mg/20 mg) compared with coadministered reference tablets. It was a randomized, single-dose, 3-way crossover pilot study in healthy white (n = 12) and Chinese (n = 12) adults. Three treatments (FDC1, FDC2, and reference) were administered after fasting with a washout period of 12-17 days. The pharmacokinetics of amlodipine and rosuvastatin were studied for all subjects (pooled) and by ethnicity. Safety and tolerability were also evaluated. Both FDCs met the bioequivalence criteria (90% confidence intervals falling within the range of 0.80-1.25) for AUC0-t and Cmax for amlodipine and rosuvastatin. Intrasubject variability (AUC0-t and Cmax ) was in the region of 23%-25% for rosuvastatin and 7%-10% for amlodipine. The FDC formulations demonstrated similar bioavailability to coadministered commercially available amlodipine and rosuvastatin. All treatments were generally well tolerated.

Analytical characterization of an orally-delivered peptide pharmaceutical product.

The characterization of orally-delivered peptide pharmaceuticals presents several challenges to analytical methods in comparison to characterization of conventional small-molecule drugs. These challenges include the analysis and characterization of difficult-to-separate impurities, secondary structure, the amorphous solid-state form, and the integrity of enteric-coated drug delivery systems. This work presents the multidisciplinary analytical characterization of a parathyroid hormone (PTH) peptide active pharmaceutical ingredient (API) and an oral formulation of this API within enteric-coated sucrose spheres. The analysis of impurities and degradation products in API and formulated drug product was facilitated by the development of an ultrahigh-performance liquid chromatography (UHPLC) method for analysis by high-resolution mass spectrometry (MS). The use of UHPLC allowed for additional resolution needed to detect impurities and degradation products of interest. The secondary structure was probed using a combination of solution-state NMR, infrared, and circular dichroism spectroscopic methods. Solid-state NMR is used to detect amorphous API in a nondestructive manner directly within the coated sucrose sphere formulation. Fluorescence and Raman microscopy were used in conjunction with Raman mapping to show enteric coating integrity and observe the distribution of API beneath the enteric-coating on the sucrose spheres. The methods are combined in a multidisciplinary approach to characterize the quality of the enteric-coated peptide product.

Effects of food and antacids on the pharmacokinetics of eltrombopag in healthy adult subjects: two single-dose, open-label, randomized-sequence, crossover studies.

BACKGROUND: Eltrombopag is the first orally self-administered, small-molecule, nonpeptide thrombopoietin receptor agonist for the treatment of chronic idiopathic thrombocytopenic purpura. OBJECTIVE: The aim of these studies was to assess the effect of food and antacids on the pharmacokinetic and safety profiles of eltrombopag. METHODS: Two independent, single-dose, open-label, randomized-sequence, crossover studies of oral eltrombopag were conducted in healthy adult volunteers. The first study (study A) compared eltrombopag 50 mg (tablets or capsules) administered in the fasted state or tablets with a high-fat, high-calcium breakfast. The second study (study B) investigated eltrombopag tablets (75 mg) administered in the fasted state; immediately after a low-fat, low-calcium meal or a high-fat, low-calcium meal; 1 hour before a high-fat, low-calcium meal; or with an antacid containing aluminum hydroxide and magnesium carbonate. Vital signs were recorded and electrocardiogram and clinical laboratory tests were performed at screening, within 24 hours before and within 48 hours after each dose of study medication. Symptom assessment was performed and adverse events (AEs) were assessed previous to study drug administration through follow-up in terms of severity and relationship to study medication. RESULTS: In study A, 18 male subjects (mean age, 23.0 years; weight, 70.3 kg; white race, 94.4%) who received a high-fat, high-calcium breakfast had reduced bioavailability of eltrombopag in terms of AUC(0-infinity)) by 59% (geometric mean ratio [GMR], 0.41; 90% CI, 0.36-0.46) and C(max) by 65% (GMR, 0.35; 90% CI, 0.30-0.41) compared with subjects in a fasted state. In study B, the bioavailability in 26 subjects (14 male, 12 female; mean age, 35.6 years; weight, 76.0 kg; white race, 65.4%) was not significantly changed when administered with food that was low in calcium, despite the fat content (GMRs ranged from 0.87-1.03 for AUC(0-infinity) and 0.85-1.01 for C(max) across the 3 studied meals). Mean plasma AUC(0-infinity)) and C(max) values decreased by approximately 70% (GMR, 0.30; 90% CI, 0.24-0.36 for AUC(0-infinity)) and 0.24-0.38 for C(max)) when administered with a metal cation-containing antacid. No serious AEs were reported and all AEs were rated as mild to moderate in intensity. The most frequently reported AE was headache (study A, 6.3%; study B, 12.0%-29.2%). CONCLUSIONS: Concomitant administration of eltrombopag with high-calcium food or an antacid containing aluminum and magnesium was associated with significantly reduced systemic exposure, whereas low-calcium meals were not. A single dose of eltrombopag was generally well tolerated in these healthy volunteers.