OBJECTIVETo investigate the pharmacokinetics (PK), pharmacodynamics, and safety of single-dose RM-131 in type 2 diabetic patients with gastrointestinal cardinal symptoms (GCSI) and previously documented delayed gastric emptying (DGE).RESEARCH DESIGN AND METHODSIn a randomized crossover study, 10 female patients received RM-131 (100 μg s.c.) or placebo and underwent scintigraphic gastric emptying (GE) and colonic filling at 6 h (CF6) of a solid-liquid meal administered 30 min postdosing. Adverse events, plasma glucose, and hormonal levels were assessed. GCSI daily diary (GCSI-DD) was completed during treatments. PK was assessed in this cohort and healthy volunteers (HVs).RESULTSAt screening, HbA1c was 7.2 ± 0.4% (SEM) and total GCSI-DD score was 1.32 ± 0.21. RM-131 accelerated GE t1/2 of solids (P = 0.011); mean difference (Δ) in solid GE t1/2 was 68.3 min (95% CI 20–117) or 66.1%. There were numerical differences in GE lag time, CF6 solids, and GE t1/2 liquids (all P < 0.14). With a significant (P < 0.014) order effect, further analysis of the first treatment period (n = 5 per group) confirmed significant RM-131 effects on GE t1/2 (solids, P = 0.016; liquids, P = 0.024; CF6, P = 0.013). PK was similar in DGE patients and HVs. There were increases in 120-min blood glucose (P = 0.07) as well as 30–90-min area under the curve (AUC) levels of growth hormone, cortisol, and prolactin (all P < 0.02) with single-dose RM-131. Only light-headedness was reported more on RM-131.CONCLUSIONSRM-131 greatly accelerates the GE of solids in patients with type 2 diabetes and documented DGE. PK is similar in diabetic patients and HVs.

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Cysteamine bitartrate capsules (Cystagon) have been approved by the US Food and Drug Administration for use in patients with nephropathic cystinosis. Plasma cysteamine concentrations were virtually identical at various times following ingestion of either cysteamine hydrochloride or Cystagon capsules in 24 normal control subjects. A transfer study was done with eight cystinosis patients who had been receiving either cysteamine hydrochloride or phosphocysteamine for many years. The plasma cysteamine concentration was significantly higher 2h after Cystagon and the leukocyte cystine content was significantly lower at all times after Cystagon compared to older forms of the drug. These differences are probably the result of greater patient compliance in taking the capsules compared to the older, liquid forms of the drug. A new method for following the course of renal glomerular deterioration in diseases such as cystinosis has been published recently. This method was used to re-analyse data on the efficacy of cysteamine treatment and to re-analyse new data on treating cystinosis patients with either of two doses of cysteamine (1.30 g/m2 per day and 1.95 g/m2 per day). This new method agrees well with other methods and shows that both doses of drug are equally effective in maintaining glomerular function.

These mechanical manipulation and PK studies demonstrated that DETERx beads retained their ER properties after mechanical tampering and chewing by study subjects.

In this whitepaper, the Manufacturing Technical Committee (MTC) of the Product Quality Research Institute has updated the 1997 Transdermal Drug Delivery Systems Scale-Up and Post Approval Change workshop report findings to add important new product development and control principles. Important topics reviewed include ICH harmonization, quality by design, process analytical technologies, product and process validation, improvements to control of critical excipients, and discussion of Food and Drug Administration’s Guidance on Residual Drug in Transdermal and Related Drug Delivery Systems as well as current thinking and trends on in vitro–in vivo correlation considerations for transdermal systems.

This study determines if the anatomic region affected percutaneous absorption in the rhesus monkey, an animal model with some relevance to man. Percutaneous absorption of testosterone (13.3 microgram/cm2) from the ventral forearm was 8.8 +/- 2.5%. Absorption from the chest was slightly less (5.3 +/- 0.6%) while that from the cheek was about the same (9.6 +/- 0.2%). Absorption from the scalp was greatly increased (20.4 +/- 2.7%), that from the vagina was the greatest (63.1 +/- 2.6%). As previously noted in man, anatomic variation in skin absorption exists in the rhesus. The ratio of scalp absorption to ventral forearm absorption in the rhesus was similar to that in man. The next objective was to determine the percutaneous absorption of testosterone when applied as a single dose or on a repetitive basis. There was no substantial difference in total absorption when 13.3 microgram/cm2 was applied as a single dose or when the 13.3 microgram/cm2 was applied three times, totaling 40 microgram/cm2. However, when 40 microgram/cm2 was applied as a single dose, absorption was substantially increased over 13.3 microgram/cm2 applied either once or three times. These results confirm previously reported results done with single versus repetitive doses of hydrocortisone.