Evaluation of epiandrosterone as a long-term marker of testosterone use.

Identification and evaluation of long-term markers is crucial in prolonging the detection window for anabolic steroid abuse in sport. Recently, sulfoconjugated epiandrosterone was identified as a potential long-term marker for the abuse of certain endogenous anabolic agents, including testosterone, which continues to be widely used as a performance enhancing agent in sport. To evaluate the applicability of epiandrosterone sulfate as a marker for testosterone use, administration studies were conducted with multiple modes of testosterone administration - transdermal, intramuscular, and subcutaneous. A modified sample preparation method was used to collect both glucuronidated and sulfoconjugated analytes of interest. Carbon isotope ratio measurements from the administration studies are presented here. Epiandrosterone was less effective than the conventionally used target compounds for detection of the low dose application (transdermal gel). With intramuscular administration, epiandrosterone was more diagnostic than with transdermal administration, but it did not prolong the detection window more than the conventional target compounds. With subcutaneous administration, the doses administered to the subjects were varied and the effect on the epiandrosterone values was dependent on the magnitude of the dose administered. Epiandrosterone does not appear to be a useful marker in the detection of low dose testosterone administration. It is responsive to higher dose administration, but it does not provide an extension of the detection window relative to conventional target compounds.

Modeling Subcutaneous Absorption of Long-Acting Insulin Glargine in Type 1 Diabetes.

OBJECTIVE: Subcutaneous (sc) administration of long-acting insulin analogs is often employed in multiple daily injection (MDI) therapy of type 1 diabetes (T1D) to cover patient's basal insulin needs. Among these, insulin glargine 100 U/mL (Gla-100) and 300 U/mL (Gla-300) are formulations indicated for once daily sc administration in MDI therapy of T1D. A few semi-mechanistic models of sc absorption of insulin glargine have been proposed in the literature, but were not quantitatively assessed on a large dataset. The aim of this paper is to propose a model of sc absorption of insulin glargine able to describe the data and provide precise model parameters estimates with a clear physiological interpretation. METHODS: Three candidate models were identified on a total of 47 and 77 insulin profiles of T1D subjects receiving a single or repeated sc administration of Gla-100 or Gla-300, respectively. Model comparison and selection were performed on the basis of their ability to describe the data and numerical identifiability. RESULTS: The most parsimonious model is linear two-compartment and accounts for the insulin distribution between the two compartments after sc administration through parameter k. Between the two formulations, we report a lower fraction of insulin in the first versus second compartment (k = 86% versus 94% in Gla-100 versus Gla-300, p < 0.05), a lower dissolution rate from the first to the second compartment ([Formula: see text] versus 0.0008 min-1 in Gla-100 versus Gla-300, p << 0.001), and a similar rate of insulin absorption from the second compartment to plasma ([Formula: see text] versus 0.0016 min-1 in Gla-100 versus Gla-300, p = NS), in accordance with the mechanisms of insulin glargine protraction. CONCLUSIONS: The proposed model is able to both accurately describe plasma insulin data after sc administration and precisely estimate physiologically plausible parameters. SIGNIFICANCE: The model can be incorporated in simulation platforms potentially usable for optimizing basal insulin treatment strategies.

Multiple-Condition Analysis in a Retrievable Subcutaneous Animal Model for Drug Screening on Full Pancreatic Tissue Digest.

The lack of understanding on how to treat pancreas-related diseases and develop new therapeutics is partly due to the unavailability of appropriate models. In vitro models fail to provide a physiological environment. Testing new drug targets in these models can give rise to bias and misleading results. Therefore, we developed an in vivo model for drug testing on full pancreatic digests, which maintains the interactions between endo- and exocrine tissues and allows retrieving the samples for further analyses. The use of full pancreatic digest eliminates the need to isolate islets, reducing time and cost. In this model, four different conditions can be implanted subcutaneously within the same animal. Each condition consists of full pancreatic tissue digests embedded in alginate beads. All alginate beads in one animal contained full pancreatic digest of the same donor and, after 5-day implantation, were retrieved for analysis focusing on survival, function, and/or organization. Proof-of-principle of the platform was evidenced by showing the effect of hyaluronic acid and vascular endothelial growth factor on the overall function of the full pancreatic digest and on endothelial cells in the pancreatic digest, respectively. Retrieval from identical animals allows direct comparison between conditions. Metabolism (MTT) quantification, dithizone staining, and glucose-stimulated insulin secretion assessment allow to discriminate, using a minimal number of animals, between treatments and validate the system. Because of its simplicity, the model is highly adaptable to specific needs of the user.

Modeling Subcutaneous Absorption of Fast-Acting Insulin in Type 1 Diabetes.

OBJECTIVE: Subcutaneous (sc) administration of fast-acting insulin analogues is the key in conventional therapy of type 1 diabetes (T1D). A model of sc insulin absorption would be helpful for optimizing insulin therapy and test new open- and closed-loop treatment strategies in in silico platforms. Some models have been published in the literature, but none was assessed on a frequently-sampled large dataset of T1D subjects. The aim here is to propose a model of sc absorption of fast-acting insulin, which is able to describe the data and precisely estimate model parameters with a clear physiological interpretation. METHODS: Three candidate models were identified on 116 T1D subjects, who underwent a single sc injection of fast-acting insulin and were compared on the basis of their ability to describe the data and their numerical identifiability. RESULTS: A linear two-compartment model including a subject-specific delay in sc insulin absorption is proposed. On average, a delay of 7.6 min in insulin appearance in the first compartment is detected, then the insulin is slowly absorbed into plasma (in 23% of the subjects) with a rate of 0.0034 min-1, while the remaining diffuses into the second compartment, with a rate constant of 0.028 min-1, and then finally absorbed into plasma with a rate constant of 0.014 min-1. CONCLUSION: Among the three tested models, the one proposed here is the only one able to both accurately describe plasma insulin data after a single sc injection and precisely estimate physiologically plausible parameters. The model needs to be further tested in case of variable sc insulin delivery and/or multiple insulin doses. SIGNIFICANCE: Results are expected to help the development of new open- and closed-loop insulin treatment strategies.

Pharmacokinetics and Safety of Risperidone Subcutaneous Implants in Stable Patients With Schizophrenia.

A subcutaneous risperidone implant (RI) formulation was developed to improve medication adherence in schizophrenia. Two phase 1 studies were conducted to evaluate the pharmacokinetics of RI in adult patients with schizophrenia. In study 1, all subjects were stable on 4 mg oral risperidone; subsequently, the first subject received 375 mg RI for 1 month, and the remaining subjects received 375 mg RI for 3 months. In study 2, all subjects were stable on oral risperidone 4 mg, 6 mg, or 8 mg and subsequently received RI 480 mg, 720 mg, or 960 mg, respectively, for 6 months. Blood samples were collected at prespecified time points. Various pharmacokinetic parameters were determined in both studies. In both studies risperidone total active moiety plasma concentrations following RI increased slowly, reached therapeutic levels within approximately 2 days, and remained relatively stable. In study 1, the average concentration for RI was 81.3% of the oral trough concentration and 27.5% of the oral peak concentration. In study 2, the steady-state concentration for RI was comparable to the oral trough concentration of the corresponding dose. Patient disease status remained stable with no major safety issues. RI may represent an alternative formulation for schizophrenia treatment with a lower peak-to-trough plasma drug ratio than oral risperidone.