Simulate SubQ: The Methods and the Media.

For decades, there has been a growing interest in injectable subcutaneous formulations to improve the absorption of drugs into the systemic circulation and to prolong their release over a longer period. However, fluctuations in the blood plasma levels together with bioavailability issues often limit their clinical success. This warrants a closer look at the performance of long-acting depots, for example, and their dependence on the complex interplay between the dosage form and the physiological microenvironment. For this, biopredictive performance testing is used for a thorough understanding of the biophysical processes affecting the absorption of compounds from the injection site in vivo and their simulation in vitro. In the present work, we discuss in vitro methodologies including methods and media developed for the subcutaneous route of administration on the background of the most relevant absorption mechanisms. Also, we highlight some important knowledge gaps and shortcomings of the existing methodologies to provide the reader with a better understanding of the scientific evidence underlying these models.

Biopredictive tools for the development of injectable drug products.

INTRODUCTION: Biopredictive release tests are commonly used in the evaluation of oral medicines. They support decision-making in formulation development and allow predictions of the expected in-vivo performances. So far, there is limited experience in the application of these methodologies to injectable drug products. AREAS COVERED: Parenteral drug products cover a variety of dosage forms and administration sites, including subcutaneous, intramuscular, and intravenous injections. In this area, developing biopredictive and biorelevant methodologies often confronts us with unique challenges and knowledge gaps. Here, we provide a formulation-centric approach and explain the key considerations and workflow when designing biopredictive assays. Also, we outline the key role of computational methods in achieving clinical relevance and put all considerations into context using liposomal nanomedicines as an example. EXPERT OPINION: Biopredictive tools are the need of the hour to exploit the tremendous opportunities of injectable drug products. A growing number of biopharmaceuticals such as peptides, proteins, and nucleic acids require different strategies and a better understanding of the influences on drug absorption. Here, our design strategy must maintain the balance between robustness and complexity required for effective formulation development.

Implantation Failures and Miscarriages in Frozen Embryo Transfers Timed in Hormone Replacement Cycles (HRT): A Narrative Review.

The recent advent of embryo vitrification and its remarkable efficacy has focused interest on the quality of hormone administration for priming frozen embryo transfers (FETs). Products available for progesterone administration have only been tested in fresh assisted reproduction technologies (ARTs) and not in FET. Recently, there have been numerous concordant reports pointing at the inefficacy of vaginal preparations at delivering sufficient progesterone levels in a sizable fraction of FET patients. The options available for coping with these shortcomings of vaginal progesterone include (i) rescue options with the addition of injectable subcutaneous (SC) progesterone at the dose of 25 mg/day administered either solely to women whose circulating progesterone is <10 ng/mL or to all in a combo option and (ii) the exclusive administration of SC progesterone at the dose of 25 mg BID. The wider use of segmented ART accompanied with FET forces hormone replacement regimens used for priming endometrial receptivity to be adjusted in order to optimize ART outcomes.

Treatment with Volanesorsen, a 2'-O-Methoxyethyl-Modified Antisense Oligonucleotide Targeting APOC3 mRNA, Does Not Affect the QTc Interval in Healthy Volunteers.

The aim of this study was to assess the effect of volanesorsen on the corrected QT (QTc) interval. This thorough QT study enrolled 52 healthy male and female subjects who were randomized at a single site in a four-way crossover study. Subjects were randomly assigned to 1 of 12 treatment sequences and crossed over into four treatment periods over the course of which each subject was to receive a single therapeutic dose of volanesorsen as a 300 mg subcutaneous (SC) injection, a single supratherapeutic dose of volanesorsen as 300 mg intravenous (IV) infusion, a single oral (PO) dose of moxifloxacin (positive control), and placebo dose. The study demonstrated that volanesorsen 300 mg SC and 300 mg IV did not have a clinically relevant effect on ΔΔQTcF exceeding 10 ms. The largest mean effect at any postdose time point was 3.0 ms (90% confidence interval [CI]: 0.8-5.2) after SC dosing and 1.8 ms (90% CI -0.4 to 4.0) after IV dosing. Volanesorsen, at the studied therapeutic and supratherapeutic doses, does not have a clinically meaningful effect on the QTc.

Flare-Up Phenomenon of Intradermal Test with Anaphylactic Reaction to Paracetamol (Acetaminophen).

BACKGROUND: Paracetamol is a Non-Steroidal Anti-Inflammatory Drug (NSAID) that can produce hypersensitive reactions mediated by specific immunological mechanisms (IgE or T celldependent) or by a non-immunological mechanism (inhibition of cyclooxygenase COX-1). OBJECTIVE: An 80-year-old man with a history of allergy to pyrazolones, with good tolerance to other NSAIDs was referred to our allergy department because he presented a generalized urticaria after the administration of Intravenous (IV) paracetamol. METHODS: We performed an Intradermal Test (IDT) with paracetamol (0.02mg/ml) and later a Single Blind Oral Challenge Test (SBOCT) with oral paracetamol. RESULTS: IDT reading at 15min showed negative result so an SBOCT was performed with oral paracetamol. With an accumulative dose of 250mg, after 20min, he developed discomfort, nausea and dizziness, urticarial, hypotension (BP 80/40) as well as flare-up phenomenon was observed in the site of the IDT with paracetamol. Tryptase levels during the reaction and 2hrs later were increased. CONCLUSION: We present an anaphylactic shock due to sensitization to paracetamol because of a type I hypersensitivity mechanism, diagnosed by SBOCT and a positive IDT because of flare-up phenomenon, in a patient with previous pyrazolones allergy and with tolerance to other NSAIDs. Some relevant patents are also summarized in this paper.

The rapid kinetics of optimal treatment with subcutaneous methotrexate in early inflammatory arthritis: an observational study.

BACKGROUND: Methotrexate (MTX) is standard treatment for RA. Absorption is better in subcutaneous MTX (scMTX), which may impact speed of onset. In RA, earlier time to remission improves long-term results. Our objectives were to determine rapidity of response of subcutaneous methotrexate in early rheumatoid arthritis. METHODS: The change in several disease activity measures (including DAS28) from 0 to 6 weeks (early period) and 6 to 12 weeks (late period) was compared. The proportion achieving DAS28/CDAI/SDAI remission and/or low disease activity state was also compared. RESULTS: One hundred three patients were included from a single site between 2008 and 2014. All received MTX (98.0 % scMTX, 98 % 25 mg/week). There were no dropouts. There was a significantly greater early change in DAS28 (-1.9 vs. -0.2, p < 0.00); this effect was seen for several outcome measures. By 6 weeks, 59 % had achieved either DAS28 remission or low disease activity state, with 74 % achieving either state by 12 weeks. There were a larger proportion of patients achieving CDAI and DAS28 remission in the early versus late period (p < 0.0002 for both). There was significant improvement when using combination MTX and HCQ, however sample size was small (n = 9). The use of intra-articular steroids with MTX yielded the most disease measures that demonstrated early significant improvement. CONCLUSION: Subcutaneous MTX is rapid, as the change in many disease activity scores was significantly greater between 0-6 weeks compared to 6-12 weeks. Combination MTX + HCQ gave added value, although generalizability is limited by combination cohort sample size. Intra-articular steroid injections may contribute to the early effect.