An Investigation Into Local Infusion Site Pain After Infusion of Ultra Rapid Lispro Excipients Across Sites and Depths.

BACKGROUND: This phase 1, randomized, one-day, five-period crossover study in adults with type 1 diabetes on continuous subcutaneous insulin infusion investigated local infusion site pain following infusion of the excipients of ultra rapid lispro (URLi; without insulin) across infusion sites and depths. METHODS: Forty participants (mean age, 40.5 years; body mass index [BMI], 27.5) were randomized to one of five infusion site sequences consisting of the arm, thigh, buttock (6 mm cannula depth), and abdomen (6 and 9 mm depth). Basal infusion of sodium citrate and treprostinil in diluent with magnesium chloride was initiated (10 µL/h) and at three, six, and nine hours after basal initiation, 15 unit-equivalent boluses (150 µL) were given. Participants rated their pain on a 0 to 100 mm validated visual analog scale (VAS) at 5 minutes pre-bolus and 1 and 15 minutes post-bolus. RESULTS: At one minute post-bolus, increased VAS scores were occasionally reported. Most one minute post-bolus scores were ≤10 mm (little to no discomfort) while 7 of 577 were >45 mm (generally considered clinically meaningful pain). Painful infusions were reported more frequently for the arm, and mean VAS scores were higher for the arm compared with the thigh and abdomen. The VAS score distributions were similar between cannula depths. By 15 minutes post-bolus, VAS scores returned to pre-bolus levels. CONCLUSIONS: Local infusion site discomfort after infusion of URLi excipients was reported by a small subset of participants; it was transient, tolerable, and dependent on infusion site but not infusion depth. Given differences within individuals, patients may consider using a different infusion site if they experience discomfort. CLINICALTRIAL.GOV IDENTIFIER: NCT05067270.

Combinations of common SNPs of the transporter gene ABCB1 influence apparent bioavailability, but not renal elimination of oral digoxin.

Effects of different genotypes on the pharmacokinetics of probe substrates may support their use as phenotyping agents for the activity of the respective enzyme or transporter. Digoxin is recommended as a probe substrate to assess the activity of the transporter P-glycoprotein (P-gp) in humans. Current studies on the individual effects of three commonly investigated single nucleotide polymorphisms (SNPs) of the ABCB1 gene encoding P-gp (C1236T, G2677T/A, and C3435T) on digoxin pharmacokinetics are inconclusive. Since SNPs are in incomplete linkage disequilibrium, considering combinations of these SNPs might be necessary to assess the role of polymorphisms in digoxin pharmacokinetics accurately. In this study, the relationship between SNP combinations and digoxin pharmacokinetics was explored via a population pharmacokinetic approach in 40 volunteers who received oral doses of 0.5 mg digoxin. Concerning the SNPs 1236/2677/3435, the following combinations were evaluated: CGC, CGT, and TTT. Carriers of CGC/CGT and TTT/TTT had 35% higher apparent bioavailability compared to the reference group CGC/CGC, while no difference was seen in CGC/TTT carriers. No significant effect on renal clearance was observed. The population pharmacokinetic model supports the use of oral digoxin as a phenotyping substrate of intestinal P-gp, but not to assess renal P-gp activity.

A HILIC-MS/MS assay for the quantification of metformin and sitagliptin in human plasma and urine: A tool for studying drug transporter perturbation.

This article describes the development and validation of a HILIC-MS/MS method for the simultaneous quantification of metformin and sitagliptin from human plasma and urine. The presented method uses quick sample preparation and fast chromatography allowing for high sample throughput. The quantification is performed using multi-reaction monitoring and ESI positive mode with stable isotope labelled internal standards for both metformin and sitagliptin. Excellent linearity in the selected calibrations ranges, low inter-day variability (CV% <6.7%), and high accuracy (95.5-104.1%) were obtained. Adequate retention was attained for both analytes by hydrophilic interaction liquid chromatography using a plain silica column in combination with a mobile phase composed of ammonium formate, acetonitrile, formic acid and water in gradient separation mode.

Quantification of adefovir and pitavastatin in human plasma and urine by LC-MS/MS: A useful tool for drug-drug interaction studies.

As a tool to be used in transporter-mediated drug-drug interaction studies, a sensitive LC-MS/MS method for the simultaneous quantification of adefovir and pitavastatin in human plasma and adefovir in urine was developed and successfully validated. Plasma samples were processed by protein precipitation using methanol with a subsequent concentrating step. Urine samples were diluted using 0.1% formic acid. Separation was achieved on a Synergy Polar-RP reversed phase column (50 × 4.6 mm, 2.5 µm) in gradient elution using a mobile phase composed of water and 0.1% formic acid and a mixture of methanol and acetonitrile (50:50, v/v) containing 0.1% formic acid at a flow rate of 1.0 mL/min. The linear range covered concentrations from 0.273 to 52.6 ng/mL for adefovir and from 0.539 to 104.2 ng/mL for pitavastatin in human plasma, respectively. The calibration curve for adefovir in urine ranged from 0.104 to 10.0 µg/mL. The weighted linear regression (1/conc2) implied excellent linearity with correlation coefficients ≥0.999.

A Clinical Drug-Drug Interaction Study Assessing a Novel Drug Transporter Phenotyping Cocktail With Adefovir, Sitagliptin, Metformin, Pitavastatin, and Digoxin.

A new probe drug cocktail containing substrates of important drug transporters was tested for mutual interactions in a clinical trial. The cocktail consisted of (predominant transporter; primary phenotyping metric): 10 mg adefovir-dipivoxil (OAT1; renal clearance (CLR )), 100 mg sitagliptin (OAT3; CLR ), 500 mg metformin (several renal transporters; CLR ), 2 mg pitavastatin (OATP1B1; clearance/F), and 0.5 mg digoxin (intestinal P-gp, renal P-gp, and OATP4C1; peak plasma concentration (Cmax ) and CLR ). Using a randomized six-period, open change-over design, single oral doses were administrated either concomitantly or separately to 24 healthy male and female volunteers. Phenotyping metrics were evaluated by noncompartmental analysis and compared between periods by the standard average bioequivalence approach (boundaries for ratios 0.80-1.25). Primary metrics supported the absence of relevant interactions, whereas secondary metrics suggested that mainly adefovir was a victim of minor drug-drug interactions (DDIs). All drugs were well tolerated. This cocktail may be another useful tool to assess transporter-based DDIs in vivo.

CD25 and indoleamine 2,3-dioxygenase are up-regulated by prostaglandin E2 and expressed by tumor-associated dendritic cells in vivo: additional mechanisms of T-cell inhibition.

Immune tolerance is a central mechanism counteracting tumor-specific immunity and preventing effective anticancer immunotherapy. Induction of tolerance requires a specific environment in which tolerogenic dendritic cells (DCs) play an essential role deviating the immune response away from effective immunity. It was recently shown that maturation of DCs in the presence of PGE2 results in upregulation of indoleamine 2,3-dioxygenase (IDO) providing a potential mechanism for the development of DC-mediated Tcell tolerance. Here, we extend these findings, demonstrating a concomitant induction of IDO and secretion of soluble CD25 after DC maturation in the presence of PGE2. While maturation of DCs induced IDO expression on transcriptional level, only integration of PGE2 signaling led to up-regulation of functional IDO protein as well as significant expression of cell-surface and soluble CD25 protein. As a consequence, T-cell proliferation and cytokine production were significantly inhibited, which was mediated mainly by IDO-induced tryptophan depletion. Of importance, we demonstrate that different carcinoma entities associated with elevated levels of PGE2 coexpress CD25 and IDO in peritumoral dendritic cells, suggesting that PGE2 might influence IDO expression in human DCs in the tumor environment. We therefore suggest PGE2 to be a mediator of early events during induction of immune tolerance in cancer.