Phase I studies of the safety, tolerability, pharmacokinetics, and pharmacodynamics of DS-1211, a tissue-nonspecific alkaline phosphatase inhibitor.

Tissue-nonspecific alkaline phosphatase (TNAP) hydrolyzes and inactivates inorganic pyrophosphate (PPi), a potent inhibitor of calcification; therefore, TNAP inhibition is a potential target to treat ectopic calcification. These two first-in-human studies evaluated safety, tolerability, pharmacokinetics (PKs), and pharmacodynamics (PDs) of single (SAD) and multiple-ascending doses (MAD) of DS-1211, a TNAP inhibitor. Healthy adults were randomized 6:2 to DS-1211 or placebo, eight subjects per dose cohort. SAD study subjects received one dose of DS-1211 (range, 3-3000 mg) or placebo, whereas MAD study subjects received DS-1211 (range, 10-300 mg) once daily, 150 mg twice daily (b.i.d.), or placebo for 10 days. Primary end points were safety and tolerability. PK and PD assessments included plasma concentrations of DS-1211, alkaline phosphatase (ALP) activity, and TNAP substrates (PPi, pyridoxal 5'-phosphate [PLP], and phosphoethanolamine [PEA]). A total of 56 (DS-1211: n = 42; placebo: n = 14) and 40 (DS-1211: n = 30; placebo: n = 10) subjects enrolled in the SAD and MAD studies, respectively. In both studies, adverse events were mild or moderate and did not increase with dose. PKs of DS-1211 were linear up to 100 mg administered as a single dose and 150 mg b.i.d. administered as a multiple-dose regimen. In multiple dosing, there was minimal accumulation of DS-1211. Increased DS-1211 exposure correlated with dose-dependent ALP inhibition and concomitant increases in PPi, PLP, and PEA. In two phase I studies, DS-1211 appeared safe and well-tolerated. Post-treatment PD assessments were consistent with exposure-dependent TNAP inhibition. These data support further evaluation of DS-1211 for ectopic calcification diseases.

Pharmacokinetic/pharmacodynamic drug-drug interactions of avatrombopag when coadministered with dual or selective CYP2C9 and CYP3A interacting drugs.

AIMS: Avatrombopag, a thrombopoietin receptor agonist, is a substrate of cytochrome P450 (CYP) 2C9 and CYP3A. We assessed three drug-drug interactions of avatrombopag as a victim with dual or selective CYP2C9/3A inhibitors and inducers. METHODS: This was a three-part, open-label study. Forty-eight healthy subjects received single 20 mg doses of avatrombopag alone or with one of 3 CYP2C9/3A inhibitors or inducers: fluconazole 400 mg once daily for 16 days, itraconazole 200 mg twice daily on Day 1 and 200 mg once daily on Days 2-16, or rifampicin 600 mg once daily for 16 days. Pharmacokinetics, pharmacodynamics (platelet count) and safety of avatrombopag were evaluated. RESULTS: Coadministration of a single 20-mg dose of avatrombopag with fluconazole at steady-state resulted in 2.16-fold increase of AUC of avatrombopag, prolonged terminal elimination phase half-life (from 19.7 h to 39.9 h) and led to a clinically significant increase in maximum platelet count (1.66-fold). Itraconazole had a mild increase on both avatrombopag pharmacokinetics and pharmacodynamics compared to fluconazole. Coadministration of rifampicin caused a 0.5-fold decrease in AUC and shortened terminal elimination phase half-life (from 20.3 h to 9.84 h), but has no impact on maximum platelet count. Coadministration with interacting drugs was found to be generally safe and well-tolerated. CONCLUSIONS: The results from coadministration of fluconazole or itraconazole suggest that CYP2C9 plays a more predominant role in metabolic clearance of avatrombopag than CYP3A. To achieve comparable platelet count increases when avatrombopag is coadministered with CYP3A and CYP2C9 inhibitors, an adjustment in the dose or duration of treatment is recommended, while coadministration with strong inducers is not currently recommended.

A single-dose, 3-way crossover pharmacokinetic comparison between immediate-release oxycodone hydrochloride with aversion technology (IRO-A, Oxecta), IRO-a with Niacin, and Oxycodone Hydrochloride (Roxicodone) in healthy adults under fasting conditions.

Snorting and intravenous use are common routes of administration for advanced opioid abusers. A tablet form of immediate-release oxycodone (IRO) developed using Aversion Technology combines immediate release (IR) oxycodone HCl with inactive functional excipients that are intended to discourage tampering associated with intranasal and intravenous abuse (IRO-A; Oxecta, Pfizer). The purpose of this single-dose, open-label, randomized, 3-period, 3-treatment crossover study was to evaluate the bioequivalence of IRO-A to the marketed immediate-release oxycodone HCl (IRO; Roxicodone, Xanodyne Pharmaceuticals Inc., Newport, KY). IRO-A was also compared with IRO-A with niacin, a product previously developed containing the same functional excipients plus niacin as an aversive agent to discourage oral overconsumption. Healthy adults (N = 40) aged 18-55 years received single 15-mg doses of IRO-A, IRO-A with niacin (60 mg), or IRO after fasting overnight. Naltrexone was administered to diminish opioid effects. Doses were separated by a ≥7-day washout. Plasma samples taken at designated time points were analyzed using liquid chromatography with tandem mass spectrometry. Geometric mean ratios for ln-transformed parameters for IRO-A and IRO were 92%, 104%, and 104% for Cmax, AUClast (AUC is area under the concentration-time curve), and AUCinf; 90% confidence intervals were within the accepted 80%-125% range. IRO-A was also bioequivalent to IRO-A with niacin. Adverse events were mild to moderate in intensity and typical of opioid therapy (nausea, headache, vomiting). Flushing only occurred when the subjects received the IRO-A with niacin treatment (9/37 subjects). The results demonstrated that IRO-A is bioequivalent to IRO and IRO-A with niacin. With features designed to discourage tampering associated with common forms of abuse, IRO-A may provide an alternative to conventional immediate-release oxycodone formulations.

Dose proportionality and the effects of food on bioavailability of an immediate-release oxycodone hydrochloride tablet designed to discourage tampering and its relative bioavailability compared with a marketed oxycodone tablet under fed conditions: a single-dose, randomized, open-label, 5-way crossover study in healthy volunteers.

BACKGROUND: An immediate-release oxycodone hydrochloride formulation (IRO-A) indicated for moderate to severe pain was designed (by adding functional excipients) to discourage tampering associated with intranasal and intravenous abuse of prescription opioids. OBJECTIVES: The primary objective of this study was to determine the dose proportionality of oxycodone in IRO-A tablets under fasted conditions. Secondary objectives were to assess food effects on the pharmacokinetics of IRO-A tablets, to compare the relative bioavailability of oxycodone in IRO-A tablets versus marketed oxycodone hydrochloride (IRO) tablets under fed conditions and to evaluate the single-dose safety profile of the IRO-A tablets in healthy volunteers pretreated with naltrexone. METHODS: This open-label, single-dose, randomized, 5-way crossover study was conducted in healthy adults who received each of the following treatments, separated by a washout period of ≥7 days: IRO-A 1 × 5 mg, 2 × 5 mg, and 2 × 7.5 mg under fasted conditions, and IRO-A 2 × 7.5 mg and IRO 1 × 15 mg after a high-fat, high-calorie breakfast. Naltrexone was administered to minimize untoward pharmacologic effects of oxycodone. Dose proportionality (IRO-A), food effects (IRO-A), and relative bioavailability in a fed state (IRO-A and IRO) were assessed by using bioequivalence criteria (90% CIs between 80% and 125% for C(max) and AUC). RESULTS: Of the 35 adults enrolled in the study, 33 completed at least 1 dosing period. Most participants were male (54%) and white (69%), with a mean (SD) age of 32.6 (11.1) years and mean weight of 75.5 (12.3) kg. Plasma levels of oxycodone in IRO-A suggested dose-proportional pharmacokinetics; 90% CIs for dose-normalized C(max), AUC(0-last), and AUC(0-∞) fell within the 80% to 125% range. Concomitant food intake with IRO-A resulted in an ~14% reduction in oxycodone C(max) and an ~21% increase in AUC(0-last). The bioavailability of oxycodone from IRO-A tablets in the fed state was comparable with IRO tablets based on AUC parameters, although C(max) was ~16.5% lower. Reported or observed treatment-emergent adverse events were monitored throughout the study and were similar for IRO-A and IRO tablets. Nausea, headache, abdominal pain, and dizziness were the most common and are consistent with known effects of oxycodone after naltrexone blockade. CONCLUSIONS: Plasma levels of oxycodone in IRO-A tablets were compatible with proportional single-dose pharmacokinetics from 5 to 15 mg under fasted conditions. Administration of IRO-A with food suggested increased overall bioavailability relative to fasting conditions and a reduction in peak systemic exposure of oxycodone that is not expected to be clinically significant. When comparing IRO-A tablets with IRO tablets in the fed state, the overall systemic exposure of oxycodone was comparable, and peak systemic exposure was lower.