BACKGROUND:Methylnaltrexone has been shown to be effective for treating opioid-induced constipation (OIC) in chronic settings, but its effects on acute OIC have not been studied.
This randomized, double-blind, parallel-group multiple-ascending-dose study evaluated the safety, tolerability, and pharmacokinetics of tramadol hydrochloride in healthy adults to inform dosage and design for a subsequent QT/QTc study. Healthy men and women, 18 to 45 years old (inclusive), were sequentially assigned to the tramadol 200, 400, or 600 mg/day treatment cohort and within each cohort, randomized (4:1) to either tramadol or placebo every 6 hours for 9 oral doses. Of the 24 participants randomized to tramadol (n = 8/cohort), 22 (91.7%) completed the study. The AUC of tramadol increased approximately 2.2- and 3.6-fold for the (+) enantiomer and 2.0- and 3.5-fold for the (-) enantiomer with increasing dose from 200 to 400 and 600 mg/day, whereas the C increased 2.1- and 3.3-fold for the (+) enantiomer and 2.0- and 3.2-fold for the (-) enantiomer. Overall, 21 participants (87.5%) participants reported ≥1 treatment-emergent adverse event; most frequent were nausea (17 of 24, 70.8%) and vomiting (7 of 24, 29.2%). Vomiting (affected participants and events) increased with increasing dose from 200 to 600 mg/day but was mild (5 of 24) or moderate (2 of 24) in severity. All tested dosage regimens of tramadol showed acceptable safety and tolerability profile for further investigation in a thorough QT/QTc study.
158 Background: The unique expression of PSMA type II transmembrane glycoprotein on prostate cancer cells provides a potentially attractive target for antibody therapy. PSMA ADC, a fully humanized antibody to PSMA linked to the potent antitubulin agent monomethyl auristatin E (MMAE), binds PSMA and is internalized within the prostate cancer cell where cleavage and release of free MMAE occur, causing cell cycle arrest and apoptosis. We report results from an ongoing phase I dose escalation study of PSMA ADC in patients (pts) with taxane refractory metastatic prostate cancer (metCRPC). Methods: Eligibility requirements included pts ≥18 years with metCRPC after failure of a taxane- containing regimen and ECOG status of 0 or 1. PSMA ADC is administered by IV infusion Q3W for up to 4 cycles. Adverse events, PK, PSA, circulating tumor cells, clinical disease progression and immunogenic response to PSMA ADC continue to be assessed. Serum concentrations of PSMA ADC and total antibody are measured by an enzyme-linked immunosorbent assay (ELISA) method, and free MMAE is measured by liquid chromatography/mass spectrometry/mass spectrometry (LC/MS/MS) method. Dosing cohorts ranged from 0.4 mg/kg to 1.8 mg/kg. Results: The demographics of 15 subjects enrolled in the four dosing cohorts (0.4, 0.7, 1.1 and 1.8 mg/kg) were similar. Treatment has to date been generally well tolerated and the most common laboratory abnormalities were reversible changes in liver and hematological parameters. Exposure to PSMA ADC and serum half life (t1/2) increased in a dose-proportional manner. Similar PK metrics were observed after the first and third doses. Exposure to free MMAE was also dose proportional and approximately <0.1% of PSMA ADC. Conclusions: In this first-in-human evaluation, PSMA ADC appears to exhibit dose-proportional PK and limited release of free MMAE. Ongoing enrollment allows for assessment of potential clinical utility of this unique potential treatment of metCRPC. [Table: see text]
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