Oral paclitaxel and encequidar in patients with breast cancer: a pharmacokinetic, safety, and antitumor activity study.

Background: Paclitaxel is widely used for the treatment of metastatic breast cancer (MBC). However, it has a low oral bioavailability due to gut extrusion caused by P-glycoprotein (P-gp). Oral paclitaxel (oPAC) may be more convenient, less resource-intensive, and more tolerable than its intravenous form. Encequidar (E) is a first-in-class, minimally absorbed, gut-specific oral P-gp inhibitor that facilitates the oral absorption of paclitaxel. Objectives: To investigate the pharmacokinetics (PK), overall response rate (ORR), and safety of weekly oral paclitaxel with encequidar (oPAC + E) in patients with advanced breast cancer. Design: This is a multicenter, single-arm, open-label study in six medical centers in Taiwan. Methods: Patients with advanced breast cancer were administered 205 mg/m2 oPAC and 12.9 mg E for 3 consecutive days weekly for up to 16 weeks. Plasma samples were collected at weeks 1 and 4. PK, ORR, and safety were evaluated. Results: In all, 28 patients were enrolled; 27 had MBC; 23 had prior chemotherapy; and 14 had ⩾2 lines of prior chemotherapy. PK were evaluable in 25 patients. Plasma paclitaxel area under the curve (AUC)(0-52 h) at week 1 (3419 ± 1475 ng h/ml) and week 4 (3224 ± 1150 ng h/ml) were equivalent. Best overall response in 28 evaluable patients was partial response (PR) in 11 (39.3%), 13 (46.4%) stable disease (SD), and 1 (3.6%) with progressive disease (PD). No patient achieved complete response (CR). The clinical benefit rate (CR + PR + SD) was 85.7%. Major adverse events among the 28 treated patients were grade 3 neutropenia (25%), grade 4 neutropenia (18%), with febrile neutropenia in 4%, and grade 3 diarrhea (4%). No treatment-related deaths occurred. Grade 2 peripheral neuropathy occurred in 1 (4%) patient and grade 3 peripheral neuropathy in 1 (4%) patient. Conclusions: oPAC + E produced a consistent therapeutic plasma paclitaxel exposure during treatment. There was a high rate of radiologically assessed clinical benefit, and a low rate of neurotoxicity which may provide advantages over IV paclitaxel. Registration: ClinicalTrials.gov Identifier: NCT03165955.

Sinonasal and gastrointestinal bacterial composition and abundance are stable after 1 week of once-daily oral antibiotic treatment for chronic rhinosinusitis.

BACKGROUND: Despite the widespread prescription of antibiotics for the treatment of chronic rhinosinusitis (CRS), their efficacy remains uncertain. Limited penetration of systemic antibiotics into the sinonasal mucosa has been reported previously by this group. This study aimed to investigate the short-term effects of antibiotics on the sinus and gut microbiota as well as any relationships these had with drug distribution. METHODS: Thirty subjects undergoing functional endoscopic sinus surgery for CRS were randomized to one of three groups: (1) doxycycline (100 mg daily for 7 days); (2) roxithromycin (300 mg daily for 7 days); and (3) control (no antibiotics given). Sinonasal and stool samples collected before and after treatment were analyzed using 16S ribosomal RNA (rRNA) gene-targeted amplicon sequencing and Droplet Digital polymerase chain reaction (PCR) for bacterial community composition and the quantification of bacterial DNA, respectively. RESULTS: There were no significant major bacterial community shifts or changes to bacterial diversity and load following the treatment period in all patient groups. Non-significant trend reductions were observed in gut microbial diversity with antibiotics. For the roxithromycin group, sinonasal bacterial diversity was negatively correlated with serum drug levels and reduced overall compared to controls (p < 0.05). The relative abundance of Staphylococcus ASV129 in sinonasal samples reduced with increasing mucus doxycycline levels (p = 0.01). CONCLUSION: Antibiotic prescription for CRS should be further investigated because of preliminary evidence of poor sinonasal drug penetration, unproven efficacy, and the potential impact of dysbiosis in the sinuses and off-target sites. Further studies should consider distinguishing the presence of DNA from viable and nonviable bacteria.

Oral antibiotics used in the treatment of chronic rhinosinusitis have limited penetration into the sinonasal mucosa: a randomized trial.

Despite the widespread prescription of antibiotics for patients with chronic rhinosinusitis (CRS), the extent to which drug distribution to the sinonasal mucosa occurs remains largely undefined. Twenty subjects undergoing functional endoscopic sinus surgery (FESS) for CRS were randomized to one of two groups: 1) doxycycline (100 mg daily for seven days) 2) roxithromycin (300 mg daily for seven days). Drug levels were measured using liquid chromatography-tandem mass spectrometry in sinonasal mucus, sinonasal tissues and serum at steady state. Doxycycline concentrations measured in the mucus were significantly lower compared to that in the serum (mean mucus/serum ratio = 0.16, p < 0.001) and the tissue (mean mucus/tissue ratio = 0.18, p < 0.0001). Roxithromycin concentrations in the mucus were also significantly lower compared to that in the serum (mean mucus/serum ratio = 0.37, p = 0.002) and the tissue (mean mucus/tissue ratio = 0.60, p < 0.001). Although the efficacy of doxycycline and roxithromycin in sinonasal mucus in vivo cannot be predicted solely from reported minimum inhibitory concentrations, given the added complexity of bacterial biofilm antimicrobial tolerance, these results suggest that low mucosal penetration of antibiotics may be one of the factors contributing to the limited efficacy of these agents in the treatment of CRS.

Safety and efficacy of extended release ketamine tablets in patients with treatment-resistant depression and anxiety: open label pilot study.

BACKGROUND: Ketamine's defining side effects are dissociation and increased blood pressure/heart rate. An oral formulation with delayed absorption could minimize these effects. We recently reported safety and tolerability data for an extended release ketamine tablet in healthy volunteers. METHODS: To assess safety, tolerability, efficacy, and pharmacokinetics of an extended release oral ketamine tablet in patients with treatment-resistant depression/anxiety. This was a multiple dose open-label flexible dose uncontrolled study in seven patients with treatment-resistant depression/anxiety, who had all previously demonstrated mood improvement to subcutaneous ketamine. Assessments included ratings of anxiety, depression and dissociation, safety and tolerability, and blood samples for ketamine pharmacokinetics and brain-derived neurotrophic factor (BDNF) concentrations. RESULTS: Improvements in anxiety and depression ratings occurred gradually over 96 h; all patients had >50% improvements in mood ratings. Ketamine was safe and well tolerated, with no changes in vital signs, and a single brief report of dissociation. Ketamine may induce its own metabolism, as the ratio of norketamine to ketamine increased out to 96 h. Serum BDNF concentrations did not change during the study. CONCLUSION: Ketamine's safety/tolerability may be improved with an extended release oral formulation. Onset of mood improvement is slightly delayed compared with parenteral dosing. These data support the further development of extended release ketamine tablets for treatment of resistant depression and anxiety disorders.

Bioequivalence Study of 2 Capsule Formulations of Fingolimod 0.5 mg Assessing Both Parent Drug and Active Metabolite in New Zealand Healthy Subjects (Truncated Design).

Fingolimod is indicated for the treatment of patients with the relapsing-remitting form of multiple sclerosis. The primary study objective was to evaluate the bioequivalence of a test formulation, 0.5 mg fingolimod HCl capsule (Lebrina, Asofarma Sociedad Anónima Industrial y Comercial, Argentina) relative to a reference formulation, 0.5 mg fingolimod capsule (Gilenya, Novartis Pharmaceutical, Australia). In a single-center, randomized, single-dose, single-blinded, 2-way crossover study, 33 New Zealand healthy subjects of both sexes were enrolled to receive a 0.5-mg dose of 3 capsules of each fingolimod formulation under fasting conditions, with a 42-day washout period between administrations. Additional pharmacokinetic information regarding its main active metabolite, fingolimod phosphate, was also provided. The point estimate and 90% confidence intervals of the ratios of maximum concentration and area under the plasma concentration-time curve from time 0 to 72 hours were 99.07 (95.83-102.41) and 97.64 (95.33-100.00) for fingolimod, and 95.60 (90.95-100.49) and 98.54 (96.19-100.96), for fingolimod phosphate. Primary parameters, maximum concentration and area under the plasma concentration-time curve from time 0 to 72 hours for fingolimod and fingolimod phosphate were found to have no significant difference when test and reference formulations were compared. Fingolimod and fingolimod phosphate of both formulations were within the accepted 90% confidence interval limits of 80.00% and 125.00%. No significant differences between the test and reference drug products were detected in any of the pharmacokinetic parameters estimated. Notwithstanding the primary conclusion of bioequivalence is focused on the measurement of the parent compound, compliance with the same criteria by the active metabolite reinforces the comparability between the pharmacokinetic profiles of both formulations (ClinicalTrials.gov Identifier: NCT03757338).

Steady-State Clozapine and Norclozapine Pharmacokinetics in Maori and European Patients.

BACKGROUND: Clozapine is the most effective drug for treatment-resistant schizophrenia, but its use is limited by toxicity. Because ethnicity has been reported to affect clozapine metabolism, we compared its steady state pharmacokinetics in New Zealand Maori and European patients. METHODS: Clozapine and norclozapine steady state bioavailability was assessed over 24h under fasting and fed conditions in 12 Maori and 16 European patients treated for chronic psychotic illnesses with stable once-daily clozapine doses. Plasma clozapine and norclozapine concentrations were assessed using liquid chromatography with tandem mass spectrometry; pharmacokinetic parameters were calculated using standard non-compartmental methods, and compared using unpaired t-tests. FINDINGS: Mean pharmacokinetic parameters (AUC, Cmax and Cmin) for clozapine and norclozapine were virtually identical in Maori and European subjects, under both fed and fasted conditions. DISCUSSION: Clozapine bioavailability does not vary between Maori and European patients, and thus does not need to be considered in prescribing decisions. Additional studies are needed to identify if there are differences between Maori and European populations for drugs metabolized by other enzyme pathways.

Ascending-dose study of noribogaine in healthy volunteers: pharmacokinetics, pharmacodynamics, safety, and tolerability.

Noribogaine is the active metabolite of the naturally occurring psychoactive substance ibogaine, and may help suppress withdrawal symptoms in opioid-dependent subjects. The objectives of this Phase I study were to assess the safety, tolerability, pharmacokinetic, and pharmacodynamic profiles of noribogaine. In this ascending single-dose, placebo-controlled, randomized, double-blind, parallel-group study in 36 healthy drug-free male volunteers, 4 cohorts (n = 9) received oral doses of 3, 10, 30, or 60 mg or matching placebo, with intensive safety and pharmacokinetic assessments out to 216 hours, along with pharmacodynamic assessments sensitive to the effects of mu-opioid agonists. Noribogaine was rapidly absorbed, with peak concentrations occurring 2-3 hours after oral dosing, and showed dose-linear increases of area under the concentration-time curve (AUC) and Cmax between 3 and 60 mg. The drug was slowly eliminated, with mean half-life estimates of 28-49 hours across dose groups. Apparent volume of distribution was high (mean 1417-3086 L across dose groups). No safety or tolerability issues were identified in any cohort. No mu-opioid agonist pharmacodynamic effects were noted in pupillometry or cold-pressor testing. Single oral doses of noribogaine 3-60 mg were safe and well tolerated in healthy volunteers.