Simulated Target Attainment of Multidose Regimens of Dalbavancin for Prolonged Durations of Therapy.

Background: Dalbavancin is a long-acting lipoglycopeptide antibiotic that is increasingly utilized for infections that require prolonged treatment durations despite the lack of Food and Drug Administration approval for these indications. There is no consensus regarding optimal dosing of dalbavancin for these infections and no available pharmacokinetic studies to identify optimal dosing for long-term use. Methods: An in silico pharmacokinetic simulation was performed to assess the predicted dalbavancin concentration resulting from commonly utilized dosing regimens, in addition to modified regimens. The primary endpoint evaluated was days of median 24-hour free area under the curve over the minimum inhibitory concentration (AUC/MIC) >27.1, the established PK target. Results: A dosing regimen of 1500 mg on day 0 and day 7 resulted in median AUC/breakpoint value above the target for 57 days (lower 95% confidence interval [CI], 37 days). A modified regimen of 1500 mg on day 0 and day 21 resulted in an additional 11 days of median AUC/breakpoint target attainment. The other standard dosing regimen modeled was 1000 mg on day 0, then 500 mg weekly for 5 doses. This regimen achieved the AUC/breakpoint target for 76 days (lower 95% CI, 59 days). This regimen was modified to 1000 mg on day 0, then 500 mg on days 14 and 28, which shortened the median effective treatment duration by 14 days but required 3 fewer doses. Conclusions: These simulated results, when combined with the favorable observational data, support the use of commonly reported dalbavancin regimens for prolonged therapy durations. In addition, these pharmacokinetic/pharmacodynamic data support extending the dosing interval beyond the frequently reported weekly regimens, which should be investigated further with a clinical trial.

Reference Range of Hydroxychloroquine Blood Levels That Can Reduce Odds of Active Lupus and Prevent Flares.

OBJECTIVE: Recent data show that lower hydroxychloroquine (HCQ) doses are associated with a two- to six-fold higher risk of lupus flares. Thus, establishing an effective reference range of HCQ blood levels with upper and lower bounds for efficacy may support individualizing HCQ dosing to prevent flares. METHODS: HCQ levels in whole blood and Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) were measured during the baseline visit and again during a standard of care routine follow-up visit. Active cross-sectional lupus at baseline was defined as SLEDAI ≥6; a within subject flare was defined as a subsequent three-point increase in SLEDAI with clinical symptoms requiring therapy change. We examined associations between active lupus and HCQ blood levels at baseline and flares and HCQ levels during 6 to 12-month routine lupus follow-up visits using mixed regression analysis. RESULTS: Among 158 baseline patient visits, 19% had active lupus. Odds of active lupus were 71% lower in patients with levels within a 750 to 1,200 ng/mL range (adjusted odds ratio 0.29, 95% confidence interval 0.08-0.96). Using convenience sampling strategy during a pandemic, we longitudinally followed 42 patients. Among those patients, 17% flared during their follow-up visit. Maintaining HCQ levels within 750 to 1,200 ng/mL reduced the odds of a flare by 26% over a nine-month median follow-up. CONCLUSION: An effective reference range of HCQ blood levels, 750 to 1,200 ng/mL, was associated with 71% lower odds of active lupus, and maintaining levels within this range reduced odds of flares by 26%. These findings could guide clinicians to individualize HCQ doses to maintain HCQ levels within this range to maximize efficacy.

Pharmacokinetic analysis of acute and dietary exposure to piperonyl butoxide in the mouse.

Piperonyl butoxide (PBO) is a popular insecticide synergist present in thousands of commercial, agricultural, and household products. PBO inhibits cytochrome P450 activity, impairing the ability of insects to detoxify insecticides. PBO was recently discovered to also inhibit Sonic hedgehog signaling, a pathway required for embryonic development, and rodent studies have demonstrated the potential for in utero PBO exposure to cause structural malformations of the brain, face, and limbs, or more subtle neurodevelopmental abnormalities. The current understanding of the pharmacokinetics of PBO in mice is limited, particularly with respect to dosing paradigms associated with developmental toxicity. To establish a pharmacokinetic (PK) model for oral exposure, PBO was administered to female C57BL/6J mice acutely by oral gavage (22-1800 mg/kg) or via diet (0.09 % PBO in chow). Serum and adipose samples were collected, and PBO concentrations were determined by HPLC-MS/MS. The serum concentrations of PBO were best fit by a linear one-compartment model. PBO concentrations in visceral adipose tissue greatly exceeded those in serum. PBO concentrations in both serum and adipose tissue decreased quickly after cessation of dietary exposure. The elimination half-life of PBO in the mouse after gavage dosing was 6.5 h (90 % CI 4.7-9.5 h), and systemic oral clearance was 83.3 ± 20.5 mL/h. The bioavailability of PBO in chow was 41 % that of PBO delivered in olive oil by gavage. Establishment of this PK model provides a foundation for relating PBO concentrations that cause developmental toxicity in the rodent models to Sonic hedgehog signaling pathway inhibition.

Single-Dose Psilocybin Treatment for Major Depressive Disorder: A Randomized Clinical Trial.

Importance: Psilocybin shows promise as a treatment for major depressive disorder (MDD). Objective: To evaluate the magnitude, timing, and durability of antidepressant effects and safety of a single dose of psilocybin in patients with MDD. Design, Setting, and Participants: In this phase 2 trial conducted between December 2019 and June 2022 at 11 research sites in the US, participants were randomized in a 1:1 ratio to receive a single dose of psilocybin vs niacin placebo administered with psychological support. Participants were adults aged 21 to 65 years with a Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition diagnosis of MDD of at least 60 days' duration and moderate or greater symptom severity. Exclusion criteria included history of psychosis or mania, active substance use disorder, and active suicidal ideation with intent. Participants taking psychotropic agents who otherwise met inclusion/exclusion criteria were eligible following medication taper. Primary and secondary outcomes and adverse events (AEs) were assessed at baseline (conducted within 7 days before dosing) and at 2, 8, 15, 29, and 43 days after dosing. Interventions: Interventions were a 25-mg dose of synthetic psilocybin or a 100-mg dose of niacin in identical-appearing capsules, each administered with psychological support. Main Outcomes and Measures: The primary outcome was change in central rater-assessed Montgomery-Asberg Depression Rating Scale (MADRS) score (range, 0-60; higher scores indicate more severe depression) from baseline to day 43. The key secondary outcome measure was change in MADRS score from baseline to day 8. Other secondary outcomes were change in Sheehan Disability Scale score from baseline to day 43 and MADRS-defined sustained response and remission. Participants, study site personnel, study sponsor, outcome assessors (raters), and statisticians were blinded to treatment assignment. Results: A total of 104 participants (mean [SD] age, 41.1 [11.3] years; 52 [50%] women) were randomized (51 to the psilocybin group and 53 to the niacin group). Psilocybin treatment was associated with significantly reduced MADRS scores compared with niacin from baseline to day 43 (mean difference,-12.3 [95% CI, -17.5 to -7.2]; P <.001) and from baseline to day 8 (mean difference, -12.0 [95% CI, -16.6 to -7.4]; P < .001). Psilocybin treatment was also associated with significantly reduced Sheehan Disability Scale scores compared with niacin (mean difference, -2.31 [95% CI, 3.50-1.11]; P < .001) from baseline to day 43. More participants receiving psilocybin had sustained response (but not remission) than those receiving niacin. There were no serious treatment-emergent AEs; however, psilocybin treatment was associated with a higher rate of overall AEs and a higher rate of severe AEs. Conclusions and Relevance: Psilocybin treatment was associated with a clinically significant sustained reduction in depressive symptoms and functional disability, without serious adverse events. These findings add to increasing evidence that psilocybin-when administered with psychological support-may hold promise as a novel intervention for MDD. Trial Registration: ClinicalTrials.gov Identifier: NCT03866174.

Clinical utility of a regional precision medicine molecular tumor board and challenges to implementation.

PURPOSE: Molecular tumor boards provide precision treatment recommendations based on cancer genomic profile. However, practical barriers limit their benefits. We studied the clinical utility of the precision medicine molecular tumor board (PMMTB) and described challenges with PMMTB implementation. METHODS: An observational cohort study included patients reviewed by the PMMTB between September 2015 to December 2017. Patients who had consented to the registry study were included. The primary endpoint of this study was time on treatment (ToT) ratio. Clinical utility was established if the primary endpoint had least 15% of patients achieving a ToT ratio of ≥1.3. RESULTS: Overall, 278 patients were presented to the PMMTB and 113 cases were included in the final analysis. The PMMTB identified at least one nonstandard of care (SOC) clinically actionable mutation for 69.0% (78/113) of cases. In patients who received non-SOC treatment, 43.8% (7/16) achieved a ToT ratio of 1.3 or more (p < 0.001). Fifty-nine patients did not receive non-SOC recommendations. Reasons for not pursuing treatment included 35.6% having response to current treatment, 20.3% died prior to starting or considering PMMTB recommendations, 13.6% pursued other treatment options based on clinician discretion, another 10.2% pursued other treatment options because clinical trials recommended were not geographically accessible, 8.5% had rapid decline of performance status, 6.8% lacked of financial support for treatment, and 5.1% were excluded from clinical trials due to abnormal laboratory values. CONCLUSION: The regional PMMTB non-SOC recommendations benefitted a majority of patients and additional processes were implemented to assist with non-SOC treatment accessibility.

Phase 2 study of anti-disialoganglioside antibody, dinutuximab, in combination with GM-CSF in patients with recurrent osteosarcoma: A report from the Children's Oncology Group.

PURPOSE: Novel effective therapies are urgently needed in recurrent osteosarcoma. GD2 is expressed in human osteosarcoma tumours and cell lines. This study evaluated the disease control rate (DCR) in patients with recurrent osteosarcoma treated with the anti-GD2 antibody dinutuximab plus cytokine therapy as compared to historical outcomes. METHODS: AOST1421 was a single-arm Phase 2 study for patients with recurrent pulmonary osteosarcoma in complete surgical remission. Patients received up to five cycles of dinutuximab (70 mg/m2/cycle) with granulocyte-macrophage colony-stimulating factor (GM-CSF). Two different dinutuximab infusion schedules were studied: 35 mg/m2/day over 20 h (2 days) and 17.5 mg/m2/day over 10 h (4 days). Primary end point was DCR, defined as a proportion of patients event free at 12 months from enrolment. The historical benchmark was 12-month DCR of 20% (95% CI 10-34%). Dinutuximab would be considered effective if ≥ 16/39 patients remained event free. Secondary objectives included toxicity evaluation and pharmacokinetics. RESULTS: Thirty-nine eligible patients were included in the outcome analysis. Dinutuximab did not demonstrate evidence of efficacy as 11/39 patients remained event free for a DCR of 28.2% (95% CI 15-44.9%). One of 136 administered therapy cycles met criteria for unacceptable toxicity when a patient experienced sudden death of unknown cause. Other ≥ Grade 3 toxicities included pain, diarrhoea, hypoxia, and hypotension. Pharmacokinetic parameters were similar in the two schedules. CONCLUSIONS: The combination of dinutuximab with GM-CSF did not significantly improve DCR in recurrent osteosarcoma. Dinutuximab toxicity and pharmacokinetics in adolescent and young adult osteosarcoma patients were similar to younger patients. Other strategies for targeting GD2 in osteosarcoma are being developed.

Safety, Pharmacokinetic, and Pharmacodynamic Study of a Sublingual Formula for the Treatment of Vasovagal Syncope.

BACKGROUND: Vasovagal syncope is a common cause of syncope which, if recurrent, can have multiple negative consequences such as injury and occupational disability. Various medications can be used to decrease the recurrence of vasovagal syncope but there are no drugs that can be used by patients to interrupt a perceived vasovagal episode. METHODS: A phase I study was performed to evaluate the tolerability and safety of a gel formulation containing capsaicin (1 mg), phenylephrine HCL (PE) and caffeine citrate (200 mg) (CPC) in normal adult volunteers. Secondary objectives were to characterize the pharmacokinetics (PK) of the CPC formulation and the highest dose of PE needed to achieve a target increase in systolic BP of at least 40 mmHg. After receiving the first dose, a second dose of the CPC mixture was administered at 2 h. Suboptimal changes in systolic blood pressure (SBP) were noted at PE doses of 0.6, 1.2, and 1.8 mg, therefore a second cohort was studied at PE doses of 10, 20, and 30 mg. Blood samples were collected in rapid sequence and were assayed for all three drugs. RESULTS: A total of 17 subjects received the drug with no serious adverse effects reported. All doses were well tolerated, although the capsaicin content usually caused expected temporary oral and gastric discomfort. One subject did not complete the study because of a vasovagal reaction that was associated with the frequent blood sampling. There was a 5-25 min lag in the appearance of measurable blood concentrations of capsaicin and phenylephrine. Most subjects had baseline caffeine concentrations from dietary use, with a gradual increase noted after 15 min consistent with GI absorption. Although the intended criterion of a 40 mmHg increase in SBP was not reached, a clinically significant increase in BP for at least 15 min was noted in the six subjects who received the highest dose of PE (30 mg), with a gradual decline over the next 2 h. CONCLUSION: The ternary mixture of capsaicin, phenylephrine, and caffeine was well tolerated when administered as two sublingual/oral doses over a 2-h period.

Exposure-Response Analysis to Assess the Concentration-QTc Relationship of Psilocybin/Psilocin.

Psilocybin is being developed for treating major depressive disorder. Psilocybin is readily dephosphorylated to psilocin upon absorption. The potential for psilocin proarrhythmic effect was assessed using a concentration-QTc interval (C-QTc) analysis from an open-label single ascending dose study of psilocybin. Psilocybin doses ranged from 0.3 to 0.6 mg/kg. This trial showed a significant but shallow C-QTc relationship. At the clinical dose of 25 mg, the mean psilocin maximum concentration is 18.7 ng/mL, and the associated mean (upper 90% confidence interval of mean) QTcF change is 2.1 (6.6) milliseconds. Given the short half-life of psilocin of about 4 hours, there would be no accumulation after monthly oral doses used in clinical trials. The upper limit of the 90% confidence interval of the model-predicted mean ΔQTcF crossed 10 milliseconds at a psilocin concentration of 31.1 ng/mL. At a supraclinical psilocin maximum concentration of about 60 ng/mL, ΔQTcF remains low, with a mean (upper limit of the 90% confidence interval) of 9.1 (17.9) milliseconds. This analysis enabled the characterization of the C-QTc relationship and prediction of QTc prolongation at the expected clinical and possible higher psilocybin doses.

A Phase 1 and pharmacokinetic study evaluating daily or weekly schedules of the humanized anti-GD2 antibody hu14.18K322A in recurrent/refractory solid tumors.

Hu14.18K322A is a humanized anti-GD2 monoclonal antibody with a single point mutation that reduces complement-mediated cytotoxicity, with a maximum tolerated dose (MTD) of 60 mg/m2 daily for 4 days in children with recurrent/refractory neuroblastoma. We report additional results of a Phase 1 trial to determine the MTD and safety profile of hu14.18K322A in patients with osteosarcoma, and of an alternative schedule of weekly hu14.18K322A administration in patients with neuroblastoma or osteosarcoma. Eligible patients with recurrent/refractory osteosarcoma received hu14.13K22A daily x4 every 28 days in a Phase 1 traditional 3 + 3 dose escalation design. Additional patients with osteosarcoma were then enrolled to receive hu14.18K322A once weekly for 4 weeks per course. Patients with recurrent/refractory neuroblastoma were also enrolled on the weekly schedule at 50 mg/m2/dose. Six patients with osteosarcoma treated on the daily schedule received a median of 2 (range 1-6) courses; the recommended daily dose was established as 60 mg/m2. Three patients had stable disease (SD) as best overall response. Five patients (3 neuroblastoma, 2 osteosarcoma) enrolled on the weekly schedule received a median of 1 (1-3) course; 2 achieved SD as best overall response. Pain, fever, hematologic toxicities, hyponatremia, and ocular/visual abnormalities were common toxicities among both schedules. Dose-limiting toxicities attributed to hu14.18K322A included anorexia and fatigue (n = 1). Pharmacokinetic profiles were similar between daily and weekly schedules. The recommended dose for patients with osteosarcoma receiving daily hu14.18K322A x4 is 60 mg/m2. Patients receiving the weekly schedule experienced similar pharmacokinetics and toxicity profile as the daily schedule.

A Two-Dose Oritavancin Regimen Using Pharmacokinetic Estimation Analysis.

BACKGROUND: Antibiotics for the treatment of complicated, multidrug-resistant Gram-positive infections are limited, especially when prolonged treatment is necessary. Oritavancin is approved for the treatment of serious skin infections as a 1200 mg single-dose regimen, but case reports describe supplemental doses given at weekly intervals ranging from 800 mg to 1200 mg.   OBJECTIVE: This study determined population pharmacokinetic estimates for a 1200 mg single dose with and without an 800 mg dose 1 week apart. METHODS: A simulated oritavancin 1200 mg dose was infused over 3 h followed 7 days later by a simulated 800 mg dose infused over 3 h for pharmacokinetic estimation. RESULTS: The oritavancin dosing displayed predictable linear pharmacokinetics and therapeutic concentrations. The total and free oritavancin concentrations remained above the susceptibility breakpoint (0.12 mg/L) for 8 weeks and 4.6 weeks, respectively, with the two-dose regimen. This was significantly greater than the single-dose regimen. This regimen also results in a greater area under the drug concentration-time curve (AUC) above the susceptibility breakpoint compared to the single-dose regimen (p < 0.001), and it maintains a high AUC:minimum inhibitory concentration (MIC) ratio against organisms with MICs up to 0.25 mg/L. CONCLUSION: These results along with the observational clinical reports of success and safety with this dosing scheme of 1200 mg followed by 800 mg 7 days later provide evidence for further evaluation of this approach when prolonged oritavancin treatment may be indicated.

The experimental effects of psilocybin on symptoms of anxiety and depression: A meta-analysis.

The current meta-analysis examined the effects of psilocybin in combination with behavioral interventions on anxiety and depression in samples with elevated symptoms. Across four studies (one uncontrolled; three randomized, placebo-controlled; N = 117), within-group pre-post and pre-follow-up effects on anxiety and depression were large (Hedges' gs=1.16 to 1.47) and statistically significant. Across three placebo-controlled studies, pre-post placebo-controlled effects were also large (gs = 0.82 to 0.83) and statistically significant. No serious adverse events were reported. Limitations include the small number of studies and risk for bias within studies. Results tentatively support future research on psilocybin for the treatment of anxiety and depression.

High dose psilocybin is associated with positive subjective effects in healthy volunteers.

AIM: The aim of the current study was to investigate the relationship between escalating higher doses of psilocybin and the potential psilocybin occasioned positive subjective effects. METHODS: Healthy participants ( n=12) were given three escalating doses of oral psilocybin (0.3 mg/kg; 0.45 mg/kg; 0.6 mg/kg) or (18.8-36.6 mg; 27.1-54.0 mg; 36.3-59.2 mg) a minimum of four weeks apart in a supervised setting. Blood and urine samples, vital signs, and electrocardiograms were obtained. Subjective effects were assessed using the Mystical Experience Questionnaire and Persisting Effects Questionnaire. RESULTS: There was a significant linear dose-related response in Mystical Experience Questionnaire total score and the transcendence of time and space subscale, but not in the rate of a complete mystical experience. There was also a significant difference between dose 3 compared to dose 1 on the transcendence of time and space subscale, while no dose-related differences were found for Mystical Experience Questionnaire total scores or rate of a mystical experience. Persisting Effects Questionnaire positive composite scores 30 days after completion of the last dose were significantly higher than negative composite scores. Persisting Effects Questionnaire results revealed a moderate increase in sense of well-being or life satisfaction on average that was associated with the maximum Mystical Experience Questionnaire total score. Pharmacokinetic measures were associated with dose but not with Mystical Experience Questionnaire total scores or rate of a mystical experience. CONCLUSIONS: High doses of psilocybin elicited subjective effects at least as strong as the lower doses and resulted in positive persisting subjective effects 30 days after, indicating that a complete mystical experience was not a prerequisite for positive outcomes.

The Adherence Rate Threshold is Drug Specific.

INTRODUCTION: Patient adherence to a medication regimen is usually expressed as an adherence rate, defined as the proportion of prescribed doses actually taken. An adherence rate threshold, above which the therapeutic effect is maintained, is typically assigned an arbitrary value, commonly 0.8. OBJECTIVE: Here, we determined the value of the adherence rate threshold objectively in different drugs of the same class, using statins as an example. METHODS: We used pharmacokinetic/pharmacodynamic (PK/PD) modeling to predict serum levels of low-density lipoprotein cholesterol (LDL-C) in patients taking simvastatin 20 mg or atorvastatin 5 mg once daily for 30 days. LDL-C reduction was modeled for adherence rates of 1.0, 0.8, 0.6, 0.4, and 0.2. The results were expressed as the percentage of time spent at the LDL-C goal (< 70 mg/dL). The adherence rate threshold was defined as the minimum adherence rate that resulted in the same amount of time at goal as perfect adherence (i.e., a rate of 1.0). RESULTS: For simvastatin, an adherence rate of 0.8 resulted in a significant decrease in time at the LDL-C goal compared to perfect adherence (54.8% versus 85.1%; P < 0.001), and rates < 0.8 resulted in progressively less time at goal. For atorvastatin, the rates of 0.8 and 0.6 resulted in essentially the same amount of time at goal as perfect adherence (87.8% and 87.7%, respectively, versus 88.1%; P > 0.05 for both), with less time at goal only occurring at rates ≤ 0.4 (P < 0.001). Thus, the adherence rate thresholds are > 0.8 for simvastatin and between 0.4 and 0.6 for atorvastatin. CONCLUSION: These results indicate that a value of 0.8 cannot be applied universally.

A Pilot Trial of Humanized Anti-GD2 Monoclonal Antibody (hu14.18K322A) with Chemotherapy and Natural Killer Cells in Children with Recurrent/Refractory Neuroblastoma.

Purpose: Anti-GD2 mAbs, acting via antibody-dependent cell-mediated cytotoxicity, may enhance the effects of chemotherapy. This pilot trial investigated a fixed dose of a unique anti-GD2 mAb, hu14.18K322A, combined with chemotherapy, cytokines, and haploidentical natural killer (NK) cells.Experimental Design: Children with recurrent/refractory neuroblastoma received up to six courses of hu14.18K322A (40 mg/m2/dose, days 2-5), GM-CSF, and IL2 with chemotherapy: cyclophosphamide/topotecan (courses 1,2), irinotecan/temozolomide (courses 3,4), and ifosfamide/carboplatin/etoposide (courses 5,6). Parentally derived NK cells were administered with courses 2, 4, and 6. Serum for pharmacokinetic studies of hu14.18K322A, soluble IL2 receptor alpha (sIL2Rα) levels, and human antihuman antibodies (HAHA) were obtained.Results: Thirteen heavily pretreated patients (9 with prior anti-GD2 therapy) completed 65 courses. One patient developed an unacceptable toxicity (grade 4 thrombocytopenia >35 days). Four patients discontinued treatment for adverse events (hu14.18K322A allergic reaction, viral infection, surgical death, second malignancy). Common toxicities included grade 3/4 myelosuppression (13/13 patients) and grade 1/2 pain (13/13 patients). Eleven patients received 29 NK-cell infusions. The response rate was 61.5% (4 complete responses, 1 very good partial response, 3 partial responses) and five had stable disease. The median time to progression was 274 days (range, 239-568 days); 10 of 13 patients (77%) survived 1 year. Hu14.18K322A pharmacokinetics was not affected by chemotherapy or HAHA. All patients had increased sIL2Rα levels, indicating immune activation.Conclusions: Chemotherapy plus hu14.18K322A, cytokines, and NK cells is feasible and resulted in clinically meaningful responses in patients with refractory/recurrent neuroblastoma. Further studies of this approach are warranted in patients with relapsed and newly diagnosed neuroblastoma. Clin Cancer Res; 23(21); 6441-9. ©2017 AACR.

Pharmacokinetics of Escalating Doses of Oral Psilocybin in Healthy Adults.

INTRODUCTION: Psilocybin is a psychedelic tryptamine that has shown promise in recent clinical trials for the treatment of depression and substance use disorders. This open-label study of the pharmacokinetics of psilocybin was performed to describe the pharmacokinetics and safety profile of psilocybin in sequential, escalating oral doses of 0.3, 0.45, and 0.6 mg/kg in 12 healthy adults. METHODS: Eligible healthy adults received 6-8 h of preparatory counseling in anticipation of the first dose of psilocybin. The escalating oral psilocybin doses were administered at approximately monthly intervals in a controlled setting and subjects were monitored for 24 h. Blood and urine samples were collected over 24 h and assayed by a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay for psilocybin and psilocin, the active metabolite. The pharmacokinetics of psilocin were determined using both compartmental (NONMEM) and noncompartmental (WinNonlin) methods. RESULTS: No psilocybin was found in plasma or urine, and renal clearance of intact psilocin accounted for less than 2% of the total clearance. The pharmacokinetics of psilocin were linear within the twofold range of doses, and the elimination half-life of psilocin was 3 h (standard deviation 1.1). An extended elimination phase in some subjects suggests hydrolysis of the psilocin glucuronide metabolite. Variation in psilocin clearance was not predicted by body weight, and no serious adverse events occurred in the subjects studied. CONCLUSIONS: The small amount of psilocin renally excreted suggests that no dose reduction is needed for subjects with mild-moderate renal impairment. Simulation of fixed doses using the pharmacokinetic parameters suggest that an oral dose of 25 mg should approximate the drug exposure of a 0.3 mg/kg oral dose of psilocybin. Although doses of 0.6 mg/kg are in excess of likely therapeutic doses, no serious physical or psychological events occurred during or within 30 days of any dose. CLINICAL TRIALS IDENTIFIER: NCT02163707.

Compatibility of cefepime and vancomycin during simulated Y-site administration of prolonged infusion.

PURPOSE: The physical and chemical compatibility of cefepime and vancomycin at concentrations typically used in prolonged-infusion cefepime infusions was assessed. METHODS: Samples from a typical Y-site configuration of standard-infusion vancomycin and prolonged-infusion cefepime were collected at various time points during the simulated 4-hour infusion. Samples were analyzed by visual inspection, spectrophotometry, and high-performance liquid chromatography (HPLC). Infusion antibiotics were reconstituted in pairwise combinations of 0.9% sodium chloride injection and 5% dextrose injection to determine the effects of solvent selection on stability. Infusion simulations were performed in triplicate without light protection under fluorescent lighting at room temperature (22.5 °C). Experimental replicates were not run simultaneously but on sequential days due to the considerable time (~12 hours) required to analyze samples obtained from a single infusion simulation and the known time-dependent instability of reconstituted cefepime beyond 24 hours. Physical stability was assessed visually for evidence of particulate formation, haze, precipitation, color change, and gas evolution. Samples were also assessed spectrophotometrically at 600 nm at the time of collection and 24 hours after collection. RESULTS: Cefepime was compatible with vancomycin at the concentrations tested. The solvent selected (0.9% sodium chloride or 5% dextrose) to reconstitute either antibiotic had no impact on compatibility. Solutions were indistinguishable from positive and negative controls (heat-degraded cefepime and freshly reconstituted cefepime, respectively) at all time points assessed in terms of visual clarity, spectrophotometric absorbance, and HPLC recovery. CONCLUSION: Cefepime and vancomycin were physically and chemically compatible during simulated Y-site administration of prolonged-infusion cefepime.

Intravenous lidocaine for neuropathic pain: a retrospective analysis of tolerability and efficacy.

OBJECTIVES: This study was designed to describe the efficacy and toxicity of intravenous (i.v.) lidocaine infusions for the treatment of neuropathic pain initially administered at a flat-rate trial dose of 500 mg over 30 minutes. SETTING: Academic, tertiary care hospital and infusion center. METHODS: Data were retrospectively collected and analyzed for efficacy, correlations between infusion rates with adverse effects, patterns of infusion rate adjustments, and infusion frequencies. RESULTS: The average rate for all infusions was 9.1 mg/min. Efficacy was seen in 45 patients (65%), and all but eight patients (12%) required infusion rate reductions from the initial test rate of 16.7 mg/min due to adverse effects. Fifty-five patients experienced adverse effects, with light-headedness as the most frequently reported side effect. CONCLUSION: The flat-dose trial used under the University of Wisconsin Health protocol for i.v. lidocaine administration did not cause serious adverse events, but few patients who responded to this trial dose tolerated subsequent infusions at the trial rate. Due to the lack of serious adverse events, administering an aggressive trial dose to elicit an analgesic response appears to be rational. If patients show a benefit from the trial dose, the need for reductions in infusion rate of subsequent doses should be anticipated.