Population pharmacokinetic rationale for intravenous contezolid acefosamil followed by oral contezolid dosage regimens.

Contezolid is a novel oxazolidinone antibiotic with a promising safety profile. Oral contezolid and its intravenous (IV) prodrug contezolid acefosamil (CZA) are in development for treatment of diabetic foot and acute bacterial skin and skin structure infections (ABSSSI). The prodrug CZA is converted to active contezolid via intermediate MRX-1352. This study aimed to provide the pharmacokinetic rationale for safe, effective, and flexible dosage regimens with initial IV CZA followed by oral contezolid. We simultaneously modeled plasma concentrations from 110 healthy volunteers and 74 phase 2 patients with ABSSSI via population pharmacokinetics (using the importance sampling estimation algorithm), and optimized dosage regimens by Monte Carlo simulations. This included data on MRX-1352, contezolid, and its metabolite MRX-1320 from 66 healthy volunteers receiving intravenous CZA (150-2400 mg) for up to 28 days, and 74 patients receiving oral contezolid [800 mg every 12 h (q12h)] for 10 days. The apparent total clearance for 800 mg oral contezolid with food was 16.0 L/h (23.4% coefficient of variation) in healthy volunteers and 17.7 L/h (53.8%) in patients. CZA was rapidly converted to MRX-1352, which subsequently transformed to contezolid. The proposed dosage regimen used an IV CZA 2000 mg loading dose with 1000 mg IV CZA q12h as maintenance dose(s), followed by 800 mg oral contezolid q12h (with food). During each 24-h period, Monte Carlo simulations predicted this regimen to achieve consistent areas under the curve of 91.9 mg·h/L (range: 76.3-106 mg·h/L) under all scenarios. Thus, this regimen was predicted to reliably achieve efficacious contezolid exposures independent of timing of switch from IV CZA to oral contezolid.IMPORTANCEThis study provides the population pharmacokinetic rationale for the dosage regimen of the intravenous (IV) prodrug contezolid acefosamil (CZA) followed by oral contezolid. We developed the first integrated population model for the pharmacokinetics of the MRX-1352 intermediate prodrug, active contezolid, and its main metabolite MRX-1320 based on data from three clinical studies in healthy volunteers and phase 2 patients. The proposed regimen was predicted to reliably achieve efficacious contezolid exposures independent of timing of switch from IV CZA to oral contezolid.

A Phase 1 pharmacokinetic study of a single-dose bioadhesive clindamycin 2% gel for bacterial vaginosis.

OBJECTIVES: To evaluate pharmacokinetics (PK) of a single dose of an investigational 2% clindamycin phosphate vaginal gel in healthy women by assessment of plasma and vaginal clindamycin concentrations over 7 days, and assess safety. METHODS: Single-centre, Phase 1, single-dose PK study. Blood and vaginal samples were collected daily and safety was evaluated through to Day 7. RESULTS: Twenty-one subjects were enrolled; 20 completed the study. Plasma clindamycin concentrations demonstrated quantifiable values in all subjects through to 24 h post-dose, remaining above the limits of quantification (LOQ) through to 48 h for the majority of subjects. Systemic exposure (AUC0-t) was 1179 (range 62-3822) h·ng/mL. Arithmetic mean AUC0-24 was 818 (range 51-3287) h·ng/mL. Vaginal clindamycin phosphate levels were relatively high 24 h following administration in 15/21 subjects (6 subjects had values >400 µg/g and 9 had values of 100-400 µg/g). The levels dropped in most participants to below the LOQ 2 days following dosing. In a few participants, levels remained elevated for several days. Maximal amounts of vaginal clindamycin occurred on Day 2 with a mean value of 30.3 µg. One treatment-emergent adverse event (TEAE) of moderate-severity headache not related to study drug was reported and resolved on Day 1. No TEAEs were related to physical examinations, pelvic examinations, laboratory values or vital signs. CONCLUSIONS: The vaginal concentrations of clindamycin phosphate plus the clindamycin plasma profile over time are consistent with release of drug from the investigational gel over 24 to 72 h. A single dose was well tolerated.

Comparing the Pharmacokinetics of 2 Novel Intravenous Tramadol Dosing Regimens to Oral Tramadol: A Randomized 3-Arm Crossover Study.

Tramadol is a dual-mechanism (opiate and monoamine reuptake inhibition) analgesic. Intravenous (IV) tramadol has been widely prescribed outside the United States. However, there have not been studies comparing the pharmacokinetics (PK) of IV dosing regimens to that of oral tramadol. In this phase 1, open-label, single investigational center, 3-treatment, 3-period, multidose crossover study, we compared 2 novel IV dosing regimens (IV tramadol 75 mg and IV tramadol 50 mg) to oral tramadol 100 mg given every 6 hours (the highest approved oral dosage in the United States) Compared to the oral regimen, IV tramadol 50 mg administered at hours 0, 2, and 4 and every 4 hours thereafter reached initial tramadol peak serum concentration (Cmax ) more rapidly, while resulting in similar overall steady-state Cmax and area under the plasma concentration-time curve. IV tramadol 75 mg administered at hours 0, 3, and 6 and every 6 hours thereafter had higher Cmax and greater fluctuation in peak to trough tramadol concentration. The primary metabolite M1 (a potent µ agonist) had lower area under the plasma concentration-time curve and Cmax for both IV regimens than for the oral regimen. IV tramadol at both doses was well tolerated, with adverse event profiles consistent with the known pharmacological effects of tramadol. IV tramadol 50 mg is now in phase 3 development in patients with postsurgical pain.

Coadministration of probenecid and cimetidine with mirogabalin in healthy subjects: A phase 1, randomized, open-label, drug-drug interaction study.

AIMS: The primary aim of this study was to assess the individual effects of probenecid and cimetidine on mirogabalin exposure. METHODS: This phase 1, open-label, crossover study randomized healthy adults to receive three treatment regimens, each separated by ≥5-day washout: a single oral dose of mirogabalin 15 mg on day 2, mirogabalin 15 mg on day 2 plus probenecid 500 mg every 6 h from days 1 to 4, and mirogabalin 15 mg on day 2 plus cimetidine 400 mg every 6 h from days 1 to 4. RESULTS: Coadministration of mirogabalin with probenecid or cimetidine increased the maximum and total mirogabalin exposure. The geometric mean ratios of Cmax and AUC(0-t) (90% CI) with and without coadministration of probenecid were 128.7% (121.9-135.7%) and 176.1% (171.9-180.3%), respectively. The geometric mean ratios of Cmax and AUC(0-t) (90% CI) with and without coadministration of cimetidine were 117.1% (111.0-123.6%) and 143.7% (140.3-147.2%), respectively. Mean (standard deviation) renal clearance of mirogabalin (l h-1 ) was substantially slower after probenecid [6.67 (1.53)] or cimetidine [7.17 (1.68)] coadministration, compared with mirogabalin alone [11.3 (2.39)]. Coadministration of probenecid or cimetidine decreased mirogabalin mean (standard deviation) apparent total body clearance [10.5 (2.33) and 12.8 (2.67) l h-1 , respectively, vs. 18.4 (3.93) for mirogabalin alone]. CONCLUSIONS: A greater magnitude of change in mirogabalin exposure was observed when coadministered with a drug that inhibits both renal and metabolic clearance (probenecid) vs. a drug that only affects renal clearance (cimetidine). However, as the increase in exposure is not clinically significant (>2-fold), no a priori dose adjustment is recommended.

An Open-Label Crossover Study of the Pharmacokinetics of the 60-mg Edoxaban Tablet Crushed and Administered Either by a Nasogastric Tube or in Apple Puree in Healthy Adults.

BACKGROUND: Edoxaban is an orally active, direct factor Xa inhibitor indicated to reduce the risk of stroke and systemic embolism in non-valvular atrial fibrillation and for the treatment of venous thromboembolism. OBJECTIVES: This study assessed the pharmacokinetics, safety, and tolerability of the edoxaban 60-mg tablet crushed and administered via a nasogastric tube in a water suspension or orally mixed in apple puree. METHODS: This phase 1, open-label, crossover study randomized 30 healthy adults to receive three edoxaban treatment regimens (oral 60-mg edoxaban tablet, or 60-mg edoxaban tablet crushed and administered via a nasogastric tube or orally in apple puree) in one of six treatment sequences. RESULTS: Total edoxaban exposure was similar between the intact and crushed tablet regimens (mean area under the plasma concentration-time curve from time zero to infinity: whole tablet, 2132 ng·h/mL; nasogastric tube, 2021 ng·h/mL; apple puree, 2076 ng·h/mL). Mean maximum plasma concentration, area under the plasma concentration-time curve from time zero to the time of the last measurable concentration, terminal half-life, and apparent total body clearance values were also similar. Time to maximum plasma concentration was significantly shorter for the nasogastric tube suspension and apple puree vs. the whole tablet [Hodges-Lehmann estimate of median difference (90% confidence interval): -0.75 (-1.25, -0.28); p = 0.0003 and -0.62 (-0.99, -0.26); p = 0.0024, respectively]. The maximum plasma concentation, area under the plasma concentration-time curve from time zero to infinity, and area under the plasma concentration-time curve from time zero to the time of the last measurable concentration were similar between treatment regimens; 90% confidence interval of the geometric least-squares means ratios were within the predefined 80-125% bioequivalence criterion. The safety and tolerability of edoxaban did not differ between treatment regimens. CONCLUSION: The results support the use of edoxaban tablets crushed and administered either via a nasogastric tube or orally mixed in apple puree in patients who are unable to swallow solid oral dose formulations.

Safety of ragweed sublingual allergy immunotherapy tablets in adults with allergic rhinoconjunctivitis.

A sublingually administered allergy immunotherapy tablet (AIT) is under development to treat ragweed (Ambrosia artemisiifolia)-induced allergic rhinoconjunctivitis (ARC). This study investigates the optimal tolerable dose of once daily ragweed pollen AIT.Subjects 18-50 years old with ragweed-induced ARC were enrolled at two U.S. centers in a double-blind, placebo-controlled,dose-escalation study outside ragweed season. Groups (12 subjects each) were to be randomized 3:1 to 28 days of active treatment (groups assigned in sequence to 3, 6, 12, 24, 50, or 100 units of Ambrosia artemislifolia major allergen 1 [Amb a 1 U],without dose buildup at any level) or matching placebo. Recruitment to 50 Amb a 1-U was discontinued because of adverse events (AEs) after four AIT subjects were enrolled; 100 Amb a 1-U was not initiated. Fifty-three subjects were randomized (AIT,n = 40; placebo, n = 13); four discontinued, all because of AEs (AIT, n = 3; placebo, n = 1). Treatment-related AEs (TRAEs) were more frequent with AIT (73%) than placebo (31%), increasing with dose level. AIT TRAEs were mostly mild (94%) or moderate(5%). No serious TRAEs or anaphylactic shock occurred. The most common TRAEs with AIT were localized pruritus, nasal irritation, and throat irritation. Median onset for common AIT application site reactions was 24 ≤ hours after first treatment (median duration, 15-50 minutes). AIT increased immunoglobulin (Ig) significantly more than placebo (ragweed-specific IgE [6, 12, and 24 Amb a 1-U]; IgG4 [all doses]; p < 0.05). Three subjects in dose groups ≥ 24 Amb a 1-U experienced symptoms suggestive of systemic reaction. Of tested doses, ragweed AIT 24

Single therapeutic and supratherapeutic doses of laropiprant, a selective prostaglandin D2 receptor 1 antagonist, do not prolong the QTcF interval in healthy volunteers.

Laropiprant (LRPT), a prostaglandin D(2) receptor-1 antagonist shown to reduce niacin-induced flushing symptoms, has been combined with niacin for treatment of dyslipidemia. This study evaluated the effects of LRPT (50 mg and 600 mg, respectively) on the QT interval with Fridericia's correction (QTcF). QTcF measurements were made over a 24-hour period following administration of single-dose moxifloxacin 400 mg, LRPT 50 mg, LRPT 600 mg, or placebo. The primary hypothesis was supported if the 90% confidence intervals (CIs) for the least squares (LS) mean differences between placebo and LRPT in change from baseline in QTcF interval were <10 milliseconds at every time point. The upper limits of the 90% CIs for LS mean differences from placebo in changes from baseline in QTcF intervals for LRPT 50 mg and 600 mg were <5 milliseconds at every time point. The lower limits of the 90% CIs for placebo-adjusted LS mean changes from baseline in QTcF intervals for moxifloxacin exceeded 0 milliseconds at every time point, demonstrating the sensitivity of this assay to detect increases in the QTcF interval. In conclusion, single doses of LRPT 50 mg and 600 mg do not prolong the QTcF interval relative to placebo and are generally well tolerated.

Effects of aspirin when added to the prostaglandin D2 receptor antagonist laropiprant on niacin-induced flushing symptoms.

Niacin is an effective lipid-modifying therapy whose use has been limited by suboptimal tolerability. The adverse effect of flushing is due to prostaglandin D2 (PGD2)-mediated cutaneous vasodilation. Adjunctive treatment with the PGD2 receptor antagonist laropiprant significantly reduces the incidence and severity of niacin-induced flushing. The objective of this study was to assess the effect of aspirin pretreatment on flushing symptoms with extended-release (ER) niacin/laropiprant in healthy volunteers. A randomized, double-blind, placebo-controlled crossover study compared patient-rated flushing following pretreatment with aspirin 325 mg versus placebo administered 30 minutes before ER niacin 2 g/laropiprant 40 mg. Flushing responses were assessed using participant-reported overall symptom severity score (OSSS), including individual characteristics of redness, warmth, tingling, or itching. The overall incidence and severity of flushing were comparable for participants receiving aspirin or placebo before ER niacin 2 g/laropiprant 40 mg. The difference in 3-day average OSSS between treatments was 0.2 (P=.180). Profiles of flushing severity, frequency, and bothersomeness were comparable for the aspirin/ER niacin/laropiprant and ER niacin/laropiprant regimens. All treatments were safe and well tolerated. Coadministration of aspirin 325 mg daily with ER niacin 2 g/laropiprant 40 mg does not further reduce residual flushing symptoms associated with ER niacin 2 g/laropiprant 40 mg alone.