Lei Ma

A new solid oral tablet formulation of posaconazole: a randomized clinical trial to investigate rising single- and multiple-dose pharmacokinetics and safety in healthy volunteers

Objectives Posaconazole is an extended-spectrum triazole with proven efficacy as antifungal treatment and prophylaxis. The marketed oral suspension should be taken with food to maximize systemic absorption. A new solid oral tablet has been developed with improved bioavailability that can be administered without regard to food. The aim of this study was to evaluate rising single- and multiple-dose pharmacokinetics, safety and tolerability of the new tablet. Methods This was a single-centre, randomized, placebo-controlled, Phase I, rising single- and multiple-dose study of healthy subjects aged 18–65 years who received a posaconazole tablet as 200 mg once daily, 200 mg twice daily or 400 mg once daily. The 24 subjects were studied in two cohorts of 12 subjects each (9 active and 3 placebo). Results After single or multiple oral dose administration of posaconazole tablets (200 and 400 mg), exposure increased in a dose-related manner. Peak posaconazole concentrations were attained at a median Tmax of 4–5 h. Mean half-life was similar for 200 and 400 mg posaconazole doses (25 and 26 h). The accumulation ratio upon multiple doses over 8 days was ∼3 for 200 and 400 mg once daily and ∼5 for 200 mg twice daily. Cavg values exceeded 1300 ng/mL. The posaconazole oral tablet was safe and well tolerated, although mild, transient elevations in liver function were reported in some patients. Conclusions Posaconazole exposure increased in a dose-related manner. The pharmacokinetics of this new solid oral tablet of posaconazole supports the clinical evaluation of once-daily dosing regimens for fungal infections.

Single-Dose Phase I Study To Evaluate the Pharmacokinetics of Posaconazole in New Tablet and Capsule Formulations Relative to Oral Suspension

ABSTRACT Posaconazole oral suspension, a marketed extended-spectrum triazole with proven efficacy as antifungal treatment and prophylaxis, should be taken with food to maximize absorption. New tablet and capsule formulations have been developed in an attempt to optimize absorption and bioavailability. The aims of this exploratory open-label, partially randomized, 2-part, 4-way, single-dose crossover study in 16 healthy adults were to characterize pharmacokinetics for posaconazole tablet and capsule formulations relative to those for posaconazole oral suspension under fasted and fed conditions and to assess safety and tolerability. Under fasted conditions, posaconazole exposures (area under the curve [AUC]) for the tablet and capsule formulations were similar (mean AUC from time zero to infinity [AUC0–∞], tablet A, 11,700 ng · h/ml [coefficient of variation {CV}, 26%]; tablet B, 11,300 ng · h/ml [CV, 22%]; capsule, 11,000 ng · h/ml [CV, 25%]) and were substantially higher than the exposure for the oral suspension (mean AUC0–∞, 3,420 ng · h/ml [CV, 44%]). Tablets and capsule showed less variability in exposure than the oral suspension. In fed subjects, tablets and capsule resulted in similar AUC values (mean AUC0–∞, tablet A, 11,900 ng · h/ml [23%]; tablet B, 12,400 ng · h/ml [CV, 25%]; capsule, 12,300 ng · h/ml [CV, 28%]) and slightly higher exposure than the oral suspension (mean AUC0–∞, 8,750 [CV, 24%]). Median times to the maximum concentration of drug in plasma were 4 to 5 h (fasted conditions) and 6 to 8 h (fed conditions). Mean half-lives values were similar for all formulations under fed and fasted conditions (23.1 to 29.2 h). Consistent with previous data, exposure for the oral suspension increased 2.5- to 3-fold when it was given with a high-fat meal. Conversely, exposures for tablets and capsule were not markedly affected by food. All formulations of posaconazole at 100 mg were safe and well tolerated.

Effect of posaconazole on the pharmacokinetics of simvastatin and midazolam in healthy volunteers.

Objectives: The aim of the study is to determine the effect of posaconazole, an extended-spectrum triazole, on the pharmacokinetics of the HMG-CoA reductase inhibitor, simvastatin. Methods: This randomized, fixed-sequence, parallel-group, single-center, open-label study was conducted in 35 healthy volunteers randomly assigned to receive one of three doses of oral posaconazole: 50, 100 or 200 mg. All subjects received single doses of the reference drug midazolam (2 mg oral) alone on day -9; simvastatin (40 mg oral) alone on day -6; posaconazole (50, 100 or 200 mg) on days 1 – 7 once daily (q.d.); posaconazole plus midazolam (day 8); posaconazole alone (days 9 – 10); posaconazole plus simvastatin (day 11) and posaconazole alone (days 12 – 13). Results: Relative to simvastatin alone, posaconazole (50, 100 and 200 mg q.d.) significantly increased the Cmax and AUC of simvastatin (5- to 11-fold increase in AUC) and simvastatin acid (5- to 8-fold increase in AUC) during co-administration. Relative to midazolam alone, posaconazole (50, 100 and 200 mg q.d.) significantly inhibited CYP3A4-mediated metabolism of midazolam (three to sixfold increase in AUC). Conclusion: These findings support the classification of posaconazole as a strong CYP3A4 inhibitor. Simvastatin, or other statins predominantly metabolized by CYP3A4, should not be co-administered with posaconazole. Other statins, whose metabolism/elimination is not affected by CYP3A4 inhibition, should be considered for co-administration.

Safety and pharmacokinetics of the novel BACE inhibitor MK-8931 in healthy subjects following single- and Multiple-Dose administration

Background:Alzheimer’s disease (AD) is a common, debilitating neurodegenerative disorder afflicting the aging population. Synaptic accumulation of Aß-protein oligomers and tau might be responsible for the neurological damage in AD. Thus, special interest has emerged in developing treatments that reduce the formation or facilitate the clearance of these oligomers. Utilizing molecular modeling and structure based design techniques we generated a series of novel organic heterocyclic compounds that are capable of recognizing the aggregated Aß-protein molecule and promoting clearance. Using cell-free and cell-based assays, a compound denominated NPT-400 with activity in the high nanomolar range was identified for pharmacokinetic (PK) and preliminary efficacy studies in APP transgenic (tg) mice. Methods: The mThy1-hAPP751 transgenic mouse was utilized for efficacy studies. This mouse combines the Swedish (K670M/N671L) and London (V717I) APPmutations, and these animals develop AD-like neuropathology and behavioral deficits starting at 3-4 months of age. Female non-tg and tg mice (w5 mo of age) received a single injection of vehicle or NPT-400-3 (IP, 10 mg/kg) three times per week for 6.5 weeks. Behavioral assessments were conducted during week 4 of treatment including locomotor activity and water maze. At the completion of treatment, brains were hemisected and tissue sections were processed for immunolabeling and confocal analysis, and homogenates were analyzed for levels of Abeta-protein by ELISA and immunoblot. For PK studies, wildtype C57Bl6 mice received IVor PO NPT-400-3 compound at 10 mg/kg and blood and plasma levels were analyzed at 0-24 hrs. Results: Treatment with NPT-400-3 resulted in a statistically significant normalization of locomotor activity accompanied by amelioration of the synaptic and dendritic pathology in the neocortex and hippocampus. By immunoblot and ELISA the levels of monomeric and oligomeric Aß-protein were statistically significantly reduced in the brains of the APP tg mice. PK studies showed that NPT400-3 is stable in plasma, is orally bioavailable and penetrates the brain with a B/P ratio of 0.8. Conclusions:NPT-400-3 is an orally bioavailable, brain penetrating Aß-protein stabilizing organic compound that reduces the accumulation of Aß-protein oligomers and ameliorates behavioral deficits and neuropathology in APP tg mice without overt adverse effects.

Determination of Posaconazole Levels in Toenails of Adults with Onychomycosis following Oral Treatment with Four Regimens of Posaconazole for 12 or 24 Weeks

ABSTRACT Pharmacokinetic data from a randomized, parallel-group, multicenter study are presented. Adults with toenail onychomycosis (n = 146) received posaconazole (100 mg, 200 mg, or 400 mg) once daily (QD) for 24 weeks or 400 mg QD for 12 weeks. The posaconazole concentration in the great toenail exhibited a dose-related increase starting at week 2 for 24 weeks and a mean toenail-to-plasma concentration ratio of approximately 3:1 at the end of treatment for the 400-mg 24-week dose.

A study to evaluate the pharmacokinetics and pharmacodynamics of single and multiple oral doses of the novel BACE inhibitor MK-8931 in Japanese subjects

loid in the cerebral cortex (P 1⁄4 0.0001) and corpus callosum (P 1⁄4 0.001). In addition, the TBI rats treated with estrone had reduced cortical lesion volume and cortical levels of TUNEL + staining (w80%). Conclusions: Estrone given acutely after brain injury decreases cortical neuronal cell death and white matter injury. These results suggest that other estrogens in addition to estradiol may afford individuals protection secondary brain injury after TBI.

Development and application of a mathematical model of modulation of cerebrospinal fluid Aβ40 after treatment with gamma- and beta-secretase inhibitors

Background:A mathematical model representation of key amyloid pathway physiology to describe A b 40 modulation in CSF was developed to: (1) quantify clinical drug potency of g-secretase (GS) and b -secretase (BACE1) inhibitors; (2) enable benchmarking across compounds; (3) facilitate dose selection for efficacy trials. Methods: Lumbar CSF A b 40 concentration data in healthy adults treated with placebo; GS inhibitors MK-0752 or semagacestat (from literature); or BACE inhibitor MK8931 were available. Model-predicted drug brain concentrations were used as driver for CSFA b 40 modulation. An Emax relationship described inhibition of A b 40 production and a distribution delay between brain and lumbar CSFA b 40 was incorporated. An additive baseline drift model informed by study-specific placebo data allowed for drift correction. Data were fit using non-linear mixed effects modeling and model performance was qualified. This model was combined with population PK models to predicted dose response profiles for brain and CSFA b 40 inhibition. Trial performance predictions were made taking into account AD population demographics and knowledge on non-compliance. Results: An E max inhibition model combined with delay compartments best described the CSF A b 40 response upon inhibition of GS or BACE. Maximum inhibition (E max) estimates were 0.87, 0.86, 0.96 and for plasma concentration at 50% of maximum (EC 50) were 933 ng.mL -1, 6250 ng.mL -1, 10.2 ng.mL -1 for semagacestat, MK-0752, and MK-8931, respectively. Dose response profiles demonstrated greater potency and achievable CSFA b 40 suppression with MK-8931 compared to other compounds at clinically feasible doses. CSF A b 40 reductions between 50-75%, and between 75-100% from baseline were predicted to be achieved in 90% of the patients at doses of 12 and 40 mg MK-8931, respectively. Conclusions: CSF A b 40 response following placebo and GS or BACE inhibition were characterized by a common model framework. Comparative analysis among compounds suggests that semagacestat produces only limited (<11%) inhibition of Ab production. MK-8931 showed superior potency in the expected therapeutic dose range resulting in almost full suppression of CSFA b 40. Simulations indicate that 12 and 40 mgMK-8931 inhibit Ab production by>50% and >75%, respectively, suggesting that clinical trials in AD with MK8931 may provide a more robust test of the amyloid hypothesis, compared to semagacestat.