Evaluation of the pharmacokinetic drug-drug interaction between the antiretroviral agents fostemsavir and maraviroc: a single-sequence crossover study in healthy participants

Background Fostemsavir is an oral prodrug of temsavir, a first‐in‐class attachment inhibitor that binds HIV‐1 gp120, preventing initial HIV attachment and entry into host immune cells. Objective The pharmacokinetic interaction was determined between temsavir and maraviroc, a CCR5 allosteric inhibitor indicated for CCR5-tropic HIV-1 that may be co-administered with fostemsavir as part of combination antiretroviral therapy in heavily treatment-experienced adults with multidrug-resistant HIV-1 infection. Methods This was a Phase 1, open-label, single-sequence, 3-period crossover study evaluating the effect of fostemsavir on maraviroc pharmacokinetics and the effect of maraviroc on temsavir pharmacokinetics (ClinicalTrials.gov, NCT02480894). Fourteen healthy participants received fostemsavir 600 mg twice daily (BID) for 4 days in Period 1 (followed by a 3-day washout), maraviroc 300 mg BID for 5 days in Period 2, and fostemsavir 600 mg BID with maraviroc 300 mg BID for 7 days in Period 3. Study drugs were administered orally with a standard meal. Results Following fostemsavir and maraviroc co-administration, maraviroc area under the plasma concentration-time curve over the dosing interval (AUCτ) increased 25% (from 1914 to 2382 ng.h/mL) and maraviroc plasma concentration at the end of the dosing interval (Ctrough) increased 37% (from 36.5 to 49.9 ng/mL), but there was no change in maximum observed concentration (Cmax). Following fostemsavir and maraviroc co-administration, temsavir AUCτ and Cmax increased 10-13% and Ctrough decreased 10%. Conclusions Co-administration of fostemsavir and maraviroc did not result in clinically relevant changes in maraviroc or temsavir exposure. Fostemsavir and maraviroc may be co-administered without dose adjustment of either antiretroviral agent

Pharmacokinetics, metabolism and excretion of radiolabeled fostemsavir administered with or without ritonavir in healthy male subjects

The pharmacokinetics, elimination, and metabolism of fostemsavir (FTR), a prodrug of the HIV-1 attachment inhibitor temsavir (TMR), were investigated in healthy volunteers. FTR was administered with and without ritonavir (RTV), a protease inhibitor previously shown to boost TMR exposures. In vitro studies were also used to identify the enzymes responsible for the metabolism of TMR.Total recovery of the administered dose ranged from 78% to 89%. Approximately 44% to 58% of the dose was excreted in urine, 20%–36% in faeces, and 5% in bile, as TMR and metabolites. RTV had no effect on the recovery of radioactivity in any matrix.Compared to FTR alone, pre-treatment of subjects with RTV increased the exposure of TMR by ∼66% and reduced the exposure of plasma total radioactivity by ∼68%.The major route of TMR elimination was through biotransformation. TMR, M28 (N-dealkylation), and M4 (amide hydrolysis) were the major circulating components in plasma. Pre-treatment with RTV increased the amount of TMR present, decreased the amount of circulating M28, and M4 was unchanged.CYP3A4 metabolism accounted for 21% of the dose, forming multiple oxidative metabolites. This pathway was inhibited by coadministration of RTV. The pharmacokinetics, elimination, and metabolism of fostemsavir (FTR), a prodrug of the HIV-1 attachment inhibitor temsavir (TMR), were investigated in healthy volunteers. FTR was administered with and without ritonavir (RTV), a protease inhibitor previously shown to boost TMR exposures. In vitro studies were also used to identify the enzymes responsible for the metabolism of TMR. Total recovery of the administered dose ranged from 78% to 89%. Approximately 44% to 58% of the dose was excreted in urine, 20%–36% in faeces, and 5% in bile, as TMR and metabolites. RTV had no effect on the recovery of radioactivity in any matrix. Compared to FTR alone, pre-treatment of subjects with RTV increased the exposure of TMR by ∼66% and reduced the exposure of plasma total radioactivity by ∼68%. The major route of TMR elimination was through biotransformation. TMR, M28 (N-dealkylation), and M4 (amide hydrolysis) were the major circulating components in plasma. Pre-treatment with RTV increased the amount of TMR present, decreased the amount of circulating M28, and M4 was unchanged. CYP3A4 metabolism accounted for 21% of the dose, forming multiple oxidative metabolites. This pathway was inhibited by coadministration of RTV.</p

Properties of Portland Cement Made From Contaminated Sediments

Hundreds of millions of cubic meters of contaminated sediments are dredged from US harbors and waterways annually for maintenance of navigation, environmental remediation, or both. In recent years, inexpensive ocean dumping has been largely eliminated as a disposal alternative causing a crisis in the management of sediment. This paper presents a new beneficial use alternative for contaminated dredged material, which is to use dredged material as a feedstock in the conventional manufacture of Portland cement. The paper demonstrates the efficacy of the process at the bench and pilot scales, and presents a summary of practical and economic considerations. A bench scale manufacture was carried out with feedstock mixtures containing 1–12% dredged material from the New York/New Jersey (NY/NJ) harbor. The clinkers were quantitatively analyzed with X-ray powder diffraction and differences in phase concentrations were observed in the clinker samples manufactured with dredged material (decreased alite and increased belite) suggesting that additional burn time was needed to account for the quartz present in the sediments. The free chloride concentrations in the clinker samples were below ACI limits for cement used with reinforcing steel; however, the chloride in the dredged material remains a manufacturing concern and is expected to increase annual maintenance costs. A pilot scale manufacture was carried out in a batch rotary kiln; X-ray diffraction analysis and ASTM tests for strength, soundness, and setting time suggested that with better optimized burning conditions, dredged material can be successfully incorporated into full scale manufacture

Darapladib single dose AUC_(0-∞) relative to repeat dose AUC_(0–24) in individual healthy Chinese and Western healthy subjects.

<p>Darapladib single dose AUC_(0-∞) relative to repeat dose AUC_(0–24) in individual healthy Chinese and Western healthy subjects.</p

Median concentration-time profiles of darapladib following single and multiple dose administration over a period of 96 hours on linear-linear scale (A) and log- linear scale (B) truncated at 96 hours and (C) log-linear to the final observation.

<p>Median concentration-time profiles of darapladib following single and multiple dose administration over a period of 96 hours on linear-linear scale (A) and log- linear scale (B) truncated at 96 hours and (C) log-linear to the final observation.</p

Darapladib pharmacokinetic and pharmacodynamic parameters in healthy Chinese and Western subjects.

<p>^a = Values are expressed as geometric mean [Coefficient of Variation %]</p><p>^b = Values are expressed as mean (95% Confidence Interval)</p><p>Ro = Observed accumulation ratio; Rp = Predicted accumulation ratio; Rs = Steady-state accumulation ratio; RC_max = C_max accumulation ratio; AUC_(0-τ) = Area under the concentration-time curve over the dosing interval; AUC_(0-∞) = Area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite time; CI: Confidence Interval; IC50: darapladib plasma concentration causing 50% inhibition of plasma Lp-PLA2 activity. Data in Western subjects from separate study LPL112498 (Clinical Trial. Gov: NCT00743860).</p><p>Darapladib pharmacokinetic and pharmacodynamic parameters in healthy Chinese and Western subjects.</p

Pharmacokinetic parameters of metabolite SB-553253 following single and multiple once daily dosing of darapladib enteric coated tablet 160 mg.

<p>^a Values are expressed as geometric mean (% between subject coefficient of variation)</p><p>^b Values are expressed as median (range)</p><p>^c In the majority of subjects the concentrations of SB553253 were generally not quantifiable for a sufficient duration of time to calculate t_½</p><p>C_max = maximum plasma concentration; T_max = Time of occurrence of C_max; AUC_(0-τ) = Area under the concentration-time curve over the dosing interval; AUC_(0-∞) = Area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite time; t_1/2 = Terminal phase half-life; Cτ = Pre-dose (trough) concentration; NA: Not applicable; N = Number of subjects</p><p>SB-553253 to Darapladib Cmax and AUC_(0-τ) ratios are also presented.</p

Subject disposition flow diagram where n is number of subjects in each category.

<p>Subject disposition flow diagram where n is number of subjects in each category.</p