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

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

Single and Multiple Dose Pharmacokinetics, Pharmacodynamics and Safety of the Novel Lipoprotein-Associated Phospholipase A₂ Enzyme Inhibitor Darapladib in Healthy Chinese Subjects: An Open Label Phase-1 Clinical Trial

<div><p>Background and Objectives</p><p>Darapladib is a lipoprotein-associated phospholipase A₂ (Lp-PLA₂) inhibitor. This study evaluated the pharmacokinetics, pharmacodynamics and safety of darapladib in healthy Chinese subjects.</p><p>Methods</p><p>Twenty-four subjects received darapladib 160 mg orally, approximately 1 hour after a standard breakfast, as a single dose and once daily for 28 days. Non-compartmental methods were used to determine the single and multiple dose pharmacokinetics of darapladib and its metabolite SB-553253. Repeat dose Lp-PLA₂ activity and safety were evaluated.</p><p>Results</p><p>Systemic exposure (AUC_(0-T), Cmax geometric mean (CVb%)) of darapladib was higher after multiple-dosing (519 ng.h/mL (33.3%), 34.4 ng/mL (49.9%)) compared to single-dose administration (153 ng.h/mL (69.0%), 17.9 ng/mL (55.2%). The steady-state accumulation ratio was less than unity (Rs = 0.80), indicating time-dependent pharmacokinetics of darapladib. Darapladib steady-state was reached by Day 14 of once daily dosing. Systemic exposure to SB-553253 was lower than darapladib with median (SB-553253: darapladib) ratios for AUC_(0-τ) of 0.0786 for single dose and 0.0532 for multiple dose administration. On Day 28, pre-dose and maximum inhibition of Lp-PLA₂ activity was approximately 70% and 75% relative to the baseline value, respectively and was dependent of darapladib concentration. The most common adverse events (≥ 21% subjects) were abnormal faeces, abnormal urine odour, diarrhoea and nasopharyngitis.</p><p>Conclusion</p><p>Darapladib 160 mg single and repeat doses were profiled in healthy Chinese subjects. Single dose systemic exposure to darapladib in healthy Chinese subjects was consistent with that observed previously in Western subjects whereas steady-state systemic exposure was approximately 65% higher in Chinese than Western subjects. The Lp-PLA₂ activity and adverse event profile were similar in healthy Chinese and previous reports in Western subjects. Ethnic-specific dose adjustment of darapladib is not considered necessary for the Chinese population.</p><p>Trial Registration</p><p>ClinicalTrials.gov <a href="https://clinicaltrials.gov/ct2/show/NCT02000804?id=NCT02000804&rank=1" target="_blank">NCT02000804</a></p></div

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

Accumulation ratios for darapladib and SB-553253 for multiple relative to single dosing of darapladib.

<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; CVw%: within-subject coefficient of variation; GLS mean = Geometric least square mean; NA: Not applicable</p><p>Accumulation ratios for darapladib and SB-553253 for multiple relative to single dosing of darapladib.</p

Emax model parameters for darapladib concentrations and associated LpPLA₂ activity in healthy Chinese subjects.

<p><b>*</b> Precision expressed as coefficient of variation (CV).</p><p><b>**</b> Expressed as % coefficient of variation.</p><p><b>***</b> Expressed as nmol/min/mL. IC₅₀: darapladib plasma concentration causing 50% inhibition of plasma Lp-PLA₂ activity. E₀: baseline plasma Lp-PLA₂ activity.</p><p>Emax model parameters for darapladib concentrations and associated LpPLA₂ activity in healthy Chinese subjects.</p

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

Platelet Aggregation Unchanged by Lipoprotein-Associated Phospholipase A₂ Inhibition: Results from an In Vitro Study and Two Randomized Phase I Trials

<div><p>Background</p><p>We explored the theorized upregulation of platelet-activating factor (PAF)– mediated biologic responses following lipoprotein-associated phospholipase A₂ (Lp-PLA₂) inhibition using human platelet aggregation studies in an in vitro experiment and in 2 clinical trials.</p><p>Methods and Results</p><p>Full platelet aggregation concentration response curves were generated in vitro to several platelet agonists in human plasma samples pretreated with rilapladib (selective Lp-PLA₂ inhibitor) or vehicle. This was followed by a randomized, double-blind crossover study in healthy adult men (n = 26) employing a single-agonist dose assay of platelet aggregation, after treatment of subjects with 250 mg oral rilapladib or placebo once daily for 14 days. This study was followed by a second randomized, double-blind parallel-group trial in healthy adult men (n = 58) also treated with 250 mg oral rilapladib or placebo once daily for 14 days using a full range of 10 collagen concentrations (0–10 µg/ml) for characterizing EC₅₀ values for platelet aggregation for each subject. Both clinical studies were conducted at the GlaxoSmithKline Medicines Research Unit in the Prince of Wales Hospital, Sydney, Australia. EC₅₀ values derived from multiple agonist concentrations were compared and no pro-aggregant signals were observed during exposure to rilapladib in any of these platelet studies, despite Lp-PLA₂ inhibition exceeding 90%. An increase in collagen-mediated aggregation was observed 3 weeks post drug termination in the crossover study (15.4% vs baseline; 95% confidence interval [CI], 3.9–27.0), which was not observed during the treatment phase and was not observed in the parallel-group study employing a more robust EC₅₀ examination.</p><p>Conclusions</p><p>Lp-PLA₂ inhibition does not enhance platelet aggregation.</p><p>Trial Registration</p><p>1) Study 1: ClinicalTrials.gov <a href="http://www.clinicaltrials.gov/ct2/show/NCT01745458?term=NCT01745458&rank=1andwww.clinicaltrials.gov/ct2/show/NCT01750827?term=NCT01750827&rank=1" target="_blank">NCT01745458</a> 2) Study 2: ClinicalTrials.gov <a href="http://www.clinicaltrials.gov/ct2/show/NCT00387257?term=NCT00387257&rank=1" target="_blank">NCT00387257</a></p></div